08: Regulation of Coagulation/Prothrombotic Disorders

Question 1

Coagulation inhibitors

Answer 1

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

Question 2

Diseases of anticoagulant protein deficiency

Answer 2

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

Question 3

Activated Protein C Resistance (Factor V Leiden)

Answer 3

• 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

Question 4

Prothrombin G20210 –> A

Answer 4

• 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

Question 5

Chronic inflammatory disease

Answer 5

• 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

Question 6

Nephrotic syndrome/protein-losing enteropathy

Answer 6

• 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

Question 7

Antiphospholipid Antibody Syndrome (Lupus Anticoagulant)

Answer 7

• 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

Question 8

Thrombotic Thrombocytopenic Purpura

Answer 8

• 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

Question 9

Heparin-induced thrombocytopenia** (HIT)**

Answer 9

• 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

Question 10

Pre-test probability of HIT

Answer 10

Question 11

DIC Testing (Acute)

Answer 11

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

Question 12

Cryoprecipitate

Answer 12

Replace fibrinogen in DIC

Question 13

Fresh frozen plasma (FFP)

Answer 13

Replace factors (not fibrinogen) in DIC