Hematology Flashcards
(337 cards)
1
Q
What are the cellular components of blood?
A
RBCs (erythrocytes)
WBCs (leukocytes)
Platelets (thrombocytes)
2
Q
What is in the soluble component of blood (plasma)?
A
Electrolytes
Proteins
Lipids
3
Q
How are blood cells different from other cells of the body?
A
Short life span (except lymphocytes)
Multiplicity of cell types
Widely distributed
BM must respond quickly to needs for additional cells
Stem cells must be maintained
4
Q
What is hematopoiesis?
A
Formation and development of blood cells and other formed elements (RBCs, platelets too)
5
Q
What is the average life spans of RBCs, granulocytes, platelets?
A
RBC = 4 months
Granulocytes <10 hours
Platelets = 1 week
6
Q
How can you identify hematopoietic stem cells morphologically?
A
You cannot identify them in bone marrow smear
7
Q
What is the potency of hematopoietic stem cells?
A
Pluripotent
Repopulate all cellular lineages - erythroid, myeloid, lymphoid, platelets
8
Q
Where is the initial site of primitive hematopoiesis?
A
Yolk Sac
9
Q
What is the first site of definitive hematopoiesis?
A
liver
10
Q
What is the progression of hematopoiesis locations?
A
Yolk sac - liver - bone marrow and spleen
11
Q
What is the predominant blood forming organ after birth?
A
Bone marrow
12
Q
How do stem cell divisions occur to preserve self-renewal and differentiation?
A
Asymmetrically more often - 1 cell divides into stem cell and commited cell
Not as common is symmetric - 1 cell divides int 2 stem or commited cells
This is regulated by stromal cells, growth factors
13
Q
What distinguishes precursor cells from hematopoietic stem cells and hematopoietic progenitor cells?
A
ARE morphologically identifiable
No self-renewal capacity (although progenitor cells don’t either)
Uni-potent only - committed to 1 lineage
14
Q
What cell type of hematopoeisis is most active in the cell cycle?
A
Precursor cells - mitotically active
15
Q
What is the normal myeloid to erythroid ratio?
A
3-3.5:1
16
Q
What areas have hematopoeitic capabilities throughout ontogeny?
A
Yolk Sac
Aorta-gonad-mesonephros (AGM) region
Liver
Spleen
Bone marrow
17
Q
What are the two things that can happen to make someone anemic?
A
Problem in bone marrow (failure of production)
Peripheral destruction
18
Q
What information does a bone marrow biopsy provide that an aspirate cannot?
A
Architecture of the bone marrow
19
Q
What are reticulocytes?
A
Slightly larger, slightly bluer red blood cells that have just left the bone marrow (polychromasia)
Good indicator of bone marrow dysfunction
20
Q
What is the reticulocyte count?
A
Percentage of reticulocytes (number of reticulocytes per 100 RBC’s)
21
Q
What is the absolute reticulocyte count?
A
Actual number of reticulocytes in given volume of blood (retic. count * #RBCs)
22
Q
What does the absolute reticulocyte count tell you?
A
Bone marrow production
23
Q
What are normal number of red blood cells in blood?
A
5-6 million
24
Q
What is a normal absolute reticulocyte count?
A
50-100,000 reticulocytes/uL/day
25
What is the WHO definition of anemia?
Hgb \< 13gm% in men
Hgb \<12gm% in women
26
What is wrong in this bone marrow aspirate?
Acute leukemia
27
What is myelophthisis?
Infiltration of marrow with something that shouldn't be there (metastatic cancer, for instance, or TB)
28
What is leukoerythroblastosis?
Presence of immature young red and white cell precursors in blood (where they don't belong)
29
What is leukoerythroblastosis a sign of?
Something infiltrating the marrow - something is causing the cells to leave before they are mature
30
What can be used to stimulate blood cell production in bone marrow patients?
Recombinant erythropoietin (in case of kidney failure, for instance)
Thrombopoietin agonists
31
What is aplastic anemia?
Anatomic and physiologic failure of bone marrow that results in loss of hematopoietic cells from the bone marrow with fatty repacement of bone marrow (aplasia) and reduction, below normal, of WBC, RBC and platelet counts (pancytopenia)
32
What does this bone marrow biopsy reveal?
Aplasia
33
What is the peak incidence age of aplastic anemia?
mid 20s, decreased incidence above 60 years old
34
What people have higher incidence of aplastic anemia?
Far east have 2-4x higher incidence
35
What are some etiologies of aplastic anemias?
Acquired
Inherited
36
What are some drugs that are always associated with aplastic anemia?
Chemotherapies
Benzene
37
What are some drugs that are sometimes associated with aplastic anemia?
38
What are some viruses that infect bone marrow cells?
Parvovirus
Herpesvirus (CMV, EBV)
Retrovirus (HIV)
39
What ist he mechanism of parvovirus mediated bone marrow failure?
Direct cytotoxicity
40
What is the mechanism of bone marrow failure in EBV infection?
Immune mediation
41
What is the mechanism of bone marrow failure in dengue virus infeciton?
Inhibition of growth
42
What is the mechanism of bone marrow failure in CMV infection?
Accessory cell target
43
What hepatitis is responsible for hepatitis-associated BM failure?
non-A, non-B, non-C
2-3 months after acute hepatitis
2-5% of patients with aplastic anemia have history of hepatitis
Probably immune mediated
44
What is important about hepatitis associated BM failure with respect to how it can be treated?
Responds to immunosuppression
45
What molecular phenomenon has been identfied in 30-50% of patients iwth acquired aplastic anemia?
Shortened telomeres
46
What is the working hypothesis of acquired aplastic anemia?
Results from immune dysregulation of hematopoiesis caused by (asymptomatic) viral infections or environmental toxins
Drugs, chemicals and viruses may interact with cellular components, altering normal cellular recognition sites and resulitng in a loss of self-tolerance
47
What defines severe aplastic anemia?
BM biopsy cellularity \<25% plus 2 of 3:
Granulocytes \<500/ul
Platelets \< 20,000/ul
Reticulocyte count \< 40,000/ul
48
What defines very severe aplastic anemia?
Severe AA with granulocytes \<200/ul
49
What defines moderate aplastic anemia?
Not severe
Stable, depressed counts for \> 3 monhts
50
What is a patient's survival with aplastic anemia inversely correlated with?
Degree and duration of neutropenia
51
What do patients with apastic anemia die from?
Infection - neutropenia
52
How do you treat aplastic anemia?
Withdraw offending agents (drugs)
Supportive care (transfusions, etc, if needed)
Immunosuppression
Stem cell transplant
53
What is the most common immunosuppression used in aplastic anemia?
Antithymocyte globulin (ATG)
Cytolytic to lymphocytes
Can cause an allergic reaction though (serum sickness); very toxic
54
What is a big risk with immunosuppression treatment in aplastic anemia?
20% evolve to MDS/AML at 10 years
10% evolve to overt paroxysmal nocturnal hemoglobinuria
55
What are benefits of allogenic stem cell transplants in aplastic anemia?
It is curative
However, can cause GVHD, secondary malignancies, and can be rejected and hard to come across
56
What is fanconi anemia?
Most common inherited bone marrow failure
Autosomal (and x linked) recessive
Chromosomal instability and hypersensitivity to DNA damage
50-75% have physical abnormalities
57
What are the physical abnormalities of fanconi anemia?
Cafe au lait spots, hyperpigmentation
Short stature, microsomia, hypoplastic or absent thumbs, radial aplasia, microcephaly
Horseshoe kidney, hydronephrosis
Infertility
58
Why do you need to identify fanconi anemia as the cause of anemia before proceeding with treatment?
FA patients are susceptible to DNA damage (impaired repair)
Do not want to irradiate
59
How do you treat fanconi anemia?
Androgens
G-CSF
Modified stem cell transplant (cures BM failure, but does not alter risk of solid tumors
60
How do you diagnose fanconi anemia?
Increased chromosome breakage in lymphocytes cultured with DNA cross linking agents
61
What term is used for the premature destruction of red blood cells?
Hemolysis
62
What factor will be elevated in folate deficiencies?
Homocysteine
63
What is the origin of megaloblastic anemias?
Impaired DNA synthesis
64
What are the sequellae of B12 and/or folate deficiency?
Megaloblastic anemia (you get reticulocytopenia, leukopenia, and thrombocytopenia too)
65
If anemic, and BM is not the problem, what will you find on blood labs?
Elevated absolute reticulocyte count - compensation!
66
What do you find on bone marrow aspirate in anemias with no issues in the BM (hemolysis)?
Erythroid hyperplasia - bone marrow turns on production of red cells
67
Why do RBCs get destroyed?
Poor flexibility through spleen
68
What do you find in labs in intramedullary hemolysis?
Decreased reticulocytes indicative of ineffective erythropoiesis
69
What is hemolysis?
Premature produciton of RBCs
70
What is extravascular hemolysis?
"outside the blood" - by macrophages in reticuloendothelial system (spleen, for instance)
71
What does the fact that RBC's are biconcave contribute to their ability to function/
Makes them malleable and able to squeeze through tight spaces - deformable
72
What are RBC's broken down into?
Hemoglobin -\> Biliverdin -\> Bilirubin
Bilirubin enters to blood as unconjugated; gets conjugated in liver (secreted to bile and blood, some secreted via kidney)
73
When does unconjugated bilirubin elevate?
Hemolysis that exceeds the ability of liver to conjugate it
Elevated bilirubin is sign of active hemolysis
74
What is elevated unconjugated bilirubin indicative of?
Active hemolysis
75
What occurs in intravascular hemolysis?
Hemoglobinemia that gets filtered through kidneys -\> hemoglobinuria
76
When do you see hemoglobinuria?
Intravascular hemolysis (also see hemoglobinemia)
77
When do you see hemoglobinemia?
Intravascular hemolysis (also see hemoglobinuria)
78
When can you see jaundice?
Unconjugated bilirubinemia (hemolysis)
79
What are consequences of hemolysis?
Jaundice
Splenomegaly
Marrow erythroid hyperplasia
Reticulocytosis
Increased LDH
Decreased haptoglobin
Hemoglobinemia (intravascular)
Hemoglobinuria (intravascular)
Hemosiderinuria (intravascular)
Coomb's Test - specific for presence of Abs on surface of red cells
80
What is the most common antibody produced in immune-mediated hemolysis?
IgG - "warm", extravascular
81
Why is IgM-mediated hemolysis intravascular?
Binds complement, destroyed intravascularly
"cold" Ab affinity is greater at extremities in the cold
Mycoplasma pneumonia - also IgM
Mononucleosis - also IgM
82
What is a direct Coomb's Test?
Detects presence of antibodies on RBC's directly (IgM, IgG, complement)
83
What is an indirect Coomb's Test?
Detects presence of Antibodies in blood that are specific to RBCs (not bound to RBCs though)
84
What are hereditary hemolytic disorders?
Spherocytosis, elliptocytosis
85
What is the most common enzymatic defect that leads to hemolytic anemia?
G6PD deficiency
Oxidant stress (infection, acidosis, meds) leads to precipitation of Hgb on RBC membrane and within RC resulting in intra and extravascular hemolysis
Reticulocytes have higher G6PD, so the hemolysis is self limiting
86
Why is G6PD hemolysis self-limited?
Oxidant stress (infection, acidosis, meds) leads to precipitation of Hgb on RBC membrane and within RC resulting in intra and extravascular hemolysis
Reticulocytes have higher G6PD, so the hemolysis is self limiting
87
What is DIC?
Disseminated Intravascular Coagulation
Formation of blood clots throughout body - microangiopathic (small blood vessels) hemolytic anemia
RBC's sheared through clots - form schistocytes, see polychromasia, nucleated RBCs
88
What do you see here?
Microangiopathic hemolytic anemia (mechanical trauma)
Can be caused by DIC, Thrombotic thrombocytopenic purpura, Prosthetic heart valvs, eclampsia
RBC's sheared into schisocytes
89
What is the most abundant protein in the human body?
Hemoglobin
90
What allows hemoglobin to be packed in such high concentrations in blood?
Very soluble
91
What is the main funciton of hemoglobin?
Oxygen (and CO2) transport
92
What is the main structure of hemoglobin?
2 α family and 2 β family globin chains
93
Where does oxygen bind in hemoglobin?
In iron within the heme molecules within the globin chains of hemoglobin (4 chians with 1 heme group each binds a total of 4 molecules of oxygen)
94
What is significant about the synthesis of α-globin and β-globin?
It is balanced - produce the same amount of both
95
What is the predominant form of hemoglobin in prenatal life?
Hgb F - 2α and 2γ chains
(embryonic hemoglobin exists very briefly before then)
96
What occurs at around birth with respect to hemoglobin?
Hemoglobin F to Hemoglobin A switch (α2γ2 to α2β2)
97
What is the most important function of hemoglobin?
Reversibly binds oxygen - grabs on and lets go of it (variable affinity)
Bohr Effect: decreased pH leads to decrease in hemoglobin's affinity for oxygen (unloading)
2,3, DPG is a glycolysis biproduct, binds to β chain N termini of Hgb molecule, leading to T confirmation and decreased oxygen affinity (unloading)
98
Why does hemoglobin have decreased affinity for oxygin in tissues?
Bohr effect: low pH decreases Hgb affinity for oxygen
2,3 DPG - glycolysis biproduct that binds to β chain N-term of Hgb, leading to taut confirmation and decreased oxygen affinity
99
What are qualitative hemoglobin disorders?
Hemoglobinopathies - defects in the structure
E.g. sickle cell disorder
100
What are quantitative hemoglobin disorders?
Thalassemia
101
What are hemoglobinopathies?
Qualitative disorders of hemoglobin (i.e. structure)
E.g. Sickle Cell Disease
102
What are thalassemia syndromes?
Quantitative defects in Hemoglobin - decreased produciton of normal globin chains
E.g. β-thalassemia
103
Which populations are more affected by Sickle Cell?
African Americans (1 in 500)
104
Why do WBC's often get elevated in Sickle Cell Disease?
Reticulocytes can be counted as WBC's on peripheral smear (you have elevated reticulocytes)
105
What is the cause of Sickle Cell Disease?
Point mutation in β-globin gene
Substitution of Valine for Glutamic Acid causing abnormal hemoglobin, known as HgS
106
What is Hemoglobin S?
Abnormal Hemoglobin form found in Sickle Cell
Caused by point mutation in β-globin gene (Val for Glutamic Acid at position 6)
107
Why does Hgb S cause Sickle Cell Anemia?
Hgb S polymerizes into rod-like structures which alters the cell morphology of RBCs
Cause microvascular occlusion - increased adhesion of sickled cells to endothelium
Compromised blood flow (organ infarction) and chronic extravascular hemolysis (by spleen)
108
Why do you hav evasculopathy in Sickle Cell anemia?
Free heme scavenges nitric oxide and causes vasoconstriction, endothelial damage, pulmonary HTN
109
Why do you have thrombosis in Sickle Cell patients?
Flipping of membrane phosphatidylserine lipids exposes negatively charged glycolipids that activate the coagulation cascade
110
What physiological states promote sickling in Sickle Cell disease?
Hypoxia
Infection
Dehydration
Acidosis
111
Why do chronic hemolysis patients need to have folic acid supplements?
Bone marrow needs to be producing more RBC's. Can't let them become folate deficient
112
How do you diagnose Sickle Cell Disease?
Prenatal - chorionic villous biopsy, fetal DNA
Post-natal: all newborns screened
Hemoglobin electrophoresis
113
What do you find on physical exam in Sickle Cell patients?
Jaundice, leg ulcerations
114
What do you find in peripheral blood smear in Sickle Cell patietns?
Sickled cells
115
What CBC abnormalities do you see in Sickle Cell disease?
Elevated White
Anemia
Hemoglobin of 7
Low hematocrit
High reticulocyte
116
How do you treat Sickle Cell Disease?
Analgesics, Folic Acid, prophylactic penicillin, vaccinations, avoid dehydration, surveillance
Hydroxyurea increases HgBF adn decreases HgbS)
Iron Chelation
Stem cell transplantation is potentially curative (but risky)
117
What is Sickle Cell Trait?
Clinically normal heterozygous for beta-S globin gene
Hyposthenuria (inability to concentrate urine)
Sudden death in military recruits (and athletes?) has been reported
118
What is β-thalassemia?
β globin chain synthesis is decreased or absent
119
What is α-thalassemia?
α-globin chain synthesis is decreased or absent
All four alpha globin genes are defective - incompatible with life
120
Where do you see increased incidences of thalassemias?
Mediterannean, Middle East, Africa, India, SE Asia
121
What is β-0-Thalassemia?
Complete absence of β globin chian production
122
What is β-+-thalassemia?
Decreased produciton of β globin chain (not total loss)
123
What is the pathophysiology of β-thalassemia?
Unbalanced chain synthesis
Decreased absolute produciton of HgbA causing hypochromic, microcytic anemia
Compensatory increase in non-beta globin chains (HgbF HgbA2)
124
What do you see on blood smear in β-thalassemia?
Hypochromic, microcytic anemia
125
What happens to the excess α chains in β-thalassemia?
Accumulate in RBC's and form α4 tetramers which precipitate in RBC's (Heinz bodies)
RBC's are prematurely destroyed in marrow and outside of marrow
Compensatory increase in marrow erythropoiesis and extramedullary hematopoiesis (hepatosplenomegaly)
126
What are heinz bodies?
Precipitates in RBCs of excess alpha chains of globin seen in β-thalassemia
127
Where are RBC's destroyed in β-thalassemia?
Marrow (intramedullary hemolysis)
Spleen (extravascular hemolysis)
128
Why do you see hepatosplenomegaly in β-thalassemia patients?
Extramedullary erythropoiesis - would see bone marrow in liver and spleen
129
What are mainstays of therapy of β-thalassemia?
Chronic transfusion therapy with iron chelation (don't want to have too much iron)
130
What is α-thalassemia trait?
1 alpha glbin gene defective (asymptomatic, silent carrier)
131
What is α-thalassemia minor?
2 α globin genes defective
mild hypochromic microcytic anemia, splenomegaly
132
What is hemoglobin H disease?
3 α globin genes are defective
Hemoglobin H (β4) precipitates in RBCs leading to intramedullary and extravascular hemolysis
Mild to moderate hypochromic microcytic anemia and splenomegaly
133
What is transfusion medicine?
branch of medicine concerned with collection and infusion of blood and blood components
134
What is the purpose of blood banking?
transfusion of correct blood product ot the corrrect patient, at the correct time
135
What are the components of collected blood?
Plasma
platelets
White cells
Red cells
136
Identify the layers
137
What is the hematocrit of a unit of RBCs in transfusion?
~60%
138
Why do you give patients RBCs?
Oxygen carrying capacity
139
What are platelet concentrates?
Apheresis units useful to give to patients for clotting
140
Why do you give patients platelets?
For clotting
141
How long can you keep RBC's?
42 days in the fridge
142
How long can you keep platelet concentrates?
5 days (at room temp)
143
What is the purpose of Fresh Frozen Plasma?
Clotting, NOT volume replacement
144
How long does Fresh Frozen Plasma last?
1 year (kept forzen)
145
What is cryoprecipitate?
Small volume product when you slowly thaw Fresh Frozen Plasma and you take the precipitate
Given for clotting in specific deficiencies
146
What is the difference between plasma and cryo?
Cryo has big proteins
147
What is the basis for blood typing?
Agglutination - need to be within 20 nm (electrostatic forces), so IgG is not responsible (too small)
This is IgM mediated 
148
Schema for hemagglutination
149
What is the basis for ABO blood typing?
Determined by presence of abscence of enzyme
Type 0 = no enzyme
Type A = N-acetylgalactosaminyl transferase
Type B = D-galactosyl transferase
Type AB = Both
150
What ABO enzyme do type O patients have?
No enzyme
151
What ABO enzyme do type A patients have?
N-acetylgalactosaminyl transferase
152
What ABO enzyme do type B patients have?
D-galactosyl transferase
153
What ABO enzyme do type AB patients have?
N-acetylgalactosaminyl transferase (A) and D-galactosyl transferase (B)
154
Where are ABO antigens found?
RBC's, WBCs, Platelets, Epithelial Cells, Spermatozoa, Gastric mucosa
155
Where are ABO antigens secreted?
Sweat, Saliva, Semen, Breast milk, Tears, Digestive juices
156
How can ABO typing be used in inheritance?
O = OO
A = AA/AO
B= BB/BO
AB = AB
Do the punnet squares
157
What antibodies do type A patients have?
Anti-B
158
What antibodies do type B patients have?
Anti A
159
What antibodies do type O patients have?
Anti A and Anti B
160
What antibodies do AB type patients have?
None
161
What is the universal RBC donor type?
O
162
What is the univerasl platlet donor type?
AB
163
What is Front type testing?
Patient RBCs and seperate reagent antibodies (IgM) against A and B
164
What is Back type ABO testing?
Patient's serum/plasma and seperate reagent RBC's of type A and B antigens
165
What happens if you transfuse the wrong blood type?
Anti A and Anti B antibodies are IgM and fix complement, which can cause intravascular hemolysis (acute hemolytic transfusion reaction)
166
What are the Rh blood groups?
Blood group composed of ~50 antigens
Most commonly and colloquially refers to the antigen D
Rh+ = have D expression; Rh - = No D expression
167
Why is the Rh blodo typing system important?
Highly antigenic - patients will react against it if they are Rh-
168
How do you perform an antibody screen?
Patient plasma and reagent RBCs with known RBC antigens at 37C
Wash and incubate with anti-human IgG
If agglutination occurs, antibodies for RBC antigens is present
169
What is a crossmatch?
Last check for "compatible" RBCs prior to transfusion (checks ABO compatability)
W/ no atypical antibodies (electronic, immediate spin crossmatch - Donor RBC + patient plasma)
w/ atypical antibodies (RBC from donor + patient plasma (RT, 37C and w/ anti IgG)
170
What are viral complications of transfusion?
HIV, HBV, HCV, HTLV, CMV, West Nile
Window period is small since the testing is molecular
HAV, EBV, Parvovirus B19 and others are NOT screened for
171
What are bacterial complications to transfusions in RBCs?
Yersinia enterocolitica, pseudomonas fluorescens
They proliferate in cold
172
What are bacterial complications to transfusing platelets?
Most organisms can proliferate at storage temperatures
Staph epidermidis, Bacillus cereus
173
What are problems that patients can develop with bacterial infected blood transfusions?
Sepsis
Shock from preformed bacterial toxins
174
What are non-viral/non-bacterial infectious complications of blood transfusions?
Malaria
Babesiosis
Toxoplasmosis
Trypanosomiasis (Chagas Disease)
Reckettsia (Lyme Disease)
Prions (Mad Cow, CJD)
175
What is acute intravascular hemolysis?
Usually due to anti-A and anti-B antibodies
Causes DIC, acute renal failure, shock
176
What is delayed (extravascular) hemolysis?
Antibodies to non-self RBC antigens
Causes decreased hematocrit, maybe fever and malaise
177
What is allo-immunization?
Antibodies to non-self RBC antigens
For patients with many transfusions, get difficulty obtaining compatible blood and HDN
178
What is iron overload?
Seen in patients with lots of transfusions
179
What is non-hemolytic febrile transfusion reactions?
Complication seen with transfusions due to leukocytes
180
What is allo-immunization to HLA antigens?
Platelet transfusion refractoriness and transplant rejection - Leukocyte mediated transfusion complication
181
What are leukocyte-mediated transfusion complicaitons?
Non-hemolytic febrile transfusion reactions
Allo-immunization to HLA antigens
GvHD
Immuno-modulation
182
What is post-transfusion purpura?
Anti-HLA antibodies or anti-platelet antigen antibodies causes platelet depletion - causes bruising
183
What are platelet-associated complications in transfusions?
Post-transfusion purpura
Refractoriness to platelet transfusions
Allergic-like reactions
184
What are plasma-associated complications of transfusions?
Allergic reactions (hives, but can be more severe)
Anaphylaxis (IgE anti-IgA in IgA deficient individuals (rare, but fatal)
Transfusion-related acute lung injury (TRALI) - Anti-granulocyte/anti-HLA antibodies in donor plasma, which causes granulocytes to plug pulmonary vasculature
185
What is TRALI?
Transfusion associated acute lung injury
Anti-granulocyte/Anti-HLA antibodies in donor plasma that causes granulocyte plugging of pulmonary vasculature
Non-cardiogenic pulmonary edema
Treat w. aggresive respiratory support including oxygen and mechanical ventilation
Rapid onset (within 6 hours of transfusion)
186
What is one of the most common complications with transfusions?
Circulatory overload (must take it into account)
187
What do you do when you suspect a transfusion reaction in a patient?
Stop the transfusion
Maintain IV access and administer normal saline
Trat symptoms and report to transfusion service
188
What is hemostasis?
Control of bleeding vs control of clotting
Control of bleeding = platelets, fibrin formation
Control of clotting = vessel wall, endogenous anti-coagulant system, fibrinolysis
189
What are the components of the hemostasis system?
Platelets
Fibrin-forming system
Fibrinolytic system
Endogenous anticoagulant system
Vessel wall
190
What are platelets/thrombocytes (synonyms)?
Anuclear cells wtih 7-10 day lfie span
Typically present in 150-400 x10^3 /ul
Complex structure with many granules with proteins and clotting factors within them
Have important surface receptors (GP Ib and αIIβIII - fibrinogen receptor)
191
What two main surface receptors do platelets have?
GP Ib
αIIβIII
192
What is the funciton of platelets?
First line of defense in hemostasis at site of vessel injury (form platelet plug) - Adhesion, activation, aggregation
Platform for fibrin formation
Mediate inflammation, vascular constriciton, and fibroblast profileration
193
Where are coagulation factors produced?
Liver
194
How do coagulation factors circulate as?
Pro-enzymes (zymogens) - need to be activated, and then activate each other
195
Which coagulation factors are cofactors?
V, VIII, and HMWK
196
Which coagulation factors require vitamin K for normal biosynthesis?
II, VII, IX, X
197
How much of each coagulation factor is required for adequate hemostasis?
20-40%, typically
198
What is VonWillebrand Factor (vWf)⇆
Glycoprotein with multimers of 2-50 subunits
Prodcued by megakaryocytes (stored in platelet α granules) and endothelial cells
Mediates adhesion to subendothelial collagen via platelet glycoprotein receptor Ib (GPIb)
Carrier for factor VIII - prevents its degradation
199
What prevents the degradation of factor VIII?
VonWillebrand Factor
200
What is the goal of hemostasis?
Formation of a fibrin clot that plugs up bleedign at the site of vascular injury
201
What is thrombin?
Potent protease that converts fibrinogen to fibrin and is generated through a series of proteolytic enzymatic reactions known as the coagulation cascade
202
What clotting components are in the subendothelial collagen?
Collagen, and tissue factor - a transmembrane protein found within adventitia of blood vessels, monocytes and other tissues
203
WHat occurs when blood vessel wall is injured?
Collagen and tissue factor are exposed to the blood
Collagen binds von willebrand factor
204
What occurs after vWf binds to collagen in cell wall injury?
Platelets aggregate (adhesion) and release their granule contents
This allows for aggregation of platelets
205
What is the primary hemostatic plug in vessel injury?
Platelet aggregation, which is then covered by fibrin
206
What initiates the coagulation pathway?
Exposure of tissue factor at site of vessel injury and on surface of platelets
207
What happens when Tissue factor binds to factor VII (VIIa)?
More VIIa is activated, which mediates activation of factor X (X to Xa) via serine protease activity
Xa activates prothrombin to thrombin (II to IIa)
Thrombin activates lots of stuff
208
What does thrombin activate?
platelets, V, VIII, XI and XIII
209
What occurs during hte amplificaiton phase of coagulation?
Tissue factor and VIIa activate IX to IXa
Forms tenase complex when combined with VIIIa to activate X to Xa
210
What is teh "common pathway" of coagulation?
From X-Xa down
211
What is the Boost phase of coagulation?
Thrombin activates XI to XIa, which activates IX to IXa
Drives more fibrin formation
212
What is released when fibrinogen is cleaved by thormbin to fibrin monomers?
Fibrinopeptide A and B - can tell us that coagulation is occuring
213
What occurs after thrombin acts on fibrinogen to produce fibrin monomers?
Factor XIIIa mediates cross-linked fibrin polymer clot formation
214
How do you assess hemostasis clinically?
History - site of bleedign, kind of bleeding, inciting event; family hx; meds; other medical problems
Physical exam
Peripheral blodo smear - platelets; RBC changes (schistocytes - DIC: target cells - liver disease; burr cells - renal disease)
215
What is this?
Senile purpura
216
What is this?
Echymosis
217
WHat is this?
Hemoarthrosis
218
What is this?
Petechiae
219
What are coagulation tests?
Prothrombin time
Partial thromboplastin time
Thrombin time
Mixing studies
Clotting factor assays
Fibrinogen level
Fibrin degradation prodcuts
D-Dimer
Bleedign time
Platelet aggregation studies
220
What is prothrombin time?
Plasma + calcium + phospholipid + tissue factor
221
How is prothrombin time reported?
INR (International normalized ratio)
222
What is partial thromoplastin time?
Plasma + calcium + phospholipid + "surface"
Differs from prothrombin time in that it uses surface instead of tissue factor
223
What is thromin time?
Plasma + thrombin
224
What are the differences between what prothrombin time, partial thromboplastin time and thromibn time measure?
225
WHat lab test measures the "contact" pathway?
Partial thromboplatin time
226
What lab test measures the internal pathway of coagulation?
Prothrombin time - uses tissue factor
227
What are the major acquired disorders of coagulation?
Impaired coagulation factor synthesis (Vit. K def.; Liver disease; Warfarin anticoagulants)
Consumption (or loss) of factors (DIC; Massive transfusion; nephrotic syndrome)
Inhibitors of coagulation (Factor inhibitors; antiphospholipid antibodies)
228
What is classic hemophilia?
Hemophilia A
X-linked recessive disorder; 30% are sporadic though
Decreased or absent factor VIII coagulant activity
229
What disease is caused by decreased or absent factor VIII coagulant activity?
Hemophilia A (classic hemophilia)
230
What is hemophilia A?
Classic hemophilia
X-linked recessive; can be sporadic though
Absent or decreased factor VIII coagulant activity
231
What are symptoms of Hemophilia A?
Bleeding (joints, muscles, GU, GI, CNS, post dental
Correlates with factor levels (lower the worse)
Complications include chronic arthropathy, narcotic addictions, transfusion transmitted disease, and inhibitor (antibody) formation
  
232
What are lab findings in hemophilia A
Prolonged PTT with normal PT
Decreased FVIII levels
Can do gene mutation analysis
233
How do you treate hemophilia A?
Recombinant FVIII (expensive!)
Desmopressin - stimulates secretion of vWF and VIII from endothelial cells
For inhibitors - FEIBA (factor eight inhibitor bypassing activity), recombinant FVIIa, immunosuppression
234
What is Hemophilia B (Christmas Disease)?
Looks exactly like Hemophilia A, but is caused by a deficiency of factor IX
235
What disease is caused by deficeincy of factor IX?
Hemophilia B
236
What is Hemophilia C?
Factor XI deficiency
Autosomal recessive (9% of Ashkenazi jews are carriers)
Prolonged PTT, Normal PT, decreased XI
Variable bleeding
237
What disease is caused by factor XI deficiency?
Hemophilia C
238
What are deficiencies of XII, HMWK, Prekallikrein associated with?
NOT associated with bleeding
239
What is the most common inherited bleedign disorder?
Von Willebrand Disease
240
What is Von Willebrand Disease?
Autosomal dominant
Mucocutaneaous bleeding
Prolonged "bleeding time", usually low VWF levels
Prolonged PTT (VWF is carrier molecule for VIII)
Treat with DDAVP (releases VWF from endothelial cells)
241
What is prothrombin time in Von Willebrand Disease?
Normal
PTT is prolonged
Bleedign time is prolonged
242
What is the Partial Thromboplastin time (PTT) in Von Willebrand Disease?
Prolonged
243
What is "bleeding time"?
Measures ability of platelets to adhere and form small clot at cut in forearm - quantitative measurement of platelet adhesion issue
Platelet disfunction (Von Willebrand Disease; NSAIDS, aspirin,...) or Low platelet number will increase this
244
How does Vitamin K deficiency cause disorder of coagulation?
Causes impaired production of II, VII, IX, X (both pathways affected)
Pts have prolonged PT, PTT times, and correction with mixing.
245
How do you get vitamin K deficiency?
Poor nutrition (found in leafy plants and oils)
Poor absorption or biliary obstruction (fat soluble)
Antibiotics can deplete intestinal bacteria that make Vit. K
246
Why can you get bleeding in liver disease?
Factor deficiencies (all made in liver)
Biliary obstruction can impair vit. K absorption
Consumption of clotting facotr
Thrombocytopenia secondary to hypersplenism
Prolonged PT, PTT, hypofibrinogenemia
247
What is DIC??
Disseminated Intravascular Coagulation - Consumptive Coagulopathy
Activation of clotting throughout vascular tree with dissemminated fibrin deposition resulting in consumption of clotting factors and platelets
Always secondary to tissue injury that releases tissue factor or endothelial injury that exposes collagen
Clinical: Diffuse bleeding, purpura, petichiae; microvascular thrombi; microangiogpathic hemolytic anemia
Labs: Prolonged PT, PTT, decreased fibrinogen, elevated fibrin degradation products, elevated D dimer
Treat underlying cause
248
What are clinical features of DIC?
Diffuse bleedign, purpura, petechiae
Microvascular thrombi (ischemia, gangrene)
Microangiopathic hemolytic anemia
249
What will labs be for patient with DIC?
Prolonged PT, PTT
Decreased fibrinogen, elevated fibrin degradation products, elevated D Dimer
250
What are platelet disorders?
Too few (thrombocytopenia)
Too many (Thrombocytosis)
Dysfunctional
251
Why do you look at peripheral blood smear in low platelet count patients?
Pseudothrombocytopenia - secondary to platelet clumping from EDTA-associated agllutinins
252
What is pseudothrombocytopenia?
Secnodary to platelet clumping from EDTA-associated agglutinins
May give falsely decreased platelet count
253
What is this?
Pseudothrombocytopenia
254
What is immune thrombocytopenia?
Autoantibodies to platelets - removed from circulation by reticuloendothelial system
INcreased megas in BM
large platelets on blood smear
255
How do you treat immune thrombocytopenia?
Steroids, IVGG
Splenectomy
Win-RHo (anti-D antibody)
Rituximab
256
What is the most common medication-mediated thrombocytopenia?
Heparin associated thrombocytopenia
Occurs 4-14 days post exposure
Antibodies to heparin complexed with platelet factor 4
Paradoxiacl arterial or venous thrombosis secondary to action of antibodies on endothelial cells and activation of platelets
STOP HEPARIN IMMEDIATELY and give non-heparin anticoagulation
257
What do you do with patients wiht heparin associated thrombocytopenia?
STOP HEPARIN IMMEDIATELY and give other anti-coagulant
258
Why do you get thrombosis in heparin associated thrombocytopenia?
Secondary to action of antibodies on endothelial cells and activation of platelets
259
What is thrombocytosis?
Increased number of platelets
Primary - myeloproliferative diseases, thrombosis and bleeding risk
Reactive - infection, malignancy, iron deficiency, bleeding
260
What are acquired qualitative disorders of platelets?
Aspirin - irreversibly blocks COX-1 and interferes with platelet thromboxane production
NSAIDs - reversibly inhibit COX and COX-2 inhibitors decrease prostacyclin; it inhibits platelet function, the reduciton of PGI by COX-2 inhibitors may explain increased cardiovascular risk (activated platelets)
Uremia - accumulation of toxic metabolites interfere with platelet function
Myeloproliferative disorders
261
What are inherited qualitative disorders of platelets?
Von Willebrand Disease - most common inherited bleedign disorder; mucocutaneous bleeding, increaed bleedign time, PTT
Glanzmann Thrombasthenia - abnromal αΙΙbβ3 (platelet fibrinogen receptor; impaired aggregation); mucocutaneous bleeding
Bernard Soulier Syndrome - abnormality of GPIb, impaired adhesion
262
What factors regulate clotting?
intact endothelium
Normal blood flow (stasis, turbulent flow, etc.)
Destruction of fibrin clot (fibrinolysis)
Elimination of activated clotting factors (removal by liver, inactivation by antithrombin, protein C, protein S or tissue factor pathwya inhibitor)
263
What is the effect of Nitric oxide on clotting?
vasodilator, inhibitor of platelet aggregation
264
What is the effect of prostacyclin on clotting?
vasodilation, inhibits platelet aggregation
265
What is the effect of thrombomodulin on clotting?
receptor for thrombin, complex activates protein C which inhibits VIIIa and Va
266
What is the effect of tissue factor pathway inhibitor on clotting?
Inactivates VIIa and Xa
Produced by endothelial cells
267
What is fibrinolysis?
Enzymatic destruciton of fibrin clot by plasmin
268
What controls fibrinolysis? Why?
Things can dampen fibrin clot so that you can actually clot when you need to
α2 antiplasmin acts on plasmin and plasminogen activator inhibitor 1 acts on tissue plasminogen activator
269
How does elimination of activated clotting factors regulate clotting?
Removal by liver
Inactivation by endogenous anti-coagulant systems (protein C, Protein S, antithrombin III and tissue factor pathway inhibitor)
270
What is the protein C protein S system?
Vitamin K dependent factors made in the liver
Protein C is activated by thrombin bound to its endothelial receptor, thrombomodulin
Activated protein c (APC) along with protein S, inhibits Va and VIIIa
Part of the endogenous anti-coagulant system
271
WHat is antithrombin III?
Serine protease inhibitor (serpin)
made in liver
Complexes with serine proteases and inactivates them (XIIa, XIa, Xa, IXa, and thrombin)
Binds to heparan sulfate on endothelial cells which undergoes conformational change which potentiates ATIIIs ability to inactivate thrombin
This is how exogenous heparin works
272
How does exogenous heparin work?
Binds antithrombin and mediates inactivaiton of clotting factors
273
What is tissue factor pathway inhibitor?
Made by endothelial cells
Circulates in plasma and inactivates Xa and tissue factor/VIIa complex
Heparin stimulates release of TFPI, potentiating its anticoagulant effect
274
HOw does protein C protein S system work?
275
HOw does antithrombin III work?
276
How does TFPI work?
277
When does thrombosis occur?
Breakdown in balance between thrombogenic factors and protective mechanisms
278
What are thrombogenic factors?
Virchow's Triad
Vessel wall damage
Static or turbulent flow
Coagulable state of blood (hypercoagulability) - activation of platelets/clotting
279
What is Virchow's Triad??
Vessel wall damage
Static or turbulent flow
Coagulable state of blood (hypercoagulability) - activation of platelets/clotting
280
What is hypercoagulability?
Acquired and inherited conditions resulting in increased tendency to develop thrombosis
281
What is thrombophilia?
Inherited tendency to develop thrombosis
282
When do you see thrombophilia?
Younger individuals (\<50 years old) where you see venous thromboemobolism in abnormal places or arterial thrombosis (ATIII deficiency)
Acquired risk factors further increase incicdence of thrombosis in these patients
283
What is the most common thrombophilic disorder?
Factor V Leiden mutation
284
What is Factor V Leiden mutation?
Most common mutation in patients wtih venous thrombosis
Mutated factor V is resistant to inactivation by activated protein C
Provided survival advantage when bleedign was a risk (not so great now)
285
What is prothrombin gene mutation (G202010A)?
Results in 20% increase in amount of prothrombin in blood
Cause of thrombosis in 20-30% of individuals
Thrombophilia disease
286
What is protein C and protein S deficiency?
Autosomal dominant thrombophilia disease
Impaired inactivation of Va and VIIIa
Homozygous is incompatible with life
Hets have 3x risk of thromboembolism
287
What is Warfarin Skin necrosis?
In patients with protein C or S deficiency - thrombosis of vessels in subcutaneous fat in these patients that receive anti-coagulation with warfarin
Common in abdominal vessels
288
What is antithrombin III deficiency?
Rare, autosomal dominant thrombophilia
Quantitative and qualitative defects in ATIII
Ineffective inhibition of XIIa, XIa, Xa, IXa and thrombin (increased venous thromboembolism)
One mutation predisposes to areterial thrombosis
289
What is inherited hyperhomocysteinemia?
Enzyme deficiencies lead to elevated homocystine
Increased risk of arterial and venous thromboembolism
Unclear mechanism
290
What are some acquired risk factors for hypercoagulability?
Preganancy
Immobilization
Malignancy
Obesity
Birth control pills
Acquired ATIII deficiency (liver disease, nephrotic syndrome)
Blood disease
Heparin induced thrombocytopenia
Antiphospholipid syndromes
291
What blood issue do you suspect here?
DVT
292
What is antiphospholipid syndrome??
Antibodies that attach phospholipids
Interfere with negatively charged phospholipid used in clotting assays, so they will paradoxically present with a prolonged aPTT
Seen in collagen vascular disease, liver disease, malignancies and normal people
Associated iwth venous and arterial **thrombosis**
Mixing studies with no correction!
293
What is the most common cause of drug-induced thrombocytopenia?
Heparin
Antibodies to heparin are complexed with platelet factor 4
Paradoxical arterial or venous thrombosis secondary to action of antibodies on endothelial cells and activation of platelets
Tx by STOPPING HEPARIN IMMEDIATELY, and putting them on anticoagulation (non-heparin)
294
What is a concern with warfarin in pregnant women?
Teratogenic
295
What is the defect in Glanzmann Thrombasthenia?
Abnormal GPIIb/IIIa - decreased fibrinogen binding, absent platelet aggregation, abnormal clot retraction, decreased platelet fibrinogen
296
What is a unifying characteristic of all of the hematologic malignancies?
They are all clonal - all arose from a single cell
297
What are the myeloproliferative disorders?
Chronic Myelogenous Leukemia
Polycythemia Vera
Essential Thrombocytothemia
Agnogenic Myeloid Metaplasia (Myelofibrosis)
298
What define the acute leukemias?
Clonal, stem cell disorders
Impaired differentiation of hematopoietic cells resulting in block of their development into mature, functioning blood cells
Marrow replaced by immature leukemic blasts
Can't differentiate between the different acute leukemias, just that it IS an acute leukemia
299
What is Acute Myelogenous Leukemia (AML)?
Rare
Median age at diagnosis = 65-70
Risk factors are Benzene, ionizing radiation, chemo
300
How do you diagnose/classify acute leukemias?
Cytochemistry (used less now)
Immunophenotype - flow cytometry with CD antigens
Cytogenetics
Molecular analysis (FISH, PCR)
301
What are features of acute leukemia on bone marrow aspirate?
Hypercellularity, blastic - high nuclear to cytoplasmic ratio
AML can be identified by Auer Rods
302
What are Auer Rods?
Accumulation of granules seen in AML only
303
What is this?
Burkitt's Leukemia
304
What are clinical features of acute leukemia?
Leukocytosis:
50% normal or low WBC
Neutropenia
Hyperleukocytosis (\> 50,000)
Anemia
Thrombocytopenia
Coagulopathy
Organ Infiltration
305
What are complications seen in acute leukemia?
Infection secondary to neutropenia (bacterial, fungal, viral)
Bleeding
Hyperleukocytosis - in CNS and lungs
Extramedullary inflitration - gingival hyperplasia, CNS
306
How do you treat acute leukemias?
Supportive care (hydration, allopurinol, antibiotics, transfusions, growth factors)
Induction chemotherapy (7+3, ATRA)
Post remission therapy
307
What is a different between MDS and MPS?
MPS - full maturation of all cell lineages
MPS - extramedullary hematopoiesis
308
What is a unique feature of myeloproliferative neoplasms?
You see extramedullary hematopoiesis
309
Is development of marrow fibrosis a unique feature of myeloproliferative neoplasms?
NOPE - but it is seen
310
What are the philadelphia chromosome-positive myeloproliferative neoplasms?
Chronic myelogenous leukemia
311
What are the philadelphia chromosome neagitve myeloproliferative neoplasms?
Polycythemia rubra vera
Essential thromobcythemia
Primary myelofibrosis
Chronic eosinophilic leukemia
Chronic neutrophilic leukemia
Systemic Mast Cell
312
What is the basis chronic myelogenous leukemia?
t(9;22)
BCR-ABL fusion protein has constitutive tyrosine kinase activity
Resistance to apoptosis
313
What can increase the risk of CML?
Ionizing radiation exposure, benzene exposure, etc
314
What are clinical features of CML?
Fatigue, fevers, sweats, bone pain (most are asymptomatic, though)
Splenomegaly - extramedullary hematopoiesis
Granulocytosis, Thrombocytosis, Basophilia, Anemia
315
How do you diagnose CML?
Cytogeneitc - Philadelphia chromosome
FISH - for BCR-ABL = this is not specific, though ! ALL!
316
How do you track the course fo treatment in CLL?
BCR-ABL PCR levels
317
How do you treat CLL?
Irradiation, chemo, Stem cell transplant
TYROSINE KINASE INHIBITORS - imatinib, dasatinib, nilotinib (Gleevec)
318
What are features of polycythemia vera?
Elevated hemoglobin/hematocrit
White count, red count, platelets too
Spurious due to decreased plasma volume
True due to increase in red cell mass (primary or secondary)
319
What can cause primary polycythemia?
(in the setting of low EPO levels)
Polycythemia vera
Activating mutations of EPO receptor
Chuvash polycythemia
Idiopathic familial polycythemia
320
What is the first lab test you perform when you identify a patient with polycythemia?
EPO levels - high or low? primary or secondary?
321
Who gets polycythemia vera?
Median age 60
men more than women
322
What are clinical features of polycythemia vera?
Plethora - redness in face
Headache, weakness, diziness
Pruritis (after showering)
Gout (hyperuricemia)
Venous and arterial thrombosis - Budd Chiari (hepatic vein thrombosis)
Bleeding
323
What is the MCV of patients in polycythemia vera?
Low - iron deficiency
324
How is Polycythemia Vera diagnosed?
Low EPO levels
Bone marrow aspirate and biopsy
Cyotgenetic and molecular studies
325
What is the molecular basis for polycythemia vera?
Mutated JAK-2 in cells
Disrups normal inhibitory regulation of JAK2 - results in constituitive activity in absence of hematopoetic growth factors
May confer proliferative and survival advantage (EPO/TPO independence)
326
What are complications of polycythemia vera?
Thrombosis (Budd-Chiari)
Increased blood viscosity
Qualitative and quantitative platelet defects
Bleeding
Transforming to stent phase
Transforming to AML
Solid tuomrs
327
How do you treat polycythemia vera?
Phlebotomy (Hct \<45%)
Myelosuppression (hydroxyurea, anagrelide, chlorambucil, 32Phosphorous)
Antiplatelet agents
328
Who gets essential thrombocythemia?
females (2:1)
Median age at 60
Near normal life expectancy
329
What is the pathogenesis of essential thromobcytothemia?
Clonal
TPO independence
Decreased c-MPL expression
JAK2 mutations in 50%
330
How do essential thrombocythemia patients present?
Thrombocytosis (often \> 1 million)
Splenomegaly
Thrombosis
Bleeding
Transformation to myelofibrosis, Polycythemia vera
Transformation to AML
331
Where does essential thormobcythemia bleeding present?
Skin, mucous membranes, GI tract
Platelets are \> 1 million
Use aspirin, NSAIDs
Can have acquired von Willebrand Disease
332
How do you treat essential thromobcythemia?
Vasomotor symptoms/microvascular thrombi - low dose aspirin
Bleeding - avoid NSAIDS and ASA \> 325 mg
High risk for thrombosis - **Hydroxyurea**
333
What is an important mainstay of treatment of essential thromobcythemia?
Aspirin and Hydroxyurea
334
What is primary myelofibrosis?
Clonal disease
Progressive marrow fibrosis
Extramedullary hematopoiesis
Cytosis, initially followed by cytopenias
Jak2 mutation in 50%
Leukemic transformation in 10-20%
335
What do you see on blood smear of primary myelofibrosis?
Tear drops, leukoerythroblastosis
336
What do you see in bone marrow of primary myelofibrosis?
Fibrosis - increased reticulin fibrosis
337
How do you treat primary myelofibrosis?
Supportive - EPO, transfusions, splenectomy
Thalidomide (anti-angiogenic, anti-TNFα)
Etanercept (TNFα receptor)
**JAK2 inhibitor (Ruxolitinib)**
**Allogenic stem cell transplantation**
