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USMLE STEP 1 - OLD > Hematology > Flashcards

Hematology Flashcards

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USMLE® Step 1 flashcards
1
Q

Function:

  • Primary hemostasis?
  • Secondary hemostasis?
A

Primary hemostasis: To form a weak platelet plug

Secondary hemostasis: To stabilize the weak platelet plug formed by primary hemostasis

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2
Q

Primary hemostasis:

  • First step?
  • Mechanism by which first step occurs (2)?
A

Transient vasoconstriction of damaged blood vessel 2/2:

(1) Reflex neural stimulation
(2) Endothelin release (vasoconstrictor) from damaged endothelial cells

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3
Q

Primary hemostasis:

- Second step?

A

Platelet adhesion to the surface of the damaged blood vessel

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4
Q

Primary hemostasis:

- Mechanism by which platelets adhere to the surface of the damaged blood vessel?

A

Damaged endothelial cells release von Willebrand factor (vWF) from Weibel-Paladie bodies, which binds the exposed subendothelial collagen. Platelets then bind vWF using their Gp1b receptor.

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5
Q

Primary hemostasis:

  • Platelet receptor that binds vWF?
  • Cell types responsible for vWF synthesis?
  • Endothelial cell Weibel-Palade bodies contain what 2 products?
A

Platelet receptor: Gp1b

vWF: Weibel-Palade bodies (endothelial cells), α-granules (platelets)

Weibel-Palade bodes: vWF and P-selectin

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6
Q

Primary hemostasis:

  • Third step?
  • Mechanism by which third step occurs?
A

Platelet degranulation

Platelet adhesion to the damaged blood vessel induces a conformational change that mediates degranulation of multiple platelet mediators.

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7
Q

Platelets:

  • Dense granules contain what 2 products?
  • α-granules contain what 4 products?
  • Other degranulated platelet product not contained within granules?
  • Function of platelet factor 4 (PF4)?
  • Function of platelet factor 3 (PF3)?
A
  • Dense granules: ADP and Ca2+
  • α-granules: vWF, fibrinogen, platelet-derived growth factor (PDGF), and platelet factor 4 (PF4)
  • Thromboxane A2 (TXA2)
  • Platelet factor 4 (PF4): Heparin-neutralizing factor
  • Platelet factor 3 (PF3): Phospholipid substrate on the surface of platelets required for the clotting sequence
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8
Q

Primary hemostasis:

  • Degranulated ADP binds what receptor?
  • Function of ADP granulation?
A

ADP released from dense granules binds to platelet P2Y12 ADP receptors

ADP binding promotes expression of a functional Gp2b/a3 receptor on platelet surface.

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9
Q

Primary hemostasis:

  • Mechanism by which platelets synthesize TXA2?
  • Function of degranulated TXA2 (2)?
A

Platelet cyclooxygenase (COX) synthesizes PGH2. Thromboxane A2 synthase then converts PGH2 into TXA2.

TXA2 (1) vasoconstricts the damaged blood vessel and (2) promotes platelet aggregation by enhancing Gp2b/3a receptor binding to fibrinogen.

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10
Q

Platelet pharmacology:

  • Aspirin: Mechanism of action?
  • NSAIDs: Mechanism of action?
A

Aspirin: IRREVERSIBLY inhibits platelet COX

NSAIDs: REVERSIBLY inhibit platelet COX

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11
Q

Primary hemostasis:

  • Fourth step?
  • Mechanism by which fourth step occurs?
  • Platelet receptor that binds fibrinogen?
A

Platelet aggregation

Platelets bound to vWF at the site of blood vessel damage bind fibrinogen at their Gp2b/3a receptors (binding enhanced by TXA2). Fibrinogen serves as a linking molecule, aggregating platelets together to form a platelet plug.

Gp2b/3a

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12
Q

Disorders of primary hemostasis:

  • Most common overall symptom?
  • Petechiae are pinpoint areas of hemorrhage in the subcutaneous tissue that develop when RBCs lead through what aspect of the blood vessel?
  • Mechanism by which thrombocytopenia mediates the development of petechiae?
A
  • Epistaxis
  • Post-capillary venular gaps in the blood vessel endothelium
  • Platelets stabilize the vascular endothelial-cadherin complex at the intracellular adherens junctions, particularly in the post-capillary venules, thereby preventing RBCs from leaking into the interstitium.If platelet counts fall below critical levels, these adherens junctions disassemble, and RBCs extravasate into the interstitium.
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13
Q

Idiopathic thrombocytopenic purpura (ITP):

- Mechanism by which ITP causes thrombocytopenia?

A

Autoimmune production of IgG antibodies directed against platelet Gp2b/3a receptors (type II HSR).

Ab-coated platelets are consumed by splenic macrophages.

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14
Q

Idiopathic thrombocytopenic purpura (ITP):

  • IgG antibodies against platelet Gp2b/3a produced by?
  • Antibody-coated platelets?
A
  • SPLENIC PLASMA CELLS produce IgG antibodies against platelet Gp2b/3a
  • SPLENIC MACROPHAGES consume these antibody-coated platelets
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15
Q

Idiopathic thrombocytopenic purpura (ITP):

  • Patient population in which acute ITP occurs?
  • Patient population in which chronic ITP occurs?
  • Treatment options (3)? Mechanisms?
A

Acute: Children, usually 2/2 viral infection or immunization/vaccination.

Chronic: Adults, usually women of childbearing age.
–> IgG antibodies against platelet antigens can cross the placenta and cause short-lived thrombocytopenia in newborns. Short-lived because maternal-derived IgG is eventually degraded.

Treatment:

1) Corticosteroids - Children usually respond well.
2) IVIG - IgG blocks the macrophage Fc receptors –> Inhibits binding of macrophage Fc receptor (FcR) to the IgG autoantibodies, thereby preventing phagocytosis and destruction of the Ab-coated platelets.
(3) Splenectomy - Eliminates the primary source of the autoantibody (splenic plasma cells) and the cells responsible for autoantibody-coated platelet destruction (splenic macrophages).

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16
Q

Idiopathic thrombocytopenic purpura (ITP):

  • Platelet count?
  • Bleeding time?
  • PT/PTT?
  • Bone marrow biopsy?
A
  • Thrombocytopenia
  • Increased bleeding time
  • Normal PT/PTT
  • Increased megakaryocytes on BM biopsy
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17
Q

Microangiopathic hemolytic anemia:

  • Genetic deficiency in thrombotic thrombocytopenic purpura (TTP)?
  • Mechanism by which genetic deficiency in TTP mediates disease?
  • Treatment options (2)?
A

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)

  • ADAMTS13 deficiency
  • ADAMTS13 (vWF metalloproteinase) cleaves vWF multimers into monomers, which are then degraded. ADAMTS13 deficiency inhibits this process, thereby leading to the accumulation of large, uncleaved vWF multimers that result in abnormal platelet adhesion, leading to the formation of platelet microthrombi.
  • ADAMTS13 deficiency is typically 2/2 an acquired autoantibody against the vWF metalloproteinase.
  • Treatment: Plasmaphoresis (removes autoantibody against ADAMTS13) and corticosteroids (decreases synthesis of this autoantibody).
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18
Q

Microangiopathic hemolytic anemia:

  • Classic trigger for hemolytic uremic syndrome (HUS)?
  • Mechanism by which this trigger causes HUS (2)?
A

HEMOLYTIC UREMIC SYNDROME

  • E. coli O157:H7 dysentery
  • E. coli verotoxin (1) damages endothelial cells, exposing subendothelial collagen and causing platelet microthrombi, and (2) decreases/inhibits ADAMTS13.
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19
Q

Microangiopathic hemolytic anemia:

  • Clinical pentad present in both TTP and HUS?
  • Dominant clinical finding in TTP?
  • Dominant clinical finding in HUS?
A

(1) Skin and mucosal bleeding (thrombocytopenia)
(2) Microangiopathic hemolytic anemia with schistocytes
(3) Fever
(4) Renal failure
(5) Neurologic (CNS) involvement

TTP: Neurologic involvement > renal failure

HUS: Renal failure > neurologic involvement

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20
Q

Microangiopathic hemolytic anemia (TTP/HUS):

  • Platelet count?
  • Bleeding time?
  • PT/PTT?
  • Blood smear
  • Bone marrow biopsy?
A
  • Thrombocytopenia
  • Increased bleeding time
  • Normal PT/PTT
  • Schistocytes
  • Increased megakaryocytes on BM biopsy
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21
Q

Bernard-Soulier syndrome:

  • Genetic deficiency?
  • Impairs what aspect of primary hemostasis?
  • Platelet count?
  • Bleeding time?
  • PT/PTT?
  • Blood smear
  • Ristocetin test?
  • vWF antigen assay?
A

Gp1b deficiency –> Impairs platelet adhesion

  • Mild thrombocytopenia
  • Increased bleeding time
  • Normal PT/PTT
  • Enlarged platelets
  • Abnormal ristocetin test
  • Normal vWF antigen assay
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22
Q

Glanzmann thrombasthenia:

  • Genetic deficiency?
  • Impairs what aspect of primary hemostasis?
  • Platelet count?
  • Bleeding time?
  • PT/PTT?
  • Blood smear
A

Gp2b/3a deficiency –> Impairs platelet aggregation

Normal platelet count

  • Increased bleeding time
  • Normal PT/PTT
  • Blood smear shows NO platelet clumping
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23
Q

Disorders of primary hemostasis:

  • Autoantibody directed against platelet antigens (Gp2b/3a)?
  • Autoantibody directed against ADAMTS13?
  • Genetic deficiency of Gp1b?
  • Genetic deficiency of Gp2b/3a?
A
  • Idiopathic thrombocytopenic purpura (ITP)
  • Thrombotic thrombocytopenic purpura (TTP)
  • Bernard-Soulier syndrome
  • Glanzmann thrombasthenia
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24
Q

Ticlopidine:

- Mechanism of action?

A

Inhibits P2Y12 ADP receptor on platelets –> Degranulated ADP binds this receptor and induces expression of functional Gp2b/3a

“Inhibits ADP-induced Gp2b/3a expression”

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25
Q

Clopidogrel (Plavix)

- Mechanism of action?

A

Inhibits P2Y12 ADP receptor on platelets –> Degranulated ADP binds this receptor and induces expression of functional Gp2b/3a

“Inhibits ADP-induced Gp2b/3a expression”

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26
Q

Abciximab:

- Mechanism of action?

A

mAb that binds to and inhibits Gp2b/3a receptor

“Inhibits Gp2b/3a directly”

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27
Q

What is the mechanism by which secondary hemostasis stabilizes the platelet plug?

A

Coagulation cascade generates thrombin, which converts fibrinogen in the platelet plug to fibrinFibrin is cross-linked to yield a stable platelet-fibrin thrombus (clot)

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28
Q

Which organ is responsible for the synthesis of (inactive) coagulation cascade factors?

A

Liver

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29
Q

Coagulation factors of extrinsic pathway?

A

Factor 7

30
Q

Coagulation factors of intrinsic pathway?

A

Factors 8, 9, 11, 12

31
Q

Coagulation factors of common pathway?

A

Factors 1, 2, 5, 10

32
Q

How is the extrinsic pathway activated?

A

Damaged endothelial cells release tissue thromboplastin (factor 3) at the site of the blood vessel injury, which activates factor 7 to form factor 7a

33
Q

Activated factor 7 has what 2 functions?

A

1) Activates factor 9 to form factor 9a (intrinsic pathway)2) Activates factor 10 to form factor 10a (common pathway)

34
Q

How is the intrinsic pathway activated?

A

Damaged endothelial cells at the site of the blood vessel injury expose subendothelial collagen, which activates factor 12 (Hageman factor) to form factor 12a

35
Q

Activated factor 12 has what 2 functions?

A

1) Activates factor 11 to form factor 11a (intrinsic pathway)2) Catalyzes the conversion of prekallikrein to kallikrein

36
Q

Kallikrein has what 2 functions?

A

1) Catalyzes the conversion of plasminogen to plasmin (fibrinolytic pathway)2) Catalyzes the conversion of HMWK to bradykinin

37
Q

Bradykinin has what 3 functions?

A

1) Increased vascular permeability2) Vasodilation3) Pain

38
Q

Activated factor 11 has what function?

A

Activates factor 9 to form factor 9a (intrinsic pathway)Note - Factor 7a (extrinsic pathway) also activates factor 9 to form factor 9a

39
Q

What are the 2 mechanisms by which the common pathway is activated?

A

1) Factor 7a activates factor 10 to form factor 10a2) Factor 9a and factor 8 complex with Ca2+ and PF3 (phospholipid substrate) to activate factor 10 to form factor 10a

40
Q

How is thrombin activated?

A

Factor 10a and factor 5 complex with Ca2+ and PF3 (phospholipid substrate) to form the “prothrombin complex”Prothrombin complex activates factor 2 (prothrombin) to form factor 2a (thrombin)

41
Q

Thrombin has what 2 functions?

A

1) Catalyzes conversion of factor 1 (fibrinogen) to factor 1a (fibrin monomers)2) Activates fibrin-stabilizing factor (factor 13) to form factor 13a

42
Q

Activated factor 13 has what function?

A

Converts soluble fibrin monomers (factor 1a) to insoluble fibrin and enhances protein-protein cross-linking to strengthen the fibrin clot

43
Q

Prothrombin time (PT):Evaluates what part of coagulation cascade?Followed in monitoring what anticoagulant?

A

Extrinsic pathwayCoumadin (Warfarin)

44
Q

Partial thromboplastin time (PTT):Evaluates what part of coagulation cascade?Followed in monitoring what anticoagulant?

A

Intrinsic pathwayHeparin

45
Q

Disorders of secondary hemostasis present with symptoms of which 2 clinical findings?

A

Deep tissue bleeding into muscles/joints and re-bleeding after surgical procedures (e.g., circumcision, wisdom tooth extraction)

46
Q

Hemophilia A:Genetic deficiency?Mode of inheritance?

A

Factor 8 deficiencyX-linked recessive

47
Q

Hemophilia A:Platelet count?Bleeding time?PT/PTT?

A

Normal platelet countNormal bleeding timeElevated PTTNormal PTDecreased factor 8

48
Q

Hemophilia A: Treatment of mild disease?Treatment of severe disease?

A

Mild - Desmopressin acetate (ADH analog), which increases vWF release from Weibel-Palade bodies of endothelial cells. vWF binds and stabilizes circulating factor 8 such that it does not degrade. Severe - Recombinant factor 8

49
Q

Hemophilia B:Genetic deficiency?Mode of inheritance?

A

Hemophilia B = Christmas diseaseFactor 9 deficiencyX-linked recessiveClinically resembles hemophilia A

50
Q

Hemophilia C:Genetic deficiency?Mode of inheritance?

A

Factor 11Autosomal recessive (AR)

51
Q

Coagulation factor inhibitor diseases are those in which one acquires an autoantibody against a coagulation factor.Which coagulation factor is most frequently involved? Which patient population usually gets this disease?

A

Factor 8 usually involved - Typically seen in patients with hemophilia A who receive recombinant factor 8 as treatment

52
Q

Which study distinguishes hemophilia A from anti-factor 8 acquired inhibitor disease? How?

A

Mixing study - Normal plasma (which includes factor 8) is mixed with patient plasma.In patients with hemophilia A, mixing study corrects PT/PTT because it adds back factor 8 into plasma.In patients with anti-factor 8 acquired inhibitor disease, mixing study does not correct PT/PTT because factor 8 added into patient plasma is inhibited by the anti-factor 8.

53
Q

vWF disease:Mode of inheritance?Treatment?

A

Autosomal dominant (AD)Desmopressin - Increases vWF release from Weibel-Palade bodies of endothelial cells. Note - Oral contraceptives act in a manner similar to desmopressin.

54
Q

Why is vWF disease a mixed primary and secondary hemostasis disorder?

A

PRIMARY HEMOSTASIS - Damaged endothelial cells release vWF from Weibel-Paladie bodies, which binds the exposed subendothelial collagen. Platelets bind vWF using the GP1b receptor. vWF deficiency prevents platelet adhesion to the damaged blood vessel.SECONDARY HEMOSTASIS - vWF binds and stabilizes circulating factor 8. vWF deficiency decreases the half-life of factor 8, disturbing normal coagulation cascade function.

55
Q

Vitamin K in secondary hemostasis:Mechanism of activation?Function?

A

Vitamin K is activated by epoxide reductase in the liver.Vitamin K gamma-carboxylates factors 2, 7, 9, 10, protein C and protein S on glutamic acid residues.Gamma-carboxylation is necessary for coagulation factors to bind Ca2+ and PF3 - Creates Ca2+-binding sites that interact with PF3 on platelet surface.

56
Q

In which 3 patient populations does vitamin K deficiency occur? Why?

A

Newborns - Bacteria that colonize the GI tract are responsible for vitamin K synthesis. Newborns have immature GI flora, especially those delivered via C-section. IM vitamin K injections are given as ppx to all newborns to prevent hemorrhagic disease of the newborn.Patients treated with longterm ABX therapy - ABX therapy disturbs the normal GI flora that synthesize vitamin K.Patients with malabsorption diseases - Malabsorption leads to deficiencies in fat-soluble vitamins (D, E, A, K).

57
Q

What is the mechanism by which large-volume transfusions contribute to disordered secondary hemostasis?

A

Dilution of coagulation factors 2/2 transfusions, resulting in a relative deficiency.

58
Q

Heparin-induced thrombocytopenia (HIT):Mechanism of disease?Clinical findings?Treatment?

A

Mechanism - Production of IgG antibodies directed against heparin-PF4 complex. IgG binds heparin-PF4 complex and destroys platelets. Immune complexes also break free from platelets and damage endothelial cells, activating the coagulation cascade.Clinical findings - Severe thrombocytopenia and vessel thrombosis 5-14 days after starting heparin.Treatment - Discontinue heparin and initiate thrombin inhibitor therapy (lepirudin and bivalirudin). Do NOT initiate warfarin therapy b/c these patients are at an increased risk of developing warfarin skin necrosis.

59
Q

What are the causes of disseminated intravascular coagulation (DIC)?

A

STOP Making New ThrombiSepsis (Gram negative)TraumaObstetric complications PancreatitisMalignancyNephrotic syndromeTransfusionsAlso, rattlesnake bitesObstetric complications = amniotic fluid embolism, retained dead fetus

60
Q

DIC 2/2 Gram negative sepsis is commonly caused by what 2 infections?

A

E coli, N meningitidis

61
Q

What is the mechanism by which amniotic fluid embolism causes DIC?

A

Tissue thromboplastin (factor 3) in amniotic fluid activates coagulation cascade

62
Q

DIC 2/2 malignancy is commonly caused by what 2 cancers?

A

APL - Auer rods activate coagulation cascadeAdenocarcinoma (pancreas, prostate, breast, lung) - Mucus activates coagulation cascade

63
Q

What coagulation factors are commonly decreased in DIC?

A

1, 2, 5, 8

64
Q

DIC:Platelet count?Bleeding time?PT/PTT?Blood smear?D-dimer assay?

A

ThrombocytopeniaIncreased bleeding timeIncreased PT/PTTSchistocytesIncreased D-dimers and decreased fibrinogen

65
Q

What are the 4 mechanisms by which plasmin mediates fibrinolysis?

A

1) Cleaves insoluble fibrin monomers into fibrin split products (D-dimers)2) Cleaves soluble fibrinogen into fibrinogen split products3) Destroys factors 5 and 84) Catalyzes conversion of C3 –> C3a, thereby activating the complement system

66
Q

What are the 5 mechanisms by which plasmin is activated to mediate fibrinolysis?

A

1) tPA catalyzes plasminogen –> plasmin2) Urokinase (derived from human urine)3) Streptokinase (derived from streptococci)4) Factor 12a5) KallikreinFactor 12a catalyzes conversion of prekallikrein to kallikrein, which then catalyzes conversion of plasminogen to plasmin

67
Q

Which serine protease inhibitor (serpin) synthesized in the liver inactivates plasmin?

A

α2-antiplasmin

68
Q

What is the mechanism by which radical prostatectomy causes a disorder of fibrinolysis?

A

Release of urokinase (derived from human urine) activates plasmin

69
Q

What is the mechanism by which liver disease (e.g., cirrhosis) causes a disorder of fibrinolysis?

A

Reduced synthesis of α2-antiplasmin

70
Q

What is the mechanism by which open heart surgery causes a disorder of fibrinolysis?

A

Cardiopulmonary bypass causes a decrease in α2-antiplasmin and an increase in tPA

71
Q

Disorders of fibrinolysis classically resemble DIC. What are the two laboratory findings that distinguish these two disease processes?

A

DIC presents with (1) fibrin split products (D-dimers) and (2) thrombocytopenia

72
Q

What is the treatment for a disorder of fibrinolysis? Mechanism?

A

N-aminocaproic acid inhibits the conversion of plasminogen to plasmin

USMLE STEP 1 - OLD (12 decks)

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