08: Regulation of Coagulation/Prothrombotic Disorders Flashcards
1
Q
Coagulation inhibitors
A
- Tissue factor pathway inhibitor (TFPI): complexes with VIIa/TF/Xa –> inactivates Xa.
- Antithrombin III: binds and inactivates IXa, Xa, XIa, thrombin; stimulated by **heparin **w/ heparin cofactor II.
- 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
- Plasminogen (tertiary hemostasis): release of **tPA **from endothelial cells converts plasminogen to plasmin –> fibrin cleaved
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
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
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
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
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
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
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
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
10
Q
Pre-test probability of HIT
A
11
Q
DIC Testing (Acute)
A
- PT↑
- aPTT variable
- Fibrinogen ↓
- Thrombin time↑
- Factor levels variable
- Platelet count ↓
- RBC fragmentation present
- Fibrin split products present
12
Q
Cryoprecipitate
A
Replace fibrinogen in DIC
13
Q
Fresh frozen plasma (FFP)
A
Replace factors (not fibrinogen) in DIC