Factor V Deficiency

Etiology

Factor V deficiency may either be inherited or acquired. These forms arise from different causes, explained below.

Inherited Factor V Deficiency

Inheritance follows an autosomal recessive pattern, with F5 gene (1q23) mutations transmitted either homozygously or heterozygously. Heterozygous carriers are typically asymptomatic. In contrast, homozygotes and compound heterozygotes, possessing germline variants of 2 different mutations at the same genetic locus, may exhibit a wide range of signs and symptoms, from mild to severe bleeding.

Factor V deficiency is categorized into types 1 and 2. Type 1 involves a quantitative reduction in factor V activity and antigen levels. Type 2 involves qualitative dysfunction, with decreased coagulant activity despite normal or low factor V antigen levels.[11][12] Over 190 mutations have been identified, predominantly missense and nonsense mutations, followed by small deletions, splicing mutations, and, less frequently, small and large insertions, large deletions, and complex rearrangements. Symptoms typically manifest before age 6. Rarely, factor V deficiency is coinherited with factor VIII deficiency.

Combined Congenital Factor V and Factor VIII Deficiency

Combined factor V and factor VIII deficiency (F5F8) is extremely rare, accounting for about 3% of all rare coagulopathies.[13] The condition occurs most often in regions where consanguineous marriages are common, such as the Middle East and South Asia.

F5F8 is inherited in an autosomal recessive pattern. The congenital deficiency results from mutations in either the LMAN1 or MCFD2 genes, which encode components of the transport apparatus responsible for moving factors V and VIII from the endoplasmic reticulum to the Golgi complex. The LMAN1 gene is located on chromosome 18 (18q21.32) and contains 13 exons, whereas the MCFD2 gene is located on chromosome 2 (2p21) and contains 4 exons. Combined F5F8 deficiency is associated with significant hemorrhagic complications, most notably obstetrical bleeding.

Factor V-related bleeding is managed with FFP and tranexamic acid. Bleeding from factor VIII deficiency requires the addition of factor VIII concentrate.

Acquired Factor V Deficiency

Acquired factor V deficiency is less common than the inherited form and results from the production of factor V inhibitors. Reported risk factors include surgery involving bovine thrombin, certain antibiotics (particularly β-lactams), malignancies, infections, liver disease, and autoimmune disorders.[14] COVID-19 vaccination has also been associated with acquired factor V deficiency, as well as deficiencies of factors VIII and XIII.[15]

Current clinical recommendations include performing mixing tests with prolonged incubation, as some factor V inhibitors may be “slow responders.”[16] Factor V deficiency has been reported in cases of chronic myelogenous leukemia, particularly during phases of extreme leukocytosis.[17] Predicting bleeding episodes in this condition is challenging, as symptoms may not consistently correlate with factor V inhibitor levels, the duration of inhibitor presence, aPTT and prothrombin time prolongation, or factor V activity.

Epidemiology

Factor V deficiency is a rare bleeding disorder with an estimated prevalence of 1 per 1 million live births. The condition is typically inherited in an autosomal recessive pattern, affecting both sexes equally, with nearly 200 confirmed mutations. No specific ethnic group has been identified as being at increased risk. However, the deficiency occurs more frequently in regions where consanguineous marriages are common.[18] Recent genetic work identified a homozygous mutation of exon 16 (Met1736Val) in a family in Taiwan.[19]

Pathophysiology

Congenital factor V deficiency, although rare, can cause uncontrolled bleeding, with the triggers for spontaneous episodes remaining unknown. Acquired factor V inhibitors, in contrast, are frequently associated with exposure to bovine thrombin. Such exposure may induce antibodies against bovine factor V that, through cross-reactivity, stimulate autoantibody production against human factor V.[20]

Family history is an important consideration in genetic bleeding disorders. However, the absence of similar complaints among the patient’s relatives suggests a possible noninheritable factor V deficiency, although further evidence is required. Factor V deficiency is distinct from the more common factor V Leiden mutation, which produces resistance to activated protein C and prevents inhibition of factor V’s procoagulant activity. Individuals with factor V Leiden mutations have an increased risk of venous thromboembolism.

History and Physical

History

Factor V deficiency can present with a wide array of bleeding symptoms. The inherited form can manifest in infants, while the acquired form can present at any age and may be more challenging to diagnose. When inherited, symptoms usually appear before age 6, though some mild congenital forms may not manifest until adulthood. Bleeding due to inherited factor V deficiency is indistinguishable from that in other coagulation disorders.

In patients with a known family history, cord blood sampling at birth can enable early diagnosis and intervention. Neonatal signs and symptoms reported in the literature include umbilical stump bleeding, nipple bleeding, epistaxis, gum bleeding, and subcutaneous hematomas. Life-threatening intracranial hemorrhage may also occur and often initially presents as hydrocephalus or seizures in infants, warranting an immediate workup to prevent significant morbidity and mortality.[21][22]

Manifestations of factor V deficiency in older children and adults often include mucocutaneous and soft tissue bleeding such as ecchymosis, easy bruising, petechiae, epistaxis, hemoptysis, hematemesis, melena, hemarthrosis, hematuria, menorrhagia in women, and prolonged bleeding after surgery or trauma. Serious internal hemorrhage may also occur, and if not recognized early, mortality can reach 15% to 20%.

For the congenital type, obtaining an accurate family history of bleeding diathesis is key to early diagnosis. Identifying consanguinity within the family may also help. For the acquired type, critical information includes recent surgical procedures with bovine thrombin exposure, malignancies, infections, liver disease, antibiotic use (particularly the β-lactam group), or autoimmune disease.

Physical Examination

Bleeding in patients with factor V deficiency may be external or internal. A thorough physical examination is critical to diagnosis and management. Vital signs must be checked to assess hemodynamic status. Tachycardia and hypotension may indicate hemodynamic compromise in a bleeding patient. The oral and nasal cavities must be inspected for mucosal bleeding. Chest auscultation is essential for patients presenting with hemoptysis. Trauma-prone areas such as the extremities must be inspected for ecchymoses, petechiae, or subcutaneous hematomas. The genitals should also be examined, particularly in individuals with hematuria or menorrhagia.

Patients presenting with hematemesis or melena require a detailed abdominal examination, including a digital rectal examination. Abdominal tenderness or distension may be noted. Patients with neurological manifestations such as seizures, altered mental status, or focal neurological deficits should undergo a detailed neurological assessment. A bulging anterior fontanelle suggests increased intracranial pressure in infants. Unresponsiveness, apnea, and pulselessness are signs of cardiorespiratory arrest. Resuscitation measures must be initiated immediately in such cases, regardless of the cause.

Evaluation

Laboratory evaluation should be initiated when clinical findings suggest a bleeding disorder. Studies that may yield the appropriate diagnosis include coagulation tests, factor assays, inhibitor screening, and molecular genetic testing, as explained below.

Coagulation Tests

Factor V deficiency prolongs both prothrombin time and aPTT but leaves thrombin time unaffected. These prolonged clotting times are not specific to factor V deficiency but suggest a defect within the common pathway. Additional testing for other common pathway factors, such as fibrinogen, factor II, and factor X, is necessary to specify the defect. Liver disease can also prolong prothrombin time and aPTT due to decreased clotting factor synthesis. After confirming factor V deficiency, mixing studies help distinguish between a lack of factor V and the presence of an anti–factor V inhibitor. Correction of clotting times after mixing indicates factor V deficiency, whereas failure to correct suggests the presence of an inhibitor.

Factor Assays

Factor V assays reveal reduced activity levels, with the deficiency classified as mild (>10%), moderate (1% to 10%), or severe (<1%). All factor activity levels should be measured to determine whether a coexisting deficiency is present, as in combined factors V and VIII deficiency.

Inhibitor Screening

Nonspecific inhibitor screening may involve lupus anticoagulant testing and enzyme-linked immunosorbent assay (ELISA) for β-2 glycoprotein and cardiolipin antibodies, which may be elevated in acquired factor V deficiency. The Bethesda assay, which measures inhibitors against a specific coagulation factor in the blood, confirms the diagnosis.

Molecular Genetic Analysis

The F5 gene, located on chromosome 1q24.2 and spanning 25 exons, consists of 6 domains: A1, A2, A3, B, C1, and C2. Sequencing DNA from peripheral blood leukocytes can identify mutations within this gene to diagnose inherited factor V deficiency. Missense mutations are most often located (61.5%) in domains A2 and C2, with an additional 20% in the B domain. A single heterozygous mutation typically results in factor V activity levels around 50%, whereas homozygous or compound heterozygous mutations often lead to levels below 10%. Mutations in the MCFD2 and LMAN1 genes cause combined factor V and VIII deficiency, as these genes are involved in the transport of these coagulation factors.[23]

Treatment / Management

Treatment depends on the condition's etiology and severity. Mild inherited factor V deficiency may be managed with antifibrinolytics, while more severe phenotypes often require FFP transfusions to replenish factor V levels. Factor V deficiency is uncommon. Thus, a specific factor V concentrate is not commercially available. Other blood products (eg, platelets, prothrombin complex, or cryoprecipitate) contain minimal factor V, making FFP the primary therapy for moderate-to-severe cases. FFP sustains factor V levels above 25% to 30% during bleeding episodes or invasive procedures, with higher levels required to ensure hemostasis in severe or life-threatening hemorrhages.

Asymptomatic patients with acquired factor V deficiency do not require treatment because the inhibitors present in the blood are transient. A multifactorial approach is often necessary for patients undergoing surgery or those experiencing significant bleeding. Measures to control bleeding include transfusion of FFP, platelets, prothrombin complex concentrate, and recombinant activated factor VII. Although platelet α-granules contain minimal factor V, platelet transfusions alone have achieved a 71% success rate in treating acquired factor V deficiency by protecting factor V from inhibitors and promoting hemostasis.

Recombinant activated factor VII, commonly used for inhibitors in hemophilia A or B, can also manage bleeding by directly activating factor X, bypassing the requirement for factor V or other coagulation factors.[24] Immunosuppression remains the gold standard for eliminating factor V inhibitors. Corticosteroids, cyclophosphamide, and rituximab, alone or in combination, suppress anti–factor V autoantibody production with a 63% success rate. High-dose intravenous immunoglobulin (60% success rate) and plasmapheresis (53% success rate) also reduce circulating factor V inhibitors.[25]

Differential Diagnosis

Disorders affecting the coagulation cascade and platelet function cannot be differentiated based solely on clinical presentation. Additional diagnostic testing is required for accurate identification of the condition.

Coagulation Cascade Abnormalities

Coagulation studies can determine specific protein and factor deficiencies. Hemophilia A and B, the most common inherited bleeding disorders, are routinely included in the differential diagnosis. Hemophilia A (factor VIII deficiency), B (factor IX deficiency), and C (factor XI deficiency) typically present with isolated aPTT prolongation. These disorders are distinguished from factor V deficiency by measuring factors VIII, IX, or XI, which are decreased, with a normal prothrombin time.

Disorders producing prolonged prothrombin time and aPTT with a normal thrombin time include deficiencies of common pathway factors (II or X), combined factor V and VIII co-deficiency, vitamin K-dependent factor deficiencies (II, VII, IX, X), and liver disease. Afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia also cause prolonged prothrombin time and aPTT, but thrombin time is likewise prolonged in these conditions. Thrombotic or hemorrhagic events can occur, although many patients remain asymptomatic.

Platelet Dysfunction

Von Willebrand disease, the most common inherited bleeding disorder, occurs with a variable clinical spectrum ranging from mild mucosal bleeding in type 1 to severe hemorrhage resembling hemophilia in type 3. Laboratory findings include prolonged or normal aPTT, normal prothrombin time, normal-to-low platelet count, and normal-to-low factor VIII level. Less common inherited platelet function disorders include Glanzmann thrombasthenia (αIIbβ3 integrin deficiency or defect) and Bernard–Soulier syndrome (GPIb-IX-V complex deficiency or defect). These disorders show normal prothrombin time and aPTT, reflecting impaired platelet adhesion or aggregation independent of the coagulation cascade.[26]

Prognosis

Congenital and acquired factor V deficiency are both exceedingly rare. Data are insufficient to determine the long-term prognosis of affected individuals. However, mortality rates as high as 21% have been documented in patients who present with severe bleeding manifestations.

Complications

Complications of factor V deficiency may occur as early as the neonatal period. Although uncommon, intracranial hemorrhage poses diagnostic challenges in newborns and carries a high mortality rate. Thrombotic events, while less frequent, can arise from factor V's prothrombotic effect, with reported cases including deep vein thrombosis, cerebral infarction, and limb gangrene. Prompt recognition of factor V deficiency is essential to initiate treatment and prevent potentially life-threatening outcomes.