A case of unusual acquired factor V deficiency

Xiao-lu Ma, Wu-chao Wang, Chang Du, Ting Zhang, Tai-feng Li, Yang Guo, Ji-hong Zhu

1 Department of Emergency, Peking University People's Hospital, Beijing 100044, China

2 Department of Gastroenterology, Beijing Jishuitan Hospital, Beijing 100096, China

3 Department of Pharmacy, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Dear editor,

Factor V deficiency is a rare bleeding disorder, which includes congenital and acquired factor V deficiencies. Congenital factor V deficiency (CFVD) is an autosomal recessive disorder with an estimated prevalence of 1:1,000,000.[1]However, acquired factor V deficiency (AFVD) is even rarer, as only approximately 200 case reports or case series describing this disorder have been reported in the literature. We herein report this very unusual case of a patient with AFVD. In this case, not only were the prothrombin time (PT) and activated partial thromboplastin time (APTT) corrected following a mixing study, but repeated factor V inhibitor test results were also negative. We diagnosed this elderly male patient with AFVD based on a previously normal coagulation panel, no previous bleeding tendency or family bleeding history, normal factor V activity for siblings and children, and successful corticosteroid treatment.

CASE

An 84-year-old male presented to our emergency room complaining of macroscopic hematuria with melena for 1 d. His medical history included hypertension and cerebral infarction. Thereafter, he was administered with aspirin and atorvastatin. Physical examination on admission revealed that vital signs were stable and that there were no ecchymosis spots.

His hemoglobin level was 110 g/L, and his platelet count was normal upon laboratory examination. His routine urinalysis showed that red blood cells were more than 99,999/μL and occult blood test was positive. His fecal occult blood test was also positive. Liver function, electrolyte, and creatinine were normal. His PT was prolonged at 61.2 s, and his APTT was prolonged at 181.3 s. His fibrinogen was normal. Susceptibility to rodenticide poisoning was considered, but no rodenticide or other common toxicants were found on toxicology testing. A mixing study was then conducted. However, PT and APTT were corrected with a 50% normal plasma mixing study at time 0 and 2 h after incubation at 37 °C. Afterwards, a comprehensive coagulation factor profile was conducted that revealed a meaningful reduction in factor V activity to 0.2% and normal activity of other coagulation factors.

This patient was immediately administered vitamin K, prothrombin complex concentrates (PCCs), and fresh frozen plasma (FFP) following hospitalization. His macroscopic hematuria and melena gradually resolved. However, the coagulation panel could only be temporarily improved and worsened again the next day (Figure 1). Although repeated factor V inhibitor test results were negative in the Bethesda assay, the poor response to multiple transfusions did not support CFVD. Meanwhile, it was found that he had a normal coagulation panel 9 years ago. Moreover, CFVD was ruled out considering that he was an elderly male with no previous bleeding tendency or family bleeding history and normal factor V activity for siblings and children. Therefore, intravenous methylprednisolone was administered at 60 mg/day for 6 d. Unfortunately, his factor V activity decreased to 0.1%, and the coagulation panel did not improve significantly. The patient was then given intravenous immunoglobulin for 6 d and methylprednisolone (200 mg/day) for 4 d followed by oral prednisone at 60 mg/day. Factor V activity was retested and increased to 2.7% during this period. The coagulation panel improved, and he was then transferred to a local hospital. His coagulation panel was corrected 1 month after discharge (Figure 1), although his local hospital could not test factor V activity. He was clinically diagnosed with AFVD based on these findings. No apparent cause was found because autoimmune markers were negative and positron emission tomography/computed tomography (PET/CT) had no positive indication.

Figure 1. Changes of PT and APTT after immunosuppressive treatment. PT: prothrombin time; APTT: activated partial thromboplastin time. MP: methylprednisolone; PDN: prednisone; PCCs: prothrombin complex concentrates; IG: immunoglobulin; FFP: fresh frozen plasma.

DISCUSSION

A typical evaluation for all individuals with a bleeding disorder should begin with a complete blood count and a c oagulation panel. A mixing study is required if both PT and APTT are significantly prolonged, which can distinguish between a deficiency (which is corrected) and an inhibitor (which cannot be corrected). A comprehensive coagulation factor profile or a test for coagulation factor inhibitors can then be conducted. This indicates an A FVD if factor V is deficient and inhibitors are positive.

A FVD can appear at any age, and patients have no previous bleeding tendency or family bleeding history. The clinical manifestations vary greatly, ranging from asymptomatic h ematological laboratory abnormalities to l ife-threatening h emorrhaging.[2]The most common clinical manifestations are v arious mucosal bleeding. Similarly, our patient had macroscopic hematuria and melena. A FVD identification is usually associated with prolonged PT and APTT, and they cannot b e corrected with a mixing study. I n t his case, b oth P T and APTT were corrected w ith the mixing study. Factor V inhibitor in our patient was suggested to be of a slower response type. A 2- h our incubation period in a m ixing study is recommended because of factor VIII inhibitors,[3]which may not be suitable for slow-response factor V inhibitors. The coagulation panel may not be corrected if the mixing test is incubated for more than 2 h. Therefore, a prolonged incubation period is recommended when factor V inhibitors are suspected, but the exact incubation period needs to be further studied.

A FVD is mainly due to a ntibody inhibitors, but the precise mechanisms remain unclear. A ccording to a previous study, it may have three distinct antibodies: spontaneous a utoa ntibodies, antibodies that c ross-react with anti-bovine factor V, and a lloantibodies.[4]Factor V inhibitors have been described in patients with a p revious surgery history, antibiotic use, b ovine protein exposure, infections, malignancies, autoimmune diseases, and transfusion.[5]In this case, r epeated factor V inhibitor test results were negative. A negative antibody i nhibitor can be explained by the following reasons. First, n eutralizing antibody in the patient may be rare, and the currently available Bethesda assay cannot detect it. Second, the antibody may be a c learance-facilitating antibody. Test results in the Bethesda assay will be negative if the patient has a clearance-facilitating antibody. M oreover, idiopathic cases were also found with an increase in AFVD reports. Wang et al[6]systematically reviewed 200 AFVD cases from 1955 to 2016 for their underlying causes and found that idiopathic cases accounted for 14.5%. Likewise, our patient was an idiopathic case because no clear cause w as identified. He t ook aspirin before, and the clinical manifestation was melena. Gastrointestinal mucosal lesions were considered to have been caused by aspirin. However, gastroscopy could not be performed due to a p oor coagulation panel. A poor coagulation panel is believed to have caused various mucosal bleeding combined with hematuria. The case was considered idiopathic given the patient’s denial of surgical history, antibiotic use, bovine protein exposure, transfusion, and negative toxicology testing, autoimmune markers and PET/CT.

AFVD treatments are based on two steps: bleeding control and a ntibody inhibitor e radication.[5]PCCs and FFP are our first choice for bleeding control. Factor V is present in plasma (80%) and platelets (20%).[7]T herefore, platelet transfusion has been used in bleeding patients. Recombinant activated factor VII, which acts as a bypassing agent, has also been successfully used in AFVD patients.[6]Theoretically, f actor V concentrates should be the best t herapeutic option, but no such product is available. Antibody inhibitor eradication includes c orticosteroids, immunoglobulin, c yclophosphamide, r ituximab, p lasmapheresis, and immunoadsorption. Corticosteroids and immunoglobulin are the most commonly used treatments, but there is no consensus on the specific dose and time. Cyclophosphamide and rituximab are used as second-line treatments, sometimes i n combination with corticosteroids. Extracorporeal methods, such as plasmapheresis and immunoadsorption, can also reduce factor V inhibitors.[6]

C ONCLUSION

We herein present an unusual AFVD case. With this case report, we hope that A FVD will be taken into account in elderly patients who have a mixing study that can be corrected and a negative inhibitor. E arly AFVD recognition and timely initial treatments appear to be crucial.

Funding:None.

Ethical approval:Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

Conflicts of interest:All authors have disclosed no conflicts of interest.

Contributors:XLM and WCW contributed equally to this study. XLM drafted the manuscript. WCW contributed to the manuscript revision. All authors read and approved the final manuscript.