Continuing Education Activity

Factor V deficiency is a rare bleeding disorder that can be inherited or acquired. Symptoms can range from mild mucosal bleeding to severe, life-threatening hemorrhages. To prevent morbidity and mortality, appropriate diagnosis and treatment are necessary. This activity outlines the evaluation and management of patients with factor V deficiency and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Summarize the presentation of a patient with factor V deficiency.
• Outline the causes of factor V deficiency.
• Explain the therapeutic management options for a patient with factor V deficiency.
• Review management approaches for factor V deficiency.

Introduction

Factor V deficiency, also known as Owren disease or parahemophilia, is a rare type of bleeding disorder that can be either inherited or acquired. Dr. Paul Owren first identified it in Norway in 1943.[1][2] The disease manifests itself similarly to other factor deficiencies, with symptoms ranging from minor mucosal bleeding to severe and life-threatening hemorrhages.[3] According to the literature, the severity of bleeding generally correlates to factor Va) levels; however, some patients experience mild bleeding symptoms even with factor Va levels below 1%.[4][5] Factor V deficiency can be categorized into mild, moderate, or severe based on the percentage of factor V in the plasma (>10%, 1 to 10%, <1%, respectively).[2][6]

Initial laboratory values show a prolonged prothrombin time (PT) and partial thromboplastin time (aPTT) with a normal thrombin time (TT). A low plasma level of factor V can confirm the diagnosis. The distinction between inherited and acquired forms of factor V deficiency is made by mixing plasma studies. In this test, normal plasma is added to the patient's plasma which has been determined to prolong the PT and aPTT. Normalization of the PT and aPTT occurs in the case of inherited forms, as the missing factor is replaced using the normal plasma. In acquired forms, the PT and aPTT remain prolonged after the addition of normal plasma due to the presence of an inhibitor in the patient's plasma.[6] 

This test is not specific to only factor V deficiency but helps determine if the prolongation of coagulation studies results from a factor deficiency vs. an inhibitor. Treatment varies depending on whether the factor V deficiency is inherited vs. acquired. When inherited, the mainstay of treatment is to transfuse fresh frozen plasma (FFP), which provides the patient with factor V. In mild cases, antifibrinolytics may be adequate to achieve hemostasis. The mainstay of treatment for acquired factor V deficiency can be more challenging and requires control of bleeding symptoms and elimination of autoantibodies against factor V. Bleeding control is achieved with FFP, platelet transfusions, prothrombin complex concentrates, antifibrinolytics, and/or recombinant activating factor VII, whereas factor V inhibitor eradication is accomplished with immunosuppression.[7]

Etiology

Factor V deficiency can be either inherited or acquired. 

Inherited Factor V Deficiency

• Inheritance is autosomal recessive.
• Mutations at the F5 gene (1q23) can be inherited in a homozygous or heterozygous pattern.
• Heterozygous carriers are usually asymptomatic, whereas homozygotes and compound heterozygotes can present with a broad array of signs and symptoms ranging from minimal to severe bleeding.[5]
• Factor V deficiency is classified into Type 1 and Type 2 deficiency. Type 1 is quantitative (factor V activity and antigen levels are reduced), whereas Type 2 is qualitative (factor V is dysfunctional, leading to decreased coagulant activity while factor V antigen can be low to normal).[8][9]
• One hundred ninety mutations have been identified, with the majority being missense and nonsense mutations. These are followed by small deletions, splicing mutations, and, less commonly, small and large insertions, large deletions, and complex rearrangements.[2][3]
• Symptoms usually present before the age of 6 years.
• Rarely can be co-inherited with Factor VIII deficiency.

Acquired Factor V Deficiency

• Less common than the inherited form.
• It occurs secondary due to factor V inhibitor production.
• Risk factors include surgery involving bovine thrombin, antibiotics (particularly the beta-lactam group), malignancies, infections, liver disease, and autoimmune disorders.[7] 
• Bleeding episodes can be difficult to predict since symptoms do not always correlate with factor V inhibitor levels, duration inhibitor has been present, aPTT and PT prolongation, or factor V activity.[6]

Epidemiology

Factor V deficiency is a rare bleeding disorder. The estimated prevalence is one per 1 million live births. It is inherited in an autosomal recessive pattern causing males and females to be equally affected, with nearly 200 confirmed mutations. Although no specific predisposed ethnicity has been identified, the disease has a higher incidence amongst countries where consanguinity is more prevalent.[10]

Pathophysiology

Factor V, also known as proaccelerin or labile factor, is a non-enzymatic coagulation protein that plays a crucial role in the coagulation cascade. The liver produces approximately 80%, with the remaining 20% being synthesized within alpha granules of platelets and megakaryocytes.[7] 

Once factor V is activated by either thrombin or factor Xa, it becomes the plasma cofactor of the prothrombinase complex. This complex, composed of calcium, phospholipids, factor Va, and factor Xa, aids in converting prothrombin to thrombin. Thrombin then activates factor XIII and fibrin leading to clot formation. Once hemostasis is achieved, factor Va is deactivated by protein C.

It is valuable to note that factor V also plays a vital role in the anticoagulation pathway. Together with protein C, factor V deactivates factor VIII leading to decreased prothrombinase activity and, ultimately, decreased thrombin and fibrin production. The end product is an overall decrease in clot production. This function of activated protein C (aPC) shifts the balance towards the inhibitory regulation of coagulation.[7][11] 

It is also essential to distinguish factor V deficiency from the more common factor V Leiden mutation, which results in resistance to activated protein C and the inability of protein C to adequately block the anticoagulant effects of factor V. Individuals with factor V Leiden mutations are therefore at increased risk of venous thromboembolic events.

History and Physical

Factor V deficiency can present with a wide array of bleeding symptoms ranging from mild to life-threatening hemorrhages. The inherited form can present in infants, and obtaining an accurate family history of bleeding diathesis and assessing for consanguinity within the family may be key to early diagnosis.[2] 

The acquired form can present at any age, including adulthood, and may be more elusive to diagnose. Critical history would include recent surgical procedures with bovine thrombin exposure, malignancies, infections, liver disease, use of antibiotics (particularly the beta-lactam group), and/or autoimmune diseases.[7]

Bleeding due to inherited factor V deficiency is indistinguishable from other coagulation disorders. In patients with a known family history, cord blood sampling at the time of birth can lead to early diagnosis and intervention. Signs and symptoms that have been reported include umbilical stump and nipple bleeding, epistaxis, gum bleeding, and subcutaneous hematomas. Life-threatening intracranial hemorrhages can also occur and often initially present as hydrocephalus and seizures in infants, warranting an immediate workup to prevent significant morbidity and mortality.[12][13] 

Clinical findings in children and adults with both the inherited or acquired form can range from asymptomatic to severe. When inherited, the symptoms usually ensue before the age of six years; however, milder cases may present in adulthood. Heavy menses, recurrent epistaxis, or prolonged bleeding after surgery or trauma may yield the suspicion of a bleeding disorder.

Manifestations of factor V deficiency often include mucocutaneous and soft tissue bleeding such as ecchymosis, easy bruising, petechiae, epistaxis, hemoptysis, hematemesis, melena, hemarthrosis, hematuria, and menorrhagia in females.[7] Serious internal hemorrhage may occur, and if not recognized early, mortality can be upwards of 15 to 20%.[14]

Evaluation

Laboratory evaluation for factor V deficiency should be initiated when a bleeding disorder is suspected based on the history obtained and/or physical exam findings. Studies that will yield the appropriate diagnosis include coagulation tests, factor assays, inhibitor screening (e.g., mixing studies), and molecular genetics.

1. Coagulation tests: Factor V is part of the common pathway within the coagulation cascade, and deficiency of factor V will prolong the PT and aPTT. Thrombin time, on the other hand, will be normal.[3] While helpful in identifying an issue within the coagulation cascade, prolongation of the PT and aPTT will not differentiate amongst other factor deficiencies involving the common pathway. Measurement of levels of other common pathway factors (e.g., fibrinogen, factor II, factor X) must be performed to isolate the specific defect. Additionally, liver disease can lead to prolongation of both the PT and aPTT due to decreased hepatic production of clotting factors. Once factor V deficiency has been confirmed, mixing studies are helpful to determine if the deficiency is purely a lack of factor V or has occurred due to the presence of an anti-factor V inhibitor. If the PT and aPTT are corrected, a factor deficiency is confirmed, whereas if no correction occurs, an inhibitor is likely.
2. Factor assays: When measured, factor V activity levels will be reduced and can be categorized into mild (>10%), moderate (10%), or severe (<1%). All factor levels should be measured to identify if a co-existing deficiency exists, such as combined factor V and factor VIII deficiency.[11]
3. Inhibitor screening: Common non-specific inhibitors used for screening include lupus anticoagulant and ELISA testing against beta-2 glycoprotein and cardiolipin antibodies. Their presence will support the diagnosis of an acquired form of factor V deficiency. The Bethesda assay is performed to confirm this, which measures the level of inhibitors against a specific factor in the blood.[6]
4. Molecular genetic analysis: The F5 gene is located on the long arm of chromosome 1q24.2, spans 25 exomes, and is composed of six domains (A1, A2, A3, B, C1, and C2). DNA extracted from peripheral blood leukocytes can be sequenced to identify mutations within the F5 gene to identify an inherited cause of factor V deficiency. Missense mutations are most commonly identified (61.5%) and frequently occur at domains A2 and C2, while an additional 20% of mutations occur at the B domain. A single heterozygous mutation can lead to factor V levels around 50%, whereas homozygous or compound heterozygous mutations commonly lead to factor V levels less than 10%. The combined factor V and factor VIII deficiency noted above is due to mutations in the MCFD2 and LMAN1 genes, which are responsible for transporting the coagulation factors.[15]

Treatment / Management

Treatment depends on the etiology and severity of the disease. Mild inherited factor V deficiency may be managed with antifibrinolytics, while more severe phenotypes require fresh frozen plasma (FFP) transfusions to replenish factor V levels.[11][12] 

Due to the rarity of factor V deficiency, there is no factor V concentrate available for therapy. Additionally, the amount of factor V available in other blood products such as platelets, prothrombin complex, or cryoprecipitate is minimal. FFP, therefore, remains the mainstay of treatment for moderate to severe factor V deficiency. The goal of FFP is to maintain factor V levels above 25 to 30% when experiencing bleeding or undergoing invasive procedures. Higher levels may be necessary to achieve hemostasis in more severe or life-threatening hemorrhages.[4]

For patients with acquired factor V deficiency who are asymptomatic, treatment is usually not required since the inhibitors present in the blood are transient.[14] A multifactorial approach is often necessary for patients undergoing surgery or those experiencing significant bleeding.

Methods to control bleeding include FFP, platelet transfusions, prothrombin complex concentrate, and recombinant activated factor VII. Although the alpha-granules of platelets contain a minimal amount of factor V, platelet transfusions alone have shown a 71% success rate in treating acquired factor V deficiency due to the protective function against inhibitors and promotion of hemostasis.[7][14] 

Recombinant activated factor VII, a mainstay of treatment of inhibitors in patients with hemophilia A or B, may also be effective to control bleeding as it leads to direct activation of factor X and bypasses the need for factor V or other factors in the coagulation cascade.[16] 

However, the gold standard for eliminating the inhibitors is immunosuppression, which includes corticosteroids, cyclophosphamide, and rituximab. These agents, used alone or in combination, have been shown to suppress the production of autoantibodies against factor V with a 63% success rate. High-dose intravenous immunoglobulins and plasmapheresis also aid in reducing inhibitors in the blood, thereby increasing factor V activity. Their success rate is 60% and 53%, respectively.[17]

Differential Diagnosis

Disorders affecting the coagulation cascade and platelet function cannot be differentiated based solely on clinical presentation. Further evaluation of coagulation studies and factor levels need to be accounted for to yield an accurate diagnosis.

1. Coagulation cascade abnormalities: Performing coagulation tests can help differentiate various protein and factor deficiencies. Hemophilia A and B are the most common bleeding disorders and are always included in the differential. Hemophilia A (factor VIII deficiency), B (factor IX deficiency), or C (factor XI deficiency) all present with isolated prolongation of the aPTT. A normal PT and the measurement of factor VIII, IX, or XI levels can help distinguish these from factor V deficiency. A prolonged PT and aPTT with a normal TT can also result from other common pathway factors (II or X), combined factor V and factor VIII co-deficiency, deficiency of the vitamin K-dependent clotting factors (II, VII, IX, X), or liver disease. Afibrinogenemia, hypofibrinogenemia, and dyshypofibrinogenemia also result in prolonged PT and aPTT; however, in these cases, TT will be prolonged. These patients may present with either thrombotic or hemorrhagic events, although many are asymptomatic.[11][15]
2. Platelet dysfunction: Providers should also consider von Willebrand disease (VWD), the most common inherited bleeding disorder, which can vary in presentation from mild mucosal bleeding in type 1 to more severe hemorrhages that mimic hemophilia in type 3. Patients with vWD may have prolonged or normal aPTT, normal PT, normal to low platelet count with a normal to low factor VIII level. Platelet function defects, such as Glanzmann Thrombasthenia and Bernard Soulier syndrome, while rare, should also be considered. The PT and aPTT will be normal in platelet function disorders, as these are dysfunctions of platelet adhesion and aggregation, independent of the coagulation cascade.[18]

Prognosis

Congenital and acquired factor V deficiency are both exceedingly rare. There is not enough data in the literature to address the long-term prognosis of affected individuals. However, up to 21% mortality rate has been documented in patients who present with severe bleeding manifestations.[7][12]

Complications

Complications from factor V deficiency can occur as early as in the neonatal period. Although rare, intracranial hemorrhages can be challenging to diagnose promptly, especially in newborns, and have high mortality rates.[12] Additionally, although less common, thrombotic events can also occur due to the prothrombotic effect of factor V. Reported cases have mentioned deep vein thrombosis, cerebral infarctions, and limb gangrene. To prevent life-threatening complications, immediate treatment should start once factor V deficiency is suspected.

Consultations

A hematologist should be consulted at the earliest suspicion of a bleeding disorder. In cases with a known family history of bleeding diatheses, a pediatric hematologist should be consulted during the pregnancy so that an early and accurate diagnosis can be made.

As coagulation studies often require large amounts of blood, sampling the cord blood at the time of birth can be a valuable tool in making the proper diagnosis without having to sample large volumes of blood from the neonate. Furthermore, early consultation with hematology may be life-saving in patients with active bleeding requiring emergent blood product support. Consulting hematology early can allow for proper testing to be sent prior to administering FFP or other blood products, which may render coagulation studies useless for many days post-administration and delay appropriate treatment.

Deterrence and Patient Education

Patients need to be counseled on the nature of factor V deficiency when a diagnosis is made due to the infrequency of the disease. Because of life-threatening complications, an alert bracelet should be worn for prompt recognition and appropriate medical intervention. In addition, it is important to educate family members regarding prophylactic measures and possible complications, especially when undergoing surgery.

Women of childbearing age ought to be counseled on the inheritance of the disease and potential outcomes and may require treatment during pregnancy or delivery to prevent bleeding. Lastly, affected individuals need to follow up routinely with a hematologist. Close communication with healthcare providers is mandatory in case of a bleeding event.

Enhancing Healthcare Team Outcomes

When dealing with rare disorders, it is essential to establish care coordination amongst specialists. For factor V deficiency, patients require routine follow-up with a hematologist. For elective surgeries, prophylaxis and measures to control bleeding are discussed between the hematologist and surgeon or other specialists performing the procedure. For any emergency-related hemorrhage, hematologists need to be involved and transfusion medicine physicians for appropriate product availability. Furthermore, it is necessary to notify the pharmacy quickly when certain products are requested urgently.

Communication and team effort are critical for patient safety and improving outcomes. Patients must follow in a high-risk obstetrics clinic when pregnant for close monitoring. Parents should be counseled on the inheritance of factor V deficiency in future children and may benefit from a consultation with a geneticist. In the pediatric population, neonatologists and pediatricians should be mindful of family history and presentation of disease when not yet diagnosed. Intracranial hemorrhages are a lethal complication if not promptly diagnosed and difficult to treat if etiology is unknown.

Factor V deficiency is extremely rare; therefore, the article is at a level 3 based on the evidence provided in publications.