What is the clinical significance of abnormal factor V levels in patients with suspected coagulation disorders and a history of bleeding or thrombotic events?

Clinical Significance of Factor V Levels

Abnormal factor V levels have limited clinical significance in thrombotic risk assessment, but critically important implications for bleeding disorders—low levels (<50% activity) indicate a rare hereditary bleeding disorder requiring specific management, while normal or elevated levels do not predict thrombotic risk and should not guide anticoagulation decisions. 1, 2

Factor V Deficiency (Low Levels): Bleeding Risk

Diagnostic Thresholds and Clinical Manifestations

• Factor V activity <50% indicates true factor V deficiency, a rare autosomal recessive bleeding disorder with an estimated incidence of 1 per 1 million in the general population 3
• The most common bleeding manifestations are mucosal bleeding (epistaxis, menorrhagia, gingival bleeding) and postoperative hemorrhage, though hemarthroses, intramuscular hemorrhages, and intracranial hemorrhage can occur 1, 3
• Factor V levels correlate poorly with bleeding severity—patients with the same factor V level may have vastly different bleeding phenotypes, making clinical history more important than the absolute number 1

Critical Diagnostic Distinction

• Both PT and aPTT will be prolonged in true factor V deficiency, distinguishing it from isolated factor VIII or IX deficiency 4
• Measure both factor V activity AND antigen levels to differentiate true deficiency from pseudohomozygous APC resistance: in true deficiency both are ~50%, while in pseudohomozygous APC resistance activity is ~50% but antigen is normal 4
• Factor V deficiency can be acquired in settings of rheumatologic disorders, malignancies, antibiotic use, and most commonly with topical bovine thrombin exposure 1

Treatment Approach for Low Factor V

• Fresh frozen plasma (FFP) remains the mainstay of treatment as no factor V-specific concentrate is widely available, though a plasma-derived FV concentrate has shown efficacy 1, 3
• Antifibrinolytics provide significant benefit for mucosal bleeding and should be used as adjunctive therapy 1
• For refractory bleeding or patients with inhibitors, consider prothrombin complex concentrates, recombinant activated factor VIIa, or platelet transfusions (since platelets contain factor V in alpha-granules) 1

Factor V Levels and Thrombotic Risk: No Clinical Utility

High Factor V Levels

• Neither elevated nor low factor V antigen levels are associated with venous thromboembolism risk—a study of 474 thrombosis patients versus 474 controls found no association between factor V levels (range 41-305 U/dL) and thrombotic events 2
• Factor V levels increase by 7.6 U/dL per decade of age but this physiologic increase does not confer thrombotic risk 2
• Factor V levels do not modify the thrombotic risk associated with elevated factor VIII levels, despite correlation between the two factors 2

Low Factor V Levels and APC Resistance

• Low factor V levels do NOT create an APC-resistant phenotype or increase thrombotic risk when factor V Leiden is absent 2
• The normalized APC ratio is not influenced by factor V antigen levels in subjects with or without factor V Leiden 2
• Pseudohomozygous APC resistance (heterozygous factor V Leiden combined with heterozygous true factor V deficiency) can present with severe thrombosis, but this is driven by the factor V Leiden mutation, not the low factor V level per se 4

Factor V Leiden vs. Factor V Levels: Critical Distinction

Factor V Leiden Testing (Not Factor V Levels)

• Factor V Leiden (R506Q mutation) is the only molecular analysis of the factor V gene indicated for thrombotic risk assessment—it accounts for 90-95% of APC resistance cases 5
• The lifetime thrombosis risk for factor V Leiden heterozygotes is approximately 10%, while homozygotes exceed 80% 5, 6
• Testing for factor V Leiden should be considered in patients with venous thromboembolism, particularly those with early-onset events, unusual thrombosis sites, recurrent thrombosis, or family history 5

Comprehensive Thrombophilia Workup

• When ordering factor V Leiden testing, simultaneously consider testing for prothrombin 20210A mutation and plasma homocysteine levels, as venous thrombosis is multifactorial and multiple genetic risk factors commonly coexist 5
• Functional coagulation assays for antithrombin III, protein C, and protein S should be performed as part of comprehensive thrombophilia evaluation 5
• Compound heterozygosity (factor V Leiden plus prothrombin 20210A) confers high recurrence risk and may warrant indefinite anticoagulation 5, 6

Neuraxial Anesthesia Considerations

• For patients with factor V deficiency requiring neuraxial anesthesia, maintain factor V levels ≥50 IU/dL during the procedure and while epidural catheters remain in situ 5
• This threshold parallels recommendations for hemophilia and other coagulation factor deficiencies 5
• Individualized risk assessment must account for bleeding history severity, not just laboratory values 5

Common Pitfalls to Avoid

• Do not use factor V antigen or activity levels to assess thrombotic risk—they have no predictive value for venous thromboembolism 2
• Do not confuse factor V deficiency with factor V Leiden—these are entirely different entities with opposite clinical implications (bleeding vs. thrombosis) 4, 7
• Do not assume low factor V levels create APC resistance—this only occurs when combined with factor V Leiden mutation 4, 2
• Do not rely solely on factor V levels to predict bleeding severity—clinical bleeding history is more informative than laboratory values 1
• In suspected child abuse cases with intracranial hemorrhage, recognize that factor V deficiency is extraordinarily rare (probability 1 in 5-10 million for causing ICH) and should not be invoked without compelling laboratory evidence 5