Acquired factor V inhibitor complicating warfarin therapy
Authors: Benjamin Gartrell
Journal: American Journal of Hematology (2011)

Factor V is a procofactor that exists in both the plasma (80%) and within platelet alpha-granules (20%) [1]. Factor V is converted into its active form by thrombin. Factor Va serves as cofactor for factor Xa in the prothrombinase complex, which forms on the platelet surface and produces thrombin via limited proteolysis of prothrombin. Acquired factor V inhibitors are rare with an annual incidence reported between 0.09 and 0.29 cases per million persons [2, 3]. Factor V inhibitors may be alloantibodies that develop following exposure to bovine thrombin-derived fibrin sealant [4]. In patients exposed to topical thrombin preparations, the incidence of factor V inhibitors may be significantly higher [5]. Factor V inhibitors may also develop as autoantibodies with a number of reported associations including antibiotics [6, 7], sepsis [8], malignancies [9], and autoimmune illnesses [10-12]. The clinical presentation of factor V inhibitors ranges from abnormal coagulation studies with no associated bleeding to life threatening hemorrhage. Here, we report an unusual case of a factor V inhibitor developing in an elderly woman anticoagulated with warfarin who had persistently abnormal coagulation studies after its discontinuation. This raises significant issues regarding differential diagnosis, work-up, and therapeutic intervention. An 80-year-old African-American woman was admitted to our hospital with respiratory complaints and was found to have abnormal coagulation. Past medical history was significant for diabetes mellitus, chronic renal insufficiency, coronary artery disease, heart failure, and atrial fibrillation for which she was anticoagulated with warfarin. The patient had recent hospital admissions for a suspected gastrointestinal bleed, lower extremity cellulitis, and hypoglycemia. Endoscopy revealed no gastrointestinal bleeding. A course of doxycycline and cephalexin was given for cellulitis during the second hospitalization. There was no surgery or exposure to bovine thrombin during these hospitalizations. At the time of the third discharge, which was 1 month after the episode of cellulitis and the exposure to antibiotics, the prothrombin time (PT) was 16.2 s (normal, 11.5–15.5 s) and the international normalized ratio (INR) was 1.3. The patient was discharged on warfarin and 24 days later, as an outpatient, the PT was noted to be 75.2 s. Warfarin was held and vitamin K was given, but the PT remained 59.2 s 20 days later. Forty-seven days following her most recent discharge, the patient was readmitted with dyspnea. At the time of admission, the PT was noted to be 54.6 s with an INR of 5.8. The activated partial thromboplastin time (APTT) was found to be >150 s (normal, 23.6–35.7 s). The platelet count was 169 × 103/μL. She was treated with antibiotics, steroids, diuretics, and bronchodilators. Her respiratory status worsened and intubation and mechanical ventilation were required on the third hospital day. Although vitamin K deficiency usually prolongs the PT more than the APTT, the coagulopathy was initially attributed to depletion of vitamin K-dependent factors secondary to antecedent warfarin use. A total of 10 mg of Vitamin K was given orally and another 10 mg given subcutaneously without significant improvement in the PT or APTT. There was no bleeding. There was no evidence of disseminated intravascular coagulation. The D-dimer was 0.31 mcg/mL (normal, <0.5 mcg/mL), and the fibrinogen was 334 mg/dL (normal, 175–450 mg/dL. A mixing study was ordered (Table I). Neither the PT nor the APTT corrected suggesting a circulating anticoagulant. Factor levels were obtained (Table II). The factor V level was 3% (normal, 50–150%). Factor II was 68% (normal, 50–150%). Factors VII, VIII, and X demonstrated circulating anticoagulant effect with recovery to normal levels with serial dilutions (from 16, 65, and 22% to 60, 205, and 66% respectively). The factor V inhibitor level was found to be 17 Bethesda units/mL. The thrombin time was 20.6 s (normal, <21.0 s). A review of all recent hospitalizations was conducted, and there was no surgical procedure or exposure to bovine thrombin. Interestingly, the mixing study suggested time dependence as the PT and APTT were longer after 1 h of incubation. Time dependence is often associated with factor VIII inhibitors but has been reported with factor V inhibitors as well [13]. There was no bleeding but a recommendation was made to transfuse one unit of single donor platelets before invasive procedures. This recommendation was based on the use of platelet transfusions to control active bleeding associated with acquired factor V inhibitors [14]. Using this strategy, central venous catheters were placed without bleeding. For inhibitor suppression, prednisone was initiated at 1 mg/kg daily. The APTT improved from 134.9 to 115.1 s and the PT from 50.6 to 36.8 s after 13 days of prednisone. Unfortunately, the patient died of sepsis before a repeat factor V level was obtained. The development of factor V inhibitors, in the absence of bovine thrombin exposure, has been reported only rarely in the medical literature. In a review by Knöbl and Lechner, 105 cases were reported over a greater than 40-year period. Bleeding manifestations occurred in 60% of these patients with surgical site bleeding, hematuria, gastrointestinal bleeding, and hematomas being the most common hemorrhagic complications. Only 32.6% of patients with alloantibodies following exposure to bovine thrombin developed bleeding. There was a statistically significant association between residual factor V levels and bleeding [15]. In another review by Ang et al. in which patients with factor V inhibitors acquired after exposure to bovine thrombin were not included, 73 cases were identified from 1950 to 2008 plus an additional three newly reported cases. Of these patients, 68.4% had documented bleeding with the mucous membranes being the most common site. Intracranial bleeds occurred in 14% of patients. Fatal bleeding events occurred in 12% of patients. All cause mortality was 31%. There was a nonsignificant trend toward lower factor V levels and a higher PT in bleeders versus nonbleeders and a statistically significant prolongation in APTT in bleeders versus nonbleeders. There was no association between inhibitor level and bleeding risk [2]. This is reminiscent of the lack of association between the titre of factor VIII inhibitors and bleeding risk [16]. The optimal treatment of bleeding in patients with factor V inhibitors is not known. The rarity of the disease has precluded a rigorous evaluation of treatment strategies. Fresh frozen plasma and prothrombin complex concentrates (PCC) have generally not been effective in controlling bleeding [15]. A recent report demonstrated the successful use of recombinant activated factor VII to control bleeding due to a factor V inhibitor [17]. Similarly, activated PCC has also been used successfully in a factor V inhibitor [7]. Platelet transfusions have been successfully used to treat active bleeding caused by factor V inhibitors [14]. Factor V on the platelet surface may serve as a source of factor V that is protected from inhibitors. This may explain the utility of platelet transfusions in these patients [18]. One interesting study evaluated the potential mechanism of bleeding in patients with factor V inhibitors. The inhibitors were found to target the C2 domain in all cases but interfered with prothrombinase activity only in those cases associated with bleeding [19]. In the review by Knöbl, the median duration of factor V inhibitors was 9.7 weeks. Those inhibitors associated with known precipitants all resolved by 1 year and had a median duration of 8 weeks. In contrast, idiopathic factor V inhibitors had only a 61.7% probability of resolution after a median of 22.9 weeks [14]. Various methods have been used to suppress factor V inhibitors including corticosteroids [9, 20], cyclophosphamide [20], and rituximab [6]. However, given the transient nature of some factor V inhibitors in the absence of suppression therapy and the rarity of this condition, it is premature to evaluate the true benefit of these strategies. In fact, Knöbl et al. found no difference in terms of disappearance of the inhibitor or survival in those who received suppressive therapy compared with those who did not [14]. As with other immune-mediated bleeding disorders, rapid inhibitor clearance has been achieved with the use of intravenous immunoglobulin [21] and plasma exchange [10]. This is an informative case of an idiopathic factor V inhibitor developing in an elderly woman on warfarin. She developed strikingly abnormal coagulation studies in the outpatient setting with prolongation of the PT and APTT. She had no exposure to bovine thrombin, surgery, or a history of malignancy. There was an exposure to antibiotics, but the INR was 1.3, 1 month following this exposure. The differential diagnosis for combined prolongation of PT and APTT includes vitamin K deficiency, liver dysfunction, warfarin use, congenital factor deficiency, the development of an acquired inhibitor of coagulation, disseminated intravascular coagulation, and a lupus anticoagulant. This case of a factor V inhibitor exemplifies the necessity to consider other causes of coagulopathy in patients on warfarin when the coagulopathy does not respond to cessation of warfarin and supplementation with vitamin K. In such situations, as in this case, the differential diagnosis of abnormal studies of coagulation must be revisited. Benjamin Gartrell*, * Division of Hematology/Oncology, Department of Medicine, The Tisch Cancer Institute, The Mount Sinai School of Medicine, New York.