z-Haematology Flashcards
(990 cards)
1
Q
What is the lineage of erythrocytes?
A
Hematopoietic stem cell –> CFU-GEMM –> BFU-E –> CFU-E –> Pronormoblast –> Normoblasts –> Late normoblast –> Reticulocyte –> Erythrocyte
2
Q
Are nucleated normoblasts seen in the peripheral blood?
A
Not unless extramedullary erythropoiesis is occuring.
3
Q
What is erythropoietin?
A
Erythropoietin is the hormone that regulate erythropoiesis.
4
Q
Where is erythropoietin produced?
A
90% is produced in the peritubular interstitial cells of the kidney and 10% is produced in the liver and elsewhere.
5
Q
What is the stimulus for the production of erythropoietin?
A
oxygen tension in the tissue of the kidneys. (Anything that leads to hypoxia in the kidney will stimulate erythropoietin production)
6
Q
What transcription factors are activated by erythropoietin?
A
GATA-1 and FOG-1 are activated by erythropoietin and activate genes that are specific to erythrocytes.
7
Q
What happens if erythropoietin production is not shut off and persists chronically?
A
Red marrow will expand first into fatty marrow and then into extramedullary sites. Marrow cavity expansion in infants may lead to bone deformities.
8
Q
What down regulates erythropoietin production?
A
When oxygen levels in the tissue return to normal the erythropoietin drive is reduced.
9
Q
When is serum erythropoietin high?
A
When a tumor secreting erythropoietin is causing polycythemia.
10
Q
When is serum erythropoietin low?
A
Severe renal disease and polycythemia rubra vera both cause low erythropoietin
11
Q
When is erythropoietin given therapeutically?
A
(1) End-stage renal disease(2) Autologous blood transfusions(3) Anemia of chronic disease(4) Myelodysplasia or Myeloma
12
Q
What differentiates Reticulocytes from erythrocytes?
A
Reticulocytes still have RNA and protein synthesis machinery in the cytoplasm.
13
Q
What is often given with therapeutic erythropoietin to improve its effect?
A
Iron supplements are often administered with therapeutic erythropoietin.
14
Q
What are some adverse reactions associated with erythropoietin therapy?
A
Adverse side effects are a rise in blood pressure and platelet count and local injection site reactions.
15
Q
What are some precursors required for erythropoiesis?
A
Iron, cobalt, vitamin B12, folate, vitamin B6, vitamin C, Vitamin E, thiamine, riboflavin, androgens, and thyroxine.
16
Q
What is the structure of the dominant adult hemoglobin?
A
Hb A has 2 alpha chains and 2 beta chains with a heme group.
17
Q
When do erythrocytes switch from fetal to adult hemoglobin?
A
At about 3-6 months after birth.
18
Q
Where does heme synthesis occur?
A
Heme synthesis occurs in the mitochondria and begins with the condensation of glycine and succinyl CoA.
19
Q
What is the rate limiting enzyme in heme synthesis?
A
ALA-Synthase (aminolaevulinic acid synthase)
20
Q
What coenzyme is important for heme synthesis?
A
vitamin B6 (pyridoxal phosphate)
21
Q
How does hemoglobin’s structure relate to its function?
A
When oxygen binds hemoglobin the molecule is stabilized by the contacts between the various parts of the hemoglobin molecule. When oxygen dissociates from hemoglobin the beta chains of the hemoglobin are pulled apart and 2,3-DPG binds to hemoglobin decreasing the overall affinity of the molecule for oxygen.
22
Q
What is the normal arterial oxygen saturation?
A
95% with a mean O2 tension of 95mmHg
23
Q
What is the normal venous oxygen saturation?
A
70% with a mean O2 tension of 40mmHg.
24
Q
How does high 2,3-DPG, H+ ions, and CO2 effect a hemoglobin curve?
A
They shift the curve to the right (oxygen is given up more easily by hemoglobin)
25
Why does fetal hemoglobin have a higher affinity for oxygen than adult hemoglobine?
Because it does not bind 2,3-DPG.
26
What is Methhemaglobinemia?
Methhemaglobinemia is a state in which heme carries iron in the oxidized Fe3+ state instead of the normal Fe2+ state. The result is usually cyanosis. (can be from NADH deficiency or mutated hemoglobin or toxicity)
27
What is the Embden-Meyerhof pathway?
The EM pathway is a series of biochemical reactions that metabolize glucose to lactate (anaerobic metabolism)
28
Why is the Embden-Meyerhof pathway essential for Red cell function?
Because ATP is need to maintain the red cell shape/flexibility and to maintain the sodium/potassium gradients across a leaky membrane. Additionally the NADH produced reduces Fe3+ methhemaglobin to Fe2+ hemaglobin, and helps to produce 2,3-DPG.
29
Why is the pentose phosphate shunt important to RBCs?
Because it produces NADPH which is important for heme iron reduction and maintenance of the RBC membrane.
30
What proteins form an integral part of the RBC cytoskeleton?
Spectrins.
31
What is anemia?
Anemia is a reduction in the hemaglobin concentration in the blood.
32
What is the adult cutoff for Anemia?
Hb less than 13.5g/dL in adult males.Hb less than 11.5g/dL in adult females.
33
What is the cutoff for anemia between the ages of 2 to puberty?
Hb less than 11g/dL
34
What is the cutoff for anemia in infants?
Hb less than 14g/dL
35
What blood test findings often accompany reduced hemaglobin?
decreased RBC count and decreased packed cell volume (PCV).
36
How is blood plasma volume related to anemia?
increased or decreased plasma volume can lead to changes in the hemaglobin and RBC concentrations.
37
What are the clinical features of anemia?
(1) increased stroke volume(2) tachycardia(3) Altered O2 dissociation curve
38
What four factors most influence the clinical manifestations of anemia?
(1) Speed of onset(2) Severity(3) Age(4) Haemaglobin O2 dissociation curve.
39
How doe speed of onset effect the clinical manifestations of anemia?
Rapid onset causes more severe symptoms compared with less rapid onset because there is less time for cardiovascular compensation.
40
How does severity effect the clinical manifestations of anemia?
Mild anemias not lower than 9-10g/dL Hb often do not show substantial signs or symptoms. Although, even lower values may show few symptoms in healthy patients.
41
How does the Hemoglobin O2 dissociation curve impact the clinical manifestations of anemia?
In response to anemia the body will alter the dissociation curve of hemoglobin by producing more 2,3-DPG or by producing the lower affinity Hb S.
42
What are the symptoms of anemia?
Sob (often with exercise), weakness, lethargy, palpitation, headaches. Sometimes older patients exhibit signs of cardiac failure. Occasionally retinal hemorrhages may occur in more severe cases.
43
What are the signs of Anemia?
General signs include pallor of mucus mambranes, hyperdynamic circulation, tachycardia, cardiomegaly, and a systolic flow murmur at the apex. Other signs are specific for particular kinds of anemias.
44
What are the Red cell classifications for anemia?
Anemia can be classified as microcytic, normocytic, or macrocytic depending on the Red cell indices.
45
Under what normal conditions is the MCV (mean corpuscular volume) elevated
MCV may be high briefly in the newborn and during pregnancy.
46
Why are leukocyte and platelet counts useful when anemia is suspected?
They are useful for differentiating between anemia and pancytopenia ( a drop in the numbers of all blood cells)
47
In what anemias may the leukocyte and platelet counts be raised?
In anemias due to hemolysis, hemorrhage, infection, or leukemias the platelet and Leukocyte counts are often raised.
48
What is the normal range for a reticulocyte count?
.5-2.5% or 25-125x10^9 cells per liter. Will be higher during anemia due to erythropoietin.
49
What is the timeline for erythropoietin release?
In acute hemorrhage the erythropoietin response is seen in about 6h, the reticulocyte count rises within 2-3 days, and peaks around 6-10 days.
50
What is a blood film used for?
Blood films are used to examine the morphological appearance of blood cells. This may be useful in the diagnosis of anemias and other disorders.
51
Why is erythropoiesis considered inefficient?
Because 10-15% of erythroblasts die in the marrow without producing any mature erythrocytes. Some anemias show an increased inefficiency of erythropoiesis.
52
How can the effectiveness of erythropoiesis be evaluated?
By examination of the bone marrow, hemaglobin levels, and reticulocyte levels.
53
How is total erythropoiesis assessed?
By examining the cellularity of the marrow for the myeloid:erythroid ratio (which is normally 2.5:1 to 12:1)
54
How is effective erythropoiesis assessed?
By the reticulocyte count. Usually the reticulocyte count increases in proportion to the degree of anemia when effective, If erythropoiesis is not effective then the reticulocyte count will not rise with anemia.
55
Are immature Leukocytes (phagocytes and lymphocytes) found in normal peripheral blood?
No only mature phagocytes and lymphocytes are found in peripheral blood
56
What sorts of granules are found in neutrophils?
Primary appear at the premyelocyte stage and contain MPO, acid phosphatase, and other acid hydrolases.Secondary granules appear at the myelocyte stage and contain collagenase, lactoferrin, and lysozyme.
57
What is the average lifespan of a neutrophil in the peripheral blood?
6-10 hours.
58
What are myeloblasts?
Myeloblasts are the earliest recognizable precursors of neutrophils. (They make up 4% of normal bone marrow)
59
What is the lineage of the neutrophil?
myeloblast --> Promyelocyte --> Myelocytes --> Metamyelocytes --> Bands --> Neutrophils
60
What are the morphological characteristics of monocytes?
Oval indented nucleus, clumped chromatin, bluish cytoplasm, many vacuoles in the cytoplasm.
61
What is the lineage of the monocyte?
myeloblast --> promonocyte --> Monocyte --> Immature macrophage --> Mature macrophage.
62
To what cell type are basophils closely related?
Basophils are very closely related to mast cells.
63
What is more abundant in the bone marrow; myeloid cells or erythroid cells?
Myeloid cells are the most abundant in the bone marrow by a factor of 2:1 to 12:1. (Neutrophils and metamyelocytes are the most abundant specific types)
64
Are more granulocytes found in the bone marrow or the peripheral blood?
10-15 times more granulocytes are found in the bone marrow than in the peripheral blood.
65
What happens to granulocytes that are released from the bone marrow?
They spend about 6-10 days in the circulation. Then they marginate and move into the tissues where they spend 4-5 days carrying out their phagocytic function before they are destroyed or they senesce.
66
What growth factors stimulate granulocyte growth, maturation, functioning?
(1) IL-1(2) IL-3(3) IL-5 (eosinophils)(4) IL-6(5) IL-11(6) GM-CSF(7) G-CSF(8) M-CSF
67
What is the result of the clinical application of G-CSF?
G-CSF will increase the numbers of Neutrophils.
68
What is the result of the clinical application of GM-CSF?
GM-CSF given intravenously has been shown to increase the numbers of neutrophils, eosinophils, and monocytes.
69
Why is G-CSF given after chemotherapy, radiotherapy, or bone marrow transplant?
G-CSF is given to accelerate hematopoietic recovery thus reducing the post-therapy neutropenic period.
70
Why is G-CSF given to treat acute myeloid leukemia?
G-CSF is used in AML post treatment speed up bone marrow recovery. Sometimes it is given with treatment to move cells into the cell cycle thus increasing sensitivity to antineoplastics.
71
Why is G-CSF used to treat Acute lymphoblastic leukemia?
G-CSF is used to reduce the severity of neutropenia after treatment of ALL.
72
How is G-CSF used to treat myelodysplasia?
G-CSF is used in conjunction with erythropoietin to improve bone marrow function without stimulating malignant transformation.
73
Why is G-CSF used to treat Severe Neutropenia?
G-CSF is found to be effective at stimulating replacement neutrophils in cases of severe neutropenia.
74
Why is G-CSF given to donors before peripheral blood stem cell transplants?
Because G-CSF will increase the number of multipotent progenitors in the circulation that can be harvested
75
Why is G-CSF given to treat lymphomas?
G-CSF is given to reduce infection, delay giving chemotherapy, and shorten hospitalization after chemotherapy.
76
How long do monocytes circulate in the blood?
20-40 hours
77
How long do mature macrophages live for?
months to years
78
What are the three basic functions of neutrophils and monocytes?
(1) Chemotaxis(2) Phagocytosis(3) Killing and digestion
79
What is neutrophil and monocyte chemotaxis?
Neutrophils and monocytes are attracted by chemicals, such as chemokines or complement, to bacteria or sites of inflammation.
80
On what cells do CXC chemokines act?
Neutrophils
81
On what cells do CC chemokines act?
Monocytes, basophils, eosinophils, and natural killer cells.
82
What is the oxygen dependent intracellular killing/digestion pathway?
superoxide, hydrogen peroxide and other ROS react with MPO and halides to destroy ingested material/cells.
83
What is the non-oxidative microbicidal pathway?
microbicidal proteins such as cathepsin G, lysozyme, elastase, lactoferrin, and nitric oxide kill the ingested microbe.
84
What are some disorders associated with defective chemotaxis?
Lazy leukocyte syndrome, corticosteroid therapy, acute/chronic myeloid leukemia, myelodysplasia, and myeloproliferative syndromes.
85
What causes disorders of phagocytosis?
Phagocytic disorders most commonly are the result of defective opsonization.
86
What are the disorders of leukocyte killing mechanisms?
(1) Chronic granulomatous disease(2) MPO deficiency(3) G6PD deficiency(4) Chediak Higashi syndrome.
87
What is the Pelger-Heul anomaly?
A congenital condition characterized by bilobed or unsegmented neutrophils in the peripheral blood. Autosomal dominant
88
What is the May-Hegglin anomaly?
May-Hegglin anomaly is characterized by neutrophils that contain basophilic inclusions of RNA. There may be associated thrombocytopenia with giant platelets. Autosomal dominant.
89
What is Chediak-Higashi syndrome?
Chediak-Higashi syndrome is characterized by giant granules in neutrophils, eosinophils, monocytes, and lymphocytes, accompanied by neutropenia, thrombocytopenia, and hepatosplenomegaly. Autosomal recessive.
90
What causes hypersegmented neutrophils?
Megaloblastic anemia.
91
What causes Dohle bodies and toxic granules in neutrophils?
Infection
92
What pathological conditions can cause Pelger cells (bilobed or unsegmented neutrophils)?
Acute myeloid leukemia or myelodysplasia.
93
What conditions often accompany neutrophilia?
(1) Shift to the left (increased bands in peripheral blood)(2)Toxic granules(3) Dohle bodies(4) elevated NAP score (0-400)(normal is 20-100)
94
What is the leukamoid reaction?
The leukamoid reaction is a reactive and excessive leukocytosis characterized by the presence of immature leukocytes in the peripheral blood.
95
With what conditions is a leukamoid reaction associated?
(1) severe or chronic infections(2) severe hemolysis(3) Metastatic cancer(4) More pronounced in children.
96
What is hypereosinophilic syndrome?
A condition characterized by elevated eosinophils for over 6 months with associated tissue damage.
97
What is chronic eosionophilic leukemia?
Eosinophilic syndrome due to a clonal cytogenetic abnormality in the bone marrow.
98
What are the causes of basophilia?
All rare(1) Chronic myeloid leukemia(2) Polycythemia vera(3) Myxoedema(4) smallpox(5) chickenpox(6) ulcerative colitis.
99
What are some causes of Monocytosis?
(1) infection(2) Connective tissue diseases (hypersensitivity)(3) chronic neutropenia(4) Malignancies (5) treatment with growth factors.
100
What is the normal cutoff for neutropenia?
2.5x10^9/L except in blacks and middle easterners for which 1.5x10^9/L is normal.
101
What what level of neutrophils is the patient likely to have recurrent infections?
0.5x10^9/L
102
What is Kostman's syndrome?
Kostman's syndrome is an autosomal recessive condition that presents in the first year of life with serious infections due to neutropenia. (G-CSF therapy may be helpful)
103
What is a common cause of benign neutropenia?
Increased margination of neutrophils causes a decreased blood neutrophil count.
104
What are the clinical features of severe neutropenia?
(1) infections of the mouth and throat(2) ulceration of the mouth, throat, and anus(3) Septicemia(4) pathogenic infection by usually tolerated organisms.
105
How is type of neutropenia diagnosed?
By examination of the bone marrow. (marrow aspiration of trephine biopsy).
106
How is neutropenia treated?
Neutropenia is treated by prophylactic used of antibiotics to prevent infection. Immunosuppresants may actually be effective if the neutropenia is caused by AI disease. G-CSF may be effective in some benign neutropenias.
107
What is Langerhans cell Histiocytosis?
LCH are a group of diseases that can be single organ or multi-system. The lesions found include Langerhans cells, eosinophils, lymphocytes, neutrophils, and macrophages. Additionally there are tennis racquet like birbeck bodies in the langerhans cells
108
What is hemophagocytic lymphohistiocytosis (hemophagocytic syndrome)?
It is a rare AR, or acquired disorder (EBV/Herpes/Tumors) that is characterized with fever, pancytopenia, hepatosplenomegaly, multi-organ dysfunction, lymphadenopathy, and macrophages that have ingested other leukocytes.
109
How is hemophagocytic syndrome treated?
treatment involve the underlying cause if it is known.
110
What is the Rosai-Dorfman syndrome?
Sinus histiocytosis with massive lymphadenopathy is a condition typified by chronic painless cervical lymphadenopathy with fever and weight loss. It usually subsides by itself.
111
What is the most common cause of anemia in the world?
Iron deficiency
112
Iron deficiency is the most important cause of which anemia?
Microcytic hypochromic anemia.
113
What Red cell indicies are reduced in iron deficiency anemia?
MCV (mean corpuscular volume) and MCH (mean corpuscular hemoglobin)
114
What are the indications of iron deficiency anemia on blood film?
Small (mircocytic) and pale (hypochromic) RBCs.
115
What is the major differential diagnosis for microcytic hypochromic anemia?
Thalassemia.
116
Why is iron deficiency common?
Because iron is not easily absorbed by the body and loss of iron through hemorrhage is frequent.
117
What are the three proteins involved in iron transport and storage?
Transferrin, Transferrin receptor 1, and Ferritin.
118
What is transferrin?
Transferrin can contain up to two atoms of iron and delivers the iron to tissue that express the transferrin receptor (such as RBCs) When RBCs die transferrin then recollects the released iron.
119
Where does the iron on transferrin originate?
Most of the iron bound to transferrin is recycled from RBCs. A small proportion is from the diet.
120
What is ferritin?
Ferritin is found in macrophages and is a storage molecule for Iron. Ferritin is a water soluble apoprotein shell with an iron core that contains up to 4000-5000 iron atoms.
121
What is hemosiderin?
Hemosiderin is a protein iron complex created by the lysosomal digestion of ferritin. Vissible with prussian blue stain.
122
What happens to ferritin and transferrin receptor 1 when there is iron overload?
Levels of ferritin rise and levels of transferrin receptor fall
123
What happens to ferritin and transferrin receptor when there is iron deficiency?
ferritin levels fall, and transferrin receptor levels rise
124
What regulates iron trafficking?
iron regulatory protein (IRP) and Iron response elements (IREs). IRP binds to IREs on the upstream or down stream sites of the ferritin and transferrin receptor mRNAs.
125
When is IRP able to bind to mRNAs?
Iron deficiency increases the ability of IRP to bind the mRNAs. Thus blocking ferritin translation and stabilizing transferrin receptor translation.
126
What causes the pathological findings associated with iron overload?
When transferrin is saturated excess iron accumulates in parenchymal tissues causing pathology.
127
What is Hepcidin?
Hepcidin is the major hormonal regulator of iron homeostasis. It is produced in the liver (and also an acute phase reactant)
128
What is the function of hepcidin?
hepcidin inhibits the release of iron form macrophages, intestinal epithelium, and placental cells by blocking ferroportin production.
129
When is hepcidin production reduced?
in iron deficiency, hypoxia, and ineffective erythropoiesis.
130
What is transferrin receptor 2?
A receptor that senses the degree of transferrin saturation. High saturation leads transferrin receptor 2 to stimulate hepcidin synthesis.(found in erythroid, duodenal crypt, and liver cells)
131
How much iron is consumed in the typical western diet?
10-15g a day of which only 5-10% is normally absorbed.
132
How is dietary iron absorbed in the gut?
The HCP-1 receptor absorbs heme from the lumenThe DMT-1 receptor absorbs iron from the lumenFerroportin releases iron on the basolateral surface to the blood stream.
133
How is dietary iron absorbtion regulated?
When transferrin receptor 2 on duodenal crypt cells senses iron deficiency DMT-1 is upregulated by IRP-IRE (takes 24-48 hours).
134
When are iron requirements highest?
In pregnancy, adolescence, and mentruating females.
135
Are reticuloendthelial stores of hemosiderin and ferritin present in anemia?
No they are depleted before anemia occurs.
136
What are the clinical features of iron deficiency anemia?
(1) The typical signs of anemia(2) painless glossitis(3) angular stomatitis(4) abnormal or spoon nails(5) Dysphagia(6) Neurological symptoms in children.
137
What is the dominant cause of iron deficiency?
chronic or excessive blood loss. (commonly uterine or from gastrointestinal ulcer)
138
How long does it usually take for iron deficiency from poor diet alone to develop?
About 8 years (not entirely uncommon in developing countries where lifelong poor diet is frequent).
139
What are the Red cell indicies for iron deficiency anemia?
Red cells may be microcytic and hypochromic progressively even before clinical anemia has been reached. (Poikilocytes may also be seen)
140
When are dimorphic blood films seen?
Dimorphic blood films occur with iron deficiency associated with severe folate or B12 deficiency, or with anemic patients that have just received iron supplementation or blood transfuion.
141
Is bone marrow examination essential for assesment of iron stores?
Not unless the case is particularly complicated.
142
What happens to the serum iron and the total iron binding capacity (TIBC) in iron deficiency anemia?
In iron deficiency anemia the serum iron falls and the TIBC rises so that the TIBC is less than 10% saturated.
143
When are serum transferrin receptor levels increased?
When there is iron deficiency anemia or increased erythropoiesis. But it is not increased in anemia of chronic disease or thalassemia.
144
What are the causes of reduced serum ferritin?
iron deficiency anemia increases serum ferritin
145
What causes an increase in serum ferritin?
Iron overload, damaged tissue, acute phase reaction, or possibly the anemia of chronic disease.
146
What are the most common causes of iron deficiency in pre menopausal women?
Menorrhagia or repeated pregnancies are the most common causes.
147
What often causes menorrhagia?
A clotting or platelet abnormality
148
What is the most common cause of iron deficiency in men and post menopausal women?
GI blood loss. (possible Hookworm or gluten induced enteropathy)
149
If GI bleed is negative what are some alternative causes of iron deficiency?
HematuriaPulmonary hemosiderosis (chest xr)Self laceration
150
How is iron deficiency treated?
By treatment of the underlying cause and supplemental iron.
151
What are some possible side effects of oral iron supplements?
nausea, abd pain, constipation, or diarrhea.
152
Why is iron supplementation for anemia usually continued for 6 months?
Because both functional iron levels and iron stores must be replenished.
153
When is parenteral iron administration used?
When is severe bleeding (menorrhagia, GI bleed), erythropoietin therapy, or chronic hemodialysis and oral iron is ineffective.
154
What causes oral iron to be ineffective?
oral iron is ineffective when there is malabsorption in the GI tract. (Gluten induced enteropathy, atrophic gastritis, active crohn's disease)
155
What are the characteristic features of anemia of chronic disease?
(1) Normochromic cells (or mildly hypochromic)(2) Normocytic cells
156
What happens to serum iron and TIBC in anemia of chronic disease?
They both are reduced.
157
What happens to serum transferrin receptor levels in anemia of chronic disease?
serum transferrin receptor levels remain normal.
158
What happens to bone marrow (reticuloendothelial) iron stores in anemia of chronic disease?
it remains normal
159
What happens to erythroblast iron stores in anemia of chronic disease?
erythroblast iron stores are reduced
160
How does chronic disease cause anemia?
(1) decreased iron release from macrophages ( acute phase reaction)(2) reduced RBC lifespan(3) reduced erythropoietin response (inflammatory cytokines)
161
What are the characteristics of sideroblastic anemia?
Hypochromic cells in peripheral blood.increased marrow iron.>15% of marrow erythroblasts are ring sideroblasts.
162
What causes sideroblastic anemia?
A defect in heme synthesis.(1) ALA deficiency(2) B6 deficiency(3) Lead poisoning(4) Alcoholism
163
How is sideroblastic anemia treated?
Pyradoxal-6-phosphate supplementation can be used in rare cases however repeated blood transfusions are usually the only way to maintain hemoglobin concentrations.
164
What effect does lead poisoning have on the blood?
Lead poisoning inhibits both heme and globin synthesis. It also inhibits RNA breakdown (basophilic stippling).
165
How is iron deficiency anemia differentiated from thalassemia?
iron deficiency anemia exhibits MCV and RBC counts the fall in proportion to the severity of the anemia.Thalassemia shows lower MCV regardless of anemia severity, and RBC counts are markedly increased.
166
How can iron deficiency anemia be differentiated from anemia of chronic disease other than by ferritin levels?
iron deficiency anemia will have increased serum transferrin receptor .
167
What method is used to diagnose sideroblastic anemia?
By bone marrow examination.
168
What is hereditary hemochromatosis?
Diseases characterized by excessive uptake of iron by the GI tract. (most commonly due to mutations in the HFE gene)
169
What are common characteristics of hemochromatosis?
hemochromatosis often presents with hepatic disease, endocrine disturbances, diabetes, impotence, melanin skin pigmentation. Additionally there is also low levels of hepcidin.
170
What are macrocytic anemias?
Anemias in which cells have a MCV greater than 95.
171
What is megaloblastic anemia?
Anemia characterized by cells with nuclei that are immature compared with the cytoplasm.
172
What is the underlying cause of megaloblastic anemia?
Megaloblastic anemia is usually caused by defective DNA synthesis. (commonly the result of B12 or folate deficiency.
173
What is cobalamin (55)?
Cobalamin is Vitamin B12.
174
Where is B12 created (55)?
B12 is created by microorganisms.
175
What is the structure of B12 (55)?
B12 (cobalamin) is composed of a cobalt atom at the center of a corrin ring
176
How is B12 absorbed(56)?
B12 binds to intrinsic factor (IF) forming a complex that binds the receptor cubilin. the new complex then binds a second protein called amnionless which then endocytoses the B12.
177
What happens to B12 in the blood stream (56)?
B12 in the blood stream binds to either transcobalamin or haptocorrin. However, only transcobalamin is able to deliver B12 to the bone marrow.
178
What binds more B12 haptocorrin or transcobalamin (57)?
Haptocorrin binds most of the B12.
179
What are the two biochemical functions of B12 (57)?
(1) B12 is a cofactor for methionine synthase in the synthesis of methionine(2) B12 helps to convert methylmalonyl CoA to succinyl CoA.
180
How is B12 deficiency tested for (57)?
levels of homocysteine or methylmalonic acid are assayed.
181
How is Folate absorbed(58)?
Folate is converted to THF to be absorbed by enterocytes. The enterocytes then convert THF to folate polyglutamates.
182
What is the function of folate(58)?
Folate functions in single carbon unit transfer. (synthesis of glycine or purine etc.)
183
Why does folate deficiency cause megaloblastic anemia(58)?
Folate deficiency causes megaloblastic anemia because folate is necessary for the synthesis of thymidylate (a precursor of thymine).
184
How is dihydrofolate converted to tetrahydrofolate during thymidylate synthesis(59)?
It is converted by dihydrofolate reductase?
185
What drugs inhibit dihydrofolate reductase(59)?
(1) Methotrexate (antineoplastic)(2) pyrimethamine (anti malarial)(3) Trimethoprim (antimicrobial)
186
What are the most common causes of B12 deficiency in western culture (59)?
(1) Addisonian pernicious anemia(2) Veganism (it is found in meat)(3) Gastrectomy or small intestinal lesions.(4) Nitrous oxide may inactivate B12.
187
What causes pernicious anemia(59)?
Pernicious anemia is caused by an autoimmune attack that causes atrophy of the gastric mucosa. (commonly initiated by helicobacter pylori infection)
188
What is the epidemiology of pernicious anemia(59)?
(1)Pernicious anemia is most common in females. (2)Peak age of onset is 60. (3) Occurs most in northern europeans. (4) 2-3% of patients develop carcinoma of the stomach.
189
What antibodies are present in pernicious anemia(60)?
(1) Parietal cell antibodies (against H/K ATPase) (90%) (also occurs in 16% for normal people over 60)(2) Type 1 blocking antibody against IF (50%)(3) Type 2 precipitating antibody against IF.
190
How long does it take for B12 deficiency to take effect (60)?
it takes 2 years for B12 stores to be depleted.
191
What are some secondary causes of B12 deficiency (60)?
(1) Congenital defect in B12 absorption complex(2) inadequate intake(3) atrophic gastritis (without IF antibodies) (helicobacter pylori)
192
What causes folate deficiency (60)?
Folate deficiency occurs when intake is not adequate for the level of folate utilization. Increased utilizaiton (pregnancy) or inadequate diet may be the cause.
193
What are the primary clinical features often seen in Megaloblastic anemia (60)?
Insidious with progressive onset(1) Mild jaundice (2) Glossitis(3) Angular stomatitis(4) Mild malabsorption and weight loss (epithelial abnormality)(5) melanin pigmentation
194
What is vitamin B12 neuropathy (61)?
A symetrical neuropathy affecting the peripheral nerves that is caused by the buildup of adenosyl homocystein and adenosyl methionine in nervous tissue (B12 deficiency). May also cause psychiatric problems.
195
Why are B12 and folate levels extremely important in pregnancy (62)?
Because lower levels of B12 and folate are correlated with higher incidences of neural tube defects in newborns.
196
What secondary tissue abnormalities can occur in relation to folate or B12 deficiency (63)?
(1) Sterility(2) Epithelial abnormalities(3) reversible pigmantation(4) reduced osteoblastic activity.
197
What are the serum lab findings in megaloblastic anemia (63)?
(1) MCV is increased(2) Rdw is decreased(3) WBC is moderately reduced(4) Platlets are moderately reduced(5) increased bilirubin(6) LDH is increased.
198
What cellular morphological characteristics are associated with megaloblastic anemia (63)?
(1) Large oval erythrocytes(2) Immature nuclei with normal cytoplasmic Hgb(3) hypersegmented neutrophils(4) giant metamyelocytes
199
How are folate and B12 deficiencies diagnosed (63)?
Serum B12, serum folate, and red cell folate are used to diagnose deficiency.
200
How is absorption tested as the cause of B12 deficiency (63)?
Absorption is tested by ingestion of radio labeled cyanocobalamin. This can differentiate between malabsorption and indadequate diet. When acitve IF is added gastric lesions can be differentiated from intestinal lesions. Schilling test for urinary excretion of labeled B12 is also used.
201
How can pernicious anemia be tested for (64)?
By testing for antibodies to gastric antigens.
202
How is a folate deficiency diagnosed (65)?
folate deficiency is diagnosed by dietary history.
203
How are folate and B12 deficiencies treated (65)?
treatment involves giving supplements of both vitamins unless B12 deficiency can be definitively ruled out. (Folic acid given with B12 deficiency can aggravate neuropathy.
204
What is the major concern with heart failure patients taking folate/B12 supplements (66)?
The concern is that hypokalemia may occur. Patients must be corrected with diuretics and potassium for 10 days.
205
What is the response to folate and B12 supplementation (66)?
(1) patient feels better in 24-48 hours(2) Hgb should rise by 2-3 every 2 weeks(3) Cell counts should return to normal in 7-10 days.
206
When is B12 given prophylactically (66)?
B12 is given prophylactically to patients who have had a total gastrectomy or ileal resection.
207
When is folic acid given prophylactically (66)?
(1) pregnancy(2) Chronic dialysis(3) hemolytic anemias(4) chronic myelofibrosis(5) premature babies
208
What are some secondary causes of Megaloblstic anemia (67)?
(1) congenital defects in B12 or folate metabolism(2) repeated nitrous oxide anesthesia.(3) Antifolate drugs (methotrexate)
209
Is cardiovascular disease linked to B12/folate deficiency (67)?
Yes increased levels of homocysteine are linked in mycocardial infarction.
210
Can megaloblastic anemia occur without B12 or folate deficiency (67)?
Yes (1) enzymatic deficiency in purine/pyrimidine synthesis(2) Drugs that inhibit purine or pyrimidine synthesis.
211
What can cause non-megaloblastic macrocytic anemias (67)?
(1) Lipid deposition in RBC membrane(2) Alcohol increases MCV(3) Hemolytic anemia (release of reticulocytes)
212
What is the average lifespan of an erythrocyte?
120 days
213
What facilitates the normal destruction of RBCs?
The reticuloendothelial system (BM, liver, and spleen)
214
What is heme broken down into?
protoporpherin which becomes bilirubin and iron which is recycled.
215
What happens to globin from degraded RBCs?
It broken into amino acids which are excreted.
216
What are hemolytic anemias?
Anemias caused by increased Red cell destruction.
217
Why does hemolytic anemia not present clinically until average red cell life is less than 30 days?
Because the bone marrow can compensate and produce 6-8 times the normal amount of RBCs masking the hemolysis.
218
How are hemolytic anemias classified?
Hemolytic anemias are either hereditary or acquired.
219
What are the clinical features of hemolytic anemias?
(1) pallor(2) mild jaundice(3) splenomegaly(4) pigmented urine (urobillogen) (possibly kidney failure)(5) Bilirubin gallstones.(6) occasionally ulcers around the ankle (SSD)
220
What are the laboratory features of increased Red cell breakdown?
(1) increased serum bilirubin. (more for intravascular)(2) increased urine urobillogen(3) increased fecal stercobilinogen(4) serum haptoglobins absent (5) Increased LDH(6) Plasma and urine Hgb increased(7) Urine hemosiderin (intravascular hemolysis).
221
What are the laboratory features of increased RBC production?
(1) Reticulocytosis(2) Myeloid:erythroid BM ratio of 1:1 or lower.
222
What are the RBC laboratory findings associated with damaged red cells?
(1) microspherocytes, elliptocytes, fragments(2) autohemolysis(3) Shortened RBC lifespan.
223
What are the two main locations of hemolysis?
(1) Extravascular via the reticuloendothelial system (liver and spleen)(2) intravascular.
224
What are the key laboratory features of intravascular hemolysis?
(1) hemoglobinemia(2) hemoglobinuria(3) Hemosiderinuria(4) Methaemaalbuminemia
225
What is the most common hereditary hemolytic anemia among northern europeans?
Hereditary spherocytosis.
226
What is the pathogenesis of hereditary spherocytosis?
Mutations to proteins involved in the interaction between cytoskeleton and membrane cause loss of RBC membrane. As RBCs circulate they become increasingly spherical. Eventually they get stuck in the microcirculation of the spleen and they die.
227
What are the clinical features of HS?
(1) Autosomal dominant (usually)(2) Fluctuating jaundice (particularly with Gilbert's disease)(3) Splenomegaly in most patients(4) Pigment gallstones(5) aplastic crises (often precipitated by parvovirus infection)
228
What are the hematological findings with HS?
(1) Anemia(2) microspherocytosis(3) Reticulocytes 5-20%
229
What findings help diagnose HS?
(1) osmotic fragility(2) Autohemolysis that is corrected by glucose
230
What is the treatment for HS?
Splenectomy, however this should not be done in younger patients or in patients with mild disease.
231
What is hereditary elliptocytosis?
A disease with similar clinical and lab features to HS, except for the appearance on a blood film. it also tends to be milder.
232
What causes hereditary elliptocytosis?
A mutation effecting the association of spectrin dimers into tetramers.
233
What is south-east asian ovalocytosis?
A red cell abnormality with cells that are rigid and resist invasion by malarial parasites. Most cases are asymptomatic. (mutation of the Band 3 protein)
234
How does G6PD effect RBCs?
G6PD renders RBCs susceptible to oxidant stress because it impairs their ability to form NADP.
235
What is the epidemiology of G6PD deficiency?
G6PD is X linked and affects mostly west african, mediterranian, middle eastern, and south-east asians. It imparts some resistance to malaria.
236
What are the clinical features of G6PD deficiency?
(1) Acute hemolytic anemia(2) Neonatal jaundice(3) Rarely a congenital non-spherocytic hemolytic anemia.
237
How is G6PD diagnosed?
(1) enzyme assay(2) mid crisis contracted and fragmented 'bite' cells
238
How is G6PD treated?
Whatever agent precipitated the anemic crisis is treated. Blood transfusion may be necessary if the anemia is severe enough.
239
What other Pentose phosphate shunt deficiencies can lead to hemolytic anemia?
Glutathione deficiency
240
What glycolytic defects can lead to hemolytic anemia?
several that are all uncommon. They lead to non-spherocytic hemolytic anemia. Pyruvate kinase is the most common of them.
241
How is pyruvate kinase deficiency inherited?
Autosomal recessive
242
What are the clinical features of PK deficiency?
(1) widely varying anemia(2) mild symptoms (right shift in oxygen binding due to rise in 2,3-DPG.)(3) prickle cells(4) autohemolysis not corrected by glucose.
243
What are autoimmune hemolytic anemias?
Anemias characterized by antibodies against self red cells. They give a positive coombs test.
244
How are AI hemolytic anemias classified?
AI hemolytic anemias are classified into warm and cold types.
245
What are warm autoimmune hemolytic anemias?
Red cells coated with Ig (usually IgG) and complement are taken up by RE macrophage which remove part of the membrane. This cuases spherocytosis and eventually Red cell destruction in the spleen by the RE system.
246
What are the clinical features of warm hemolytic anemia?
(1) variable hemolytic anemia(2) enlarged spleen(3) remission and relapse(4) with thrombocytopenic purpura its Evan's syndrome(5) can be caused by methyl dopa therapy
247
What are the Lab findings of warm AI hemolytic anemia?
(1) Typical signs of hemolytic anemia(2) Positive direct Coomb's test
248
How is warm AI hemolytic anemia treated?
(1) Remove the underlying cause(2) Corticosteroids (good if caused by IgG not complement)(3) Immunosuppression(4) Monoclonal antibodies (rituximab anti-CD20)(5) Splenectomy in severe refractory cases(6) Folic acid in severe cases(7) Blood transfusion
249
What are cold AI hemolytic anemias?
Auto antibody attaches to red cells in the cooler peripheral blood. Usually IgM that fixes complement leading to both intravascular and extravascular hemolysis.
250
With what is monoclonal cold AIHA associated?
idiopathic (possibly lymphoproliferative disorders)
251
WIth what is Polyclonal Cold AIHA associated?
infection such as mononucleosis or mycoplasma.
252
What are the clinical features of cold AIHA?
(1) Chronic Hemolytic anemia aggravated by cold(2) Mild jaundice (3) mild splenomegaly(4) bluish discoloration on the tips of the nose, ears, fingers, and toes.
253
What are the lab findings in Cold AIHA?
(1) Positive Coombs for complement only(2) Typical signs of hemolytic anemia(3) very little spherocytosis.
254
What is paroxysmal cold hemoglobinuria?
acute hemolysis after exposure to the cold. lysis occurs after rewarming. involves auto antibodies against blood group P antigen.
255
What is alloimmune hemolytic anemia?
Hemolytic anemia caused by antibodies in one individual against antigen from another. (ABO, Rh, etc.)
256
What are the three kinds of drug induced hemolytic anemia antibodies?
(1) Ab against drug-red cell membrane complex(2) deposition of complement after formation of drug antigen complex(3) true idiopathic AI hemolytic anemia.
257
What are red cell fragmentation syndromes?
Conditions in which physical damage is done to red cells.
258
What are causes of fragmentation syndrome?
(1) abnormal surfaces (artificial implants)(2) atriovenous malformations(3) microangiopathic hemolytic anemia
259
What are the causes of microangiopathic hemolytic anemia?
fibrin strands due to (1) DIC(2) thrombocytopenic purpura (TTP)(3) Vasculitis(4) polyarteritis nodosa(5) Burns
260
What causes march hemaglobinuria?
damage to red blood cells between the small bones of the feet due to prolonged marching or running.
261
What is PNH?
It is a disorder in which deficient synthesis of the GPI anchor causes loss of DAF and MIRL on the RBC membrane. This leads to complement mediated lysis of RBCs,
262
What are the clinical features of PNH?
(1) Hemosiderinuria (and potentially iron deficiency)(2) Thrombosis (acts on platelets too)(3) Bone marrow hypoplasia
263
How is PNH diagnosed?
Flow cytometry for CD55 (DAF) and CD59 (MIRL).
264
How is PNH treated?
(1) Eculizumab (ab against complement C5)(2) Iron therapy (for associated iron deficiency)(3) Stem cell transplant (definitive)(4) immunosuppression.
265
What are the three principle causes of intrinsic hemolytic anemia?
(1) disorders of the Red cell membrane(2) Metabolic hemolysis (G6PD, PKD, oxidative drugs)(3) Disorders of hemaglobin synthesis (sickle cell, thalassemias)
266
What are the hemolytic disorders of the cell membrane?
(1) hereditary spherocytosis(2) Hereditary elliptocytosis(3) Stomatocytosis(4) Acanthocytosis(5) Paroxysmal Nocturnal Hemaglobinuria
267
What are the Immune hemolytic anemias?
(1) Auto immune hemolytic anemia (Warm and Cold)(2) Alloimmune hemolytic anemia(3) Transfusion reactions(4) Erythroblastosis fetalis
268
What are the infectious conditions which lead to hemolytic anemia?
(1) malaria(2) Babesiosis(3) Clostridial sepsis
269
What are the categories of extrinsic hemolysis?
(1) microangiopathic conditions(2) Immune hemolytic anemias(3) Infectious conditions
270
How does hypersplenism lead to hemolysis?
enlarged spleen traps RBCs and they die early.
271
How is MCV calculated?
MCV = hct/rbc count (x10)
272
How is MCH calculated?
MCH = Hgb/ rbc count (x10)
273
How is MCHC calculated?
MCHC = Hgb/Hct (x100)
274
What are the first two proteins bound by Hgb in the serum?
Haptoglobin and then albumin (methalbumin)
275
Why are some coomb's tests negative for hemolytic anemia?
Because the spleen can remove ab coated RBCs
276
What can cause hemoytic anemia with low retic count?
parvovirus that knocks out erythropoietic cells.
277
What is the differential diagnosis with warm AI hemolytic anemia?
Lymphoma, malignancy, SLE, RA, drug induced, idiopathic.`
278
What is the differential diagnosis of cold AI hemolytic anemia?
Viral infections, mycoplasma, lymphoma, malignancy, SLE, RA, idiopathic.
279
What has the better prognosis warm or cold HA?
Cold is chronic and seasonal while warm has a much poorer prognosis.
280
What enzyme deficiency can lead to microangiopathic hemolytic anemia via vWF?
AdamTS13,
281
What proportion of the world's population is affected by mutations in the globin genes?
7% of the world population is affected by mutations in the globin genes
282
What are the structures of various types of Hgb?
Hgb A is alpha2beta2.Hgb A2 is apha2delta2Hgb F is alpha2gamma2
283
What kinds of mutations can lead to thalassemias?
Any mutation that alterers the structure, regulation or processing of globin genes can potentially lead to thalassemia.
284
What is the locus control region?
It is a genetic regulatory element situated a long way upstream of the globin genes that controls transcription.
285
What transcription factors influence expression of globin genes?
GATA-1, FoG, NF-E2
286
When is fetal hemoglobin production overtaken by adult hemoglobin production?
3-6 months after birth gamma chain production for fetal hemoglobin is decreased while beta chain production for adult hemoglobin is increased. (switch from fetal to adult)
287
What are the two basic categories of hemoglobin abnormalities?
(1) Synthesis of an abnormal hemoglobin(2) reduced synthesis of normal alpha or beta chains ( the thalassemias)
288
What are the abnormal hemaglobin diseases?
They are caused usually by point mutations in globin genes that result in unstable cyrstalline hemaglobins.(1) Hgb S(2) Hgb C(3) Hgb D(4) Hgb E
289
What secondary effects can be caused by abnormal hemaglobins?
Polycythemia, methhemaglobinemia.
290
Where is beta-thalassemia the most common?
Beta-thalassemia is most common in mediterranean ethnic groups.
291
Where is alph-thalassemia most common?
Alpha thalassemia is most common among far eastern ethnic groups.
292
What are thalassemias?
Disorders characterized by a reduced rate of synthesis of alpha or beta genes.
293
How many alpha globin genes are there?
There are two alpha globin genes on each chromosome for a total of 4 alpha genes.
294
What is hydrops fetalis?
Hydrops fetalis is caused by deletion of all four alpha globin genes. This condition is lethal in utero.
295
What is Hgb H disease?
Hgb H disease is caused by deletion of 3 alpha globin genes. This condition is characterized by (1) microcytosis(2) hypochromatosis(3) anemia (Hgb 7-11 g/dL)(4) splenomegaly(5) Hgb H which is beta4 hemaglobin
296
What are the alpha-thalassemia traits?
Deletion of 1 or 2 alpha thalassemia genes will result in slightly lowered MCV and MCH , but there is not anemia and electrophoresis is normal.
297
What causes beta thalassemia major?
beta thalassemia is caused by point mutations in beta globin genes that result in very little (beta+) or no (beta0) beta globin being produced.
298
What determines the severity of the thalassemia major?
The greater the alpha chain excess over the beta chain the more severe the anemia?
299
What is Lepore syndrome?
beta thalassemia major caused by a delta-beta fusion gene.
300
Is anemia present in beta thalassemia major?
Yes anemia will become apparent at 3-6 months of age once Hgb F has switched to Hgb A.
301
What anatomical findings are seen clinically with beta thalassemia major?
(1) splenomegaly (from red cell destruction)(2) hepatomegaly (from red cell destruction)(3) Expansion of bones (from bone marrow hyperplasia)
302
What is the result of repeated blood transfusions for beta thalassemia major?
Iron overload precipitated by ineffective erythropoiesis and inappropriately low hepcidin levels.
303
What effects does beta thalassemia major have on the endocrine system?
Iron overload causes damage to the endocrine organs.(1) hypothyroidism(2) hypoparathyroidism(3) delayed puberty(4) diabetes.
304
What is the effect on the skin of beta thalassemia major?
pigmentation due to excess melanin, hemosiderin, giving a grey appearance.
305
What is the effect of beta thalassemia major on the immune system?
those with beta thalassemia major have increased risk for infections. (particularly with splenectomy and transfusions)
306
What is the effect of beta thalassemia major on the skeletal system?
Osteoporosis is common in diabetic and well transfused patients.
307
What is the most dangerous adverse effect of iron overload?
Iron overload damages the heart.
308
What are cellular lab abnormalities seen with beta thalassemia major?
(1) microcytosis(2) hypochromatosis(3) increased reticulocyte count(4) Normoblasts, target cells, and basophilic stippling on PBS.
309
What is the result of hemoglobin electorphoresis in beta thalassemia major?
(1) almost complete absence of hemoglobin A (2) larger amounts of Hgb F.HPLC is most commonly used to diagnose beta thalassemias.
310
How should iron status be assessed in beta thalassemia major?
iron status should be assessed by monitoring serum ferritin. However, T2 MRI imaging is required to asses iron mediated damage to the heart. Urine iron excretion with chelators and liver biopsy can also be used to monitor iron status.
311
How is beta-thalassemia treated?
(1) Regular blood transfusions maintain hemoglobin levels above 10g/dL(2) Folic acid supplementation(3) Iron chelation therapy(4) Endocrine therapy to compensate for iron damaged organs.(5) Immunization against hepatitis in transfusions(6) Vitamin C (Improves iron excretion)(7) splenectomy in patients over 6yo.(8) BM transplant (definitive treatment, effective in 80% of patients)
312
What is beta-thalassemia minor?
The carrier trait for beta thalassemia
313
What are the characteristics of beta thalassemia?
(1) hypochromic, microcytic blood film(2) HIgh red cell count(3) mild anemia (hgb 10-12)
314
How is beta thalassemia minor diagnosed?
A raised Hgb A2 confirms beta thalassemia minor diagnosis.
315
What is thalassemia intermedia?
thalassemias of moderate severity with Hgb between 7-10 g/dL
316
What is delta-beta thalassemia?
Thalassemia cuased by reduced amount of beta and delta chains. typically exhibits increased Hgb F.
317
What kind of thalassemia is caused by hemaglobin lapore?
Homozygotes exhibit thalassemia intermedia while heterozygotes exhibit thalassemia trait.
318
What is hereditary persistence of fetal hemaglobin?
Genetic conditions caused by deletions or cross overs affecting the production of beta and gamma chains.
319
What is the result of beta-thalassemia combined with Hgb E trait?
It presents like thalasemia major.
320
What is the result of beta thalassemia with Hgb S trait?
It presents like sickle cell disease.
321
What is the result of beta-thalassemia trait with Hgb D?
Hypochromic, microcytic anemia of varying severity.
322
What are the three forms of sickle cell disease?
(1) Hgb SS (sickle cell disease)(2) Hgb SC (double heterozygote presents like sickle cell disease)(3) Hgb SBetathalassemia (presents like sickle cell disease)
323
What mutation causes sickle cell disease?
A Val for Glu substitution at position 6 of the beta globulin gene. Causes hemoglobin to polymerize under low oxygen tension.
324
What is the primary sign of SS disease?
severe hemolytic anemia
325
Why are symptoms of anemia mild in comparison to the severity of the anemia?
Because Hgb S gives up oxygen more readily than Hgb A shifting the O2 dissociation curve to the right.
326
What is the primary symptoms of SS disease?
Frequent and severely painful vaso-occlusive crises.
327
What can precipitate vaso-occlusive crises in SS disease?
Infection, acidosis, dehydration, or deoxygenation.
328
What are the potential complications of vaso-occlusive crises?
infarction of the bones, lung, spleen and brain (most serious).
329
What are visceral sequestration crises?
sickling of cells within organs leading to pooling of blood (Chest syndrome in lungs - must give oxygen and transfusion.)
330
What are the different kinds of crises seen in SS disease?
(1) vaso-occlusive(2) visceral sequestration(3) Aplastic crisis(4) hemolytic
331
What are aplastic crises?
aplastic crises are caused by parvovirus infection or folate deficiency and are characterized by a fall in reticulocyte and hemoglobin counts.
332
What are hemolytic crises?
Increased rate of hemolysis characterized by fall in Hgb and rise in reticulocytes
333
What are the clinical features of SS disease?
(1) Ulcers in the lower legs (due to stasis)(2) retinopathy(3) Pulmonary hypertension(4) liver damage(5) Bilirubin gallstones(6) renal infarctions(7) nocturia(8) osteomyelitis
334
What is the hemoglobin level in SS disease?
Hgb is low 6-9 g/dL
335
What are the cellular morphological findings in SS disease?
sickle cells, target cells, Howell-Jolly bodies (splenic atrophy)
336
How can SS disease be treated?
(1) Folic acid (2) Pneumococcal, haemophilus, and meningicoccal vaccination and prophylactic penicillin prevent infection.(3) Transfusions with iron chelators in patients with frequent crisis(4) Hydroxyurea (increases Hgb F)(5) stem cell transplant
337
What is hemoglobin C disease?
A genetic defect in which lysine is substitiuted for Glu at the 6 position of beta globin.(1) cells with rhomboid crystals(2) splenomegaly
338
What are the characteristics of Hgb D disease?
Mild hemolytic anemia
339
What are the characteristics of Hgb E disease?
common in south-east asia. causes microcytic and hypochromic anemia.
340
How many blood group antigens are there?
approximately 400
341
What are the naturally occurring blood group antibodies?
Anti-A and Anti-B which are usually IgM and react optimally at cold temperatures.
342
What is unique about A antigen?
There are two subgroups that react differently. A1 cells react more strongly with anti-A abs.
343
What are the immune blood group antibodies?
They occur after exposure to blood group antigens from other people. They are usually IgG and are considered warm antibodies.
344
What is the risk of infection from blood transfusion?
Donors are screened for disease however viruses esspecially those that are carried for many years asympotmatically (latent) can cause disease after blood transfusions.
345
How is hepatitis transmission prevented in blood transfusions?
Donors with a history of hepatitis are deferred. Although those with a history of jaundice can be accepted if they are negative for HBV and HCV markers.
346
How is HIV transmission prevented in blood transfusions?
Homosexuals, bisexuals, IV drug users, prostitutes, hemophiliacs, and there partners are excluded from donating as are people from large parts of sub saharan africa.
347
The UK screens for which rare virus in blood transfusions?
human T cell leukemia virus (HTLV 1 and 2)
348
For which individuals must cytomegalovirus be screened for before blood transfusion?
The immunosuppressed including(1) premature babies(2) organ transplant recipients(3) pregnant women.
349
What bacteria may transmitted by platelets?
Syphilis (platelets are stored at room temperature.)
350
What parasite can be found even in refridgerated blood?
Malaria
351
What disease is a significant problem with blood transfusions in latin america?
Chagas disease.
352
Do prions pose a blood transfusion risk?
Possibly, the UK excludes blood donation recipients as donors for this reason.
353
What infections can lyse RBCs?
(1) Malaria(2) Babesia(3) Bartonella(4) C. perfringens
354
What substance is used to keep blood from coagulating?
citrate
355
What is the risk of serious infection from a transfusion?
1 in 100,000
356
How are red cells prepared for transfusion?
Stored as packed cells not whole blood.
357
How long can transfusion blood be stored?
42 days. If older than 42 days 25% of the RBCs will lyse after transfusion.
358
What is added to O blood to make it A blood?
GalNac
359
What is added to O blood to make it B blood?
galactose
360
What is the most antigenic protein on red cell surfaces?
RhD
361
What patients have the highest chance for reaction with minor blood group antigens?
Patients that are transfused frequently.
362
What proportion of RhD- individuals will develop antibodies against RhD?
80%
363
What is a crossmatch?
It is a test for preformed antibodies against minor blood group antigens
364
What lab test is indicative of transfusion success?
Hemaglobin. direct test for oxygen carrying capacity.
365
What are the indications for a blood transfusion?
Increased HR, Increased RR, confusion, weakness, (1) Shock due to acute blood loss or volume expansion.(2) During or after Myocardial infarction(3) Hgb trendline that you cannot reverse yet
366
What are not good reasons to transfuse?
(1) patient is old and frail(2) Asymptomatic CAD(3) Expanded blood volume(4) to promote wound healing
367
What can be done in emergencies involving massive blood loss?
Type O RhD- blood can be given. It has a fairly high chance of successful transfusion.
368
How do hemolytic transfusion reactions present?
(1) fever(2) chills(3) Chest pain(4) hypotension(5) nausea(6) flushing (7) dyspnea(8) Hemoglobinuria
369
What are delayed transfusion reactions?
reaction may not manifest for several days after the transfusion.
370
What techniques are used in blood group serology?
(1) saline agglutination (good for IgM)(2) Antiglobulin Coomb's test (IgG) (detects antibodies bound to RBC surface.)(3) Indirect antiglobulin Coomb's test (detects anti RBC abs in the serum)
371
How is Patient (recipient) blood screened for compatibility (cross matching)?
(1) ABO and RhD compatibility are tested(2) serum is tested against O blood with a series of antigens (Rh D, C, c, E, e, and K.)
372
When can blood be transfused without testing?
When the patient has had blood group and antibody screens on two separate occasions both being negative, and they have no blood transfusion in between.
373
What are the two types of hemolytic transfusion reactions?
(1) immediate (2) delayed
374
What causes immediate hemolytic transfusion reactions?
Massive intravascular hemolysis caused by IgG or IgM antibodies usually against major blood group antigens.
375
What are the causes of delayed type hemolytic transfusion reactions?
Preformed antibodies against RBC antigens that are at levels too low to be detected by screening may lead to reimmunization and a hemolytic crisis may occur a few days later.
376
What are the three phases of a major hemolytic transfusion reaction?
(1) Hemolytic shock phase(2) Oliguric phase(3) Diuretic phase
377
What are the clinical features of the Hemolytic shock phase of a transfusion reaction?
Shortly after or during the transfusion(1) decrease in blood pressure(2) Urticaria(3) Precordial pain(4) sob(5) If patient is anesthetized jaundice, hemoglobinuria, and DIC may occur(6) moderate leukocytosis is usual.
378
What are the clinical features of the oliguric phase of hemolytic transfusion reactions?
renal tubular necrosis with acute renal failure.
379
What are the clinical features of the diuretic phase of hemolytic transfusion reactions?
Fluid and electrolyte imbalance as a result of acute renal failure.
380
What should be done as soon as a patient develops features suggesting a transfusion reaction?
The transfusion should be stopped and samples sent to the lab. (clerical errors are the most common cause of major transfusion reactions)
381
What tests should the lab run in the event of a transfusion reaction?
(1) blood group and cross match should be repeated on both the donor and recipient pre and post transfusion.(2) Direct Coombs on post transfusion blood.(3) recipient plasma for hemaglobinemia.(4) Test for DIC(5) test for bacterial contamination(6) Test urine for hemoglobinuria(7) later samples must be taken for mehthemaglobin/free hamglobin, and red cell/white cell antibodies.
382
How is a major hemoytic transfusion reaction managed?
They are manged by (1) treating the shock (saline, plasma, dextran, hydrocortisone, antihistamine)(2) Compatible transfusions may be required.(3) Renal dialysis if renal failure is severe enough
383
What can cause transfusion related febrile reactions?
Anti-leukocyte antibodies (HLA) in the blood.
384
What are non-hemolytic allergic reactions?
Hypersensitivity to donor plasma proteins. They may exhibit urticaria, pyrexia, dyspnea, and in severe cases anaphylactic shock.
385
What is post transfusion circulatory overload?
This is too much volume in the vascular system. Management is the same as for cardiac failure. Can be prevented by slow infusion accompanied by diuretics.
386
What can be the consequence of transfusing bacterially contaminated blood?
Circulatory collapse
387
How can graft vs host disease occur?
By the transfusion of active donor lymphocytes to a host that is immunocompromised. Can be prevented by irradiating blood before transfusion.
388
What is transfusion related acute lung injury?
Pulmonary infiltrates with chest symptoms. Results from positive transfer of leukoagglutins in donor plasma. Treatment is supportive.
389
What is post transfusion purpura?
Destruction of donor and patient platelets 7-10 days after transfusion. results from anti platelet specific antigen abs in the recipient.
390
What causes post transfusional iron overload?
Repeated transfusions in the absence of bleeding can cause iron overload. After about 50 units in adults iron overload can cause damage to the liver, heart, and endocrine glands.
391
How does citrate, phosphate dextrose (CPD) anticoagulate blood?
It binds up all the calcium
392
Why should fresh blood be used for hemolytic disease of the newborn and other potassium (K) sensitive conditions?
Because while in storage RBCs leak potassium into the plasma.
393
What happens to 2,3-DPG during RBC storage?
2,3-DPG levels drop during storage.
394
Why is leukodepletion of transfusion blood done in many countries?
(1) It reduces incidences of febrile transfusion reactions(2) reduces the incidences of HLA alloimmunization(3) Reduces the transmission of viruses such as CMV, and nvCJD prion.
395
What methods can be used to reduce the chance of circulatory or iron overload with transfusions?
(1) Iron chelation(2) diruretics (circulatory overload protection)(3) Recombinant erythropoietin therapy ( to reduce the need for transfusion)(4) Factor VIIa (reduces the need for transfusion in bleeding patients)(5) slow transfusion (prevents circulatory overload)
396
What are the three methods of autologous blood transfusion?
(1) predeposit(2) Hemodilution(3) Salvage
397
What is predeposit autologous blood transfusion?
Patient donates 2-4 units of blood in the weeks leading up to and elective surgery.
398
What is Hemodilution autologous blood transfusion?
Blood is taken from patient just before a surgical procedure and then reinfused at the end of the prodedure.
399
What is salvage autologous blood transfusion?
Blood is collected during heavy blood loss and then retransfused into the patient later.
400
What is a potential hazard of autologous transfusion?
There is a greater risk of bacterial contamination of the donated blood especially in salvage transfusion.
401
What patients are the best candidates for autologous blood transfusion?
Healthy patients with multiple anti blood cell antibodies
402
When are granulocyte concentrates given?
Sometimes they are given to patients with severe neutropenia. However, there is a risk of viral transmission and GVHD. It is not usually possible to give enough.
403
For what are platelet concentrates given?
Platelets are given to stop bleeding in patients with serious hemorrhage and thrombocytopenia or platelet disorders. Platelets concentrates can also be given prophylactically for platelet disorders to keep platelets above a certain level.
404
For what conditions is platelet transfusion contraindicated?
(1) Autoimmune TTP (unless there is massive hemorrhage)(2) HIT(3) TTP(4) hemolytic uremia syndrome
405
For what is freshly frozen plasma used?
(1) replacement of coagulation factors(2) After massive transfusions (liver disease, DIC)(3) To reduce warfarin after surgery(4) TTP
406
When is human albumin solution given?
It is a plasma expander(1) fluid replacement in plasmapharesis(2) fluid replacement in hypoalbuminemia(3) to alter osmotic effect.
407
When is salt poor human albumin solution used?
It is used for severe hypoalbuminemia when it is necessary not give electrolytes. Used in nephrotic syndrome and liver failure.
408
For what is cryoprecipitate used?
To replace fibrinogen in DIC, massive transfusion, or liver failure.
409
When is protein C given?
In severe sepsis with DIC
410
Blood loss less than what amount does not usually require transfusion in adults?
Blood loss less than 500ml usually does not require transfusion.
411
What genetic conditions are associated with hematological malignancies?
(1) Down's syndrome(2) Bloom's syndrome(3) Fanconi's anemia(4) ataxia telangiectasia(5) Kleinfelter's syndrome(6) Wiskott-Aldrich syndrome
412
What chemical is commonly linked with hypoplasia, dysplasia, and chromosome abnormalities of the bone marrow?
Benzene
413
What antineoplastic drugs can also cause hematological malignancy?
The alkylating agents predispose to AML. Etoposide is also associated with the development of secondary malignancies.
414
What happened to survivors of the atom bomb in Japan?
They suffered from increased incidences of all types of leukemia.
415
What role does infection play in the development of Acute lymphoblastic leukemia?
Children with the TEL-AML1 translocation who are exposed to a variety of normal childhood infections seem to have lower incidence second hit development of ALL.
416
With which malignancies is human T cell lymphotropic virus associated?
HTLV is associated with adult t cell leukemia and lymphoma.
417
What virus is associated with Burkitt's lymphoma?
EBV is associated with african burkitts lymphoma. EBV also causes post transplant lymphoproliferative disease (PTLD).
418
With which malignancies is HIV associated?
Lymphomas are often associated with HIV
419
With what malignancies is kaposi's sarcoma herpes virus associated.
KSHV is associated with Kaposi's sarcoma and primary effusion lymphoma.
420
What malignancy is associated with Helicobacter Pylori infection?
Gastric mucosa B cell lymphoma (MALT)
421
What genetic feature of hematological malignancies most differentiates them from solid tumors?
The high frequency of chromosomal translocations in hematological malignancies
422
What is the Philadelphia chromosome?
The philadelphia chromosome is a t(9,22) translocation that is linked to chronic myeloid leukemia and some cases of ALL.
423
What mutation of the retinoic acid receptor is linked to hematologic malignancies?
t(15; 17) translocation is linked to AML M3. The PML gene on chromosome 15 is fused to the retinoic acid receptor gene on chromosome 17.
424
How does t(15, 17) cause AML M3?
The PML-RAR fusion gene binds to its normal substrates PML and RXR preventing their normal function. This results in arrest of differentiation
425
How can AML M3 be successfully treated?
High doses of all trans retinoic acid will stimlulate differentiation in abnormal promyelocytes. But only those with t(15; 17)
426
What is core binding factor (CBF)?
CBF is a transcription factor that regulates the expression of genes such as IL-3, and GM-CSF.
427
What three CBF translocations are linked to leukemias?
(1) t(8; 21) CBF-alpha (AML1) is translocated to 8.(2) inv(16) CBF-beta is fused to MYH11 gene(3) t(12; 21) linked to pre B ALL
428
How do MYC rearrangements lead to hematologic malignancies?
The MYC oncogene is translocated to a location under the control of an immunoglobulin regulator. This leads to MYC overexpression. t(8; 14). Burkitt's lymphoma and B-ALL are linked to this mutation.
429
How does BCL-2 translocation lead to malignancy?
t(14; 18) BCL-2 translocation leads to the overexpression of BCL-2 which suppresses apoptosis. This is found in 85% of follicular lymphomas.
430
For what is PCR particularly useful in detecting in hematologic malignancies?
PCR can detect very small amounts of abnormal DNA. Therefore it is very good for detecting residual disease.
431
For what are microarrays particularly useful for determining in hematological malignancies?
microarrays are not as sensitive as PCR, but they can help differentiates types and subtypes of tumors by determining expression patterns.
432
How can flow cytometry detect malignant cells in a mixed population?
Flow cytometry can detect cell phenotype. B cell tumor populations tend to be monoclonal and therefore express only kappa or lambda light chains. Alterations of the normal kappa:lambda ratios is indicative of monoclonal expansion.
433
How does genetic information aid the management of hematologic malignancy?
Genotyping of hematologic malignancies can aid treatment because different subtypes react differently to various therapies.
434
What are the methods for determining residual disease in decreasing order of sensitivity?
(1) PCR(2) Flourescence activated cell sorting (flow cytometry)(3) Southern blot(4) Cytogenetic analysis.
435
What markers are used to detect blasts and granulocyte precursors in flow cytometry?
CD 34 is used to detect blastsCD33 is used for granulocytes.
436
What are acute hematological malignancies?
?
437
What are chronic hematologic malignancies?
?
438
What is more clinically useful genotyping or immunophenotyping?
Genotyping is more clinically useful.
439
Why are central venous catheters used for general supportive therapy for hematologic malignancies?
Central catheters give ease of access for administration of chemotherapy, and other therapeutics while also allowing blood to be easily drawn for tests.
440
What is used to support the anemia caused by malignancy and its treatment?
Red blood cell and platelet transfusions.
441
What is the usual threshold for red cell support?
Hgb lower than 8g/dL. If platelets are also needed the platelets are given first
442
What is the threshold for platelet therapy?
Platelet count of 10 x 10^9 /L
443
What is used to reverse coagulation defects?
Fresh frozen plasma
444
What is a potential hazard with large transfusions of 3 units or more?
They may cause pulmonary edema in older patients. transfusions should be given slowly and monitored very closely.
445
What can be used to prevent febrile reactions during transfusion?
Antihistamine, pethidine, or hydrocortisone can be given to reduce febrile reactions.
446
Why should blood given to immunocompromised patients be irradiated before it is given?
To eliminate leukocytes and reduce the risk of GVHD.
447
What growth factor can be used therapeutically to reduce the anemia associated with chemotherapy?
Erythropoietin (EPO)
448
Why should coagulation screens be performed regularly during chemotherapy?
Because clotting deficiency is associated with chemotherapy. (low platelet counts)
449
What is given to pre-menopausal women to prevent bleeding?
progesterone is given to stop mentruation.
450
How can nausea and vomitting associated with chemotherapy be treated?
(1) 5-HT3 serotonin inhibitors (ondansetron, granisetron) (60%)(2) Dexamthasone (20%)
451
What is tumor lysis syndrome?
The rapid lysis of tumor cells by chemotherapy may release uric acid, potassium, and phosphate leading to hypocalcemia. Allopurinol, Rasburicase, and electrolyte therapy are used prophylactially to treat tumor lysis syndrome.
452
Why should men starting chemotherapy be encouraged to store their sperm?
Because sterility is a possible adverse effect of chemotherapy for men and women. However, it is not as practical to store ova as it is for sperm.
453
Under what conditions should total nutritional support be given?
If the patient loses 10% or more of their body weight total nutritional support is warranted via an NG tube or central catheter.
454
Is pain a significant feature of hematologic malignancies?
Not usually. although multiple myeloma is associated with significant pain which can be managed with analgesia. Sometimes bone pain can be a presenting symptom of malignancy.
455
What is the major cause of morbidity and mortality associated with hematological malignancies?
Infections because of neutropenia and hypogammaglobulnemia often cause morbidity associated with malignancy or its treatment. G-CSF may sometimes be used to limit periods of neutropenia.
456
From where do infections often come from during treatment of hematological malignancy?
Normal flora often become the source of infection during hematological malignancies and treatment.
457
What bacteria commonly colonize venous catheter lines?
Gram positive skin microbes Staph and Strep
458
What bacteria commonly cause septicemia during malignancy?
Gram negative gut bacteria Pseudomonas, E. coli, Proteus, Kelbsiella..
459
How can bacterial infections be prevented during hematological malignancy?
Prophylactic antibiotics, topical antiseptics and mouthwashes, clean diet, and non absorbable GI antibiotics are used to prevent infection.
460
What is the main indication of infection during hematological malignancy?
Fever.
461
How should infection be treated during hematological malignancy?
Immediate therapy with broad spectrum antibiotics is the usual strategy. If fever does not subside change antibiotic or consider antiviral/fungal therapy.
462
What is the most common source of viral infections in individuals undergoing treatment for malignancy?
reactivation of latent viral infections (Herpes, vericells, EBV, CMV)
463
How can viral infection be treated in patients with hematological malignancies?
Aciclovir is most commonly used to control viral infections. Immunoglobulin therapy may be used to treat severe primary infections particularly in children.
464
What unique condition is associated with EBV and stem cell transplants?
Post transplant lymphoproliferative disorder (PTLD)?
465
What two major subtypes of fungus represent a major cause of morbidity and mortality in patients with hematological malignancies?
Candida yeasts and Aspergillus molds.
466
What is the most common cause of death in intensively immunocompromised patients?
Aspergillosis
467
How are fungal infections diagnosed?
(1) fever that fails to resolve after 3-4 days(2) biopsy specimen with invasive gowth (definitive)(3) PCR(4) ELISA.
468
How are Aspergillosis infections treated?
(1)Amphotericin(2) voriconazole(3) Capsofungin.
469
How are Candida infections treated?
(1) fluconazole(2) itraconazole(3) Can be treated locally if blood or urine is not infected.
470
How is pneumocystic carnii treated?
An important cause of peumonitis(1) Treated with co-trimoxazole
471
Why are alkylating agents used to treat Hematological malignancies?
The alkylating agents crosslink Purines within DNA. This impairs DNA function and results in a cell cycle block at G2 causing apoptosis.
472
What is the fundamental mechanism of the antimetabolite antineoplastic drugs?
They block metabolic pathways required for DNA synthesis
473
What are the three major groups of antimetabolites?
(1) Folate antagonists(2) Pyrimidine analogs(3) Purine analogs.
474
What is the most common folate angtagonist and what is it used for?
Methotrexate is used for ALL, AML, or high grade non-hodgkin's lymphomas. It can penetrate the CNS at higher concentrations or can be used intrathecally
475
How to the pyrimidine analogs work?
Pyrimidine analogs such as cytarabine are incorporated into DNA and block DNA polymerase during replication.
476
How do the Purine analogs work?
Purine analogs work the sam way as pyrimidine analogs. They are incorporated into DNA where they inhibit replication.
477
How do the anthracyclines work?
The anthracyclines (including the -rubicins and mitozantrone) intercalate into DNA and bind tightly with topoisomerases.
478
How does the antineoplastic Bleomycin function?
Bleomycin is a metal chelating agent that produces superoxide radicals within cells degrade DNA. Bleomycin can function on non-cycling cells
479
What is the mechanism of the vinca alkaloids?
They bind to tubulin and prevent the polymerization of microtubules. (M phase inhibitors)
480
What is the mechanism of Etopioside?
Etoposide inhibits topoisomerase action.
481
How does hydroxyurea function?
Hydroxyurea functions by inhibiting ribonucleotide reductase. It is used widely for hematologic disorders.
482
How does Imatinib function?
Imatinib binds to the bcr-abl fusion protein and inhibits its binding to ATP. Without ATP bcr-abl cannot perform its phosphorylation function. Used in CML
483
Why are corticosteroids useful for some lymphoid malignancies and myelomas?
Because corticosteroids have a lymphotoxic effect.
484
How is all-trans retinoic acid used to treat hematologic malignancies?
ATRA acts as a differentiating agent in acute premyelocytic leukmeia (APML)
485
Why is INF-alpha useful in treating some malignancies?
INF-alpha is an anti-viral and anti-mitotic substance.
486
What is the mechanism of the antineoplastic azacytidine?
Azacytidine is a demethylating agent.
487
Against what sort of malignancies are MABs particularly useful?
MABs are effective against B cell malignancies
488
For what malignancy is asparaginase particularly useful?
Acute lymphoblastic leukemia (ALL)
489
What are the platinum agents used to treat?
Lymphomas
490
For what malignancy can arsenic be used to treat?
relapsed AML M3.
491
What are leukemias?
Disorders characterized by the accumulation of white cells in the bone marrow and the blood
492
Why do leukemias causes disease?
(1) they cause bone marrow failure(2) they infiltrate organs (liver, spleen, lymph nodes, meninges, brain, skin, testes.)
493
How are leukemias classified?
Leukemias are classified as acute or chronic, and further classified as lymphoid or myeloid.
494
What are acute leukemias?
Acute leukemias are aggressive diseases characterized by malignant transformation of hematopoietic stem cells or early progenitors.
495
What three general cellular abnormalities are often present in acute leukemias?
(1) increased rate of proliferation(2) reduced apoptosis(3) A block in cellular differentiation
496
What is the dominant clinical feature of acute leukemias?
accumualtion of blast cells in the bone marrow and peripheral blood along with bone marrow failure.
497
How is acute leukemia diagnosed?
Acute leukemia is diagnosed by the presence of over 20% blast cells in the blood or bone marrow.
498
How is acute leukemia sub-divided?
(1) acute myeloid leukemia (Myeloblasts)(2) acute lymphoid leukemia (Lymphoblasts)
499
How is ALL differentiated from AML?
ALL usually shows no differentiation (except B cell ALL). AML typically shows a greater degree of differentiation.
500
What is hybrid acute leukemia?
Leukemias that show characteristics of both ALL and AML.
501
What is the epidemiology of ALL?
ALL is the most common leukemia in children. Peak age is 3-7 years old falling off after 10 years and rising slightly after 40 years old. T-ALL seems to favor males.
502
What are the three morphological clssifications of ALL?
(1) L1 has small blasts with scanty cytoplasm(2) L2 has larger blast cells with more prominent nucleoli and cytoplasm(3) L3 has largest blasts with prominent nucleoli, strongly basophilic cytoplasm and vacuoles.
503
Immunophenotyping can be used to differentiate ALL cells into what categories?
(1) Early pre-B(2) Pre-B(3) B-cell(4) T-cell
504
What clinical features are associated with bone marrow failure caused by ALL?
(1) Anemia(2) Neutropenia(3) thrombocytopenia
505
What clinical features are associated with organ infiltration caused by ALL?
(1) Tender bones(2) Lymphadenopathy(3) Hepatosplenomegaly(4) meningeal syndrome(5) fever(6) rarely testicular swelling or mediastinal compression.
506
What blood cell abnormalities are often seen with ALL?
Normochromic, normocytic anemia with thrombocytopenia. Hyper cellular bone marrow with over 20% blasts.
507
What abnormal biochemical test results may be caused by ALL?
(1) increased serum uric acid(2) Increased serum lactate dehydrogenase(3) rarely hypercalcemia(4) Lytic bone lesions.(5) enlarged thymus or lymph nodes (T-ALL)
508
What is the differential diagnosis for ALL?
(1) AML(2) Aplastic anemia(3) Marrow infiltration by other malignancies(4) Infections (mono, pertusis)(5) juvenile rheumatoid arthritis(6) Immune thrombocytopenic purpura.
509
Why is cytogenetic and molecular genetic information concerning ALL significant?
Because the cytogenetic and molecular genetic characteristics of the malignancy profoundly impact prognosis.
510
What effect does ploidy have on ALL?`
Hyperdiploid (greater than 50 chromosomes) ALL generally has as good prognosis.Hypodiploid ALL generally is associated with a poor prognosis.
511
What is the most common specific genetic abnormality in ALL?
t(12; 21) (p13; q22) TEL, AML1 translocation. This creates the TEL-AML1 fusion protein which suppresses normal AML1 which controls hematopoietic transcription.
512
What is the association between the philadelphia chromosome and ALL?
t(9; 22) philadelphia chromosome increases with age and is associated with a poor prognosis.
513
What gene is often translocated in infant leukemias?
The MLL gene
514
What is general supportive therapy for ALL?
treatment of bone marrow failure(1) Central venous cannula(2) Blood support(3) prevention of tumor lysis syndrome(4) fever must be treated promptly.
515
What therapies can be used to treat ALL?
(1) chemotherapy(2) Radiotherapy.
516
What 4 basic treatment phases are used to treat ALL (excluding B-ALL)?
(1) remission induction(2) Intensification (consolidation)(3) Central nervous system directed therapy(4) Maintenance
517
What is remission induction?
Remission induction is the attempt to kill most of the tumor cells and to induce remission (which is less than 5% blasts with no other signs or symptoms).
518
What drugs are used for remission induction?
(1) prednisolone or dexamethasone(2) Vincristine(3) asparaginase(4) daunorubicin (only in adults)\Remission is achieved in approximately 90% of patients
519
What is intensification/consolidation?
usually 2-3 courses of high dose multi-drug chemotherapy aimed at erradicating or reducing to very low number the amount of tumor cells.
520
What drugs are used for intensification?
(1) vincristine(2) Cyclophosphamide(3) Cytosine arabinoside (cytarabine)(4) daunorubicin(5) etoposide(6) mercaptopurine
521
Why is CNS directed therapy necessary in ALL?
Because ALL will invade the CSF and most antineoplastics do not readily penetrate the CNS.
522
What drugs are used for CNS targeted therapy?
(1) High dose or intrathecal methotrexate(2) C-ARA(3) cranial irradiation (avoided in children)
523
What is maintenance therapy for ALL?
2 years (3 for young boys) of daily methotrexate, monthly vincristine (with 5 day oral corticosteroids)
524
What is done in patients being treated for ALL with persistent MRD?
Stem cell transplant or increased treatment intensity.
525
What specific treatments are indicated for patients with Ph( BCR-ABL) positive ALL?
(1) stem cell transplant(2) Imatinib mesylate
526
What factors are associated with a good prognosis for ALL?
(1) low WBC(2) Female(3) B-ALL(4) Child(5) Normal or hyperploid cells(6) rapid remission(7) absent CNS disease(8) MRD negative 1-3 months
527
What factors are associated with a poor prognosis for ALL?
(1) High WBC(2) male(3) T-ALL(4) Adult(5) Philadelphia chromosome(6) slow remission(7) CNS disease present(8) MRD positive at 3-6 months(9) relapse
528
What is the epidemiology of AML?
AML is common in adults and is increasingly common with age. (minor in childhood)
529
What is the difference between primary and secondary AML?
Primary AML appears to arise de novo. Secondary AML arises after myelodysplasis, chemotherapy, or other hematological disorders.
530
What is the most common genetic abnormality in AML?
The presence of tandem repeats of the FLT-3 gene.
531
How is AML classified?
There are 8 subtypes of AML based on cytochemical staining, immunophenotype, and chromosomal changes.
532
What is the typical myeloid immunophenotype?
CD13+, CD33+, and TdT-
533
What are the clinical features of AML
(1) anemia(2) Thrombocytopenia (thus bleeding)(3) DIC (M3 variant)(4) Gum hypertrophy, skin problems, and CNS disease (M4 and M5)
534
What is a granulocytic sarcoma?
An isolated mass of leukemic blasts.
535
What investigations are necessary for AML?
Genetic investigation is essential accurate prognosis and effective treatment.
536
What are the hematological findings for AML?
(1) anemia(2) thrombocytopenia(3) neutropenia
537
What are the biochemical findings for AML?
(1) increased serum uric acid(2) Increased serum lactate dehydrogenase(3) rarely hypercalcemia(4) Lytic bone lesions.
538
What is M3 hemorrhagic syndrome?
Catastrophic hemorrhage, treatment is with platelet transfusion, FFP, and ATRA.
539
What is ATRA syndrome?
Due to neutrophilia that follows differentiation of promyelocytes.Fever, hypoxia, pulmonary infiltrates, and fluid overload after administration.
540
What is the treatment for ATRA syndrome?
Dexamethasone twice daily. ATRA is only discontinued in the most severe cases.
541
How is specific therapy conducted for AML?
Four 1 week blocks of chemotherapy. Therapy is intensive and prolonged requiring supportive care. Induction --> consolidation --> consolidation --> Further consolidation or stem cell transplant.
542
What factors are associated with a poor prognosis for AML?
(1) Monosomy 5 or 7(2) FLT-3 mutation(3) Poorly responsive disease
543
What is the prognosis for AML in patients over 70?
Very poor especially if they have other health problems. However, if they are healthy remission can be achieved.
544
How is AML relapse treated?
AML relapse is treated with stem cell transplant in patients that can handle it and have a matching donor. Arsenic trioxide may be used for M3 relapse
545
What is the overall prognosis for AML?
(1) For children and young adults 50% achieve long term cure.(2) for patients over 70 only 10% achieve a cure.
546
What form of Leukemia is associated with auer rods?
acute promyelocytic leukemia. (AML M3)
547
What are chronic myeloid leukemias?
Leukemias characterized by a slower progression than acute leukemias. Chronic leukemias are also harder to cure
548
From what cell type does CML usually originate?
CML is a clonal disorder of pluripotent stem cells.
549
CML makes up what proportion of all leukemias?
15%
550
What genetic abnormality is most commonly associated with CML?
Ph t(9; 22) philadelphia chromosome. This causes a fusion gene BCR-ABL which has excessive tyrosine kinase activity. (found in both myeloid and lymphoid cell lines)
551
What methods can be used to diagnose CML?
(1) microscopic karyotype analysis (in minority of patients.(2) FISH(3) PCR
552
What causes most of the clinical features associated with CML?
A substantial increase in total myeloid cell mass is responsible for the clinical features of CML.
553
What is the epidemiology of CML?
CML occurs in either sex, and is most prevalent between the ages of 40 and 60 years old. (can occur in all ages)
554
What are the signs and symptoms of CML?
(1) hypermetabolism (anorexia, weight loss)(2) splenomegaly(3) Anemia (pallor, dyspnea, tachycardia)(4) Bruising, hemorrhage (abnormal platelet function)(5) Gout (hyperuremia from purine breakdown)(6) Visual disturbances and priapism (rare)
555
What are the laboratory findings of CML?
(1) WBC is high(2) Basophils are high(3) Normochromic, normocytic anemia(4) Platelet count may be lower or higher (most common)(5) Neutrophil ALP score is invariably low.(6) Bone marrow is hypercellular with granulopoietic dominance.(7) Philadelphia chromosome(8) serum uric acid increased.
556
What is the first line treatment of chronic phase CML?
Imatinib is a tyrosine kinase inhibitor that is specific for BCR-ABL. It blocks the ATP binding site on BCR-ABL. Allopurinol may also be given to reduce hyperuricemia and gout.
557
What are some adverse effects of Imatinib?
(1) skin rash(2) Neutropenia(3) Muscle pains(4) Nausea(5) ThrombocytopeniaG-CSF may be given to help manage the neutropenia.
558
How is a complete cytogenetic response to treatment defined?
The complete absence of Ph+ metaphases on cytogenetic analysis.
559
How is suboptimal response defined?
Failure to achieve significant or complete cytogeneticresponse after 6 months.
560
How are patients with sub-optimal treatment response managed?
(1) They are given alternative tyrosine kinase inhibitors (dasatinib, nilotinib)(2) they may have their imatinib dose increased.(3) Allogenic stem cell transplant.
561
What alternative second line chemotherapeutics may be used?
(1) hydroxyurea (can control WBC count) (needs to be given indefinitely)(2) Busulfan (serious long term side effects)(3) alpha-interferon (used after hydroxyurea to keep WBC low) (causes flu like symptoms)
562
What is the only established curative treatment for CML?
Stem cell transplant.
563
What is the age cutoff for stem cell transplant?
Only patients younger than 65 are good candidates for SCT.
564
What is the 5 year survival rate for SCT?
50-70%
565
What is the most important prognostic indicator for CML?
Response to imatinib.
566
What is the common causes of death in CML?
Death usually occurs as a result of acute transformation, infection, or hemorrhage rather than from the chronic disease now that imatinib treatment is available.
567
What is blastic transformation or acceleration?
An acute increase in blast cells and or anemia/thrombocytopenia/granulocyte increase. It is often cause by additional mutations and may be treated as ALL or AML depending on the case. associated with a poor prognosis.
568
What is Ph negative CML?
Ph negative CML (less than 5%) lacks the BCR-ABL fusion protein. Prognosis is poor (imatinib will not work).
569
What is juvenile chronic myeloid leukemia?
A rare condition affecting younger children presents with(1) skin rash(2) lymphadenopathy(3) hepatosplenomegaly(4) recurrent infections(5) high Hgb F(6) Ph-(7) normal ALP score(8) monocytosis
570
What are eosinophilic and chronic neutrophilic leukemia?
Rare conditions involving the pure proliferation of mature cells.
571
What is chronic myelomonocytic leukemia?
A disorder classified with the myelodysplastic disorders.
572
What is pancytopenia?
A reduction in the blood cell count of all major cell lines.
573
What is aplastic anemia?
Anemia caused by aplasia of the bone marrow. Classified as primary (congenital or acquired) and secondary.
574
What is the pathogenesis of aplastic anemia?
(1) a reduction in the number of hematopoietic pluripotential stem cells.(2) A fault of the remaining stem cells (3) An immune reaction against stem cells.
575
What are the congenital aplastic anemias?
(1) Fanconi's anemia (AR)(2) Dyskeratosis congenita (XL)
576
What causes Fanconi's anemia?
Fanconi's anemia is caused by a mutation in the FAND1 gene which operates in DNA repair much like BRCA1. Cells in FA show abnormal chromosome breakages.
577
What diagnostic test can be used for FA?
Genetic analysis and Diepoxybutane test (DEB).
578
What is dyskeratosis congenita?
A mutation in the DKC1 or TERC genes both involved in maintenance of telomere length. causes nail/skin atrophy,
579
What is the usual age or presentation for Fanconi's anemia?
5-10 years old.
580
What secondary disease condition sometimes develops from Fanconi's anemia?
AML in 10% of cases.
581
What is the most common type of aplastic anemia?
Idiopathic acquired aplastic anemia
582
What is idiopathic acquired aplastic anemia?
An immune reaction targeted at hematopoietic stem cells destroys the bone marrow. Oligoclonal CTL populations secreteing INF-gamma and TNF are often involved.
583
How is idiopathic aplastic anemia treated?
(1) antilymphocyte globulin (ALG)(2) Cyclosporin
584
What are causes of secondary aplastic anemia?
(1) Radiation(2) Antimetabolites and mitotic inhibitors (temporary)(methotrexate, daunorubicin)(3) Alkylating agents (busulfan)(chronic aplasia)(4) Chloramphenicol (5) Gold.
585
Aplastic anemia may be the presenting symptom of which other diseases?
(1) ALL(2) AML(3) Myelodysplasia
586
What are the clinical features of Aplastic anemia?
(1) Anemia(2) Neutropenia (recurrent infections)(3) Thrombocytopenia (bruising and bleeding)
587
What are the laboratory findings of aplastic anemia?
(1) Normocytic/chromic anemia(2) low retic count for degree of anemia(3) WBC below 1.5/L(4) Thrombocytopenia(5) Bone marrow 75% fat with mostly lymphocytes and plasma cells.
588
How is aplastic anemia differentiated from other causes of pancytopenia?
Cytogenetic analysis is used to diagnose aplastic anemia.
589
What general measures are used to treat aplastic anemia?
(1) The cause is removed if possible(2) Supportive care with blood transfusions (Blood must be irradiated to prevent GVHD)(3) Antifibrinolytic agents (tranexamic acid) may be used to counter thrombocytopenia.
590
What specific treatments are used for Aplastic anemia?
(1) ATG or ALG (effective in 50-60% of patients)(given with corticosteroids)(2) Ciclosporin (effective in 80% with ALG)(3) Androgens (oxymetholone)(marked side effects)(4) SCT(5) G-CSF provides only minimal improvement.
591
What disorders might aplastic anemia transform into?
Very rarely(1) myelodysplasia(2) acute leukemia(3) PNH
592
What is Diamond-Blackfan syndrome?
Congenital (AR) red cell aplasia. Ribosomal protein mutation is thought to be the cause. Associated with other somatic disorders (face and heart)
593
What is the cause of acquired red cell aplasia?
(1) Idiopathic(2) Autoimmune(3) Thymoma, lymphoma, CML(4) Anti-erythropoietin antibodies
594
What are the treatments for Red cell aplasia?
(1) Corticosteroids(2) MABs (rituximab, Campath)(3) SCT
595
What infectious agent is linked with red cell aplasia?
Parvovirus B19 can cause transient RBC aplasia in disorders in patients with reduced red cell survival.
596
What is Schwachman-Diamond syndrome?
Autosomal recessive syndrome with variable cytopenia. Exocrine pancreatic dysfunction, skeletal abnormalities, hepatic impairment, short stature.
597
What are Congenital dyserythropoietic anemias?
A group of anemias characterized by ineffective erythropoiesis and multi-nucleated erythroblasts.
598
What are the findings of CDAs?
(1) low retic count(2) splenomegaly(3) possible iron overload(4) first noted in infancy or childhood
599
What is the differential diagnosis for pancytopenia?
(1) increased destruction(2) Sequestration(3) Decreased production
600
The pathophysiology of aplastic anemia is potentially driven by which fundamental factors?
(1) damate to the stem cels(2) defective bone marrow microevironment(3) Immunosuppression of hematopoiesis.
601
What are myeloproliferative disorders?
Disorders arising in marrow stem cells that are characterized by clonal proliferation of hematopoietic elements
602
What are the three disorders that are considered myeloproliferative disorders?
(1) Polycythemia rubra vera(2) Essential thrombocytopenia(3) Myelofibrosis
603
What mutation is common to PRV, ET, and myelofibrosis?
A mutation in JAK2 is found in almost all patients with PRV, and over 50% of patients with ET and myelofibrosis.
604
What is polycythemia?
Polycythemia also known as erythrocytosis is an increase in hemaglobin concentration above the upper limit of what is normal for the patients age and sex.
605
How are polycythemias classified?
Polycythemia can be absolute in which red cell mass is increased, or relative in which decreased plasma volume artificially alters the Hgb concentration. Absolute polycythemia can be classified as primary or secondary.
606
What is the cause of polycythemia rubra vera?
Polycythemia rubra vera is caused by clonal malignancy of a marrow stem cell.
607
What genetic abnormalities are found in most incidences of PRV?
(1) JAK2 mutation is found in almost 100% of patients(2) Deletions of 9p or 20q are found in most patients.
608
What are the criteria for the diagnosis of PRV?
(1) total red cell mass >32-35mL/kg(2) Oxygen saturation >92%(3) splenomegaly(4) JAK2 mutation(5) increased NAP score(6) Increased serum B12.
609
The clinical features of PRV are due to what pathological changes?
(1) hyperviscosity(2) Hypervolemia(3) Hypermetabolism
610
What are the symptoms of PRV?
(1) Headache(2) dyspnea(3) blurred vision(4) night sweats(5) pruritus especially after a hot bath
611
What are the signs of PRV?
(1) plethoric appearance(2) Splenomegaly (75%)(3) Hemorrhage and thrombosis(4) Hypertension (33%)(5) gout(6) peptic ulceration (5-10%)
612
What are the laboratory features of polycythemia rubra vera?
(1) RBCs, neutrophils, and platelets are all increased(2) Hgb and Hct are increased(3) JAK2 mutation(4) NAP score increased(5) Increased B12(6) Low erythropoietin(7) Increase blood viscosity and urate(8) Increased erythroid progenitors in the peripheral blood. prominent megakaryocytes in the BM.
613
What is the goal of PRV treatment?
(1) Maintaining the Hct at 45%(2) keeping the platelet count below 400 x 10^9
614
Why is venesection used to treat PRV?
venesection reduces the Hct, and reduced iron stores may limit erythrpoiesis. Does not control platelet counts.
615
What treatments for PRV may be considered if there is poor tolerance of venesection with persistence of other symptoms?
Myelosuppression(1) hydroxyurea(2) BusulfanThere may be a small risk of inducing malignant transformation.
616
Why is Phosphorous-32 used to treat PRV?
P-32 is used for older patients. It is concentrated in the bone marrow and releases beta radiation. It is very effective at myelosuppression.
617
What is the first line PRV drug for patients under 40 years old?
Alpha-interferon is used for patients under 40 years old. It is given subcutaneously and suppresses excess BM proliferation.
618
Why is aspirin given for PRV?
Aspirin helps limit thrombosis without significantly increasing the risk for hemorrhage.
619
To what diseases does PRV sometimes progress into?
PRV can progress to myelofibrosis (30%) and acute leukemia in 5% of patients.
620
What mutation is associated with Primary familial polycythemia?
Mutation of the von hippel-lindau protein.
621
What are the causes of secondary Polycythemia (generally speaking)?
(1) hypoxia(2) abnormally high EPO production
622
What is the differential diagnosis for Polycythemia?
(1) PRV(2) Cardiac disease(3) Lung disease(4) Erythropoietin secreting tumors
623
What is essential thrombocytopenia?
Essential thrombocytopenia is the overproduction of platelets because of megakaryocyte over proliferation. Characterized by a platelet count over 400 x 10^9
624
What are the clinical findings associate with ET?
Thrombosis, hemorrhage, and less frequently splenomegaly or splenic atrophy. Megakarycyte fragments may be seen on the blood film.
625
What risk factors guide treatment for ET?
(1) platelets greater than 1000 x 10^9(2) smoking (3) hypertension.
626
How is ET treated?
(1) hydroxyurea(2) Alpha-interferon(3) Anagrelide(4) aspirin (if patient is lower risk)
627
What is myelofibrosis?
Myelofibrosis is clonal stem cell disease characterized by generalized reactive fibrosis of the bone marrow with hemopoiesis in the spleen and liver.
628
What causes the fibrosis of the bone marrow?
Hyperplasia of abnormal megakarycytes leads to secretion of growth factors and other substances that stimulate the activity of fibroblasts.
629
What are the clinical findings of myelofibrosis?
(1) massive splenomegaly(2) Hypermetabolic symptoms(3) bleeding problems(4) gout.
630
What are the laboratory findings of myelofibrosis?
(1) Anemia (but Hgb can be increased)(2) High WBC and platelets early in disease(3) Leukopenia and thrombocytopenia later in disease(4) Trephine biopsy shows fibrotic marrow(5) teardrop poikilocytes on blood film(6) high NAP score(7) High urate and LDH.
631
How is the anemia of myelofibrosis treated?
Blood transfusion and regular folic acid is used to treat anemia.
632
How is the massive splenomegaly of myelofibrosis treated?
(1) hydroxyurea(2) Splenectomy(3) Splenic irradiation.
633
Why is allopurinol given for myelofibrosis?
Allopurinol is given to treat the hyperuricemia.
634
What is the prognosis for myelofibrosis?
Median survival is 3.5 years. Causes of death are usually heart failure, infection, and leukemic transformation.
635
What is systemic mastocytosis?
A defect of bone marrow stem cells that leads to proliferation of mast cells.
636
What mutation is commonly associated with mastocytosis?
the somatic c-kit mutation is detected in the majority of mastocytosis cases.
637
What are the symptoms of systemic mastocytosis?
Symptoms are related to the release of histamine and prostaglandins. (1) flushing (2) pruritus(3) pain (4) bronchospasm
638
What are chronic leukemias?
Diseases characterized by the accumulation of mature lymphocytes in the blood. (There is considerable overlap with lymphomas.)
639
How are CLLs diagnosed?
CLLs are diagnosed by chronic persistent lymphocytosis. Subtypes are diagnosed by cytogenetic, immunophenotypic, and genetic testing.
640
What is the most common chronic lymphoid leukemia?
Chronic lymphocytic leukemia (CML).
641
When is the peak incidence of CLL?
Between 60 and 80 years of age.
642
Where is CLL common or rare?
CLL is common in the western world but rare in the far east.
643
What factors predispose to CLL?
Close relatives with CLL are the biggest risk factor. Chemotherapy and radiotherapy do not seem to increase the risk as they do in other cancers.
644
What are the cellular characteristics of CLL?
accumualtion of relatively mature B cells with little Ig on their surface.
645
What is the epidemiology of CLL?
(1) 85% of cases over the age of 50(2) Male:female ratio is 2:1
646
What are the clinical features of CLL?
(1) symmetrical enlargement of lymph nodes.(2) Anemia(3) thrombocytopenia(4) Splenomegaly (rarely hepatomegaly)(5) Immunosuppression
647
What are the cellular findings of CLL?
(1) lymphocytosis(2) CD19+, CD5+, CD23+ B cells(3) Lymphocytes are over 25% of the BM(4) Autoimmunity against blood cells
648
What four chromosome abnormalities are most common with CLL?
(1) Del 13q14(2) tirsomy 12(3) del 11q23(4) Structural abnormalities of 17p involving p53.
649
What is the prognosis for Ig genes that are unmutated (no somatic hypermutation)?
The prognosis is unfavorable for unmutated Ig genes in CLL.
650
What is the effect of ZAP-70 mutations on the clinical outcome and prognosis for CLL?
The prognosis is poor for CLL with ZAP-70 deficiency.
651
How is CLL treated?
There are no cures for CLL. Treatment is just management of symptoms including organomegaly, hemolytic episodes, anemia, and bone marrow suppression.
652
What drugs may be used to manage CLL?
(1) Chlorambucil(2) Fludarabine(3) Alemtuzumab(4) Rituximab(5) CorticosteroidsNot all used together although fludarabine, cyclophosphamide, and rituximab may be given.
653
When is radiotherapy given to treat CLL?
Radiotherapy is given for CLL in late stage disease that is resistant to chemotherapy.
654
When is splenectomy undertaken in CLL?
When there is immune mediated cytopenia or painful enlargement of the spleen.
655
What differentiates Prolymphocytic leukemia from chronic lymphocytic leukemia?
(1) Promyelocytes are larger and have a large central nucleus.(2) PLL exhibits splenomegaly without lymphadenopathy(3) Anemia is not very common in PLL.
656
How is PLL treated?
Splenectomy with purine analogs and or rituximab are beneficial for PLL.
657
What is hairy cell leukemia?
An uncommon B cell disorder characterized by pancytopenia.
658
What are the presenting feature of hairy cell leukemia?
(1) male(2) infections(3) anemia(4) splenomegaly(5) pancytopenia.
659
How is HCL diagnosed?
HCL is diagnosed as (1) CD22+(2) CD103+(3) FMC7+(4) mild fibrosis and cellular inflitrate on bone marrow.
660
How is HCL treated?
(1) 2-chlorodeoxyadenosine or deoxycoformycin (90% success rate)(2) Alpha-interferon
661
What is splenic marginal zone lymphoma?
It is a benign disease of the elderly characterized by massive splenomegaly and circulating monoclonal b cells with a villous appearance.
662
What is plasma cell leukemia?
A rare disease characterized by high numbers of circulating plasma cells. features include pancytopenia and splenomagaly
663
What are lymphoma/leukemia syndromes?
Lymphomas that have spread into the blood stream. Commonly non-Hodgkin lymphoma.
664
What is large granulocyte lymphocytic leukemia?
Leukemia associated with circulating lymphocytes that have abundant cytoplasm and azurophilic granules. (mean age of onset is 50)
665
What are clinical features of LGLL?
Cytopenia, neutropenia, splenomegaly, and arthropathy associated with rheuatoid arthritis.
666
What is adult T cell leukemia caused by?
HTLV-1 (endemic in Japan and the caribbean)
667
What cellular morphological characteristics are seen with ATLL?
Lymphocytes with bizarre clover leaf nuclei and CD4+ phenotype.
668
What is the clinical presentation of ATLL?
(1) acute onset(2) hypercalcemia(3) hepatosplenomegaly and lymphadenopathy(4) skin lesions.
669
What is Sezary syndrome?
Patients with Sezary syndrome will have pruritic exfoliative erythroderma on the palms of the hands and the soles of the feet. This is caused by lymphocytic inflitrate.
670
What are sezary cells?
Lymphocytes with deep nuclear clefting similar to ATLL.
671
What are lymphomas?
Lymphomas are malignancies of lymphocytes that usually accumulate in lymph nodes causing lymphadenopathies.
672
What differentiates Hodgkin's from Non-Hodgkin's lymphomas?
Hodgkin's lymphomas exhibit Reed-Sternberg cells.
673
What is the pathogenesis of Hodgkin's lymphomas?
Hodgkin's lymphoma is caused by the malignant transformation of B-lymphoid cells. The characteristic RS cells seen typically posses crippled Ig genes.
674
What virus is associated with Hodgkin's lymphoma?
EBV is associated with Hodgkin's lymphoma although no causal relationship has been established.
675
What clinical feature is most commonly associated with Hodgkin's lymphoma?
Painless, non-tender, asymmetrical enlargements of superficial lymph nodes.
676
What constitutional symptoms are seen in Hodgkin's lymphoma?
(1) fever(2) pruritis(3) alcohol induced pain(4) weight loss(5) fatigue(6) cachexia.
677
What hematologic abnormalities are seen in Hodgkins' lymphoma?
HL eventually progresses to pancytopenia(1) normocytic, normochromic anemia(2) Neutrophilia/eosinophilia(3) Lymphopenia (in advanced disease)(4) Thrombocytopenia (in advanced stages)
678
How is HL diagnosed?
HL is diagnosed by histologic examination with the findings of multinucleate polyploid RS cells.
679
What is the immunophenotype of mononuclear Hodgkin's cells?
CD30+, CD15+, and B-cell antigen negative.
680
What are the 5 types of HL?
(1) Nodular sclerosing (2) Mixed cellularity(3) Lymphocyte depleted(4) Lymphocyte rich(5) Nodular lymphocyte predominant
681
What are the distinguishing characteristics of Nodular sclerosis HL?
(1) Collagen bands from the node capsule surround the abnormal tissue.(2) Lacunar RS cells.(3) Frequent eosinophilia
682
What are the distinguishing characteristics of Mixed cellularity HL?
Numerous RS cells with intermediate numbers of lymphocytes.
683
What are the distinguishing characteristics of Lymphocyte depleted HL?
(1) Usually numerous RS cells(2) sparse lymphocytes(3) Lymph node fibrosis
684
What are the distinguishing characteristics of Lymphocyte rich HL?
(1) Scanty RS cells(2) many small lymphocytes(3) both nodular and diffuse
685
What are the distinguishing characteristics of Nodular lymphocyte predominant HL?
(1) absent RS cells(2) abnormal polymorphic B cells.
686
How is clinical staging of HL achieved?
(1) clinical examination(2) imaging (CT, XR, MRI, PET)(3) possibly trephine biopsy or liver biopsy as needed.
687
What do the classifications A and B mean in relation to the staging of HL?
They distinguish whether or not constitutional symptoms are present.
688
How is HL treated?
Radiotherapy, chemotherapy, or a combination of both.
689
What is the staging system for HL?
(1) stage 1 (single lesion on 1 side of diaphragm)(2) Stage II (multiple lesions on one side.)(3) Stage III (single lesion on each side)(4) stage IV (multiple lesions on each side)
690
When is radiotherapy most useful for treating HL?
Radiotherapy is 80% effective in treating patients with type I or II HL.
691
When is chemotherapy most used to treat HL?
chemotherapy is used most frequently in stage III or IV HL.
692
What is the most commonly used chemotherapy for HL?
ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine.
693
What treatment is used if a patient relapses?
Alternative chemotherapy with or without radiotherapy and possible stem cell transplant.
694
What is the prognosis for HL?
5 year survival rates range from 50-90% based on age, stage and histology.10 year survival is 80%
695
What are some of the long term effects of HL treatment?
secondary malignancy, sterility, and myocardial infarction.
696
What is the primary sign of Non-hodgkin's lymphoma?
superficial, asymmetric, painless lymphadenopathy.
697
What are the constitutional symptoms of NHL?
(1) Fever(2) night sweats(3) weight lossThey are commonly associated with disseminated disease.
698
What are often the presenting features of NHL?
(1) Anemia(2) Neutropenia (leading to infections)(3) Thrombocytopenia (leads to bleeding/purpura)
699
What are some gross pathological signs of NHL?
(1) lymphadenopathy(2) Hepatosplenomegaly(3) Skin involvement (mycoses fungoides, and Sezary syndrome)
700
Generally speaking how are NHLs identified?
Lymph node biopsy with morphological, immunophenotypic, and genetic investigation.
701
How does light chain clonality impact the diagnosis of NHL?
Polyclonal light chains are indicative of chronic inflammation. Monoclonal light chains are indicative of malignancy.
702
What are the hematological findings associated with NHL?
(1) Normochromic, Normocytic anemia(2) Autoimmune hemolytic anemia(3) Neutropenia (advanced disease)(4) Thrombocytopenia
703
What are the biochemical findings associated with NHL?
(1) increased LDH(2) Increased uric acid.(3) paraprotein on Ig electrophoresis.
704
What translocation is associated with Burkitt's lymphoma?
t(8; 14) Burkitt's lymphoma
705
What translocation is associated with follicular lymphoma?
t(14; 18)
706
What translocation is associated with Mantle cell lymphoma?
t(11; 14)
707
What translocation is associated with anaplastic large cell lymphoma?
t(2; 5)
708
What methods are used to stage NHLs?
(1) imaging (CT, XR, MRI, PET)(2) Biopsy, BM aspiration, Trephine biopsy.
709
What are the low grade NHLs?
(1) Follicular lymphoma(2) Lymphocytic lymphomas(3) Lymphoplasmacytoid lymphomas(4) Mantle cell lymphoma(5) Marginal zone lymphoma
710
What is the most common form of NHL?
Follicular lymphoma
711
What is the pathogenesis of follicular lymphoma?
B cells undergo malignant transformation by the t(14; 18) translocation, which causes the constitutive activation of the Bcl-2 gene.
712
What is the general age range for follicular lymphoma?
Middle aged to elderly
713
What is the median survival from diagnosis for follicular lymphoma?
10 years
714
What is the presentation of follicular lymphoma?
Painless lymphadenopathy with most patients presenting in stage III or IV.
715
What is the most effective chemotherapy against follicular lymphoma?
CVP (chlorambucil/cyclophosphamide, vincristine, and prednisolone.) achieves a response in up to 90% of patients.
716
If chemotherapy is not effective enough what alternative therapies can be considered for follicular lymphoma?
(1) Rituximab(2) Autologous stem cell transplant(3) Allogenic stem cell transplant ( in younger patients)
717
What are lymphocytic lymphomas?
Lymphocytic lymphomas are considered a tissue phase of CLL and are treated as such.
718
What are lymphoplasmacytoid lymphomas?
Lymphomas associated with the production of monoclonal immunoglobulin M. Also called Waldenstroms macroglobulinemia.
719
What are the complications associated with Lymphoplasmacytoid lymphomas?
Anemia and hyperviscosity.
720
How is Lymphoplasmacytoid lymphoma treated?
Oral chlorambucil, fludarabine, or monoclonal antibodies. Plasma exchange can reduce viscosity.
721
What is mantle cell lymphoma?
A malignancy derived from pre-germinal B cells located in primary follicles or in the mantles of secondary follicles.
722
What is the characteristic phenotype of mantle cell lymphoma?
(1) CD19+(2) CD5+(3) CD22+(4) CD23-
723
What is the pathogenesis of mantle cell lymphoma?
t(11; 14) translocation that merges Bcl-1 with an Ig heavy chain gene promoter.
724
What is the clinical presentation of Mantle cell lymphoma?
(1) lymphadenopathy(2) bone marrow infiltration(3) tumor cells in the peripheral blood.
725
What histological findings are associated with mantle cell lymphoma?
Cells with characteristically angular nuclei.
726
What is the prognosis for mantle cell lymphoma?
Even though it is considered low grade the prognosis for mantle cell lymphoma is poor. The median survival is 3 years post diagnosis.
727
How is mantle cell lymphoma treated?
CVP or CHOP or fludarabine with rituximab.
728
What are marginal zone lymphomas?
Lymphomas that are typically extranodal and localized.
729
What is the pathogenesis of marginal zone lymphomas?
chronic inflammation of the tissue involved.
730
What is the most common mantle cell lymphoma?
Gastric MALT lymphoma caused by H. pylori infection.
731
How are marginal zone lymphomas treated?
Most can be treated with chemotherapy and rituximab. Splenectomy can be used for splenic marginal zone lymphoma.
732
What are the high grade NHLs?
(1) Diffuse large B-cell lymphoma(2) Burkitt's lymphoma(3) Lymphoblastic lymphomas.
733
What are diffuse large b cell lymphomas?
Malignant disorders characterized by rapidly progressive lymphadenopathy due to fast cellular proliferation.
734
What features of diffuse b cell NHL are associated with a poor prognosis?
(1) High age(2) More extranodal sites(3) higher serum LDH(4) Bulky disease (5) AIDS
735
What features of diffuse B cell NHL are associated with a good prognosis?
(1) germinal center origin(2) t(3; 27)
736
How is diffuse large B cell NHL treated?
R-CHOP is the first line therapy. Prophylactic therapy for CNS disease with MTX may also be considered.
737
What is the prognosis for diffuse large b cell lymphoma?
Long term survival is approximately 65%.
738
What is Burkitt's lymphoma?
The lymphomatous correlate of L3 ALL.
739
Where is Burkitt's lymphoma endemic?
Africa and the caribbean where there is chronic malaria exposure. It is associated with EBV infection.
740
What is the pathogenesis of Burkitt's lymphoma?
t(8; 14) moves the C-MYC oncogene under the control of an Ig heavy chain promoter thus over expressing the C-MYC oncogene.
741
What chemotherapy regimen is highly effective against Burkitt's lymphoma?
High dose methotrexate and cyclophosphamide.
742
What is peripheral t cell NHL?
Malignancy derived from post thymic T cells. Treated with CHOP. The prognosis is poor.
743
What is angioimmunoblastic lymphadenopathy?
It is a T cell malignancy of the elderly associated with(1) lymphadenopathy(2) Hepatosplenomegaly(3) Skin rashes(4) Polyclonal IgG increase
744
What is mycosis fungoides?
Mycosis funcoides is a chronic cutaneous T cell lymphoma that presents with(1) Severe pruritis(2) psoriasis like lesions
745
What is Sezary syndrome?
A T cell lymphoma with circulating T-lymphoma cells that presents with (1) dermatitis(2) generalized lymphadenopathy(3) CD4+ cells with folded nuclear chromatin.
746
What is Adult T cell lymphoma?
A malignancy of T cells that is caused by the HTLV-1. It presents with(1) hepatosplenomegaly(2) cutaneous infiltrations(3) hypercalcemia
747
What are angiocentric lymphomas?
Typically involve the sinuses or gluten induced enteropathy
748
What is anaplastic large cell lymphoma?
A T cell malignancy characterized by CD30+ cells and the t(2; 5)
749
What is paraproteinemia?
The presence of a monoclonal immunoglobulin band in the serum.
750
What is Multiple myeloma?
Multiple myeloma is a neoplastic proliferation of plasma cells usually in the bone marrow.
751
What is the epidemiology of multiple myeloma?
98% of cases occur over the age of 40 with a peak incidence in the seventh decade (60's). More common among afro-caribbeans.
752
What are the characteristics of the myeloma cell?
Myeloma cells are post-germinal center plasma cells that have undergone class switching and somatic hypermutation. The immunophenotype is (1) CD38 high(2) CD138 high(3) CD 45 low.
753
What is the cause of multiple myeloma?
The genetic changes involved in multiple myeloma are complex, but they usually involve(1) increased or dysregulated expression of cyclin D(2) Hyperploidy(3) translocation of the IgH locus.(4) 13q deletion.
754
What growth factor is important for myeloma cells?
IL-6
755
How is multiple myeloma diagnosed?
(1) monoclonal protein in serum or urine.(2) increased plasma cell in the bone marrow(3) Related organ or tissue impairment
756
What sorts of organ impairment occur in multiple myeloma?
(1) bone disease/hypercalcemia(2) renal impairment(3) anemia(4) hyperviscosity (2%)(5) amyloidosis (5%)(6) infection
757
What is smouldering or asymptomatic myeloma?
Myeloma that is characterized greater than 10% plasma cell count in the bone marrow without organ impairment.
758
What causes the bone pain and hypercalcemia associated with multiple myeloma?
In multiple myeloma over expression of RANKL by the bone marrow stroma leads to activation of oseoclasts that breakdown bone leading to hypercalcemia and pathologic fractures.
759
What are the four major signs and symptoms of multiple myeloma?
CRAB(1) Calcium increased(2) renal failure(3) anemia(4) bone lesions.
760
Why do patients with multiple myeloma experience recurrent infections?
Because multiple myeloma leads to deficient antibody production and neutropenia.
761
What leads to the renal failure associated with multiple myeloma?
Deposition of light chains and calcium in the kidneys.
762
Why do multiple myeloma patients experience increased bleeding?
Because myeloma proteins interfere with platelet function and coagulation factors.
763
How often does amyloidosis occur secondary to multiple myeloma?
Amyloidosis occurs in about 5% of multiple myeloma patients.
764
How is the presence of paraprotein in the serum assayed?
By immunoglobulin electrophoresis. (usually IgG or IgA)
765
What is unusual about the blood cells in patients with multiple myeloma?
Rouleaux formation (with normocytic/normochromic anemia)
766
What abnormal laboratory values are associated with multiple myeloma?
(1) High ESR(2) High CRP(3) elevated serum calcium(4) Elevated creatinine (20%)(5) Serum Beta-2-microglobulin increased (associated with a poor prognosis)
767
Is multiple myeloma curable?
Usually not! only younger patients who can undergo a successful allogenic stem cell transplant have a hope for a cure.
768
How is intensive therapy used to treat multiple myeloma?
Intensive therapy is reserved for patients under the age of 65. it involves chemotherapy and autologous stem cell transplant.
769
How is non-intensive therapy used to treat multiple myeloma?
In older patients melphalan is used in conjunction with prednisolone. Thalidomide or cyclophosphamide may also be used.
770
What is the effect of bortezomib on multiple myeloma?
Bortezomib is a proteosome inhibitor that stops NFkB activation
771
How is radiotherapy used to treat multiple myeloma?
Radiotherapy is useful for treating the symptoms of multiple myeloma including bone pain
772
What supportive care is given to patients with multiple myeloma to manage renal failure, bone disease, paraplegia, anemia, bleeding, and infections?
(1) rehydration and dialysis for renal failure(2) Bisphosphonates for bone disease and hypercalcemia(3) radiation for compression paraplegia(4) transfusion/EPO for anemia(5) Plasmapharesis helps with bleeding(6) Prophylaxis with antimicrobials and Ig infusions.
773
What is the prognosis for multiple myeloma?
High albumin and low beta-2 microglobulin are associated with a better prognosis. High beta-2 microglobulin and low albumin are associated with a poor prognosis. median survival is 3-4 years with non-intensive therapy
774
What are solitary plasmacytomas?
isolated plasma cell tumors usually of bone, respiratory tract, or GI tract. Lesions disappear after radiotherapy.
775
What is plasma cell leukemia?
20% or more plasma cells in the blood can be primary or secondary to multiple myeloma. The prognosis is poor
776
What is heavy chain disease?
A disorder in which cells secrete and incomplete heavy chain. Most common in mediterranean areas and starts with a malabsorbtion syndrome
777
What is Waldenstrom's macroglobulinemia (WM)?
A rare condition characterized by lymphoplasmacytoid lymphomas that secrete monoclonal IgM. Occurs most commonly in men over 50.
778
How does WM usually present?
(1) fatigue(2) weight loss(3) Neurological symptoms(4) dyspnea(5) heart failure
779
What secondary complications can result from WM?
(1) hyperviscosity (due to IgM)(2) Visual problems (engorged retina)(3) Anemia (from increased plasma volume)(4) Bleeding (due to inhibition of platelets)
780
How is WM diagnosed?
(1) monoclonal IgM(2) Lymph node in filtration by lymphoplasmacytoid cells.(3) peripheral blood lymphocytosis.
781
What specific treatments are used for WM?
Chlorambucil or cyclophosphamide are the mainstays of therapy. Rituximab may also be used. SCT may be considered in severe cases.
782
What supportive therapies are used for WM?
(1) plasmapheresis for hyperviscosity(2) EPO for anemia.
783
What is monoclonal gammopathy of undetermined significance (MGUS)?
MGUS is characterized by transient or persistent paraproteins in the serum without evidence of myeloma or other underlying disease.
784
Why does systemic amyloidosis sometimes develop secondary to myeloma?
Because the deposition of Ig light chains can cause amyloidosis.
785
What are the clinical features of amyloidois?
(1) Heart failure(2) macroglossia(3) peripheral neuropathy(4) carpel tunnel(5) renal failure
786
What are myelodysplastic syndromes?
A group of disorders associated with multipotent stem cells that causes bone marrow failure.
787
What are the characteristic features of Myelodysplasia?
Ineffective hemopoiesis and cytopenia with marrow of normal or increased cellularity.
788
What is the pathogenesis of myelodysplasia?
Damage to hematopoietic progenitors causes increased stem cell proliferation with decreased differentiation. The result is cytopenia with hypercellular bone marrow.
789
What is the epidemiology of MDS?
(1) the incidence is 4 in 100,000(2) More common in men(3) over 50% of patients are over 70.
790
What are the clinical features of MDS?
(1) anemia(2) thrombocytopenia(3) neutropenia.
791
MDS can occur as a secondary feature of what conditions?
(1) excess alcohol intake(2) Magaloblastic anemia(3) chemotherapy(4) growth factor therapy
792
What hematologic findings are associated with MDS?
(1) pancytopenia(2) Macrocytic, dimorphic, hypochromic, or normocytic anemia may be seen. (3) Low reticulocyte count.(4) Impaired abnormal granulocytes(5) Pelger anomaly
793
What are the characteristics of the bone marrow in MDS?
(1) abnormal celllularity (hypocellular 20%(2) Ring sideroblasts(3) Abnormal morphology and development of multiple cell lines.
794
What proportion of the bone marrow must be dysplastic for a diagnosis of MDS to be made?
10% or more.
795
What genetic abnormalities are associated with MDS?
(1) Monosomy 5 or 7(2) Trisomy 8(3) partial deletion of 5q(5) RAS mutation in 20% of cases(6) FMS mutation in 15% of cases
796
What factors are used to classify myelodysplastic syndromes?
Blood countMorphological appearance number of blast cells in the bone marrow or blood.
797
What is refractory anemia?
MDS that only effects the red cell lineage.
798
What is refractory anemia with multilineage dysplasia?
MDS that effects multiple cell lines.
799
What is unclassified MDS?
MDS that effects only one non-red cell lineage.
800
Why is treating MDS extremely difficult?
Many chemotherapies make the MDS worse.
801
What is low grade MDS?
(1) less than 5% blasts in the bone marrow(2) Only one cytopenia(3) favorable cytogenetics
802
How is low grade MDS treated?
(1) supportive therapy(blood transfusions)(2) EPO, G-CSF(3) Immunosuppression (ATG, ciclosporin)
803
When is supportive therapy alone used for high-risk MDS?
In elderly patients with other health problems high risk MDS may be treated only with blood/platelet transfusions, and or antimicrobial therapies.
804
For what form of MDS is single agent chemotherapy sometimes helpful?
Refractory anemia with excess blasts (RAEB) is sometimes treated with single agent chemotherapy. (Hydroxyurea, etoposide, 6-MP, C-ARA, azacytidine, or decitabine)
805
When is intensive chemotherapy used to treat MDS?
High risk MDS may be treated with intensive chemotherapy however despite high remission rates relapse is almost inevitable.
806
How can MDS be cured?
By stem cell transplant.
807
What are the criteria for high risk MDS?
(1) greater than 5% blasts(2) unfavorable cytogenetics(3) Pancytopenia
808
What are myelodysplastic/myeloproliferative disorders?
disorders characterized by dysplastic cells and increased numbers of circulating cells.
809
What is chronic myelomonocytic leukemia (CMML)?
MDS characterized by persistent monocytosis and leukocytosis.
810
What are the presenting features of CMML?
(1) skin rashes(2) gum hypertrophy(3) lymphadenopathy(4) splenomegaly (50%)
811
How is CMML treated?
Hydroxyurea, etoposide, mercaptopurine standard patients andStem cell transplant in younger patients.
812
What is the prognosis for CMML?
median survival is two years.
813
What are the five major components of the hemostatic system?
(1) coagulation factors(2) Platelets(3) coagulation inhibitors(4) fibrinolysis(5) Blood vessels
814
What is the unique process by which megakaryocytes mature?
Endomitotic synchronous replication (the expansion of the cytoplasm as the DNA is replicated without nuclear or cytoplasmic division)
815
How many platelets can on megakaryocyte produce?
1000-5000
816
How long does it take a megakaryocyte to mature from a hematopoietic stem cell to the point where it can produce platelets?
About 10 days
817
What growth factor controls megakarycyte activity and where is it produced?
TPO (thrombopoietin) stimulate megakaryocytes and is made constitutively in the liver and kidneys.
818
Why do thrombopoietin levels rise dramatically during thrombocytopenia?
Because platelets also posses the c-Mpl receptor for TPO by which they remove TPO from the circulation.
819
What is the normal platelet count?
250,000
820
What is the normal platelet lifespan?
7-10 days
821
What proportion of bone marrow platelet output is trapped in the normal spleen?
33% (can rise to 90% in cases of splenomegaly.
822
What kinds of granules to platelets posses?
alpha, dense, and lysosomes.
823
What is contained in alpha granules?
(1) PF4 ( a heparin antagonist)(2) PDGF(3) Beta-thromboglobulin(4) fibrinogen(5) vWF(6) other clotting factors.
824
What is contained in dense granules?
Dens greanules are less common and contain (1) ADP(2) ATP(3) 5-hydroxytryptamine (5-HT)(4) Calcium
825
What do the lysosomes and peroxisomes contain?
lysosome contain hydrolytic enzymes and peroxisomes contain catalase.
826
What is the open canalicular system?
A series of canalicular invaginations or tunnels through the platelet that communicate with the external environment.
827
What antigens to platelets posses?
HPA A and BABO antigensHLA class 1 but not class II
828
What is the primary function of platelets?
To form a mechanical hemostatic plug.
829
What molecule allow platelets to adhere to the ECM?
vWF
830
How do platelets adhere to vWF?
After making contact platelets are able to role over vWF via GP1b-XI-V. Next GP2b-IIIa is able to bind tightly to vWF and other adhesion molecule bind tightly to collagen.
831
How are platelets activated?
Tight binding of GPIa/IIa and other molecules facilitates a cascade that results in activation of the platelets.
832
From where is most vWF derived?
From the endothelial cells where it is both secreted and stored in Weibel Palade bodies.
833
What enzyme cleaves the ultra large vWF multimers in circulation into monomers?
ADAMTS-13
834
How do platelets aggregate?
Upon activation GPIIb/IIIa binds to fibrinogen creating cross bridges between platelets.
835
What substance contained in platelet granule plays an important positive feedback role in platelet activation?
ADP
836
What major secondary substance created de novo acts as a powerful positive feedback for platelet activation?
TXA2 (it also causes vasocontriction.)
837
What substance opposes the activity of TXA2?
prostacyclin (PGI2) (NO and PECAM-1 also inhibit platelet activation)
838
What platelet membrane phospholipid is important for the stimulation of the coagulation cascade?
Platelet factor 3
839
What two processes does platelet factor 3 facilitate?
(1) tanase involves factors IXa, VIIIa, and X in the formation of Xa(2) Prothrombinase involves factors Xa and Va, and prothrombin to produce thrombin.
840
What is the role of PDGF released from the alpha granules?
PDGF stimulates the growth of vascular endothelium.
841
How is coagulation initiated?
TF binds to factor VIIa. This complex then activates factors IX and X. Xa in turn converts small amounts of prothrombin to thrombin, and activates VIII, and XI.
842
What happens during clotting amplification?
VIIIa and IXa from an intrinsic Xase complex that activates enough Xa to allow it to work with Va, PL, and Ca to form the thrombinase complex.
843
What is the principle role of thrombin in clotting?
Thrombin cleaves fibrinogen into active fibrin.
844
What does tissue factor pathway inhibitor do?
it inhibits tissue factor, Xa, and VIIa to stop clot formation
845
What is the role of antithrombin?
Antithrombin links proteases like thrombin together thus inactivating them.
846
What is the role of protein C?
Protein C is able to destroy activated factors V and VIII.
847
What is the role of protein S?
Protein S enhances the activity of protein C.
848
How are proteins C and S activated?
Thrombin binds to thrombomodulin and the complex formed is able to activate vitamin K dependent proteins C and S.
849
How are activated clotting factors disposed of ?
The liver and other reticuloendothelial cells.
850
How is fibrinolysis stimulated?
tissue plasminogen activator released from endothelial cells converts plasminogen to plasmin which cleaves fibrin.
851
What fibrinolytic agents can be used therapeutically?
(1) tPA(2) streptokinas(3) urokinase
852
What can plasmin cleave?
Plasmin can cleave fibrinogen, fibrin, factor V, Factor VIII and many other proteins.
853
How is plasmin inactivated?
by PAI, alpha 2 antiplasmin, and alpha 2 macroglobulin.
854
What does a thrombin time testing for?
deficiency or abnormality in fibrinogen or inhibition of thrombin.
855
What is a prothrombin time testing for?
Deficiency in clotting factors VII, X, V , II
856
What is partial thrombplastin time testing for?
deficiency in clotting factors XII, XI, IX, VIII, X, V, II, fibrinogen.
857
What are the general causes of abnormal bleeding?
(1) vascular disorders(2) Thrombocytopenia(3) Defective platelet function(4) Defective coagulation
858
What is characteristic about vascular and platelet disorders?
Bleeding from mucus membranes and into the skin.
859
What is characteristic about coagulation disorders?
coagulation disorders tend to bleed into joints and soft tissue.
860
Are standard screening tests sensitive to bleeding disorders caused by vascular defects?
No because the standard screening tests only test the blood.
861
What is hereditary vascular telangiectasia?
An uncommon disorder characterized by dilated microvascular swelling throughout the body that can lead to hemorrhage.
862
How is Hereditary vascular telangiectasia treated?
(1) embolization(2) laser treatment(3) estrogens(4) tranexamic acid(5) iron supplementation.
863
Why doe Ehlers-Danlos syndrome lead to bleeding?
Because Ehlers-Danlos syndrome is a congenital abnormality of collagen that leads to defective platelet aggregation.
864
What does giant cavernous hemangioma lead to?
This disorder leads to DIC.
865
What bacterial infections are commonly associated with purpura?
Rickettsial infections are commonly associated with purpura.
866
What is Henoch-Schonlein syndrome?
An IgA mediated vasculitis that commonly follows acute upper respiratory tract infections in children. (Purpuric rash, joint swelling, hematuria)
867
Why does scurvy lead to bleeding?
Because lack of vitamin C leads to defective collagen which leads to bleeding.
868
What is steroid purpura?
long term steroid therapy (cushing's syndrome) can lead to bleeding vis defective vascular support tissue.
869
What drugs can be used to reduce bleeding by inhibiting fibrinolysis?
Tranexamic acid and aminocaproic acid.
870
What is the most common cause of thrombocytopenia?
Failure of platelet production
871
What is chronic idiopathic thrombocytopenic purpura?
It is the most common cause of thrombocytopenic purpura without anemia or neutropenia. Associated with SLE, HIV, CLL, Hodgkin's disease, hemolytic anemia.
872
What is the pathogenesis of ITP?
ITP is caused by platelet auto-antibodies that stimulate macrophages to remove platelets from the circulation. GPIIb/IIIa is often the target. Platelet life is reduced from 7-10 days to a few hours.
873
What are the clinical features of ITP?
(1) insidious onset (2) easy bruising/bleeding(3) Mucosal bleeding
874
How is ITP diagnosed?
(1) platelets are 10,000-50,000(2) Enlarged platelets(3) increased megakarycytes(4) Detection of anti GPIIb/IIIa antibodies.
875
What are the clinical features of ITP?
(1) insidious onset (2) easy bruising/bleeding(3) Mucosal bleeding
876
What is the goal of ITP treatment?
To keep the platelet count above 50,000
877
How is ITP diagnosed?
(1) platelets are 10,000-50,000(2) Enlarged platelets(3) increased megakarycytes(4) Detection of anti GPIIb/IIIa antibodies.
878
What is the goal of ITP treatment?
To keep the platelet count above 50,000
879
What is the first line treatment for ITP?
Corticosteroids (usually prednisolone)
880
What are secondary treatments for refractory ITP?
(1) splenectomy(2) High dose Ig therapy (occupies Fc receptors on macrophages)(3) Immunosuppressive drugs(4) Rituximab (anti-CD20)(5) Stem cell transplant
881
What is the first line treatment for ITP?
Corticosteroids (usually prednisolone)
882
What are secondary treatments for refractory ITP?
(1) splenectomy(2) High dose Ig therapy (occupies Fc receptors on macrophages)(3) Immunosuppressive drugs(4) Rituximab (anti-CD20)(5) Stem cell transplant
883
What can be done for patients with severe hemorrhaging and ITP?
Platelet transfusions can be a short term solution.
884
What can be done for patients with severe hemorrhaging and ITP?
Platelet transfusions can be a short term solution.
885
What is acute ITP?
ITP that occurs in children and is secondary to infections such as chickenpox or infectious mono. It is usually caused by non specific immune complexes.
886
What is acute ITP?
ITP that occurs in children and is secondary to infections such as chickenpox or infectious mono. It is usually caused by non specific immune complexes.
887
What drugs can be responsible for drug induced thrombocytopenic purpura?
Quinine, Quinidine, and heparin
888
What causes familial thrombotic thrombocytopenic purpura?
Mutations to ADAMTS-13 which cleaves vWF polymers. Platelets then adhere to the vWF fibers.
889
What causes acquired TTP?
(1) infection(2) AI/connective tissue diseases.(3) Certain drugs(4) stem cell transplant(5) cardiac surgery
890
What are the five principle features of TTP?
(1) thrombocytopenic purpura(2) Microangiopathic hemolytic anemia(3) Neurological abnormalities(4) renal failure(5) fever
891
What causes the microangiopathic hemolytic anemia and thrombocytopenia of TTP?
microvascular thrombosis.
892
How is TTP treated?
(1) plasma exchange with FFP(2) cryosupernatant(3) Rituximab(4) Immunosuppression
893
Should platelet transfusions be given in TTP or HUS?
No! platelets are contraindicated (most likely because they would cause further thrombosis.
894
What is different about HUS in children?
(1) organ damage is limited to kidneys(2) associated with E. coli and Shigella.
895
What is disseminated intravascular coagulation?
Thrombocytopenia due the consumption of platelets by inappropriate thrombosis.
896
Why does splenomegaly cause thrombocytopenia in some cases?
Because the spleen normally sequesters up to 30% of the platelets. However, in splenomegaly up to 90% of the bodies platelets may be sequestered.
897
What is massive transfusion syndrome?
Platelets do not survive well in stored blood therefore patients that receive many transfusions over a short period may experience thrombocytopenia. FFP or platelet transfusions are necessary.
898
What signs suggest a disorder of platelet function?
Prolonged bleeding time despite normal thrombocyte counts.
899
What is Glanzmann's Thrombasthenia?
An autosomal recessive disorder caused by a mutation to the GPIIb gene.
900
What is Bernard-Soulier syndrome?
This disorder is characterized by abnormally large platelets and is caused by a mutation to GPIb gene.
901
What is the defect in grey platelet syndrome?
There is almost a complete absence of alpha granules
902
What is the defect in beta-storage pool disease?
There is a deficiency of dense granules
903
What is the defect in vWF disease?
Obviously von Willebrand factor is defective.
904
What is the most common cause of defective platelet function?
Aspirin is the most common cause of defective platelet function. It inhibits TXA2 production by Cyclooxygenase
905
How does Dipyridamole inhibit platelet function?
Dipyridamole inhibits platelet function by blocking reuptake of adenosine.
906
How does Clopidogrel inhibit platelet function?
Clopidogrel inhibits the binding of ADP to its receptor on platelets. It is used for the prevention of thrombotic events.
907
What are the agents Abciximab, epitifbatide, and triofiban used for?
These agents block the receptor sites of GPIIb/IIIa. They are used for patients with coronary syndromes
908
What is the effect of hyperglobulinemia on clotting?
Hyperglobulinemia inhibits platelet adherence and aggregation.
909
What should a physician do initially when investigating a patient with a suspected blood abnormality?
A blood count and a blood film should be the first steps. A bone marrow biopsy may also be necessary.
910
If a patient has thrombocytopenia, normal or excessive numbers of megakaryocytes and no other abnormalities what is the usual diagnosis?
ITP
911
When should platelet transfusions be administered?
Platelet transfusions are necessary in thrombocytopenia or impaired platelet function before invasive procedures and during bleeding. (1) platelets should be kept above 50,000 for surgery and above 20,000 at other times(2) platelet transfusion should always be seriously considered if platelets fall below 10,000.
912
What are the most common disorders involving coagulation factors?
(1) Hemophilia A (factor VIII)(2) Hemophilia B (Factor IX)(3) vWD
913
What is the epidemiology of Hemophilia A?
30-100 out of a million. The disorder is sex linked however up to one third of the cases are due to spontaneous mutations.
914
What is the cause of Hemophilia A?
Defective or deficient factor VIII.
915
What are the clinical features/presenting symptoms of hemophilia A?
Hemophilia A causes excessive bruising and bleeding along with hemarthroses and hematomas.
916
What are hemophilic pseudotumors?
Large encapsulated hematomas with progressive cystic swelling.
917
Why did a large proportion of hemophiliacs become HIV positive?
Before the blood testing hemophiliacs would contract HIV from the many blood transfusions they would receive. (HCV as well)
918
What are the abnormal lab values associated with hemophilia A?
(1) abnormal activated partial thromboplastin time(2) Abnormal Factor VIII clotting assay. (3) Bleeding time and prothrombin time are normal.
919
How is hemophilia A treated?
(1) Factor VIII replacement (for bleeding episodes)(2) Desmopressin (DDAVP) stimulates endothelial cells to release Factor VIII. can be used for milder hemophilias)
920
What prophylactic measures can be undertaken in the treatment of Hemophilia A?
Factor VIII infusion three times a week and avoidance of rough physical contact can limit the occurance of bleeding episodes.
921
What levels of Factor VIII or IX are necessary to avoid most of the mortality and morbidity?
Factor VIII or IX levels above 1% are usually high enough to avoid morbidity.
922
What is one of the most serious complications of factor VIII therapy?
Some patients develop antibodies against factor VIII.
923
What differentiates factor VIII deficiency from factor IX deficiency?
The only difference is the specific clotting assay that used to identify it. Hemophilia B is less common.
924
What lab findings dare associated with Hemophilia B?
(1) Abnormal APTT(2) Factor IX clotting assay.
925
What is the normal role of vWF?
vWF facilitates platelet adherence to the ECM and it binds factor VIII.
926
What is the most common inherited bleeding disorder?
von Willebrand Disease. Autosomal dominant
927
What lab findings are associated with vWD?
(1) prolonged bleeding time(2) Low factor VIII levels(3) prolonged APTT(4) Low vWF(5) Defective platelet aggregation with ristocetin.(6) collagen binding function is usually reduced.
928
How is vWD treated?
(1) antifibrinolytic agents (tranexamic acid)(2) desmopressin (DDAVP)( Type 1 vWD)(3) vWF and factor VIII concentrates
929
From where is vitamin K absorbed?
Vegetables and bacterial synthesis in the gut.
930
what conditions can cause a vitamin K deficiency?
malabsorption, inadequate diet, and inhibition of vit K by drugs.
931
What clotting factors are dependent on vitamin K?
Factors II, VII, IX, X, C, And S.
932
What is the role of Vit K as a cofactor?
Vitamin K converts PIVKA into the proper clotting factors.
933
How does warfarin inhibit clotting?
Warfarin inhibits the reduction of vitamin K back into its active form after it has preformed its function. This leads to a functional vitamin K deficiency.
934
What is hemorrhagic disease of the newborn?
Newborns are usually deficient in vitamin K this leads to bleeding.
935
How is hemorrhagic disease of the newborn diagnosed?
Most findings are normal except for excessive bleeding and absent fibrin degradation products.
936
How is hemorrhagic disease of the newborn treated?
Vitamin K is given IM to all newborn infants as a prophylactic treatment. More can be added if hemorrhage occurs.
937
What can cause Vitamin K deficiency?
(1) obstructive jaundice(2) Pancreatic disease(3) Small bowl disease
938
How is vitamin K deficiency diagnosed?
(1) prolonged PT(2) prolonged APTT(3) Low Factor II, VII, IX, and X
939
How is vitamin K deficiency treated?
With prophylactic vitamin K supplements. If bleeding has already occured IV vit K can correct deficiency within 6h.
940
Disease in which organ often leads to bleeding tendency?
Liver disease of various kinds leads to a bleeding tendency.
941
What is the key event underlying DIC?
Increased activity of tissue factor
942
What conditions can trigger DIC?
(1) entry of procoagulant material into the circulation(2) Widespread endothelial damage and collagen exposure.
943
What are the clinical features of DIC?
(1) excessive bleeding(2) Microthrombotic complications.
944
What laboratory findings are associated with DIC?
(1) low platelets(2) Low fibrinogen(3) prolonged thrombin time(4) High fibrin degradation products(5) Prolonged PT and APTT
945
What histological findings are associated with DIC?
Microangiopathic hemolysis.
946
How is DIC treated?
(1) Supportive therapy with FFP or cryoprecipitate(2) Heparin or antiplatelet drugs to stop the consumption of clotting factors.(3) Recombinant protein C.
947
How is massive transfusion syndrome managed?
By platelet transfusion and clotting factor replacement.
948
What is thromboelastography?
Thromboelastography is a method of measuring hemostatic function in real time. This is useful in surgery associated with bleeding disorders.
949
What is thrombophilia?
Thrombophilia are inherited or acquired disorders that predispose to thrombosis?
950
What are the strongest independent predictors of coronary events?
The levels of factor VII and fibrinogen. Hyperhomocysteinemia has also been associated with increased risk.
951
What is Virchow's triad?
Virchow's triad is composed of three components that are extremely important for thrombus formation.(1) Slowing of blood flow(2) hypercoagulability of the blood(3) Vessel wall damage.
952
What events suggest a hereditary thrombophilia?
Younger patients that suffer from spontaneous and recurrent thromboses in abnormal locations.
953
What is the most common disorder that increases the risk of thrombosis?
Factor V leiden mutation. (4% of caucasians)
954
With what protein deficiency is skin necrosis due to dermal vessel occlusion after warfarin administration associated?
Protein C deficiency
955
Why does warfarin cause vessel occlusion associated with protein C deficiency?
Because Warfarin inhibits vitamin K dependent factors. Vitamin K is necessary for protein C to function.
956
How does prothrombin allele G20210A lead to thrombophilia?
There is increased levels of prothrombin which leads to increased thrombin and down regulation of fibrinolysis.
957
What enzyme is responsible for hyperhomocysteinemia?
A defect in cystathione beta synthase is responsible for hyperhomocysteinemia.
958
What are some causes of acquired hyperhomocysteinemia?
(1) Folate or B12 deficiency(2) B6 deficiency(3) drugs (ciclosporin)(4) renal damage.(5) smoking.
959
Do defects in fibrinogen lead to thrombosis?
Not usually, bleeding is more likely.
960
What are some common acquired risk factors for thrombosis?
(1) surgical opperations(2) Venous stasis and immobility(3) Malignancy(4) Inflammation(5) polycythemia and ET(6) increased estrogen
961
What is antiphospholipid syndrome?
The occurrence of repeated thromboses/miscarriages with the presence of anti phospholipid antibodies. These antibodies are in some cases secondary to autoimmune disease.
962
Why does glucosylceremide deficiency lead to thrombosis?
Because glucosylceremide modulates the protein C pathway.
963
Why are factor IX concentrates sometimes complicated by thrombosis?
Because factor IX concentrates often contain activated coagulation factors.
964
What factors should increase the clinical suspicion of deep vein thrombosis?
Bedridden patients with unilateral swelling or tenderness.
965
What is the first line test when DVT is suspected?
Serial compression ultrasonography
966
What is the second line test if ultrasonography is negative yet clinical signs point to DVT?
Contrast venography
967
What is a plasma D-dimer concentration assay?
Plasma D-dimers are the breakdown products of fresh thromboses. They are elevated if DVT has occured. However they may be elevated in some other conditions as well.
968
When should a pulmonary embolus be suspected?
When the patient has(1) history of DVT(2) immobilization for more than 2 Days(3) surgery(4) hemoptysis
969
What methods may be used to diagnose pulmonary embolism?
(1) chest X-ray(2) ventilation perfusion scintigraphy(3) Computed tomography pulmonary angiographty(4) MRI angiography(5) Pulmonary angiography
970
How is heparin administered?
intravenously
971
How is heparin eliminated by the body?
Heparin is inactivated by the liver and excreted in the urine.
972
What is the biological half-life of heparin?
Approximately 1 hour.
973
What is heparin's mechanism of action?
Heparin potentiates the formation of complexes between antithrombin and thrombin, IXa, Xa, and XIa. This leads to the irreversible inactivation of these factors.
974
What are the indications for Heparin?
(1) DVT(2) Pulmonary embolism(3) unstable angina pectoris(4) Prophylaxis during pregnancy (does not cross the placenta)
975
What is the treatment of choice for acute pulmonary embolus?
Continuous intravenous heparin
976
What is the preferred prophylacitic treatment for venous thrombosis?
Intermittent subcutaneous heparin.
977
What is the difference between regular heparin and low molecular weight fractionated heparin?
LMWFH has a longer half life, more predictable dose response, and has less severe side effects (50% less side effects).
978
What are some adverse effects associated with heparin?
(1) Bleeding(2) Heparin induced thrombocytopnenia(3) Osteoporosis (with more than 2 months use)
979
What are the oral anticoagulants?
Derivatives of coumarin or indandioneWarfarin is most commonly used.
980
What is the mechanism of warfarin?
Warfarin is a vitamin K antagonist.
981
Between warfarin and heparin which one is preferred during pregnancy?
Warfarin is teratogenic therefore heparin is preferred because it does not cross the placenta.
982
How is warfarin eliminated?
Warfarin is inactivated in the liver and then excreted in the bile.
983
What drug interactions are important for Warfarin?
(1) alterations in albumin binding (warfarin is 97% bound(2) Interactions involving the excretion of warfarin(3) interactions altering vitamin K absorbtion
984
What is protamine?
Protamine is able to inactivate heparin and can be used as an antidote in the event of heparin overdose/excessive bleeding.
985
How can warfarin overdose be managed?
Giving vitamin K can overcome the effects of warfarin overdose.
986
How is warfarin therapy managed during surgery?
For minor surgery tranexamine acid (an anti-fibrinolytic) can be used as a mouth rinse. However, for major surgery the warfarin must be stopped.
987
What are the 'New' anticoagulants?
(1) fondaparinux (a factor Xa inhibitor)(2) Bivalirudin (thrombin inhibitor)(3) Ximelagraten (thrombin inhibitor
988
What drugs can be used as thrombolytic agents?
(1) streptokinase(2) Acylated plasminogen streptokinase activator complex (APSAC)(3) tissue plasminogen activator (tPA)(4) Urokinase type plasminogen activator
989
What are the antiplatelet agents that can be used to fight thrombosis?
(1) aspirin (irreversible COX inhibitor)(2) Dipryidamole (phosphodiesterase inhibitor)(3) Sulfinpyrazone (competitive inhibitor of COX)(4) Ticlopidine (is mostly replaced by clopodigrel)(5) Clopodigrel (ADP receptor antagonist)
990
What are the GPIIb/IIIa inhibitors?
(1) abciximab(2) eptifibatide(3) tirofibanThey can only be used once.
