What is the significance of low Factor V, Factor VII, and Factor XII with normal Factor VIII levels?

From the Guidelines

This pattern of low factors V, VII, and XII with normal factor VIII suggests vitamin K deficiency or liver dysfunction, and the recommended approach is to administer vitamin K and evaluate for underlying causes. The significance of low Factor V, Factor VII, and Factor XII with normal Factor VIII levels can be understood by considering the role of vitamin K in the synthesis of coagulation factors. Vitamin K is essential for the synthesis of factors II, VII, IX, and X, which are involved in the coagulation cascade [ 1 ]. Factor V is not vitamin K-dependent but is synthesized in the liver, so its deficiency can indicate liver dysfunction. Factor VIII is produced outside the liver, explaining its normal level.

Recommended Approach

• Administer vitamin K: Give 10 mg of vitamin K1 (phytonadione) subcutaneously or orally, as recommended by the American College of Chest Physicians [ 1 ]. Repeat daily for 3 days if needed.
• Evaluate for underlying causes: Check liver function tests, assess nutritional status, and review medications that may interfere with vitamin K metabolism (e.g., antibiotics, warfarin).
• Monitor coagulation factors: Recheck factor levels after vitamin K administration to confirm improvement.
• Consider further testing: If factors don't normalize with vitamin K, investigate for liver disease or rare factor deficiencies.

Rationale

The use of recombinant activated factor VII (rFVIIa) has been studied in the treatment of severe bleeding after surgery, obstetric procedures, or trauma [ 1 ]. However, its efficacy remains unclear, and randomized controlled trials are scarce. In contrast, vitamin K administration has been shown to be effective in reversing vitamin K deficiency and improving coagulation factor levels [ 1 ]. The European guideline on management of major bleeding and coagulopathy following trauma recommends the use of vitamin K and prothrombin complex concentrates (PCC) for the reversal of vitamin K antagonists [ 1 ].

Key Considerations

• Vitamin K is essential for the synthesis of factors II, VII, IX, and X.
• Factor V is not vitamin K-dependent but is synthesized in the liver.
• Factor VIII is produced outside the liver, explaining its normal level.
• Prompt treatment is crucial to prevent bleeding complications.
• If bleeding is present or procedures are planned, fresh frozen plasma may be necessary for immediate factor replacement.

From the Research

Significance of Low Factor V, Factor VII, and Factor XII with Normal Factor VIII Levels

• Low levels of Factor V can be caused by mutations in the FV gene or in genes encoding components of a putative cargo receptor that transports FV (and factor VIII) from the endoplasmic reticulum to the Golgi 2
• Factor V deficiency can lead to bleeding from mucosal surfaces and postoperative haemorrhage, but the overall phenotype is less severe than patients with haemophilia A or B 2
• Combined deficiency of Factor V and Factor VIII (F5F8D) is a rare autosomal-recessive bleeding disorder caused by mutations in lectin mannose binding-1 (LMAN1) and multiple coagulation factor deficiency-2 (MCFD2) 3
• Low Factor V levels can ameliorate bleeding diathesis in patients with F5F8D, and Desmopressin (DDAVP) infusion may be considered a potential substitute for FVIII concentrates 3
• Factor VII deficiency is a rare bleeding disorder, and bleeding manifestations can range from mild to severe, but the most common are mucocutaneous bleeding 4
• Factor XII deficiency is not typically associated with bleeding, but it can increase the risk of thrombosis 4
• Normal Factor VIII levels in the presence of low Factor V, Factor VII, and Factor XII levels may indicate a mild bleeding phenotype, but the exact significance depends on the underlying cause of the factor deficiencies 2, 3, 5

Clinical Implications

• Patients with low Factor V, Factor VII, and Factor XII levels and normal Factor VIII levels may require fresh frozen plasma or dedicated single-factor concentrates for treatment of acute bleeding events or surgical management 2, 4
• Desmopressin (DDAVP) infusion may be considered a potential substitute for FVIII concentrates in patients with F5F8D 3
• Vitamin K deficiency can also affect the levels of clotting factors, including Factor VII, and may require prophylactic or therapeutic treatment with vitamin K 6