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USMLE STEP 1 - OLD > Hemostasis > Flashcards

Hemostasis Flashcards

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USMLE® Step 1 flashcards
1
Q

What is the function of primary hemostasis?

A

To form a weak platelet plug

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2
Q

What is the function of secondary hemostasis?

A

To stabilize the weak platelet plug formed by primary hemostasis

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3
Q

What is the first step in primary hemostasis?

A

Transient vasoconstriction of the damaged blood vessel

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4
Q

In primary hemostasis, what are the 2 mechanisms by which the initial vasoconstriction of the damaged blood vessel occurs?

A

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

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5
Q

What is the second step in primary hemostasis?

A

Platelet adhesion to the surface of the damaged blood vessel

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6
Q

In primary hemostasis, what is the 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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7
Q

Which platelet receptor binds vWF?

A

Gp1b

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8
Q

Which 2 cell types are responsible for vWF synthesis?

A

Endothelial cells synthesize vWF in Weibel-Palade bodies.Megakaryocytes synthesize vWF in the bone marrow. vWF is present in α-granules of platelets.

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9
Q

Endothelial cell Weibel-Palade bodies contain what 2 products?

A

vWF and P-selectin

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10
Q

What is the third step in primary hemostasis?

A

Platelet degranulation

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11
Q

In primary hemostasis, what is the mechanism by which platelets degranulate?

A

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

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12
Q

What are the 2 products stored in platelet dense granules?

A

ADP and Ca2+

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13
Q

What are the 4 products stored in platelet α-granules?

A

vWF, fibrinogen, platelet-derived growth factor (PDGF), and platelet factor 4 (PF4)PDGF - Stimulates smooth muscle hyperplasia, important in pathogenesis of atherosclerosisPF4 - Heparin-neutralizing factor

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14
Q

What is the mechanism by which platelets synthesize TXA2?

A

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

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15
Q

In primary hemostasis, what is the function of ADP degranulation by platelets?

A

ADP released from dense granules binds to platelet P2Y12 ADP receptors, which promotes expression of a functional Gp2b/a3 receptor on platelet surface.

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16
Q

In primary hemostasis, what are the 2 functions of TXA2?

A

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

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17
Q

What is the mechanism of action of aspirin in platelets?

A

Aspirin irreversibly inhibits platelet COX. Platelets regain function 48 hours after stopping aspirin.

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18
Q

What is the mechanism of action of NSAIDs in platelets?

A

NSAIDs reversibly inhibit platelet COX. Platelets regain function 12-24 hours after stopping NSAIDs.

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19
Q

What is the fourth step in primary hemostasis?

A

Platelet aggregation

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20
Q

In primary hemostasis, what is the mechanism by which platelets aggregate at the site of blood vessel injury?

A

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

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21
Q

What platelet receptor binds fibrinogen?

A

Gp2b/3a

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22
Q

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

A

Mucosal bleeding - Epistaxis, hemoptysis, GI bleeding, hematuria, and menorrhagia Skin bleeding - Petechiae, purpura, and ecchymoses

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23
Q

Petechiae are pinpoint areas of hemorrhage in the subcutaneous tissue that develop when RBCs lead through what aspect of the blood vessel?

A

Post-capillary venular gaps in the blood vessel endothelium

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24
Q

In disorders of primary hemostasis, what is the mechanism by which thrombocytopenia mediates the development of petechiae?

A

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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25
Q

What is the most common overall symptom in patients with disorders of primary hemostasis?

A

Epistaxis

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26
Q

Platelet factor 4 (PF4) in platelet α-granules provides what function?

A

Heparin-neutralizing factor

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27
Q

Platelet factor 3 (PF3) on the cell surface of platelets provides what function?

A

Phospholipid substrate required for the clotting sequence

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28
Q

What is the mechanism by which idiopathic thrombocytopenic purpura (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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29
Q

In ITP, ___ produce IgG antibodies against platelet Gp2b/3a, and ___ consume these antibody-coated platelets.

A

In ITP, SPLENIC PLASMA CELLS produce IgG antibodies against platelet Gp2b/3a, and SPLENIC MACROPHAGES consume these antibody-coated platelets.

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30
Q

Acute ITP presents in what patient population?

A

Children - Usually in response to viral infection or immunization/vaccination.

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31
Q

Chronic ITP presents in what patient population?

A

Women - Usually in those of childbearing age.

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32
Q

What is the mechanism by which chronic ITP in a pregnant female may cause short-lived thrombocytopenia in the offspring?

A

IgG antibodies against platelet antigens cross the placenta. Thrombocytopenia is short-lived because maternal-derived IgG is eventually degraded.

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33
Q

ITP:Platelet count?Bleeding time?PT/PTT?Bone marrow biopsy?

A

ThrombocytopeniaIncreased bleeding timeNormal PT/PTTIncreased megakaryocytes on BM biopsy

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34
Q

What are the treatment options for ITP?

A

Corticosteroids - Children usually respond well. IVIGSplenectomy

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35
Q

What is the mechanism by which IVIG treats ITP?

A

IVIG (IgG) blocks the macrophage Fc receptors –> Inhibits binding of macrophage Fc receptor to the IgG autoantibodies, thereby preventing phagocytosis and destruction of the Ab-coated platelets.

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36
Q

What is the mechanism by which splenectomy treats ITP?

A

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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37
Q

What is the mechanism by which thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) causes thrombocytopenia?

A

Platelets are consumed in the formation of platelet microthrombi in small blood vessels

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38
Q

What is the mechanism by which TTP and HUS causes hemolytic anemia?

A

RBCs are “sheared” as they cross the platelet microthrombi in small blood vessels, resulting in microangiopathic hemolytic anemia with schistocytes (“helmet cells”)

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39
Q

What is the genetic deficiency in TTP, and how does this mediate disease?

A

ADAMTS13 deficiencyADAMTS13 is a vWF metalloproteinase that 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, resulting in the formation of platelet microthrombi.ADAMTS13 deficiency is typically secondary to an acquired autoantibody against the vWF metalloproteinase.

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40
Q

What is the classic infectious trigger for HUS, and what are the 2 mechanisms by which this infection causes HUS?

A

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

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41
Q

What are the 5 clinical findings (pentad) in patients with TTP and HUS?

A

FeverThrombocytopenia –> Skin/mucosal bleedingMicroangiopathic hemolytic anemiaRenal failureCNS deficits In TTP –> CNS deficits > renal failureIn HUS –> Renal failure > CNS deficits

42
Q

What are the 2 treatment options for TTP?

A

Plasmaphoresis - Removes autoantibody against ADAMTS13 Corticosteroids - Decreases synthesis of this autoantibody

43
Q

TTP/HUS:Platelet count?Bleeding time?PT/PTT?Blood smear?Bone marrow biopsy?

A

ThrombocytopeniaIncreased bleeding timeNormal PT/PTTSchistocytes Increased megakaryocytes on BM biopsy

44
Q

Bernard-Soulier syndrome is a disorder of primary hemostasis caused by what genetic deficiency?

A

Gp1b deficiency –> Impairs platelet adhesion

45
Q

Glanzmann thrombasthenia is a disorder of primary hemostasis caused by what genetic deficiency?

A

Gp2b/3a deficiency –> Impairs platelet aggregation (Thrombosthenin deficiency –> Contractile element found in platelets)

46
Q

Bernard-Soulier:Platelet count?Bleeding time?PT/PTT?Blood smear?Ristocetin test?vWF antigen assay?

A

Mild thrombocytopeniaIncreased bleeding time Normal PT/PTTEnlarged platelets Abnormal ristocetin test Normal vWF antigen assay

47
Q

Glanzmann thrombasthenia:Platelet count?Bleeding time?PT/PTT?Blood smear?

A

Normal platelet countIncreased bleeding timeNormal PT/PTTBlood smear shows NO platelet clumping

48
Q

Autoantibody directed against platelet antigens (Gp2b/3a) causes which disorder of primary hemostasis?

A

Idiopathic thrombocytopenic purpura (ITP)

49
Q

Autoantibody directed against ADAMTS13 causes which disorder of primary hemostasis?

A

Thrombotic thrombocytopenic purpura (TTP)

50
Q

Genetic deficiency of Gp1b causes which disorder of primary hemostasis?

A

Bernard-Soulier syndrome

51
Q

Genetic deficiency of Gp2b/3a causes which disorder of primary hemostasis?

A

Glanzmann thrombasthenia

52
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”

53
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”

54
Q

Abciximab:Mechanism of action?

A

mAb that binds to and inhibits Gp2b/3a receptor”Inhibits Gp2b/3a directly”

55
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)

56
Q

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

A

Liver

57
Q

Coagulation factors of extrinsic pathway?

A

Factor 7

58
Q

Coagulation factors of intrinsic pathway?

A

Factors 8, 9, 11, 12

59
Q

Coagulation factors of common pathway?

A

Factors 1, 2, 5, 10

60
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

61
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)

62
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

63
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

64
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

65
Q

Bradykinin has what 3 functions?

A

1) Increased vascular permeability2) Vasodilation3) Pain

66
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

67
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

68
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)

69
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

70
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

71
Q

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

A

Extrinsic pathwayCoumadin (Warfarin)

72
Q

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

A

Intrinsic pathwayHeparin

73
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)

74
Q

Hemophilia A:Genetic deficiency?Mode of inheritance?

A

Factor 8 deficiencyX-linked recessive

75
Q

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

A

Normal platelet countNormal bleeding timeElevated PTTNormal PTDecreased factor 8

76
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

77
Q

Hemophilia B:Genetic deficiency?Mode of inheritance?

A

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

78
Q

Hemophilia C:Genetic deficiency?Mode of inheritance?

A

Factor 11Autosomal recessive (AR)

79
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

80
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.

81
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.

82
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.

83
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.

84
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).

85
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.

86
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.

87
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

88
Q

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

A

E coli, N meningitidis

89
Q

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

A

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

90
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

91
Q

What coagulation factors are commonly decreased in DIC?

A

1, 2, 5, 8

92
Q

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

A

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

93
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

94
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

95
Q

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

A

α2-antiplasmin

96
Q

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

A

Release of urokinase (derived from human urine) activates plasmin

97
Q

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

A

Reduced synthesis of α2-antiplasmin

98
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

99
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

100
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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