What initial laboratory workup is recommended for evaluating a suspected hypercoagulable state?

Hypercoagulability Laboratory Workup

Initial Screening Panel

For suspected hypercoagulable states, order a comprehensive initial panel including antithrombin III (both activity and antigen), protein C (both activity and antigen), protein S (both free and total levels), lupus anticoagulant testing, anticardiolipin antibodies, factor V Leiden mutation, prothrombin G20210A mutation, and homocysteine levels. 1, 2

Core Thrombophilia Tests

• Measure both biological activity and antigen levels of antithrombin III, protein C, and protein S as these dual measurements are essential for detecting quantitative versus qualitative deficiencies that predispose to thrombosis 1, 2

• Test for plasminogen activity and antigen levels to screen for plasminogen deficiency, and include fibrinogen testing to detect dysfibrinogenemia 1, 2

• Order factor V Leiden and prothrombin G20210A mutation testing as these are the most common inherited thrombophilias, though note that activated protein C resistance testing is unnecessary in Japanese populations where it is extremely rare 1

Antiphospholipid Antibody Syndrome Screening

• Perform lupus anticoagulant testing using dilute phospholipid APTT (dAPTT) or dilute Russell viper venom time (dRVVT) as these are simple, reliable screening tests for lupus anticoagulant 1

• Follow positive screening with a 50:50 mixing study to confirm the presence of an inhibitor rather than factor deficiency 3, 1

• Use confirmatory phospholipid neutralization tests (STACLOT or LA-CONFIRM kits) to definitively diagnose lupus anticoagulant after positive screening and mixing studies 1

• Measure anticardiolipin antibodies (IgG and IgM) and anti-beta-2-glycoprotein I antibodies as part of comprehensive antiphospholipid syndrome evaluation 2

Coagulation Activation Markers

• Order D-dimer, prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complex (TAT), and soluble fibrin polymer (TpP) to assess current hypercoagulable activity, as these markers directly correlate with the number of underlying thrombophilic abnormalities 1, 4

• Prioritize soluble fibrin polymer measurement as it may be more reflective of an impending vascular event compared to other activation markers 4

• Use TAT and PIC (plasmin-alpha2-plasmin inhibitor complex) for early detection of hypercoagulable states, particularly when evaluating for disseminated intravascular coagulation 1

Basic Coagulation Studies

• Obtain PT/INR, aPTT, fibrinogen, and platelet count as baseline screening tests to exclude other coagulation abnormalities and establish whether any PTT elevation is isolated 5, 1

• Verify specimen quality by examining the sample tube for clots and reviewing the blood smear to exclude platelet aggregates that cause spurious results 5, 3

• Redraw using citrate tube if EDTA-related pseudoprolongation is suspected, as a new citrate sample often rules out false thrombocytopenia on EDTA 5

Patient Selection for Testing

• Focus testing on patients under 50 years with unexplained thrombosis, recurrent thrombotic events, thrombosis in unusual sites (cerebral, mesenteric, portal veins), family history of thrombosis, or thrombosis without recognizable predisposing factors 2, 6

• The diagnostic yield is typically low in unselected older patients with ischemic stroke, so avoid routine screening in this population 6

• Screen patients presenting with arterial thromboembolism who are younger than typical atherosclerosis patients (ages 41-62), especially male smokers with ischemic rest pain, blue toe syndrome, or rapidly progressive claudication 7

Additional Testing for Specific Clinical Scenarios

• Include platelet aggregometry when evaluating arterial thromboembolism, as hyperaggregable platelets represent a distinct hypercoagulable mechanism 7

• Order homocysteine levels, fasting lipid profile, and glucose to identify secondary hypercoagulable contributors such as hyperhomocysteinemia, hyperlipidemia, and diabetes mellitus 2

Critical Timing and Interpretation Pitfalls

• Avoid testing protein C, protein S, and antithrombin III during acute thrombosis or while on anticoagulation, as these levels are artificially decreased and yield false-positive results for deficiency

• Do not order comprehensive factor panels without mixing study guidance when evaluating isolated PTT elevation, as this approach is inefficient and costly 3

• Recognize that multiple underlying thrombophilic abnormalities increase thrombotic risk exponentially, as coagulation activation marker levels directly correlate with the number of hypercoagulable abnormalities present 4

• Remember that approximately 5-10% of ischemic strokes are attributable to blood disorders, with higher frequency in younger patients, making selective rather than universal screening appropriate 6