14 Flashcards

Question

Pathogenesis hereditary spherocytosis

Answer 1

Pathogenesis Decreased density (insufficiency) of membrane skeletal components due to mutation in ankyrin, band 3, spectrin, or band 4.2 ankyrin and band 4.2 binds spectrin to the transmembrane ion transporter band 3 protein 4.1 binds the "tail" of spectrin to another transmembrane protein, glycophorin A Reduced stability of the lipid bilayer and loss of membrane fragments occurs as RBCs age RBC assumes spheroidal shape, is trapped in the cords of Billroth and destroyed by splenic macrophages after about 10-20 days instead of the normal 120 days RBC loss of K+ and H2O also occurs and may be due to low RBC glucose or altered pH

Answer 2

orphology Spherocytosis is distinctive but not pathognomonic small, dark-staining (hyperchromic) red cells lacking the central zone of pallor Reticulocytosis, marrow erythroid hyperplasia, hemosiderosis Moderate splenomegaly (very characteristic and consistent) due to congestion of cords of Billroth and increased number of macrophages Cholelithiasis in 40-50% of patients due to pigment stones

Answer 3

Family history, hematology findings & lab evidence | Osmotic fragility/lysis test in hypotonic solution

Answer 4

Increased RDW and MCHC

Answer 5

patients present with variable anemia, splenomegaly and jaundice If severe, like in compound heterozygotes, can present at birth and require exchange transfusion Increased risk of aplastic crisis due to parvovirus B19 infection since it stops hematopoiesis for a couple of weeks RBC counts drop to dangerous levels Hemolytic crises due to infectious mononucleosis (#1 cause is EBV; #2 is CMV) may also occur No splenomegaly Many patients will develop gall stones (pigment

Answer 6

Splenectomy after splenectomy, the spherocytes persist but the anemia is corrected Increased risk of sepsis Anemia resolves but Howell-jolly bodies (residual RNA) remain (in all asplenic patients

Answer 7

Enzyme in the hexose monophosphate shunt Normally reduces NADP → NADPH NADPH normally reduces RBC glutathione and protects against oxidative stress Oxidative stress may be due to: Fava beans, antimalarial drugs (Quinidine, primaquine, and chloroquine), sulfonamides, nitrofurantoins, infection, inflammation Resistance to Plasmodium falciparum (malaria

Answer 8

G6PD- Deficiency X-linked recessive deficiency *G6PD- (African variant) prominent in African Americans, and is less severe Episodic (not chronic) hemolysis due to oxidative stress In deficient cells, oxidative stress causes hemoglobin sulfhydryl crosslinking and protein denaturation cross-linking of reactive sulfhydryl groups on globin chains become denatured and from membrane bound precipitates called Heinz bodies (appear as dark inclusions visible with crystal violet) Heinz bodies (denatured hemoglobin) can damage the membrane enough to cause intravascular hemolysis As macrophage remove the Heinz bodies, they create "bite cells" or become spherocytic

Answer 9

G6PD Mediterranean Variant Markedly decreased t1/2 of this enzyme causes significant intravascular hemolysis with oxidative stress Protein misfolding = increased susceptibility to proteolytic degradation Prevalent in the Middle East Enzyme activity makes older RBCs prone to hemolysis with oxidative stress Self-limited because young RBC's not affected

Answer 10

Azdelta2 High HbA2 is a b thalassemia (minor trait)

Answer 11

Hereditary hemoglobinopathy due to a point mutation provides protection v. falciparum malaria Intracellular parasites consume O2 and decrease intracellular pH, which both promote sickling and distorted cells are cleared more rapidly by phagocytes keeping parasite loads down Sickling impairs PfEMP-1 membrane knob formation which normally allows the parasite to adhere to endothelial cells (cerebral malaria

Answer 12

Hereditary hemoglobinopathy due to a point mutation (6th position) (glutamate → valine) in β-globin that promotes polymerization of deoxygenated hemoglobin, leading to: Red cell distortion (extravascular) hemolytic anemia Microvascular obstruction --> most serious clinical features Ischemic tissue damage Heterozygotes only affected in settings of profound hypoxia

Answer 13

Deoxygenated hemoglobin forms RBC polymers when deoxygenated converting the free flowing cytosol into viscous gel They then form long, needlelike fibers within RBCs causing a sickle shape; rate and degree depend on: Interactions with other types of hemoglobin in the cell HbA interferes with the polymerization of the HbS Mean cell [Hb] (MCHC) decreased MCHC levels cause a milder disease, like in homo HbS patients with α-thalassemia intracellular dehydration increases the MCHC and facilitates sickling Intracellular pH: decrease in pH increases the likelihood for sickling Transit time of RBCs through microvascular beds: slower time increases the amount of deoxygenation and sickling Found most commonly in the spleen, bone marrow, and inflamed tissues

Answer 14

Compound heterozygotes with RBCs that tend to lose salt and water (dehydration) [Hb] is then increased and there is a tendency for polymerization Glutamic acid → lysine ("lyCine") Crystals are seen on blood smear More mild than sickle cell disease

Answer 15

HbF is protective, and patients often present at 6 months when these levels decline treatment of sickle cell disease with hydroxyurea enhances expression of HbF

Answer 16

Repeated damage leads to influx of Ca++ and efflux of K+ and H2O Chronically this causes RBCs to become dehydrated, dense and rigid These cells become end stage, non-deformable, irreversibly sickled cells that retain the sickle shape even when fully oxygenated Hemolysis severity is proportional to the number of irreversibly sickled cells that are sequestered and extravascularly hemolyzed

Answer 17

Higher than normal levels of adhesion molecules are expressed, which are upregulated during inflammatory reactions increased tendency for the cells to arrest while moving through microvasculature causing sickling and obstruction Vicious cycle of sickling, obstruction, hypoxia ensues Free hemoglobin binds to and inactivates NO leading to increased vascular tone and enhanced platelet aggregation Stasis, sickling and thrombosis

Answer 18

Peripheral blood: irreversibly sickled cells, reticulocytosis and target cells due to RBC dehydration Howell-jolly bodies (residual RNA) due to asplenia Massive erythroid hyperplasia and extramedullary erythropoiesis

Answer 19

splenomegaly caused by trapping of sickled red cells in the cords and sinuses during childhood chronic erythrostasis --> splenic infarction, fibrosis, and progressive shrinkage only a fibrous nubbin of fibrous splenic tissue remains by adolescence

Answer 20

Skull: prominent cheekbones and changes in the skull that resemble a "crewcut" facial bones: chipmunk facies

Answer 21

Pigment gallstones and hyperbilirubinemia Microvascular occlusions of tissue (stroke, retinal problems, growth retardation) Vascular stagnation of subcutaneous tissue → leg ulcers in adults chronic hypoxia is responsible for a generalized impairment of growth and development

Answer 22

mplication Episodes of hypoxic injury and infarction causing severe pain in the area Often no predisposing cause is identified infection, dehydration, and acidosis all favor sickling Bones, lungs, liver, brain, spleen, penis Bone crises are common in children (difficult to distinguish from acute osteomyelitis) Can manifest as dactylitis or acute chest syndrome

Answer 23

Vasoocclusive infarcts in the bones leading to swollen hands and feet extremely common and often difficult to distinguish from acute osteomyelitis Common presenting sign in African American infants ∼ 6 months old with sickle cell disease

Answer 24

Vasoocclusive crisis of the lungs in sickle cell patients Fever, cough, chest pain, pulmonary infiltrates Most common cause of death in adult patients with sickle cell anemia Often precipitated by pneumonia Causes vasodilation, slowing blood flow which increases dehydration, acidemia and deoxygenation creating a vicious cycle May require transfusion or prove fatal

Answer 25

Occurs in 45% of males after puberty and may lead to hypoxic damage and erectile dysfunction

Answer 26

Children with intact spleens have massive entrapment of sickle RBCs → rapid splenic enlargement, hypovolemia and possible shock May require transfusion or prove fatal

Answer 27

Sickle Cell Anemia: Sequestration Crises Children with intact spleens have massive entrapment of sickle RBCs → rapid splenic enlargement, hypovolemia and possible shock May require transfusion or prove fatal

Answer 28

Parvovirus B19 infection of red cell progenitors causes a transient cessation of erythropoiesis and sudden worsening of anemia Can occur in patients with sickle cell anemia

Answer 29

Hypertonicity of the renal medulla can cause damage leading to the inability to concentrate urine This increases the risk of dehydration and its attendant risk

Answer 30

Increased risk of infection due to encapsulated pathogens: Strep pneumo, haemophilus influenzae Increased risk of S. Typhi osteomyelitis, S. Pneumoniae and H. Influenzae

Answer 31

Most common cause of death in children with sickle cell anemia Can cause septicemia and meningitis Vaccinate children to reduce this risk Prophylactic antibiotics may be necessary

Answer 32

Based on clinical signs and symptoms and laboratory testing of hemoglobin Metabisulfite screen is (+) in both disease and trait Electrophoresis Prenatal amniocentesis or chorionic biopsy

Answer 33

90% survive to age 20, 50% survive to 50+

Answer 34

Hydroxyurea (DNA synthesis inhibitor) increased HbF and has an anti-inflammatory effect HSC transplant is possible

Answer 35

Heterogenous group of disorders due to inherited mutations that decrease synthesis of either the α-globin or β-globin chains that compose adult HbA (α2β2) 2 α-globin genes (4 alleles) on chromosome 16 1 β-globin gene (2 alleles) on chromosome 11 Causes anemia, tissue hypoxia and RBC hemolysis due to the imbalance of globin chain synthesis Anemia due to decreased RBC production and decreased RBC lifespan Heterozygotes are protected from falciparum malaria

Answer 36

dysregulation of the synthesis of β-globin chains Under hemoglobinized microcytic, hypochromic RBCs with subnormal O2 transport capacity RBC life span is diminished due to imbalance of α and β globin synthesis Reduced beta-globin chain synthesis from beta-thalassemia leads to RBC microcytosis, hypochromia, ineffective erythropoiesis, and excessive iron absorption. There is chronic anemia, because the major hemoglobin A1 [α2β2] is produced insufficiently. The nature of the mutation, typically affecting RNA transcript production, determines the severity of the disease.

Answer 37

Ineffective erythropoiesis | Extravascular hemolysis due to sequestration

Answer 38

Absent synthesis of the β-globin chain | Most common mutation: chain terminator creating premature stop codons

Answer 39

Absent synthesis of the β-globin chain | Most common mutation: chain terminator creating premature stop codons

Answer 40

unpaired α chains precipitate within RBC precursors → insoluble inclusions Inclusions cause membrane damage → precursor apoptosis In severe disease this causes ineffective erythropoiesis Those not destroyed are released with inclusions and membrane damage and are susceptible to splenic sequestration and extravascular hemolysis

Answer 41

Massive erythroid hyperplasia due to ineffective erythropoiesis Expansion causes erosion of the bony cortex impairing bone growth and creating skeletal abnormalities crew cut and chipmunk facies? Extensive extramedullary hematopoiesis: liver, spleen, lymph nodes Severe cachexia as nutrients is stolen from tissues that are O2 starved for erythroid progenitors Excessive absorption of dietary iron due to suppressed hepcidin and in combination with repeat transfusions leads to iron overload (secondary hemochromatosis) ineffective erythropoiesis suppresses hepcidin, a critical negative regulator of iron absorption increased absorption of iron from the gut with low hepcidin levels decreased absorption of iron from the gut with high hepcidin levels Hereditary hemochromatosis results from increased iron absorption with markedly increased iron stores. The iron accumulation in tissues results in manifestations such as hepatomegaly, skin pigmentation, diabetes mellitus, heart disease, arthritis, and hypogonadism. A 46-year-old man has had worsening arthritis and swelling of his feet for the past year. On physical examination he has rales audible in all lung fields. A chest radiograph shows cardiomegaly and pulmonary edema. Laboratory studies show Hgb 13.0 g/dL, Hct 39.1%, MCV 86 fL, platelet count 255,500/uL, and WBC count 5920/uL. His serum iron is 406 microgram/mL with iron binding capacity 440 microgram/mL and ferritin 830 ng/mL (storage form of iron is markedly elevated). Which of the following is the most likely diagnosis? Hereditary Hemochromatosis

Answer 42

Anisocytosis (variable RBC size) Poikilocytosis (variable shape) Hypochromic Target cells: hemoglobin collects in the center of the cell Basophilic stippling == indicator of toxic injury to RBCs Fragmented RBCs Massive erythroid hyperplasia (crewcut + chipmunk facies) Iron overload: hemosiderosis and 2° hemochromatosis, affecting the heart, liver and pancreas mostly

Answer 43

Individuals with alleles Β+ / β+ Β+ / β° Β° / β° have a severe, transfusion dependent anemia beginning at 6-9 months of age Hemosiderosis may occur secondary to transfusions

Answer 44

Common in Mediterranean countries, Africa, Southeast Asia

Answer 45

major red cell hemoglobin is HbF (markedly elevated) HbA2 levels are sometimes high but more often are normal or low high HbA2 is a β-thalassemia minor/trait high HbF is a β-thalassemia major Extravascular hemolysis *Hepatosplenomegaly (extramedullary hematopoiesis) Massive erythroid hyperplasia of skull (crewcut) and face (chipmunk facies) Risk of aplastic crisis due to parvovirus B19

Answer 46

Requires chronic transfusions: survival to 3rd decade Predisposed to secondary hemochromatosis (cardiac problems) May require iron chelators (EDTA) May cure with HSC transplant Untreated = early death due to anemia

Answer 47

Individuals with alleles (heterozygous) Β+ / βwild-type Β° / βwild-type Much more common Mild, asymptomatic, microcytic, hypochromic anemia Usually asymptomatic heterozygous carriers

Answer 48

Clinical Mild anemia with hypochromic, microcytic, basophilic stippling and target cells in peripheral blood Mild erythroid hyperplasia Can be mistaken for iron deficiency anemia in pregnancy as they were asymptomatic before

Answer 49

Increased HbA2 Normal HbF high HbA2 is a β-thalassemia (minor/trait) high HbF is a β-thalassemia (major) Must confirm diagnosis to rule out iron deficient anemia

Answer 50

Heterozygous variant of moderate severity May have Two defective β-globin genes and an α-globin gene defect which improves erythropoiesis effectiveness and red cell survival by lessening the imbalance in α- and β-chain synthesis One defective β-globin gene and extra copies of α-globin genes, worsening the imbalance Not transfusion dependent

Answer 51

Inherited gene deletion → absent or reduced synthesis of α-globin chains Infants: unpaired γ-globin chains form tetramers call "Hemoglobin Barts" Adults: unpaired β-globin chains form tetramers called "HbH" β and γ chains are more soluble than free α-globin chains, and form more stable homotetramers --> hemolysis and ineffective erythropoiesis are less severe than in β-thalassemia

Answer 52

4 alleles on chromosome 16 1 allele deleted = asymptomatic 2 allele deleted = mild anemia with increased RBC count Cis deletion *Asian children of affected individuals are at increased risk of clinically significant α-thalassemia symptomatic α-thalassemia is fairly common Trans deletion *African American symptomatic α-thalassemia is uncommon

Answer 53

Severe anemia HbH tetramers

Answer 54

4 alleles deleted = lethal in utero (hydrops fetalis) -- "Hemoglobin Barts"

Answer 55

Deletion of a single gene causing a barely detectable reduction in globin chain synthesis patients are asymptomatic with slight microcytosis

Answer 56

Cis deletion: Asians Α/α : -/- *offspring are at significant risk of disease Trans deletion: African Americans Α/- : α/- Microcytosis with minimal anemia and no abnormal physical signs and symptoms (asymptomatic) α-thalassemia trait is clinically similar to β-thalassemia minor

Answer 57

Deletion of three genes Most common in Asian populations Tetramers of β-globin chains form == called HbH HbH has extremely increased affinity for O2 (not useful for O2 delivery to tissues) tissue hypoxia disproportionate to the level of Hb HbH is prone to oxidation --> precipitation and intracellular inclusions promoting RBC sequestration and phagocytosis in the spleen Resembles β-thalassemia intermedia Does not require transfusions

Answer 58

Deletion of all 4 genes tetramers of γ-globin chains form called Hemoglobin Barts in the fetus Greatly increased affinity for O2 = tissue hypoxia Fetal distress beginning 3rd trimester Intrauterine fetal transfusion can save infants that used to die in utero Severe pallor, generalized edema and massive hepatosplenomegaly -- similar to hemolytic disease of newborn Lifelong dependence on transfusions (risk of iron overload) HSC transplant is curative

Answer 59

Acquired mutation of phosphatidylinositol glycan complementation Group A gene (PIGA) Only hemolytic anemia caused by an acquired genetic defect Enzyme is essential for synthesis of certain membrane associated complement regulatory proteins Absent glycosylphosphatidylinositol (GPI) = cells susceptible to destruction by complement

Answer 60

PIGA gene is X-linked and subject to lionization A single acquired mutation --> deficiency in production of GPI which attaches important proteins to the cell membrane allowing complement dysregulation PNH blood cells are deficient in three GPI-linked proteins that regulate complement activity CD55 (DAF) decay accelerated factor CD59: membrane inhibitor or reactive lysis (MIRL; most important) Membrane inhibitor of reactive lysis Potent inhibitor of C3 convertase Prevents spontaneous activation of the alternative complement pathway C8 binding protein

Answer 61

inical RBCs are abnormally susceptible to lysis or injury by complement Intravascular hemolysis caused by the C5b-C9 membrane attack complex 25% of cases = paroxysmal and nocturnal Shallow nighttime breathing = respiratory acidosis which activates complement Chronic hemolysis is typical = mild to moderate anemia Heme iron is lost in urine (hemosiderinuria) eventually leads to iron deficiency (can exacerbate the anemia

Answer 62

RBCs are abnormally susceptible to lysis or injury by complement Intravascular hemolysis caused by the C5b-C9 membrane attack complex 25% of cases = paroxysmal and nocturnal Shallow nighttime breathing = respiratory acidosis which activates complement Chronic hemolysis is typical = mild to moderate anemia Heme iron is lost in urine (hemosiderinuria) eventually leads to iron deficiency (can exacerbate the anemia) Complications Leading cause of disease-related death: Venous thrombosis (40%) of the hepatic, portal or cerebral veins 5-10% develop acute myeloid leukemia (AML) or myelodysplastic syndrome hematopoietic stem cells have suffered some type of genetic damage

Answer 63

Flow cytometry detection of RBCs deficient in GPI linked proteins (CD59

Answer 64

Eculizumab (prevents C5 conversion to c5a) Decreases hemolysis, risk of thrombosis, and required transfusions Increases risk of meningococcal infection Immunosuppression may benefit some patients with marrow aplasia Definitive treatment: HSC transplant

Answer 65

(D) CORRECT. He has paroxysmal nocturnal hemoglobinuria (PNH) an acquired stem cell disorder from mutation in the PIGA gene that renders RBCs very sensitive to complement lysis, as well as thrombosis in unusual veins. There is also risk for leukemia. The RBC markers CD55 and CD59 are reduced with PNH

Answer 66

Immunohemolytic Anemias (IHAs) -- most physicians call these "autoimmune hemolytic anemias" Definition antibodies bind to RBCs causing their premature destruction

Answer 67

Diagnosed via the presence of antibodies and/or complement on RBCs from the patient Direct Coombs antiglobulin test: patient's RBCs are mixed with donor serum -- this is a screen agglutination means patient has RBCs coated with antibodies Indirect Coombs antiglobulin test: patients serum is mixed with donor RBCs agglutination means patient has antibodies to patient's RBCs

Answer 68

Direct Coombs Antiglobulin Test patient's RBCs are mixed with antibodies specific for human immunoglobulin or complement (+) if the patient's RBC's have immunoglobulins already attached to them, which are then attacked by the antihuman antibodies added If immunoglobulin or complement is present on the RBC surface agglutination occurs (clumping) Indirect Coombs Antiglobulin Test Commercial RBCs with defined Antigens are mixed with the patient's serum (+) if patient's serum has immunoglobulins against the Antigens on the commercial/donor RBCs Characterizes the antigen target and temperature dependence of the responsible antibody Treatment: Remove initiating factors, immunosuppression or splenectomy

Answer 69

Most common type of immunohemolytic anemia 50% are idiopathic (and poorly understood). Also caused by drugs, autoimmune disorders (especially SLE), lymphoid neoplasms

Answer 70

Usually due to IgG (or less frequently IgA) antibodies -- "warm weather is Great" Extravascular hemolysis IgG coated RBCs bind Fc receptors on phagocytes Partial phagocytosis occurs as RBC membrane is removed RBC's become spherocytes that are sequestered in the spleen = splenomegaly

Answer 71

Offending agent binds to RBCs after an IV infusion 1-2 weeks after initiation of therapy, hemolysis occurs due to antibody binding to the drug or a complex of the drug and RBC membrane Extravascular hemolysis within phagocytes (most common as the antibodies act as opsonins) Commonly due to penicillins and cephalosporins

Answer 72

olerance Breaking Drugs Offending agents induce production of antibodies against RBC Antigens Particularly the Rh Antigens 10% of patients taking α-methyldopa develop auto-antibodies (direct Coombs test) and 1% have clinically significant hemolysis

Answer 73

IgM antibodies bind RBCs avidly at low temperatures (0˚C to 4˚C) -- "cold weather is MMMiserable" Acute: self-limited, rarely induce clinically important hemolysis appear transiently following infection (e.g. mycoplasma pneumonia, EBV, CMV, influenza virus, HIV

Answer 74

Chronic: symptomatic Idiopathic or associated with B cell neoplasms (eg CLL) chronic cold agglutinin immunohemolytic anemia caused by IgM antibodies is more difficult to treat

Answer 75

happens in extremity vascular beds where the temperature may fall below 30°C can lead to obstruction → pallor, cyanosis and Raynaud's Minimal complement-mediated hemolysis, but opsonized cells are phagocytosed in spleen, liver and bone marrow

Answer 76

IgG auto-antibodies bind to the P group antigen on the RBC surface in cool, peripheral regions of the body Causes paroxysmal cold hemoglobinuria which is rare and potentially fatal When RBCs circulate to warm, central regions complement mediated lysis occurs more efficiently Common in children post viral infection (transient and resolves within 1 month

Answer 77

Often due to prosthetic cardiac valves and microangiopathic disorders Luminal narrowing due to deposition of fibrin and platelets → shear stress that mechanically injures passing RBCs red cell fragments (schistocytes) == "burr cells," "helmet cells," and "triangle cells" on blood smear

Answer 78

Microangiopathic Hemolytic Anemia Most commonly seen with DIC Also occurs in TTP and HUS, malignant HTN, SLE and disseminated cancer

Answer 79

Impairment of DNA synthesis that leads to ineffective hematopoiesis and distinctive morphologic changes Abnormally large erythroid precursors (megaloblasts) and RBCs Most commonly due to vitamin B12 or folic acid deficiency (coenzymes for thymidine and methionine synthesis

Answer 80

Macro-ovalocytes: large, oval RBCs (very characteristic) appear hyperchromic due to ample hemoglobin and larger size MCHC is not elevated Anisocytosis and poikilocytosis (variable size and shape) of the RBCs Decreased reticulocyte count -- indicative that the marrow is not functioning well Severe? Nucleated RBCs Hyper-segmented neutrophils ( > 5 lobes

Answer 81

Hypercellular marrow due to increased hematopoietic precursors that may replace fatty marrow Pro-megaloblasts (most primitive cells) are large with very basophilic cytoplasm, prominent nucleoli, and fine nuclear chromatin pattern Delayed nuclear maturation with normal cytoplasmic/hemoglobin maturation that leads to nuclear to cytoplasmic asynchrony Giant metamyelocytes and band forms Large megakaryocytes with multilobate nuclei Pancytopenia as marrow hyperplasia occurs due to increased EPO but abnormal DNA synthesis = precursor apoptosis in the marrow

Answer 82

Autoimmune gastritis impairs the production of intrinsic factor (IF) that is required for vitamin B12 uptake in the gut Median age at diagnosis: 60 years old Affects all populations, especially Scandinavians Likely a genetic problem

Answer 83

ogenesis Chronic atrophic gastritis with loss of parietal cells Due to autoreactive T-cell response → gastric mucosal injury & auto-antibodies auto-antibodies do not cause pathology, but they are of diagnostic utility Anemia develops when the mass of intrinsic factor secreting cells falls below threshold Associated with other autoimmune disorders: Autoimmune thyroiditis and adrenalitis Inflammasome problems and altered innate immunity

Answer 84

Auto-Antibodies (Putthoff didn’t really talk about these) Type I: Found in plasma and gastric juice Type II: Prevent binding of IF-B12 complex to the ileal receptor Type III *85-90% of patients: recognize the α and β subunits of the gastric proton pump in the microvilli of the parietal cell Not specific (seen in 50% of older people

Answer 85

Morphology of the GI Atrophic glossitis (beefy red tongue) Fundic gland atrophy (loss of chief and parietal cells) Intestinalization as parietal cells are replaced with mucus secreting goblet cells Some of the cells may double their size (a kind of megaloblastic change

Answer 86

CNS lesions: demyelination of dorsal and lateral spinal cord tracts spastic paraparesis, sensory ataxia, and severe paresthesias in the lower limbs Megaloblastic erythroid hyperplasia Giant myelocytes and metamyelocytes Hyper-segmented neutrophils (>5 lobes) Megakaryocytes with large, multilobed nuclei

Answer 87

Moderate-severe megaloblastic anemia Leukopenia with hyper-segmented granulocytes Decreased serum B12 Increased homocysteine and methylmalonic acid methylmalonic acid will not be increased in folate deficiency hematocrit should rise ∼ 5 days after administration of B12 with increased reticulocytes -- diagnosis is confirmed following administration of "B12 challenge" and gauging response serum antibodies to intrinsic factor are highly specific for pernicious anemia cause of pernicious anemia; not the presence/absence of vitamin B12 deficiency

Answer 88

High dose or parenteral administration of B12 or folate | folate can cause worsening of the mental problems without also giving B12

Answer 89

Atrophy and metaplasia of gastric mucosa associated with pernicious anemia --> increased risk of gastric carcinoma (no change in risk after treatment) Increased homocysteine --> increased risk for atherosclerosis and thrombosis Neurological disease is due to accumulation of methylmalonic acid in the spinal cord Parenteral or high dose B12 cures the anemia and will halt or reverse the peripheral neurologic disease

Answer 90

deficiency of folic acid results in a megaloblastic anemia having the same pathologic features as that caused by vitamin B12 deficiency -- folate deficiency has no neurological sequelae suppressed synthesis of DNA is the common denominator of folic acid and vitamin B12 deficiency and it the immediate cause of megaloblastosis methylmalonic acid will be within normal limits

Answer 91

Set of diseases that can be acute or chronic Due to problems in the synthesis of heme, most are inherited, but some can also be acquired (including the most common type that arises in the liver) problems in the bone marrow leads to anemia and splenomegaly problems in the liver leads to liver damage and an increased risk in hepatocellular carcinoma

Answer 92

hronic Skin: very sensitive to sunlight leading to blisters and abnormal hair growth Teeth: staining Acute Referred pain from the thorax and abdomen Seizures, hallucinations, and general psychosis

Answer 93

Impaired absorption Achlorhydria (impairs B12 release from food) Gastrectomy causes loss of intrinsic factor Loss of exocrine pancreas function (impairs B12 release from haptocorrin) Loss of pepsin secretion Resection of the terminal ileum Malabsorption syndromes (including *fish* tapeworms Diphyllobothrium latum) Increased requirements (pregnancy, hyperthyroidism, disseminated cancer, chronic infection) Pernicious anemia (antibodies to intrinsic factor

Answer 94

FH4 Metabolic Processes Purine synthesis Conversion of homocysteine to methionine Deoxythymidylate monophosphate (dTMP) synthesis (for DNA synthesis) Reductase step (FH2 → FH4) can be inhibited by many drugs (e.g. trimethoprim) trimethoprim inhibits (bacterial) dihydrofolate reductase and halts DNA synthesis

Answer 95

``` Megaloblastic anemia within months due to: Decreased dietary intake Increased requirements (pregnancy, cancer, infancy) Impaired utilization (folate antagonists ```

Answer 96

Found in green vegetables and some animal sources, but are sensitive to heat Absorbed in the proximal jejunum

Answer 97

monly seen due to Common in chronic alcoholics, elderly and the indigent (poor) due to inadequate diet Alcoholism may lead to trapping in the liver, urinary loss and altered metabolism patients with malabsorption syndromes (celiac disease) or diffuse infiltrative disease of the small intestine may not obtain adequate amounts Phenytoin and oral contraceptives can interfere with absorption Folic acid antagonists (methotrexate) or other chemotherapy drugs inhibit metabolism particularly in bone marrow and the GI tract (rapidly growing cells that do a lot of DNA synthesis

Answer 98

Normal [methylmalonate] No neurological signs and symptoms Increased homocysteine (same as B12 anemia) but methylmalonate concentrations are normal Neurological changes do not occur in folate deficiency anemia Diagnosed via demonstration of decreased folate levels in the serum or RBCs Rule out B12 deficiency before treating with folate folate may exacerbate neurological defects of B12 deficiency

Answer 99

Folic acid administration

Answer 100

Most common nutritional disorder of the world dietary lack impaired absorption increased requirement In the Western world, most commonly due to chronic blood loss Signs and symptoms related to inadequate hemoglobin synthesis

Answer 101

Ferritin -- storage form of iron ubiquitous protein-iron complex found at highest levels in the liver, spleen, bone marrow, and skeletal muscles located in the cytosol and lysosomes partially degraded protein shells of ferritin --> hemosiderin granules plasma ferritin derived largely from storage pool of iron; directly related to body iron levels

Answer 102

mosiderin granules partially degraded protein shells of ferritin iron in hemosiderin is chemically reactive and turns blue-black when exposed to potassium ferrocyanide Prussian Blue Stain disappearance of stainable iron from macrophages in the bone marrow == diagnostically significant finding of iron deficiency in iron overloaded states (e.g. hemochromatosis), most iron is stored in hemosiderin

Answer 103

synthesized and released from the liver in response to increases in intra-hepatic iron levels Regulates iron absorption in the proximal duodenum Inhibits iron transfer from enterocyte to plasma by binding ferroportin Causes endocytosis and degradation of ferroportin hepcidin inhibits ferroportin function in macrophages and reduces the transfer of iron from the storage pool to developing erythroid precursors in the bone marrow as hepcidin levels rise, iron becomes trapped in duodenal cells that eventually slough off == excretion of iron when body is replete with iron, high hepcidin levels inhibit its absorption into the blood hepcidin levels directly related to total body iron stores

Answer 104

Anemia of Chronic Disease/Inflammation is caused in part by inflammatory mediators that increase hepatic hepcidin production TMPRSS6 mutation related anemia (didn't talk about it) Hepcidin is normally suppressed by TMPRSS6 protease when iron stores are low Dysfunctional = microcytic anemia because of inability to absorb iron No response to iron therapy Hepcidin and hemochromatosis inappropriately decreased levels in 1° and 2° hemochromatosis (systemic iron overload) Suppressed by ineffective erythropoiesis, even if iron stores are high (as happens in β-thalassemia major and myelodysplastic syndromes) Hepcidin is structurally related to defensins (intrinsic anti-bacterial activity) iron sequestration may enhance body's ability to fend off certain types of infection Haemophilus influenzae and Yersinia enterocolitica (pseudo-appendicitis) require iron for pathogenicity

Answer 105

``` Dietary lack (infants, teens, elderly and impoverished) Impaired absorption (celiac disease, steatorrhea, chronic diarrhea) Increased requirement like in growing kids and pregnancy *Chronic blood loss* (external hemorrhage or bleeding into the GI or GU tracts) Iron deficiency in men or postmenopausal women is GI bleed until proven otherwise (cancer or occult ```

Answer 106

Morphology Disappearance of stainable iron from macrophage in the bone marrow, assess with Prussian blue stain Microcytic, hypochromic anemia in blood smears, but is normocytic, normochromic in the beginning well established iron deficiency anemia is a microcytic, hypochromic anemia with modest poikilocytosis Central pallor is enlarged in RBCs and hemoglobin may only be seen in a narrow peripheral rim Poikilocytosis (pencil cells) is characteristic Mild to moderate erythroid hyperplasia

Answer 107

Koilonychia == spoon nails Alopecia Atrophic changes in the tongue and gastric mucosa Intestinal malabsorption Pica: eat non-food items like dirt and move limbs during sleep pica: desire to eat non-food substances (i.e. ice, clay) to replenish depleted iron

Answer 108

Microcytic, hypochromic anemia -- i.e. late iron deficient anemia Atrophic glossitis Esophageal webs

Answer 109

``` Decreased hemoglobin and hematocrit Microcytic, hypochromic anemia (when well established) Poikilocytosis (abnormal RBC shape) Decreased serum iron and ferritin Increased iron binding capacity Decreased transferrin % < 15 Inhibition of hepcidin synthesis ```

Answer 110

abs HCT and Hgb decreased serum iron is low plasma ferritin is low -- storage form of iron inversely related to TIBC which is high TIBC is inversely related iron saturation (and therefore directly related to plasma ferritin) serum hepcidin is low hepcidin inhibits iron absorption; in IDA, trying to absorb more iron therefore makes sense it is high

Answer 111

Most common cause of anemia in hospitalized patients Reduced proliferation of erythroid progenitors and impaired iron utilization due to: Chronic microbial infections (osteomyelitis, bacterial endocarditis, lung abscesses) Chronic immune disorders (RA, regional arteritis) Neoplasms (lung, breast, Hodgkin's lymphoma) microcytic, hypochromic anemia (may also be normocytic, normochromic

Answer 112

occur in the setting of persistent systemic inflammation IL-6 stimulates an increase in the hepatic production of hepcidin associated with low serum iron, reduced total iron binding capacity, and abundant stored iron in tissue macrophages

Answer 113

Treat the underlying condition (whatever is causing the chronic inflammation Some patients may benefit from exogenous EPO as patients generally have a low EPO level

Answer 114

Syndrome of primary hematopoietic failure and attendant pancytopenia Autoimmune is the most common cause, but HSC problems can also be inherited or acquired Idiopathic in 65% of cases

Answer 115

Whole body irradiation *dose dependent (only?)* Drugs that cause dose related, reversible marrow suppression (chemotherapy drugs, benzene) Drugs that cause unpredictable, idiosyncratic reactions that typically have little or no marrow suppression (chloramphenicol, gold salts

Answer 116

Hepatitis (non-A, non-B, non-C, and non-G type… so Hepatitis D and E) 65% are idiopathic

Answer 117

Autosomal recessive disorder caused by defective protein complex necessary for DNA repair Presents early in life; often accompanied by congenital anomalies Hypoplasia of the kidney or spleen Bone anomalies of the thumbs or radii

Answer 118

5-10% of adult onset aplastic anemia This enzyme is necessary for cellular immortality and limitless replication Deficits may lead to premature HSC exhaustion and marrow aplasia

Answer 119

hort Telomeres Seen in ∼ 50% of patients with aplastic anemia May be due to an undiscovered defect or as a consequence of excessive stem cell replication

Answer 120

extrinsic, immune-mediated suppression of marrow progenitors TH1 cells are activated against these Antigens → IFNγ and TNF to suppress and kill hematopoietic progenitors Upregulation of apoptotic genes Anti-thymocyte globulin (immunosuppressive) agents suppress autoreactive T-cell clones producing a response in 60-70% of patients intrinsic abnormality of stem cells Stem cells are antigenically altered via exposure to drugs, infectious agents, etc

Answer 121

ology Hypocellular bone marrow HSC replaced by fat cells, fibrous stroma, and scattered Lfs "Dry tap" on marrow aspiration, bone marrow biopsy necessary for diagnosis Granulocytopenia: mucocutaneous bacterial infection Thrombocytopenia: abnormal bleeding Systemic hemosiderosis if multiple transfusions are given

Answer 122

pancytopenia ultimately develops) Anemia --> Weakness, pallor, dyspnea Thrombocytopenia --> Petechiae and ecchymoses petechial bleeding is often characteristic of platelet disorders (thrombocytopenia) Neutropenia --> Persistent infections or sudden onset of fever and chills (rigors) No immune response? Fever may be absent Reticulocytopenia: RBCs are macrocytic, normochromic No splenomegaly (if present, question diagnosis

Answer 123

Causes of Pancytopenia Aplastic Anemia: hypocellular bone marrow aleukemic leukemia and myelodysplastic syndromes: hypercellular bone marrow

Answer 124

Treatment Bone marrow transplant (5 year survival > 75%) Immunosuppression in older patients or those without a suitable donor

Answer 125

Primary marrow disorder in which only erythroid progenitors are suppressed Associated with thymoma and large granular lymphocytic leukemia, drugs, autoimmune disorders, parvovirus B19, metastatic carcinoma, spent phase MPS

Answer 126

Parvovirus B19 Transient in normal individuals as they clear the infection in 1-2 weeks May lead to an aplastic crisis in patients with moderate-severe hemolytic anemias due to brief cessation of erythropoiesis Parvovirus B19 infects erythroid precursors and can lead to an aplastic crisis in persons with hemoglobinopathies. The hemoglobinopathy impairs the marrow ability to respond to the stress of the acute infection. patients who are chronically immunosuppressed (HIV) means the infection can persist due to ineffective immune response

Answer 127

Treatment Thymoma resection = 50% of patients have hematologic improvement No thymoma? Treatment with immunosuppression

Answer 128

Marrow failure where space occupying lesions replace normal marrow elements leading to: Destruction or distortion of marrow architecture Leukoerythroblastosis: abnormal release of nucleated erythroid precursors and immature granulocytic forms into peripheral smears; even more immature than bands Teardrop RBCs: deformed during their tortuous escape from the fibrotic marrow Depressed hematopoiesis Pancytopenia

Answer 129

most common cause == metastatic cancer from the breast, lung, or prostate also a feature of the spent phase of myeloproliferative disorders Myelophthisic Disease Metastatic tumor involving marrow, or marrow fibrosis, is a 'myelophthisic' process that reduces normal hematopoiesis and leads to a peripheral 'leukoerythroblastic' picture with immature RBC's and WBC's in the peripheral blood, as seen here with nucleated RBCs and white cells even more immature than bands (metamyelocytes, myelocytes) on the smear

Answer 130

Associated with an anemia proportional to the severity of the uremia Kidneys produce less EPO causing inadequate RBC production There can also be an extra-corpuscular defect that shortens the lifespan of the RBCs and platelet dysfunction with increased bleeding

Answer 131

Recombinant EPO | +/ iron replacement therapy

Answer 132

Decreased marrow function due to Toxins, infections, cirrhosis Can be exacerbated by vitamin B12 or folate deficiencies as well as excessive bleeding (varices) Predominantly erythroid progenitor suppression Slightly macrocytic anemia due to lipid abnormalities with RBC membranes acquiring phospholipid and cholesterol as they circulate

Answer 133

Abnormally high red cell count, usually with an associated increase in the hemoglobin level Relative or absolute

Answer 134

Hemoconcentration due to decreased plasma volume, commonly a result of dehydration Water deprivation Prolonged vomiting or diarrhea Excessive diuretic use Gaisbock syndrome (stress polycythemia): HTN, obese, anxious patients

Answer 135

In crease in the total red cell mass Primary (Polycythemia vera) Intrinsic abnormality of hematopoietic precursors this is a myeloproliferative disorder Secondary Red cell precursors are responding to increased levels of EPO i.e. physiologic response at high altitudes or pathophysiologic, EPO producing tumors or HIF1α stabilization Renal cell carcinomas are known to secrete erythropoietin and lead to this paraneoplastic effect with polycythemia

Answer 136

Most common cause of primary polycythemia Myeloproliferative disorder associated with mutations leading to EPO-independent growth of red cell progenitors Familial EPO receptor mutations can also induce EPO-independent receptor activation HIF-1α == hypoxia-induced factor; stimulates the transcription of the erythropoietin gene

Answer 137

May be due to: Increased fragility of vessels Platelet deficiency or dysfunction Derangement of coagulation

Answer 138

Prothrombin Time (PT) -- "Play Tennis OUTside" Assesses the extrinsic (primary pathway in vivo) and common coagulation pathways Clotting of plasma after adding exogenous tissue thromboplastin and Ca++ Prolonged due to deficiency or dysfunction of Factor V, VII, X, prothrombin or fibrinogen Factor VII is different Measured in patients taking coumadin (warfarin

Answer 139

Partial Thromboplastin Time (PTT) -- "Play Table Tennis INside" Assesses the intrinsic and common coagulation pathways Clotting of plasma after adding kaolin, cephalin and Ca++ ions Prolonged due to deficiency or dysfunction of factors V, VIII, IX, X, XI, XII, prothrombin or fibrinogen (or interfering antibodies to phospholipid) Factor VIII, IX, XI, and XII are different do this one if you suspect hemophilia Measured in patients taking heparin

Answer 140

An electronic particle counter determines this value on anticoagulated blood If abnormally low: do a peripheral blood smear and observe for clumping of platelets During automated counting this can cause a "thrombocytopenia" High counts may indicate myeloproliferative disease (essential thrombocythemia

Answer 141

Definition Relatively common, lead to petechiae and purpura without serious bleeding Can sometimes bleed into more serious places

Answer 142

Platelet counts are normal | PT, PTT and bleeding times are normal

Answer 143

Microbial damage to microvasculature (vasculitis) and DIC Often due to meningococcemia which, if not recognized, can be catastrophic Also caused by septicemia, infective endocarditis, rickettsioses, Neisseria infection

Answer 144

Cutaneous petechiae and purpura may be seen without thrombocytopenia Due to immune complex deposition with resulting hypersensitivity (leukocytoclastic) vasculitis

Answer 145

Scurvy, Ehlers-Danlos Syndrome -- Putthoff: "not common at all… never see it" Poor vascular support leads to microvascular bleeding from collagen defects Also seen in patients with Cushing syndrome where peri-vascualr supporting tissue is lost due to excess corticosteroid production → spontaneous purpura (usually older adults

Answer 146

Systemic hypersensitivity due to immune complex deposition (IgA most commonly), particularly in the glomerular mesangial region Purpuric rash, colicky abdominal pain, polyarthralgia, and acute glomerulonephritis

Answer 147

Autosomal dominant disorder of TGFβ signaling dysregulation patients have dilated, tortuous, thin-walled vessels bleeding can occur anywhere, but is most commonly under the mucous membranes of the nose (epistaxis), tongue, mouth, eyes and throughout the GI tract serious bleeding may occur Thinning of vessel walls with telangiectatic formations, AV malformations, aneurysmal dilations throughout body Vermillion border of the lip and on the tongue Autosomal dominant inheritance (chromosome 9) Endoglin (CD105) gene Most frequent symptom/presentation: recurrent epistaxis Telangiectasias and other bleeding Treatment: mostly benign and exsanguination is rare Surgery or photoablation in select patients

Answer 148

Amyloid light chain amyloidosis manifests as mucocutaneous petechiae from weakened blood vessel walls

Answer 149

Reduced platelet number < 100,000

Answer 150

<10,000 == indication for platelet transfusion < 20,000: Spontaneous (non-traumatic) bleeding 20,000-50,000: Exacerbates posttraumatic hemorrhage Most spontaneous bleeds involve small vessels of the skin and mucous membranes Most feared: intracranial bleeding PT and PTT will be normal

Answer 151

Marrow output is suppressed generally as in aplastic anemia or leukemia Megakaryocytes are selectively suppressed as with specific drugs or alcohol taken in excess May also occur in isolation in patients with HIV (can infect megakaryocytes) or myelodysplastic syndromes

Answer 152

Increased consumption or activation of platelets Mechanical injury DIC, thrombotic microangiopathies (TTP, HUS) TTP (thrombotic thrombocytopenic purpura) HUS (hemolytic uremic syndrome) Immune mediated destruction of platelets: ITP Autoimmune thrombocytopenia: allo-antibodies: transfusion or IgG crossing the placenta

Answer 153

There is a relative reduction in the number of circulating platelets (viable platelet numbers are decreased) with prolonged storage of blood for transfusion

Answer 154

Primary or secondary auto-antibodies (IgG) destruction of platelets Secondary association with SLE, HIV and B-cell neoplasms (CLL) Most commonly found in women <40 years old, 3X more likely in females

Answer 155

primary pathogenesis == auto-antibodies against platelets IgG antibodies that opsonize platelets; platelets are then removed by the spleen NO ATTENDANT SPLENOMEGALY THOUGH IgG antiplatelet antibodies directed against membrane glycoproteins IIb/IIIa -- Glanzmann Thrombocytopenia Ib/IX -- Bernard-Soulier Syndrome Opsonized platelets are destroyed by phagocytes expressing IgG Fc receptors Splenectomy removes the source of the some of the auto-antibodies and the site of platelet destruction

Answer 156

Spleen, bone marrow and blood are affected, but changes are not specific Normal sized spleen with sinusoidal congestion and prominent germinal centers, there may be megakaryocytes in the spleen Modestly increased number of bone marrow megakaryocytes Abnormally large platelets may be seen on peripheral blood smear (megathrombocytes

Answer 157

linical Insidious onset characterized by bleeding into the skin and mucosal surfaces initially as pinpoint hemorrhages (petechiae) that may become confluent (now called ecchymoses) most prominent in the dependent areas where the capillary pressure is higher Epistaxis, easy bruising, gum bleeding from minor to no trauma Patient may present with melena, hematuria, or excessive menstrual flow (menorrhagia) Treated patients rarely develop subarachnoid or intracerebral hemorrhage No splenomegaly or lymphadenopathy (consider secondary causes ie B cell neoplasm

Answer 158

Normal PT and PTT Low platelet count (those seen on peripheral blood smear are large) Normal or increased megakaryocytes

Answer 159

Diagnosis of exclusion (no reliable antibody tests)

Answer 160

almost all patients will respond to glucocorticoids (inhibit phagocyte function) but many will relapse Splenectomy normalizes patient's platelet count also increases risk for bacterial sepsis (weigh pros and cons) IVIG or rituximab (anti-CD20 antibody) in patients who relapse after splenectomy or when splenectomy is contraindicated Thrombopoietin (TPO) mimetics may also stimulate platelet production

Answer 161

Disease of childhood which appears abruptly 1-2 weeks after self-limited viral infection -- chronic form == adults effects both sexes equally (no gender preference) Auto-antibodies to platelets develop via an unknown mechanism -- same as in chronic form Self-limited with resolution in six months severe cases of thrombocytopenia can be treatment with glucocorticoids 20% of patients (usually without viral prodrome) disease persists in a chronic form, resembling the adult disease (worse outcome

Answer 162

Drugs such as quinine, quinidine (malaria drugs), and vancomycin that bind platelet glycoproteins and create antigenic determinants that are recognized by antibodies (i.e. act as haptens or participate in the formation of immune complexes that deposit on platelet surfaces) antibodies to the drug or the modified platelet molecules leads to macrophage ingestion and platelet removal True auto-antibodies may be induced by agents Platelet inhibitory agents that bind glycoprotein IIb/IIIa can also lead to the creation of an immunogenic epitope

Answer 163

Type I Occurs rapidly after the onset of therapy Likely due to direct platelet aggregating effect of the drug Little clinical significance and can resolve despite continuing therapy

Answer 164

Life threatening venous and arterial thrombosis antibodies form to HEP-PF4 complexes (platelet factor 4 is a normal component of platelet granules), activates the platelets, and promotes life-threatening thrombosis (arterial and venous) occurs even in the setting of thrombocytopenia Occurs 5-14 days after therapy begins DVT → PE PE in the setting of a thrombocytopenia thrombocytopenia usually associated with bleeding; this is different Clots of large arteries → limb loss Therapy MUST be discontinue and another anti-clotting agent must be used risk of severe HIT is lowered, but not completely eliminated, by the use of low-molecular weight heparin preparations (low molecular weight heparin cannot be used as replacement anti-coagulant therapy should severe HIT arise

Answer 165

thrombocytopenia is one of the most common hematologic manifestations of HIV infection This virus may infect megakaryocytes that express CD4 (receptor) and CXCR4 (coreceptor) Infected megakaryocytes are prone to apoptosis and have an impaired ability to produce platelets B-cell hyperplasia and dysregulation → auto-antibodies that may be directed against platelet membrane glycoprotein IIb/IIIa (opsonization

Answer 166

intravascular thrombi cause a microangiopathic hemolytic anemia and widespread organ dysfunction, and the attendant consumption of platelets leads to thrombocytopenia TTP (thrombotic thrombocytopenic purpura) pentad: fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neurologic deficits, and renal failure HUS (hemolytic uremic syndrome) associated with microangiopathic hemolytic anemia and thrombocytopenia but is distinguished by the absence of neurologic symptoms, the prominence of acute renal failure, and its frequent occurrence in kids PT & PTT are normal DIC: activation of the coagulation cascade is of primary importance and PT and PTT will be abnormal

Answer 167

Hyaline thrombi occlude the capillaries of all organs in the body Decreased ADAMTS13 (aka "vWF metalloprotease"), either acquired or inherited Normally, ADAMTS13 degrades high-molecular-weight multimers of vWF Exacerbated by endothelial injury Uncleaved multimers → abnormal platelet adhesion and microthrombi Most common in in females The pentad of fever, mental changes, renal failure, thrombocytopenia, and microangiopathic hemolytic anemia is characteristic of TTP. Platelets are activated directly, and not the coagulation system as a whole, so that the prothrombin time, partial thromboplastin time, and D-dimer are either not elevated or minimally elevated. The platelet activation leads to formation of hyaline thrombi in small arteries that promotes tissue ischemia in organs such as brain, with consequent neurologic impairment. Platelet transfusion is contraindicated

Answer 168

Most commonly due to acquired auto-antibodies to ADAMTS13 Hereditary form is a mutation of the ADAMTS13 gene, often present in adolescence with episodic signs and symptoms that needs a trigger to cause the events Acquired from has auto-antibodies directed against ADAMTS13

Answer 169

TTP Pentad: Fever, Thrombocytopenia, Microangiopathic hemolytic anemia, Transient neurological deficits, and Renal failure

Answer 170

PT and PTT are normal early in the disease | Lab tests late in the course suggest DIC

Answer 171

Plasma exchange/plasmapheresis | Untreated: 100% mortality

Answer 172

``` Signs & symptoms Fever Thrombocytopenia Microangiopathic hemolytic anemia Renal failure ```

Answer 173

Occurs due to endothelial damage by drugs or infection Children or elderly with E. Coli O157:H7 dysentery (undercooked beef) E. Coli shiga-like toxin (verotoxin) damages endothelial cells causing platelet microthrombi patients present with bloody diarrhea and then go onto HUS a few days later Irreversible renal damage and death can occur in severe case. Treatment is supportive

Answer 174

Acquired or inherited defect of complement factor H (CD46) or factor I Affected proteins normally prevent excess activation of the alternative complement pathway Immunosuppression can help patients that have auto-antibodies to the inhibitory complement factors

Answer 175

Defects of adhesion Defects of aggregation Disorders of platelet secretion (release reaction

Answer 176

Bernard-Soulier Syndrome == defective adhesion of platelets to subendothelial matrix (BS adhesion) Inherited deficiency of platelet membrane glycoprotein complex Ib-IX This is a receptor for vWF and essential for normal platelet adhesion to subendothelial matrix Patients have variable, often severe, bleeding tendency abnormally large platelets on a peripheral smear -- giant platelets absent aggregation to ristocetin will aggregate to ADP, collagen, epinephrine, or thrombin

Answer 177

lanzmann Thrombasthenia == defective platelet aggregation (Mann, Agg) Autosomal recessive deficiency or dysfunction of glycoprotein IIb/IIIa (integrin that participates in "bridge formation" between platelets by binding fibrinogen) Failure of platelets to aggregate in the presence of ADP, collagen, epinephrine, or thrombin Bleeding tendency is often severe Two teenage siblings in the same family are noted to have frequent nosebleeds and easy bruising from even minor trauma. Both have had menorrhagia since menarche. One girl's CBC shows Hgb 14 g/dL, Hct 42.3%, MCV 90 fL, platelet count 242,000/microliter, and WBC count 7720/microliter. Her prothrombin time is 12 seconds and partial thromboplastin time 25 seconds. Platelet function studies show decreased aggregation in response to ADP, collagen, epinephrine, and thrombin. Which of the following disorders are these siblings most likely to have? Glanzmann Thrombasthenia will aggregate to ristocetin; will not aggregate to ADP, collagen, epinephrine, or thrombin normal platelets

Answer 178

pirin and other NSAIDs on platelets Acquired defect in platelet aggregation Aspirin is a potent, irreversible inhibitor of COX which is required for synthesis of TxA2 and PGs Antiplatelet actions are important for prophylaxis of coronary thrombosis

Answer 179

Acquired defect in platelet function | defects in adhesion, granule secretion, and aggregation

Answer 180

Bleeding due to coagulation factor deficiencies often occurs into the gastrointestinal and urinary tracts and into weight-bearing joints (hemarthrosis) oozes blood for days after a tooth extraction develops a hemarthrosis after minor stress on a knee joint -- this is suggestive of hemophilia (A or B), not vWF

Answer 181

Normally activated by epoxide reductase in the liver Deficiency leads to impaired synthesis of factors II, VII, IX, X, Protein C -- "1972" and Protein C this is what Warfarin/Coumadin impairs Common in newborns (lack of GI colonization, bacteria produce this agent) Give prophylaxis at birth

Answer 182

Occurs in patients taking warfarin/coumadin warfarin/coumadin antidote == vitamin K Also due to chronic antibiotics (bumping off gut bacteria), severe liver disease

Answer 183

``` Bleeding/hemorrhage Prolonged PT (because this is what you check with warfarin/coumadin ```

Answer 184

Replacement of deficiency (corrects PT in 12-18 hours) | Fresh frozen plasma (liver disease or acute hemorrhage, need PT corrected ASAP

Answer 185

Bleeding manifests as large ecchymoses or hematomas after injury or as prolonged bleeding after laceration or surgery May bleed into GI or GU tracts, or into weight bearing joints (hemarthrosis) (unlike thrombocytopenia) May be acquired or inherited Acquired usually means deficiency of many factors Hereditary typically affect a single factor

Answer 186

on Willebrand Factor (vWF) Produced by endothelial cells, megakaryocytes (α-granules) vWF Stabilizes factor VIII -- "VolksWagen Factories make gr8 diesels" when vWF is deficient, Factor VIII is missing and this prolongs PTT Promotes adhesion of platelets to the subendothelial matrix This occurs via glycoprotein Ib-IX Measured using Ristocetin agglutination test

Answer 187

Factor XIII Made in Kupffer cells of the liver and sinusoidal endothelial cells (bone marrow, spleen, kidney) Binds vWF in circulation (stabilized) Unbound t1/2 = 2.4 hours Bound t1/2 = 12 hours Essential cofactor for factor IX Measured by coagulation assays with patient plasma and factor VIII deficient plasma

Answer 188

Most common inherited bleeding disorder of humans (1% of the US adult population) Autosomal dominant disorder presenting with spontaneous bleeding from mucous membranes, excess bleeding from wounds or menorrhagia (excessive menstrual bleeding) Usually mild and unnoticed until hemostatic stress (i.e. surgery or dental procedure) is encountered patients may require prophylactic desmopressin or infusions of plasma concentrates for hemostatic challenges (dental surgery)

Answer 189

``` patients have a normal platelet count Plasma protein level is reduced Consequently, factor VIII is decreased prolonged PTT vWF disease, Hemophilia A (Factor VIII) and Hemophilia B (Factor IX ```

Answer 190

Type 1 Autosomal dominant disease of mild-moderate deficiency Quantitative defect Most common subtype (70%) Usually a point mutation that leads to problems with protein maturation or that causes rapid protein clearance from plasma (incomplete penetrance) PTT may be prolonged

Answer 191

Autosomal recessive disease with very low levels and correspondingly severe clinical manifestations Quantitative defect Factor VIII stability is affected May resemble hemophilia Usually a frameshift or deletion mutation involving both alleles PTT may be prolonged Severe clinical manifestation: hemarthrosis (bleeding into joints) may be seen

Answer 192

Autosomal dominant disease with normal protein amounts expressed Qualitative defect Missense mutations → defective multimer assembly (lack of large and intermediate multimers in plasma) 25% of all cases Mild-moderate bleeding

Answer 193

Predominantly supportive treatment | May administer cryoprecipitate (replaces vWF) or DDAVP (causes release of vWF from endothelium

Answer 194

Factor VIII deficiency Factor VIII is an essential cofactor for Factor IX in the coagulation cascade Most common hereditary disease associated with life threatening bleeding % of patients based on severity Severe disease: < 1% Moderate-severe disease: 25% Mild disease: 6-50% (6-25% per Hubbard

Answer 195

Most severe: X chromosome inversion = no synthesis X-linked recessive (mostly male or unfavorably lyonized females) Point mutation can lead to no activity, but normal protein levels on immunoassay *Risk of bleeding corresponds to degree of deficiency

Answer 196

Easy bleeding and bruising Hematomas Bleeding into soft tissue and muscles Increased risk of bleeding during and after surgery Spontaneous hemorrhage in regions of the body normally subject to trauma (hemarthroses) that can lead to progressive, crippling deformities. patients may have 1-2 "target joints" No petechiae is characteristic Prolonged PTT, normal PT -- point to abnormality in the intrinsic coagulation pathway vWF disease, Hemophilia A (Factor VIII) and Hemophilia B (Factor IX) tendency of hemophiliacs to bleed at particular sites (joints, muscles, and the central nervous system

Answer 197

Recombinant factor VIII infusions (replace what is missing) 15% develop antibodies that bind and inhibit factor VIII Prior to development of recombinant factor VIII, patients received plasma from HIV patients, dooming an entire generation of patients Prophylaxis prior to surgery

Answer 198

Factor IX deficiency X-linked recessive disease clinically identical to hemophilia A Prolonged PTT, normal PT -- abnormality in the intrinsic coagulation pathway vWF disease, Hemophilia A (Factor VIII) and Hemophilia B (Factor IX

Answer 199

Assay of factor levels

Answer 200

Recombinant factor IX (replace what is missing )

Answer 201

ion Acute, subacute or chronic thrombo-hemorrhagic disease Excessive activation of coagulation and formation of thrombi in the microvasculature of the body = consumption of platelets (thrombocytopenia), fibrin, coagulation factors Fibrinolysis activation

Answer 202

Tissue hypoxia, infarction (due to microthrombi), hemorrhage (due to factor depletion + fibrinolytic mechanism activation

Answer 203

May be derived from obstetric complications, damaged tissue following trauma, burns or surgery, granules of leukemic cells in acute promyelocytic leukemia, mucus from adenocarcinomas Sepsis: endotoxins activate monocytes to release TNFα Increased tissue factor expression Decreased thrombomodulin expression = activation of clotting system + inhibition of coagulation control

Answer 204

Initiates tissue factor release from endothelial cells Promotes platelet aggregation Activates the intrinsic coagulation pathway via exposure of subendothelial connective tissue Injury may occur due to Antigen/Antibody complex deposition (SLE), hypoxia, acidosis, temperature extremes (heatstroke, burns), infections (meningococci, rickettsiae

Answer 205

Widespread deposition of fibrin in microcirculation == thrombosis; consumption of platelets --> bleeding Ischemia Microangiopathic hemolytic anemia (RBC fragmentation as the pass through narrow vessels) Hemorrhagic diathesis due to consumption of platelets and clotting factors + the activation of plasminogen Plasmin cleaves fibrin and digests factors V and VII Fibrinolysis products inhibit platelet aggregation, fibrin polymerization and thrombin

Answer 206

Thrombi can affect the brain, heart, lungs, kidneys, adrenals, spleen, and liver Bilateral renal cortical necrosis can occur May resemble ARDS if pulmonary vasculature is involved Adrenals: Waterhouse-Friderichsen syndrome "In meningococcemia, fibrin thrombi within the microcirculation of the adrenal cortex are the probable basis for the massive adrenal hemorrhages seen in Waterhouse-Friderichsen syndrome" Giant hemangiomas: Kasabach-Merritt syndrome (thrombi form in neoplasms because of stasis and recurrent trauma to fragile blood vessels

Answer 207

Most commonly due to obstetric complications (50%) procoagulants derived from the placenta, dead retained fetus, or amniotic fluid may enter circulation Most cases resolve with delivery of the fetus Commonly involves bleeding complications Rapid onset Carcinomatosis (33%) Commonly involves thrombosis complications Insidious (slow) onset

Answer 208

Acute vs. chronic presentation Acute DIC: associated with obstetric complications or major trauma; dominated by bleeding diathesis Chronic DIC: associated with carcinomatosis; tends to present with thrombotic complications

Answer 209

Microangiopathic hemolytic anemia bleed from every orifice Respiratory signs and symptoms (dyspnea, cyanosis, respiratory failure) Neuro signs and symptoms (convulsions, coma) Oliguria and acute renal failure Circulatory failure and shock

Answer 210

Variable prognosis based on underlying disorder Remove or treat the underlying cause -- quickly well established DIC is a death sentence

Answer 211

Fever and chills ± dyspnea Occurs within six hours of a transfusion of red cells or platelets Likely inflammation reaction due to donor leukocytes Increased frequency related to length of storage of product Signs and symptoms respond to antipyretics and are short lived

Answer 212

Severe and potentially life threatening if patient has been sensitized to the given antigens Most common in patients with IgA deficiency IgG antibodies recognize IgA in the blood product IgE antibodies may cause an urticarial reaction Mild, and most patients respond to antihistamines allowing the process to continue

Answer 213

Usually due to preformed IgM antibodies against donor red cells that fix complement GM makes Classic Cars -- IgM and IgG activate the classical pathway of complement Likely due to human error (ABO incompatibility) Induce complement mediated lysis, intravascular hemolysis, and hemoglobinuria Rapid onset: fever, chills, shaking and flank pain due to complement activation, not RBC lysis May rapidly progress to DIC, shock, acute renal failure or death (+) direct Coombs test

Answer 214

Due to IgG antibodies against a red cell antigen the patient was previously sensitized to (+) direct Coombs test Labs typical of hemolysis (Decreased haptoglobin, increased LDH) haptoglobin takes up free hemoglobin; therefore, haptoglobin is decreased when hemoglobin is increased in the serum in things like hemolysis antibodies to Rh, Kell, Kidd can activate complement and produce fatal reactions (similar to ABO mismatches) antibodies that do not fix complement → red cell opsonization, extravascular hemolysis, spherocytosis (minor signs and symptoms

Answer 215

Bacterial causes are often due to skin contamination at time of donation Platelets >> RBCs because platelets must be stored at room temperature Signs and symptoms resemble hemolytic and nonhemolytic reactions → may start broad spectrum antibiotics Viral causes are less frequent due to screening Infection may occur if donor is acutely infected but viral DNA is not yet detected with nucleic acid testing (HIV, Hepatitis C, Hepatitis B, (also prions) frequent donors or IV drug users who donate and get past the screening; lab error

Answer 216

Definition Severe, often fatal event of factors in transfused blood activating neutrophils in the lung microvasculature More frequent in patients with lung disease Two hit model

Answer 217

Transfused antibodies attack neutrophils FFP and platelets contain more antibodies and are more likely to lead to this complication Donations to multiparous women with exposure to multiple MHCI Antigens has a high risk Identify donor product because likely to occur in other patients receiving the product

Answer 218

Dramatic, rapid onset of respiratory failure during or soon after a transfusion patient has diffuse bilateral pulmonary infiltrates Fever, hypotension, hypoxemia

Answer 219

Unresponsive to diuretics Treatment: supportive Prognosis: guarded (5% mortality if uncomplicated, 6-7% mortality in complicated cases

Answer 220

Deficiency of a serine protease that functions to inhibit thrombin activation Increased conversion of prothrombin into thrombin (hypercoagulable state) Cofactor: heparin (amplifies activity

Answer 221

Variable presentation Early death to recurrent pulmonary emboli Recurrent lower extremity thrombophlebitis and DVT, venous insufficiency, chronic leg ulcers 50% of patients have a DVT or PE by age 30 Pregnant women have a significantly increased risk of DVT due to hypercoagulable state

Answer 222

< 50% normal activity

Answer 223

``` Prophylactic with anticoagulants warfarin/coumadin heparin if you're pregnant heparin activated anti-thrombin III Patient with DVT? Heparin in HIGH doses Replacement therapy for DVT patients that do not respond to heparin ```

Answer 224

Present similar to ATIII deficiency Recommended that patients are on warfarin to decrease risk of thromboembolic disease These proteins are depleted prior to other coagulation factors so there is a temporary increase in coagulation (as they are anticoagulant molecules)!! Vitamin K dependent enzymes C: inactivates factors V, VIII S: cofactor of C

Answer 225

Abnormality of this factor at the binding site for protein C Heterozygotes: increased risk of thromboembolic disease Homozygotes: Excessively high increase for thromboembolism

Answer 226

tment No prior episodes: monitor, DVT prophylaxis + risk reduction Prior episode: lifelong anticoagulation (if it was an unprovoked episode)

Answer 227

G-A mutation resulting in increased activity for prothrombin Inability to deactivate prothrombin Significant risk of thrombosis

Answer 228

No prior episodes: monitor, DVT prophylaxis + risk reduction | Prior episode: lifelong anticoagulation (if it was an unprovoked episode

Answer 229

anticardiolipin antibody syndrome lupus anticoagulant don't have to have lupus to have antiphospholipid it's not an anticoagulant, it’s a procoagulant -- thrombosis is major feature of disease false positive VDRL antibody syndrome Definition Circulating antibodies to phospholipid

Answer 230

Prolonged phospholipid-dependent coagulation test (PTT) -- along with vWF, Hemophilia A and B Lack of correction in 1:1 mixing studies with normal plasma DRVVT (Dilute Russell Viper Venom Time) may be more specific than PTT

Answer 231

Thromboembolism Miscarriage Thrombocytopenia Cerebral ischemia, recurrent stroke (especially in young patients!) UBO (unidentified bright objects) on MRI Connective tissue disease (seen in 50% of patients Prolonged PTT (not corrected with mixing studies) Valvular heart disease or CAD in some patients

Answer 232

No benefit from anticoagulation unless the patient has a history of thromboembolic disease With a history of multiple positive tests over 3-12 months Lifelong anticoagulation. If necessary during pregnancy: SQ heparin Hydroxychloroquine (malaria drug) may reduce thromboembolism in some patients with APS and SLE

Answer 233

patient has a prolonged clotting time Is something interfering with the test or is the patient missing clotting factors? Equal amounts of patients serum + test serum Clotting time corrects: patient is missing something Type 1 vWF disease Hemophilia A (VIII) and B (IX) Clotting time is not corrected: patient serum contains an entity that interferes with clotting eg antiphospholipid syndrome