Hypercoagulable States¶
Chris Cann
Background¶
- Virchow’s triad: 1. Hypercoagulability 2. Stasis 3. Endothelial injury
- Diagnostic thrombophilia testing indications:
- Idiopathic or recurrent VTE
- First VTE at <40 years old
- VTE in the setting of strong family history
- VTE in unusual vascular site (cerebral, renal, mesenteric)
- Recurrent pregnancy loss
- Must consider if thrombophilia testing will change clinical management
- If the unprovoked VTE warrants indefinite anticoagulation then testing may not be helpful
- However, if VTE provoked by minor risk factor (OCPs) with an underlying thrombophilia might change the decision, then testing may be informative
- Separated into Acquired and Hereditary conditions:
- Hereditary: Factor V Leiden mutation, Prothrombin mutation, Protein C or S deficiency, Antithrombin deficiency
- Acquired:
- Antiphospholipid Syndrome (APLS)
- Heparin induced thrombocytopenia (HIT)
- Major surgery/trauma
- Nephrotic Syndrome
- Smoking
- Pregnancy
- Oral Contraceptives
- Immobilization (bedridden, hip/knee replacement)
- Active malignancy
- Estrogen replacement therapy
- Note: Travel (plane, train, automobile) is NOT on this list and this is NOT considered a provoking risk factor
- Testing: all specific testing for hereditary disorders and APS should be performed at least 4-6 weeks after an acute thrombotic event or discontinuation of anticoagulant/thrombolytic therapies to avoid interference
Antiphospholipid antibody syndrome (APLS)¶
Background¶
- Most common acquired disorder (anti-phospholipid antibodies present in 3-5% population)
- Recurrent pregnancy loss, provoked DVT in young, unprovoked VTE and arterial thrombosis in young, thrombosis unusual sites, thrombosis in autoimmune disease
- This is a clinicopathologic diagnosis (need both clinical and laboratory criteria)
Evaluation¶
- Positive for at least 1 lab criterion on at least 2 occasions, at
least 12 weeks apart:
- Lupus anticoagulant: can occur in relation to drugs or infection; transient are associated with thrombotic risk
- Anticardiolipin antibodies
- B2GP1 (anti-beta2-glycoprotein) antibodies
- Must also meet at least 1 of the following clinical criteria:
- Vascular thrombosis: DVT, arterial thrombosis, or small vessel thrombosis of any organ
- Pregnancy loss: there are specific criteria for this – consult UpToDate or other resource
Management¶
- Aspirin for primary prevention; warfarin for treatment (INR 2-3)
- Do NOT use DOACs for triple positive APLS (see TRAPS trial: rivaroxaban inferior to warfarin)
- Rituximab for recurrent thrombosis despite anticoagulation (controversial) – call hematology
Heparin-induced thrombocytopenia (HIT)¶
Type 1: Mild and self-limited (not immune-mediated)
- Occurs within the first 2 days of first-time exposure
- Platelet count normalizes with continued heparin therapy
Type 2 (what we typically refer to as HIT): Immune mediated
- Fall in plt 30% to over 50% (even if plt count >150) and/or thrombotic event has occurred
- 4-10 days after new exposure to heparin derivative OR≤
- 1 day after restarting heparin derivative that had been used 30-100
days prior
- If exposed to heparin within 100 days, will have platelet drop within 24 hr
- Frequency: unfractionated heparin > LMWH; Surgical wards > medical wards
- 50% will have thrombotic event in 30 days if HIT is untreated, with 20% mortality
- Arterial thrombi are common in HIT
- HIT results from antibodies to complexes of platelet factor 4 (PF4) and heparin, further activating platelets (the activated platelets aggregate causing thrombocytopenia)
Evaluation¶
- 4T score (0-8 points):
- Thrombocytopenia (0-2 pts): degree and nadir of platelet count drop
- Timing (0-2 pts): timing of fall after initial or recurrent heparin exposure
- Thrombosis (0-2 pts): thrombosis, skin necrosis, non-necrotizing lesions, acute systemic reaction to heparin
- Other causes of thrombocytopenia (0-2 pts): more points if no alternate cause
- Solid-phase ELISA for heparin-PF4 antibodies:
- 0.2-0.4 is indeterminate
-
0.4 is positive
-
1.4 HIT is likely
-
2 confirms HIT
- The lab at VUMC will perform functional SRA reflexively for all values >0.2
Management¶
- 0-3 points: Low concern for HIT; can restart heparin
- 4-5 points: Intermediate probability (~10%) - hold heparin, start non-heparin anticoagulant
- 6 points: High probability (~50%) - hold heparin, start non-heparin anticoagulant
- Argatroban (direct thrombin inhibitor) for prophylaxis and treatment of thrombosis
- Avoid platelet transfusions as can increase thrombogenic effect
- Avoid warfarin until complete platelet recovery as may cause microthrombosis
- Hematology consult for all confirmed HIT
Factor V Leiden mutation¶
Evaluation¶
- Activated protein C resistance assay
- APC ratio in patient vs normal
- normal >2.0, heterozygotes 1.5-2.0, homozygotes <1.5
- FVL mutation is then determined via PCR
- Screen with APC assay rather than PCR initially; cost effective
Management¶
- VTE treatment same as general population
- VTE 4-8x risk in heterozygotes; 80x risk in homozygotes
- Avoid OCPs: increased risk for VTE
Prothrombin gene mutation¶
Evaluation:¶
- PCR of G20210A mutation (2-4% prevalence)
Management:¶
- VTE treatment same as general population & avoid OCPs
Protein C & S Deficiency¶
Background¶
- Autosomal dominant; first event occurs between 10-50 years of age
- Synthesized in liver and Vit K dependent, therefore low levels in hepatic dysfunction and warfarin use/vitamin K deficiency
- Protein C: low in settings of thrombosis, DIC, nephrotic syndrome, intra/post-op
- Protein S: low in infectious (HIV) and autoimmune processes (IBD)
- Protein S decreases during pregnancy (decreased free Protein S, normal total Protein S)
- Do not misdiagnose a pregnant patient with PS deficiency
Evaluation¶
- Functional Protein C & S assays
Management¶
- VTE treatment same as general population
- Avoid OCPs
- High risk patients may require protein C concentrate prior to surgery
- Increased risk of warfarin-induced skin necrosis
Antithrombin deficiency¶
Background¶
- Autosomal dominant, does not skip generations
- VTE in unusual sites (cerebral sinuses, renal veins)
- Present < 50 y/o, but rarely in first two decades
- Decreased in liver disease, nephrotic syndrome, protein losing enteropathy, burn, trauma, bypass surgery, metastatic tumors, premenopausal, OCP use, pregnancy
Evaluation¶
- Functional antithrombin activity (AT-heparin cofactor assay)
- Then perform antigen quantity testing
Management¶
- Can use Argatroban as does not require antithrombin function
- Warfarin preferred in VTE (titrate up based on expression of antithrombin deficiency)
Last update:
2022-06-24 23:35:57