Hypercoagulability Workup
When to Initiate Testing
Testing for hypercoagulable states should be reserved for specific clinical scenarios rather than performed routinely in all thrombosis patients. 1
Clear Indications for Testing:
- Thrombosis at unusual sites (cerebral, portal, mesenteric veins) 1
- Recurrent unprovoked VTE (two or more episodes) 2
- First VTE before age 50 without clear provocation 3, 4
- Family history of thrombosis in first-degree relatives 4, 5
- Warfarin-induced skin necrosis (suggests protein C/S deficiency) 4
- Thrombosis during pregnancy or oral contraceptive use 5
Do NOT Delay Anticoagulation:
Anticoagulation must be initiated immediately in acute thrombosis—never delay treatment to obtain testing. 1 This is critical because therapeutic anticoagulation itself interferes with many test results and delays increase morbidity.
Laboratory Testing Algorithm
Immediate Tests (Before or Within Hours of Anticoagulation):
Order these tests immediately upon presentation, ideally before heparin administration:
- Complete blood count with differential and platelet count to screen for myeloproliferative disorders and heparin-induced thrombocytopenia 1
- PT/INR and aPTT for baseline coagulation status and lupus anticoagulant screening 1, 2
- Lupus anticoagulant panel (must be done before anticoagulation or at least before warfarin) 2, 3
- Anticardiolipin antibodies (IgG and IgM) 2, 3
- Anti-beta-2-glycoprotein I antibodies 2
Critical Pitfall: Protein C, protein S, and antithrombin levels cannot be accurately interpreted while on warfarin or heparin. 1 If the patient is already anticoagulated, defer these tests until after completing anticoagulation therapy (typically 2-4 weeks off warfarin).
Genetic Testing (Can Be Done Anytime):
These tests are not affected by anticoagulation and can be performed at any time:
- Factor V Leiden mutation (most common inherited thrombophilia in Caucasians) 2, 1, 3
- Prothrombin G20210A mutation 2, 1, 3
Deferred Testing (After Completing Anticoagulation):
If initial testing is negative and suspicion remains high, test 2-4 weeks after stopping anticoagulation:
- Antithrombin activity (functional assay preferred over immunologic) 3, 4
- Protein C activity (functional assay) 3, 4
- Protein S activity (functional assay—free protein S is the active form) 3, 4
Important: Functional assays are superior to immunologic assays for detecting clinically significant deficiencies. 4
Special Consideration for Antiphospholipid Syndrome:
Diagnosis requires positive tests on two separate occasions at least 12 weeks apart to distinguish transient from persistent antibodies. 2 A single positive test is insufficient for diagnosis.
Risk Stratification for Heparin-Induced Thrombocytopenia (HIT)
If platelet count drops >50% or thrombocytopenia develops 5-14 days after heparin exposure:
- Calculate 4T score immediately 1
- If 4T score ≥4 (intermediate-high probability): Stop all heparin products immediately and switch to non-heparin anticoagulant (argatroban, bivalirudin, fondaparinux) 2
- Send HIT antibody testing but do not wait for results to change anticoagulation 2
Management Based on Findings
For Antiphospholipid Syndrome:
Use moderate-intensity warfarin (INR 2.0-3.0) rather than high-intensity (INR 3.0-4.5) for both arterial and venous thromboembolism. 2, 1 Two randomized trials showed no benefit and increased bleeding with higher INR targets. 2
For Inherited Thrombophilias:
Duration of anticoagulation depends on thrombosis characteristics, not thrombophilia type:
- First provoked VTE (transient risk factor): 3 months of anticoagulation 2, 6
- First unprovoked VTE: Minimum 6-12 months, consider indefinite therapy 2, 6
- Recurrent unprovoked VTE: Indefinite anticoagulation (strong recommendation) 2
- Severe thrombophilia with unprovoked VTE (antithrombin, protein C/S deficiency, homozygous Factor V Leiden, antiphospholipid syndrome): 12 months minimum, strongly consider indefinite therapy 6
Key Point: The presence of thrombophilia alone does not mandate indefinite anticoagulation after a first provoked event. 2 Clinical context (provoked vs unprovoked, recurrence) matters more than genetic findings.
Anticoagulant Selection:
Direct oral anticoagulants (DOACs) are preferred over warfarin for most VTE patients unless contraindicated (mechanical heart valves, antiphospholipid syndrome with triple positivity, severe renal impairment). 2, 7
For patients with CrCl 15-30 mL/min: Observe closely for bleeding with reduced DOAC doses. 7
Common Pitfalls to Avoid
Never delay anticoagulation to obtain testing 1—this is the single most important principle
Do not interpret protein C, protein S, or antithrombin levels while on warfarin or heparin 1—these will be falsely low
Do not diagnose antiphospholipid syndrome from a single positive test 2—requires confirmation at ≥12 weeks
Do not use immunologic assays alone for protein C/S/antithrombin 4—functional assays detect clinically relevant deficiencies
Do not test asymptomatic family members routinely 4, 5—positive results create anxiety without clear management benefit; reserve testing for family members facing high-risk situations (surgery, pregnancy)
Do not assume single subsegmental PE on CT is real 2—discuss with radiologist and consider second opinion to avoid overdiagnosis
Avoid testing during acute thrombosis for protein C/S/antithrombin 3—acute clot consumption causes falsely low levels
Special Populations
Pregnancy:
- LMWH is preferred over warfarin (warfarin is teratogenic) 2
- Use formal diagnostic algorithms including CTPA or V/Q scan if needed—these are safe during pregnancy 2
Cancer Patients:
- LMWH or DOACs preferred over warfarin for cancer-associated thrombosis 2
- Consider indefinite anticoagulation given high recurrence risk 2