08: Regulation of Coagulation/Prothrombotic Disorders Flashcards

1
Q

Coagulation inhibitors

A
  1. Tissue factor pathway inhibitor (TFPI): complexes with VIIa/TF/Xa –> inactivates Xa.
  2. Antithrombin III: binds and inactivates IXa, Xa, XIa, thrombin; stimulated by **heparin **w/ heparin cofactor II.
  3. Protein C/Protein S (cofactor)/Thrombomodulin: thrombin bound to thrombomodulin leads to aPC, which puts BREAK on clotting –> inactivation of Va and VIIIa, inhibition of tPA breakdown –> enhanced fibrinolysis
  4. Plasminogen (tertiary hemostasis): release of **tPA **from endothelial cells converts plasminogen to plasmin –> fibrin cleaved
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2
Q

Diseases of anticoagulant protein deficiency

A
  • Heterozygous protein deficiency
    • Increased venous thrombosis
    • Occasional increased arterial thrombosis
  • Homozygous protein deficiency
    • Neonatal purpura fulminans
    • Fibrinogenolysis
    • Chronic DIC
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3
Q

Activated Protein C Resistance (Factor V Leiden)

A
  • Mutation of Arg 506 –> Gln in Factor V at protein C cleaveage site
  • Hallmark: failure of aPC to prolong aPTT
  • 4x↑ risk VTE in heterozygotes, 80x↑ in homozygotes
  • Synergistic effect in combination with other anticoagulant protein deficiencies
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4
Q

Prothrombin G20210 –> A

A
  • Autosomal dominant mutation at 3’ end of non-coding sequence of prothrombin gene –> increased prothrombin synthesis (>115% nl)
  • Primary risk: pregnancy-associated thrombosis, venous thromboembolic disease
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5
Q

Chronic inflammatory disease

A
  • In inflammatory disease, ↑**C4b binding protein **(an acute phase reactant) –> binds protein S –> inactivates protein S –> ↓protein C activity (↓anticoagulation)
  • Inflammation –> ↑**IL-1 **& TNF –> downregulate thrombomodulin –> ↑free circulation thrombin –> procoagulant instead of anticoagulant protein
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6
Q

Nephrotic syndrome/protein-losing enteropathy

A
  • Loss of glomerular filtration and reabsorption capability or increased protein loss via GI tract
  • Causes excretion of large amounts of protein in the urine/stool, including:
    • Protein S
    • Albumin
    • Antithrombin III
    • Protein C
  • Large ↑C4b binding protein (high MW) –> binds any leftover protein S –> inactivates as anticoagulant
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7
Q

Antiphospholipid Antibody Syndrome (Lupus Anticoagulant)

A
  • Less than 30% actually have lupus
  • Clotting problems; bleeding in rare circumstances
  • Associated with:
    • Thrombosis: arterial & venous
    • False positive rapid plasmid reagent (RPR; test for syphilis): reacts with phospholipid Ab
    • Recurrent spontaneous abortions
  • Mechanism unknown
  • Diagnosis:
    • Antiphospholipid Antibody Assay
    • Lupus Anticoagulant Assay
      • Dx requires two abnormal tests 12 weeks apart + clinical syndrome
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8
Q

Thrombotic Thrombocytopenic Purpura

A
  • Sporadic & relapsing form
  • Cause: congenital defect of and/or antibody against vWF-cleaving ADAMTS-13
  • Universally fatal without treatment; with treatment, >90% survival
  • Presentation: microangiopathic hemolytic anemia (blood smear critical to assess), thrombocytopenia, altered mental status, fever, renal insufficiency
    • No coagulation abnormalities!
  • Treatment: plasmapheresis, corticosteroids; if refractory: rituximab, vincristine, splenectomy
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9
Q

Heparin-induced thrombocytopenia** (HIT)**

A
  • Ig-mediated allergic reaction to heparin/platelet factor 4 complex
  • Thrombocytopenia:
    • Platelet count <150K or 30-50% drop from baseline during heparin exposure
    • Onset 5-14 days after initiating heparin
  • With/without thrombotic complications
  • Heparin normally causes patients to bleed, not clot
  • Exposure risks:
    • Type of heparin: UFH>LMWH
    • Dose/duration: High dose>low dose
    • Route: IV>SC, flushes, catheters
  • Common in cardiac, ortho or ICU setting
  • Paradoxes:
    • Anticoagulant-induced thrombosis
    • Clotting disorder, not bleeding disorder
    • Platelet transfusions ↑thrombosis risk
    • Simply stopping heparin may not prevent thrombosis
    • Warfarin contraindicated as acute monotherapy
  • Pathophysiology: PF-4 binds surface of platelet –> PF-4/heparin complexes form –> IgG binds complexes –> complex activates via Fc receptor –> Fc stimulation generates procoagulant-rich microparticles
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10
Q

Pre-test probability of HIT

A
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11
Q

DIC Testing (Acute)

A
  • PT↑
  • aPTT variable
  • Fibrinogen ↓
  • Thrombin time↑
  • Factor levels variable
  • Platelet count ↓
  • RBC fragmentation present
  • Fibrin split products present
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12
Q

Cryoprecipitate

A

Replace fibrinogen in DIC

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13
Q

Fresh frozen plasma (FFP)

A

Replace factors (not fibrinogen) in DIC

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