What labs are included in a hypercoagulable workup?

Laboratory Workup for Hypercoagulable State

First-Line Essential Tests

All patients being evaluated for hypercoagulability should undergo a standardized first-line panel consisting of CBC with platelet count, PT/INR, aPTT, fibrinogen level, and D-dimer. 1

• Complete Blood Count (CBC) with platelet count is mandatory to identify thrombocytosis, polycythemia, or other hematologic abnormalities that directly contribute to thrombotic risk 1
• Prothrombin Time (PT)/International Normalized Ratio (INR) evaluates the extrinsic coagulation pathway and helps identify factor VII deficiency or vitamin K-dependent factor abnormalities 1, 2
• Activated Partial Thromboplastin Time (aPTT) assesses the intrinsic pathway and can detect deficiencies in factors VIII, IX, XI, XII, as well as lupus anticoagulant 1, 2
• Fibrinogen level is critical as elevated fibrinogen is associated with arterial thrombosis risk 1
• D-dimer levels indicate active fibrinolysis and ongoing thrombosis, though this is nonspecific 1
• Anti-PF4 antibody testing must be added immediately if the patient has recent heparin exposure (within past 100 days) and thrombocytopenia, as heparin-induced thrombocytopenia is a life-threatening hypercoagulable emergency 1

Second-Line Thrombophilia Testing

For Venous Thromboembolism

Patients with unprovoked VTE, recurrent VTE, or VTE at unusual sites require comprehensive thrombophilia testing including genetic and acquired deficiencies. 1

• Factor V Leiden mutation (most common inherited thrombophilia in Caucasians) 1
• Prothrombin gene mutation (G20210A) 1, 2
• Protein C deficiency (functional assay preferred) 1, 3
• Protein S deficiency (both free and total protein S levels) 1, 3
• Antithrombin III deficiency 1, 3
• Antiphospholipid antibody panel including lupus anticoagulant, anticardiolipin antibodies (IgG and IgM), and anti-β2 glycoprotein I antibodies 1, 2

For Arterial Thrombosis

Arterial thrombosis workup should prioritize antiphospholipid syndrome testing and platelet function abnormalities rather than inherited thrombophilias. 1

• Antiphospholipid antibody panel (same as above) is the highest yield test for arterial events 1, 2
• Homocysteine levels (fasting) to identify hyperhomocysteinemia, though treatment benefit for primary prevention remains unclear 2
• Platelet function studies including platelet aggregation studies and platelet function analyzer (PFA-100/200) when platelet-mediated hypercoagulability is suspected 1

Advanced Specialized Testing

When standard thrombophilia testing is negative but clinical suspicion remains high, consider advanced functional assays. 1

• Thrombin generation assay provides global assessment of coagulation potential and may identify subtle hypercoagulable states missed by standard testing 1
• Fibrinolysis assays assess for hypofibrinolysis, which can contribute to thrombotic risk 1
• Procoagulant platelet detection using flow cytometry with Annexin-V or GSAO combined with CD62p can identify procoagulant platelet formation, particularly useful in suspected HIT or unexplained thrombosis 1

Critical Timing Considerations

Testing must be performed at the appropriate time to avoid false results, as acute thrombosis, inflammation, pregnancy, and anticoagulation therapy significantly alter results. 1

• Protein C, Protein S, and Antithrombin III levels are consumed during acute thrombosis and will be falsely low; ideally test 2-4 weeks after acute event 1
• Warfarin therapy lowers protein C and protein S levels (vitamin K-dependent); testing should be delayed until at least 2 weeks after warfarin discontinuation 1
• Direct oral anticoagulants (DOACs) can interfere with lupus anticoagulant testing and functional assays; specialized interpretation or delayed testing is required 1
• Antiphospholipid antibodies require confirmation with repeat positive testing at least 12 weeks apart to meet diagnostic criteria 1
• Pregnancy and oral contraceptives lower protein S levels and can cause false-positive results 1

Common Pitfalls to Avoid

• Do not order hypercoagulable workup during acute thrombosis or active anticoagulation unless testing for antiphospholipid antibodies or genetic mutations (Factor V Leiden, prothrombin gene mutation), which are not affected by these conditions 1
• Do not rely solely on PT/INR and aPTT to assess thrombotic risk, as these tests can be normal or even prolonged in hypercoagulable states (paradoxically, prolonged INR and aPTT have been associated with increased thrombosis risk in cirrhosis) 2
• Do not assume a negative standard thrombophilia panel excludes hypercoagulability; consider functional platelet assays and thrombin generation testing in high-risk patients with negative initial workup 1
• Do not forget to screen for acquired causes including malignancy, myeloproliferative disorders, nephrotic syndrome, and antiphospholipid syndrome, which are more common than inherited thrombophilias 4, 5