What investigations should be sent for a suspected prothrombotic state?

Laboratory Investigations for Suspected Prothrombotic State

For patients with suspected prothrombotic states, initial testing should include complete blood count with platelet count, PT/INR, aPTT, and screening for antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), with additional thrombophilia testing reserved for specific clinical scenarios such as age under 50, recurrent thrombosis, or strong family history. 1, 2

Initial Core Laboratory Panel

The baseline workup should establish both the presence of thrombosis and identify potential underlying causes:

• Complete blood count with platelet count to assess for thrombocytopenia, polycythemia, or other hematologic abnormalities that may indicate myeloproliferative disorders 1, 3
• Prothrombin time (PT/INR) to evaluate the extrinsic coagulation pathway and identify potential factor deficiencies or anticoagulant effects 1, 3
• Activated partial thromboplastin time (aPTT) to assess the intrinsic coagulation pathway and screen for lupus anticoagulant 1, 3
• Fibrinogen level as a baseline marker and to assess for consumptive coagulopathy 1
• D-dimer can help exclude thrombosis when negative (particularly useful in venous thromboembolism), though elevated levels are nonspecific and occur in many hospitalized patients, cancer, and pregnancy 1

Antiphospholipid Antibody Screening

This is a critical component of the initial workup, as antiphospholipid syndrome is a major acquired prothrombotic state:

• Lupus anticoagulant testing should be performed in all patients with suspected prothrombotic states 1, 2
• Anticardiolipin antibodies (IgG and IgM) should be measured 1, 2
• Testing for antiphospholipid antibodies is particularly important in pregnancy-related thrombosis, as ITP in pregnancy may be associated with a prothrombotic state due to anticardiolipin antibody syndromes 1

Extended Thrombophilia Testing (Selective Use)

Additional thrombophilia testing should be reserved for specific populations rather than performed routinely, as most hereditary prothrombotic states are not established risk factors for arterial thrombosis 1, 2:

Indications for Extended Testing:

• Age under 50 years with thrombotic events 1, 2
• Recurrent thrombosis (particularly venous thromboembolism) 1, 2
• Strong family history of proven venous thromboembolism 1
• Paradoxical cerebral embolism (suggesting venous-to-arterial shunting) 2
• Thrombosis in unusual locations (cerebral venous thrombosis, mesenteric vein thrombosis) 1

Specific Tests When Indicated:

• Protein C deficiency (both functional activity and antigen levels) 1, 2, 4
• Protein S deficiency (both functional activity and antigen levels) 1, 2, 4
• Antithrombin III deficiency 1, 2
• Factor V Leiden mutation 1, 2
• Prothrombin gene mutation (G20210A) 1, 2
• Plasma total homocysteine level 1, 2

Additional Markers of Hypercoagulability (Research/Specialized Settings)

These tests indicate activation of coagulation but are not routinely necessary for clinical diagnosis:

• Thrombin-antithrombin complex (TAT) 1, 4
• Prothrombin fragment F1+2 1, 4
• Tissue-type plasminogen activator (t-PA) 4
• Plasminogen activator inhibitor-1 (PAI-1) 4

Clinical Context-Specific Testing

For Cancer-Associated Thrombosis:

• Routine blood tests and chest radiography are usually sufficient to detect occult cancer in idiopathic venous thromboembolism 1
• Extensive cancer screening is only indicated when clinically suspected based on symptoms, physical examination, or routine laboratory abnormalities 1
• Cancer patients may demonstrate elevated fibrinogen, increased platelet turnover, and elevated procoagulant factors 5

For Pediatric Stroke:

• One or more prothrombotic states are identified in 20-50% of children with arterial ischemic stroke and 33-99% with cerebral venous sinus thrombosis 1
• Protein C deficiency and genetic polymorphisms (factor V Leiden, prothrombin gene mutation) may be independent risk factors for recurrent arterial stroke in children 1
• Elevated lipoprotein(a) and homocysteine are known risk factors in childhood stroke 1

Critical Timing and Interpretation Caveats

Several important pitfalls can lead to false results:

• Acute thrombosis itself can transiently lower protein C, protein S, and antithrombin levels, making interpretation difficult 2
• Anticoagulation therapy (warfarin lowers protein C and S; heparin lowers antithrombin) interferes with testing, so ideally obtain samples before treatment or after adequate washout 2
• D-dimer levels decline with time from symptom onset, so patients presenting with subacute or chronic symptoms may have false-negative results 1
• Pregnancy is itself a prothrombotic state and alters many coagulation parameters, making interpretation challenging 1
• Liver disease, nephrotic syndrome, and inflammatory conditions can affect protein levels and coagulation tests 6

Algorithmic Approach

1. Initial presentation with thrombosis: CBC with platelets, PT/INR, aPTT, fibrinogen, D-dimer, lupus anticoagulant, anticardiolipin antibodies 1, 2

2. If age <50, recurrent thrombosis, or strong family history: Add protein C, protein S, antithrombin III, factor V Leiden, prothrombin gene mutation, homocysteine 1, 2

3. If pregnancy-related: Emphasize antiphospholipid antibody testing given association with ITP and prothrombotic state 1

4. If pediatric stroke: Broader thrombophilia panel including genetic polymorphisms, lipoprotein(a), and homocysteine 1

5. Defer extended testing if patient is acutely anticoagulated or has acute thrombosis; repeat when stable and off anticoagulation if clinically appropriate 2