What constitutes the diagnosis of a secondary hypercoagulable state?

Diagnosis of Secondary Hypercoagulable States

Secondary hypercoagulable states are acquired disorders in patients with underlying systemic diseases or clinical conditions known to be associated with an increased risk of thrombosis. 1 The diagnosis requires identifying specific underlying conditions that predispose to thrombosis, rather than inherited abnormalities of coagulation that characterize primary hypercoagulable states.

Underlying Conditions Associated with Secondary Hypercoagulability

The diagnosis of a secondary hypercoagulable state is based on identifying one or more of the following underlying conditions:

Malignancy

• Active cancer is a major cause of secondary hypercoagulability
• Tumor cells can produce and secrete procoagulant/fibrinolytic substances and inflammatory cytokines 2
• Physical interaction between tumor cells and blood components (monocytes, platelets, neutrophils) or vascular cells promotes thrombosis

Inflammatory and Autoimmune Disorders

• Antiphospholipid syndrome is a key acquired hypercoagulable state
  • Requires positive testing for antiphospholipid antibodies (aPL)
  • Two most frequent tests: anticardiolipin antibodies (more prevalent, less specific) and lupus anticoagulants (less prevalent, more specific) 3
  • According to current criteria (revised Sapporo criteria), at least two positive tests should be recorded with an interval of at least 12 weeks 3

Pregnancy and Hormonal Therapy

• Pregnancy
• Oral contraceptive use
• Hormone replacement therapy

Hematologic Disorders

• Myeloproliferative disorders
• Paroxysmal nocturnal hemoglobinuria
• Heparin-induced thrombocytopenia

Metabolic and Systemic Conditions

• Hyperlipidemia
• Diabetes mellitus
• Nephrotic syndrome
• Chronic kidney disease
  • Associated with augmented expression of tissue factor and von Willebrand factor
  • Amplified platelet activation and altered fibrinolysis 3

Acute Medical Conditions

• Sepsis/infection
• Disseminated intravascular coagulation (DIC)
  • Defined as "an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes" 3
  • Laboratory findings include decreased plasma levels of coagulation factors (including fibrinogen), thrombocytopenia, and increased plasma levels of fibrin degradation products
  • A mandatory condition for DIC diagnosis is the presence of an underlying disorder known to be associated with DIC 3

Circulatory and Vascular Factors

• Prolonged immobilization
• Trauma
• Surgery
• Vascular injury
• Heart failure with atrial fibrillation
  • Disorganized atrial contraction with reduced atrial blood flow
  • Atrial fibrosis
  • Endothelial and endocardial injury and dysfunction 3

Laboratory Evaluation

While specific laboratory tests may support the diagnosis of a secondary hypercoagulable state, the diagnosis primarily rests on identifying the underlying condition. Relevant laboratory tests may include:

• Complete blood count with platelet count
• Coagulation studies (PT, aPTT, fibrinogen)
• D-dimer levels
• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-β2 glycoprotein I)
• Inflammatory markers (CRP, ESR)
• Specific tests based on suspected underlying condition

Diagnostic Approach

1. Identify risk factors for secondary hypercoagulable states
2. Evaluate for clinical manifestations of thrombosis (arterial or venous)
3. Perform targeted laboratory testing based on suspected underlying condition
4. Exclude primary hypercoagulable states when appropriate (especially in younger patients with unusual or recurrent thrombosis)
5. Confirm the underlying condition responsible for the hypercoagulable state

Clinical Scenarios Warranting Evaluation

• Recurrent thrombotic events
• Thrombosis at unusual sites (cerebral, mesenteric, portal, hepatic veins)
• Thrombosis in the absence of traditional risk factors
• Thrombosis in the context of a known predisposing condition

Pitfalls and Caveats

• Timing of testing matters: Acute thrombosis, anticoagulation therapy, and acute phase reactions can affect test results
• Multiple factors may contribute: Secondary hypercoagulable states often involve multiple pathophysiologic mechanisms
• Distinguish from primary states: Secondary hypercoagulable states are acquired conditions, unlike inherited primary hypercoagulable disorders
• Testing for antiphospholipid antibodies: The definition of a significant positive result has not been uniformly delineated, making it difficult to give accurate prevalence data or risk of stroke associated with aPL 3
• Consider testing limitations: For protein C, protein S, or antithrombin levels, testing should be deferred or repeated at least 4-6 weeks after acute events (or up to 6 months for factor VIII) as these protein levels may be altered during acute phases 3

The diagnosis of secondary hypercoagulable states requires a thorough evaluation to identify the underlying condition predisposing to thrombosis, with laboratory testing serving as a supportive rather than definitive diagnostic tool.