Hypercoagulable States¶

Chris Cann

Background¶

Virchow’s triad:
- Hypercoagulability
- Stasis
- 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)
  - Myeloproliferative neoplasms, paroxysmal nocturnal hemoglobinuria
  - 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.

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)

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
- β 2GP1 (anti- β2-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

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

Widespread thrombosis with multi-organ failure
Intra-abdominal: Renal failure, pancreatitis, adrenal and splenic infarcts, mesenteric ischemia
Pulmonary: respiratory failure
CNS involvement including stroke
Systemic inflammatory response syndrome (due to tissue necrosis)
TMA/DIC syndrome

Evidence of multi-organ involvement (3 or more)
Confirmed by imaging techniques
Renal involvement can be defined as rise in serum creatinine by 50%, severe systemic hypertension, or proteinuria (>500mg/d)
Development of manifestations simultaneously or within 1 week
Confirmation by histopathology of small vessel occlusion
Laboratory confirmation of aPL antibodies (detected on 2 occasions 12 weeks apart)

Separated into Type 1 and Type 2
- 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 platelet 30% to over 50% (even if platelet 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)

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

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

Activated protein C resistance assay
- APC ratio in pt 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

VTE treatment same as general population
- VTE 4-8x risk in heterozygotes; 80x risk in homozygotes
Avoid OCPs: increased risk for VTE

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 pt with PS deficiency

Autosomal dominant, does not skip generations
VTE in unusual sites (cerebral sinuses, renal veins)
Present < 50, 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

Can use argatroban as does not require antithrombin function
Warfarin preferred in VTE (titrate up based on expression of antithrombin deficiency)