Clinical and laboratory diagnosis of autoimmune factor V inhibitors: A single institutional experience.

BACKGROUND: Coagulation factor V inhibitors (FV-i) may occur in patients with congenital FV deficiency or previously hemostatically normal patients (autoimmune (AI)-FV-i). Most of the published literature is confined to case reports. OBJECTIVE: Describe clinical and laboratory features of AI-FV-i identified through the Special Coagulation Laboratory at Mayo Clinic, Rochester, Minnesota. METHODS: In this retrospective study individuals with FV-i screens performed from January 1999 to February 2017 were identified through the special coagulation laboratory database. Clinical presentation, management, and outcomes were collected for our institutional patients while detailed laboratory data was collected for all tested patients. RESULTS: Of patients with FV-i managed at our institution, 2/8 (25%) patients experienced no bleeding. There was no correlation between inhibitor titers and/or FV activity (FV:C) levels and clinical bleeding. Hemostatic management included fresh frozen plasma, platelet transfusion, activated prothrombin complex concentrates, and recombinant factor VIIa. Only 2 patients received immunomodulatory treatment. FV-i mixing studies with normal pooled plasma (n = 26) demonstrated inhibition on immediate mix but progressive inhibition after 1 h of incubation could not be demonstrated. 71% of platelet neutralization procedures were falsely positive while 59% of DRVVT assays were indeterminate. CONCLUSION: FV-i demonstrates immediate inhibition on mixing studies; however our limited data does not support a time dependent inhibition. Our clinical cohort confirms the variable clinical phenotype for individuals with FV-i and supports the notion that management of FV-i should be guided by clinical symptoms and not FV:C or FV-i titer.

Acquired factor V inhibitor after exposure to topical human thrombin related to an otorhinolaryngological procedure.

Acquired factor V (FV) inhibitors occur rarely and classically develop after exposure to bovine thrombin. The clinical presentation is variable, ranging from asymptomatic with incidental laboratory abnormalities to significant bleeding. With the development of human-derived thrombin agents, bovine thrombin is less frequently used. We report a case of an acquired FV inhibitor that developed in a patient after exposure to human thrombin used as a hemostatic agent during an otorhinolaryngology surgical procedure. Our review of the literature revealed only one prior reported case of FV inhibitor after exposure to human thrombin. Hematologists and surgeons should be aware of this rare, but potentially life-threatening, complication in the postprocedural setting.

Severe postoperative hemorrhage caused by antibody-mediated coagulation factor deficiencies: report of two cases.

Antibody-mediated coagulation factor deficiencies constitute a rare disorder that may develop in elderly patients without any history of a bleeding diathesis. Patients may present with severe and sometimes catastrophic bleeding. We report two cases of postoperative hemorrhage caused by a coagulation factor deficiency. In Case 1, massive intraabdominal bleeding occurred on day 3 after pancreaticoduodenectomy for bile duct cancer, and was caused by an acquired inhibitor of coagulation factor VIII. Hemostasis was achieved and the factor VIII inhibitor titer decreased to zero with activated prothrombin complex concentrates, prednisolone, and cyclophosphamide. In Case 2, intraabdominal bleeding occurred on day 7 after hepatectomy for hepatocellular carcinoma, and was caused by an acquired inhibitor against factors II (prothrombin) and V. This patient was treated with hemostatic agents containing bovine thrombin during surgery and also with prednisolone. We report these cases to highlight that antibody-mediated coagulation factor deficiencies should be considered when an elderly patient suffers sudden postoperative hemorrhage and to stress the importance of prompt diagnosis because of the risk of potentially life-threatening hemorrhage.

Acquired factor V inhibitor developing in a patient with esophageal squamous cell carcinoma.

An 82-year-old man referred to our medical ward because of epistaxis and melena was found to have 12 Bethesda units of factor V inhibitor. He was managed for bleeding with supportive care, followed by corticosteroid therapy. The bleeding completely stopped 1 week after corticosteroid therapy. Medical history revealed dysphagia during the past 6 months and further evaluation brought to light a squamous cell carcinoma (SCC) in the esophagus. This is the first case of an acquired factor V inhibitor developing in a patient with esophageal SCC without any other risk factors such as surgery.

[Acquired factor V deficiency: a rare bleeding disorder with variable clinical presentations]. / Le déficit acquis en facteur V : une pathologie hémorragique rare à manifestations cliniques variables.

Acquired anti-factor V (FV) antibodies are uncommon and the majority of reported cases are idiopathic or associated with pregnancy, malignancy, autoimmune diseases or the use of bovine thrombin preparations. Clinical presentation is highly variable, ranging from asymptomatic to life-threatening bleeding and the optimal treatment is not clearly established. We here report two patients with different clinical presentations. The first patient presented with an acute severe rectal bleeding related to acquired FV deficiency and recurrent colon cancer while the second patient was asymptomatic with a FV inhibitor detected during a routine blood testing. We discuss treatment modalities that are not consensual.

Development of cephradine-induced acquired factor V inhibitors: a case report.

OBJECTIVE: To report a case of cephalosporin-induced factor V inhibitor development, an uncommon but potentially fatal condition characterized by severe hemorrhage. CASE SUMMARY: A 71-year-old Chinese man presented with factor V inhibitors after a 7-day cephradine course for a urinary tract infection, characterized by abnormal prothrombin time (PT) and activated partial thromboplastin time (aPTT), gross hematuria, upper gastrointestinal bleeding, and left groin hematoma. Systemic corticosteroid administration restored his factor V activity levels, PT, and aPTT to within normal limits, and hemorrhagic symptoms resolved. Three weeks after successful treatment of bleeding diathesis, he received another 8-day cephradine course for cellulitis. After another 4 weeks, he suffered from recurrent factor V inhibitors presented with abnormal PT, aPTT, and upper gastrointestinal bleeding. The patient eventually died due to hemorrhagic shock despite a second course of corticosteroids. DISCUSSION: Cephalosporins are known to cause coagulopathy via hypoprothrombinemia. Another pathway seldom mentioned in the literature is factor V inhibitor induction, which may result in factor V deficiency. In our patient, factor V deficiency due to inhibitors developed each time that the patient received repeated cephradine treatment. According to the Naranjo probability scale, the relation between the formation of factor V inhibitors and cephradine treatment was probable. CONCLUSIONS: Because cephalosporins are commonly used for their wide therapeutic index and few adverse effects, iatrogenic complications associated with these drugs may be neglected or underdiagnosed. On the basis of our patient's report, careful review of medical records to avoid reexposure to the offending drug cannot be overemphasized.

Factor V inhibitors: rare or not so uncommon? A multi-laboratory investigation.

Acquired deficiencies of, or inhibitors to, factor V are considered rare events. We report a series of 14 acquired factor V deficiencies, 10 of which were confirmed to have inhibitors to factor V, as identified within Australia in the past 5 years following a multi-laboratory investigation. The initial index case seen by one laboratory was followed within 4 months by a separate similar case. This prompted local contact with colleagues (n = 20) working in other haemostasis referral laboratories to identify the current case series. In total, nearly one-half of all haemostasis referral laboratories contacted had seen a case within the past 5 years. Clinical features and the apparent associated risk of bleeding complications generally varied, as did laboratory findings and the likely causal event. There were three females and 11 males. Age ranged from 44 to 95 years (median, 81 years). The level of inhibitor ranged from undetectable to over 250 Bethesda units. The probable cause leading to development of the inhibitors ranged from exposure to bovine thrombin, exposure to antibiotics, surgery and malignancy. Of additional interest was the apparent association of anti-phospholipid antibodies in many of the cases. For example, in the two similar index cases, with factor V inhibitor titres > 200 Bethesda units, high levels of anti-cardiolipin antibodies (> 70 GPL units) were also detected. Although less clear because of inhibitor interference, many of the cases also showed evident co-associated lupus anticoagulant activity. In conclusion, we report a series of factor V inhibitors recently identified within our geographic region that would represent an annual incidence of around 0.29 cases per million Australians. Although considered a rare finding, there is a high likelihood that most haemostasis referral laboratories will see a case every five or so years.

Anti-factor V auto-antibody in the plasma and platelets of a patient with repeated gastrointestinal bleeding.

Development of autoantibody against coagulation factor V (FV) is a rare clinical condition with hemorrhagic complications of varying severity. The aim of this study was to establish the pathomechanism of an acquired FV deficiency and characterize the FV inhibitor responsible for the clinical symptoms. A 78-year-old female was admitted to hospital with severe gastrointestinal bleeding. General clotting tests and determination of clotting factors were performed by standard methods. FV antigen and FV containing immune complexes were measured by ELISA. The FV molecule was investigated by Western blotting and by sequencing the f5 gene. The binding of patient's IgG to FV and activated FV (FVa) was demonstrated in an ELISA system and its effect on the procoagulant activity of FVa was tested in clotting tests and in a chromogenic prothrombinase assay. Localization of the epitope for the antibody was performed by blocking ELISA. FV activity was severely suppressed both in plasma and platelets. FV antigen levels were normal by ELISA using polyclonal anti-FV antibody or monoclonal antibody against the connecting region of FV, but depressed when HV1 monoclonal antibody against the C2 domain in the FV light-chain was used as capture antibody. The FV molecule was found intact. An IgG reacting with both FV and FVa was present in the patient's plasma and its binding to FV was inhibited by HV1 antibody. FV-containing immune complexes were detected in the patient's plasma and platelet lysate. The patient's IgG inhibited the procoagulant function of FVa. An anti-FV IgG was present in the patient's plasma and platelets. The autoantibody reacted with an epitope in the C2 domain of FV light chain and neutralized the procoagulant function of FVa.

Bovine thrombin induces an acquired coagulopathy in sensitized patients undergoing revision spinal surgery: a report of two cases.

STUDY DESIGN: A report of two cases is presented. OBJECTIVE: To raise awareness of bovine thrombin-induced factor V deficiency. SUMMARY OF BACKGROUND DATA: Bovine thrombin is a frequently used hemostatic agent in spinal surgery. Current preparations contain clotting factors in addition to thrombin, particularly factor V, which are immunogenic. Re-exposure of sensitized patients to bovine thrombin products during subsequent surgery may lead to the formation of antibodies that cross-react with human clotting factors, most commonly against factor V. Hemorrhagic complications have been reported in nonspinal patients due to a bovine thrombin-induced factor V deficiency. METHODS: Two spinal cases are reported, and the literature is reviewed. RESULTS: In the cases outlined, both patients underwent revision spinal surgery, with re-exposure to bovine thrombin. Both patients developed abnormal coagulation profiles, with an acquired factor V deficiency. No hemorrhagic complications occurred; however, second-stage surgery was delayed in one patient and not undertaken in the other. In both patients, the coagulopathy resolved spontaneously. CONCLUSIONS: Bovine thrombin-induced coagulopathy is well recognized in cardiac surgery but has not been reported in spinal surgical patients. Data available from cardiac surgical patients suggests that those who are sensitized to two or more bovine clotting factors are at greatest risk of hemorrhagic complications. The cases we present demonstrate that this phenomenon occurs in spinal surgical patients and serve to raise awareness of the potential danger of bovine thrombin in sensitized patients.

Acquired factor V inhibitor complicated by Hashimoto's thyroditis, primary biliary cirrhosis and membranous nephropathy.

A 59-year-old man diagnosed as having Hashimoto's thyroditis, primary biliary cirrhosis (PBC) and membranous nephropathy (MN) showed consciousness disturbance, convulsions of the upper part of his body, and rapid progression of anemia, which seemed to be derived from subdural and retroperitoneal hemorrhage, respectively. He had been diagnosed as having eosinophilia about 6 weeks before the attack. Coagulation tests revealed a prolonged activated partial thromboplastin time and prothrombin time, which could not be normalized by mixing with normal plasma. Factor V (FV) activity was severely decreased and the purified immunoglobulin G of the patient inhibited normal plasma FV activity in a dose-dependent manner, suggesting the presence of antibody-mediated circulating inhibitors specific for FV. Treatment with steroids and azathioprine as well as plasmapheresis led to improvement of his clinical symptoms, normalization of the coagulation tests, and disappearance of eosinophilia. However, the inhibitor reappeared about 7 months later in association with eosinophilia, which was also improved by steroid therapy. To our knowledge, this is the first report of the co-existence of these three kinds of immune-mediated disorders, and the first report concerning the association between acquired FV inhibitors and PBC with MN. A new unknown immune mechanism, which causes eosinophilia, may be involved in the development of the FV inhibitor in this patient.

Factor V inhibitor in neonatal intracranial hemorrhage secondary to severe congenital factor V deficiency.

We report a newborn infant girl, born to consanguineous parents, with recurrent intracranial hemorrhage secondary to congenital factor V deficiency with factor V inhibitor. Repeated transfusions of fresh-frozen plasma (FFP) and platelet concentrates, administrations of immunosuppressive therapy (prednisolone and cyclophosphamide), and intravenous immunoglobulin failed to normalize the coagulation profiles. Exchange transfusion followed-up by administrations of activated prothrombin complex and transfusions of FFP and platelet concentrates caused a temporary normalization of coagulation profile, enabling an insertion of ventriculoperitoneal (VP) shunt for progressive hydrocephalus. The treatment was complicated by thrombosis of left brachial artery and ischemia of left middle finger. The child finally died from another episode of intracranial hemorrhage 10 days after insertion of the VP shunt.

Multimodality therapy of an acquired factor V inhibitor.

Acquired inhibitors of factor V are rare causes of clinical bleeding, whose severity ranges from mild to life-threatening. Optimal treatment of patients with factor V inhibitors is uncertain. We report on our successful treatment approach in a patient with spontaneous, life-threatening intracranial bleeding caused by a factor V inhibitor. The patient deteriorated after initial treatment with fresh-frozen plasma and platelet transfusions. He was subsequently treated with a combination of plasma exchange and chemotherapy, which led to complete recovery. Our experience suggests that plasma exchange may be life-saving in cases of severe bleeding caused by factor V inhibitors. The use of plasmapheresis in conjunction with chemotherapy is an efficacious and well-tolerated treatment and should be considered in patients with factor V inhibitors.

Studies on phospholipid antibodies, APC-resistance and associated mutation in the coagulation factor V gene.

The influence of antibodies against phospholipids (PLa) on APC response was investigated in 155 women with a history of thromboembolism and/or repeated foetal losses. PLa were determined as antibodies against cardiolipin (CLa) and phosphatidyl serine (PSa) and as lupus anticoagulant (LA) tested by dilute Russell's Viper Venom time and by the Textarin/Ecarin ratio. APC-response was studied by a clotting (aPTT-based) and by an amidolytic (factor IXa-X-based) assay. A reduced response to APC (APC-resistance) was found in 49% of 65 PLa-positive and in 13% of 90 PLa-negative samples (chi 2 = 23.9; p < 0.5 x 10(-4)). It was more common in the samples with LA, as compared to CLa+PSa positive (58% vs. 30%, not significant). The presence of the mutation causing Arg506-Gln substitution in coagulation factor V was investigated in 84 samples. The occurrence of the mutation in APC-resistant patients with CLa+PSa or with LA in one of the two assays was similar to those without PLa (84% and 100%, respectively). In the absence of APC resistance, the occurrence of the mutation was similar in the samples with and without PLa (14% vs. 11%). Samples with LA, determined by both tests used, comprised a special group where the frequency of the mutation in the APC resistant samples was significantly reduced (p < 0.01). In the latter samples, the pathogenic mechanism of APC resistance may be connected with the influence on phospholipid membranes.

Liver dysfunction in haemophilia A, B and other hereditary haemorrhagic disorders.

Seventy patients with Haemophilia A, B, von Willebrand's disease and Factor V deficiency had their liver functions studied. Twenty-five patients (36%) were found to have significant "transaminitis" (elevated SGPT/SGOT). Nine patients (13%) had positive Hepatitis B surface antigen (HBsAg). The incidence of Hepatitis B surface antibody (anti-HBs) in the study group was 74%. All patients were asymptomatic at the time of study. This asymptomatic liver dysfunction will require close monitoring for clinical significance.