factor v is a coagulation protein that is present in blood plasma as a single - chain polypeptide ( approximately 80% ) and in platelet alpha - granules ( approximately 20%).1 factor v is cleaved after binding to activated platelets and serves as a cofactor for factor xa in the prothrombinase complex . this complex forms on the platelet surface and has limited proteolytic activity , converting prothrombin to thrombin to aid in blood clotting.2,3 acquired inhibitors to factor v were first reported in 195524 and develop in extremely rare cases ( 0.090.29 cases per million persons ) via development of alloantibodies or autoantibodies against factor v. patients with acquired factor v inhibitors generally present with hemorrhagic manifestations . here , we report a unique case of acquired factor v inhibitor in a patient with mantle cell lymphoma presenting with hematuria followed by thrombosis . a 64-year - old man initially presented to us with complaints of fatigue and joint discomfort for several months prior to december 2008 . he denied experiencing any fever , night sweats , and weight loss , and did not notice any swelling , recurrent infection , easy bleeding , or bruising . his past medical history included hernia repair , renal colic , gastroesophageal reflux , and osteoarthritis . upon examination , one left axillary lymph node was swollen to approximately 12 cm , and was firm and slightly tender . his spleen was palpable on inspiration , and castell s sign was positive ; however , his liver was not enlarged . a complete blood count showed normal platelet and hemoglobin levels of 206  10/l and 155 g / l , respectively , but a high white blood cell count of 18  10/l . a leukocyte differential indicated the following : lymphocytes 10.3 ; neutrophils 6.75 ; monocytes 0.58 ; eosinophils 0.23 ; and basophils 0.05 . peripheral blood flow cytometry revealed a cd19 , cd20 , cd5 , cd23 , cd10 clonal b - cell population . the proportion of this fmc7-positive population reduced to 17% during a second flow analysis one month later , suggesting the possibility of mantle cell lymphoma or cd23-negative chronic lymphoid leukemia . given that the patient was asymptomatic and showed no signs of bone marrow failure , a strategy of watchful waiting was implemented . in august 2009 , 8 months after his initial visit , the patient was admitted to the emergency room with a 2-day history of hematuria . evaluation of his blood plasma revealed a prolonged international normalized ratio ( inr ) of 6 and an activated partial thromboplastin time of 160 seconds . except for some minor skin bruising on his face , the patient had no other bleeding or bruising , nor was any area abnormal on examination . further , he had no past history of bleeding , with uneventful surgical procedures and tooth extractions in the past . on careful investigation of his coagulopathy , a prothrombin time mixing study was abnormal at 43 partially corrected to 30 seconds only ( normal 12.515.7 seconds ) , suggesting the presence of an inhibitor . the thrombin time was 15.8 seconds ( normal 15.518.3 seconds ) , serum fibrinogen level was 5.8 g / l ) , factor v level was < 0.01 u / ml ( normal 0.51.5 u / ml ) , factor viii level was 3.23 u / ml ( normal 0.51.5 u / ml ) , factor x level was 1.08 u / ml ( normal 0.51.5 u / ml ) , and factor ix level was 1.17 u / ml ( normal 0.51.5 u / ml ) . based on these results , a factor v inhibitor test was performed and indicated a factor v inhibitor titer of 80 bethesda units . the patient was started on prednisone ( 1 mg / kg , 80 mg daily ) , and after 2 weeks of treatment , the bleeding had stopped and serial measurement of factor v levels showed a dramatic increase ; moreover , within 7 weeks , factor v levels were normal and factor v inhibitor was undetectable . surprisingly , 7 weeks after initiation of steroid treatment , the patient developed an unprovoked severe pain with swelling in his right leg . a week prior to this event , his prothrombin time was 17 seconds , activated partial thromboplastin time was 28 seconds , inr was 1.4 , and the factor v assay value was 0.62 bethesda units / ml , but factor v inhibitor was undetectable . doppler ultrasound revealed deep venous thrombosis , and low - molecular - weight heparin ( dalteparin , 12,500 u ) and coumadin ( 7.5 mg ) were administered orally once daily . the patient s condition continued to improve with no further bleeding or thrombotic events , and anticoagulation was successfully discontinued after 8 months . the use of prednisone was gradually decreased over several weeks after confirmation of the disappearance of the inhibitor , and was discontinued completely in december 2009 ( figure 1 ) . screening assays to rule out inherited thrombophilia were negative for antithrombin , protein c , protein s , factor v leiden , and prothrombin 20210 gene mutations . fluorescence in situ hybridization analysis of a peripheral blood sample showed igh / ccnd1 t(11;14 ) , which confirmed the presence of a clonal b - cell population characteristic of mantle cell lymphoma . the clinical presentation of factor v inhibitors can range from asymptomatic hematological laboratory abnormalities to life - threatening hemorrhage . factor v inhibitor has been associated with a number of conditions , including antibiotic use , sepsis , malignancies,10 autoimmune illnesses , vasculitis , valproic acid use , systemic amyloidosis , cold agglutinin disease , human immunodeficiency virus infection , hematopoietic stem cell transplantation , and liver transplantation , as well as use of amiodarone and warfarin.2,1113 if bleeding occurs , it predominantly involves the mucous membranes of the gastrointestinal , airway , and urinary tracts.2 in contrast with other coagulation factor inhibitors , the level of factor v inhibitors does not correlate with the degree of clinical bleeding , and streiff et al noted that patients who developed spontaneous factor v inhibitors had more significant bleeding than those with bovine thrombin - related factor v inhibitors.14 in addition , the risk of bleeding does not seem to correlate with prolongation of prothrombin time or activated partial thromboplastin time , factor v activity , factor v inhibitor levels , or the duration of presence of factor v inhibitor.14 because factor v is an anticoagulant , reports of thrombosis in patients with acquired factor v inhibitor are extremely rare.59 activated factor v ( fva ) is subsequently inactivated by activated protein c ( apc ) , which cleaves fva at arg506 , arg306 , and arg679 . after fva is cleaved at arg506 ( fvac ) , it further interacts with apc and protein s to enhance the inactivation of activated factor viii ( fviiia ) by the aps / protein s complex , thereby indirectly acting as an anticoagulant.15,16 factor v inhibitor can hinder this cascade by decreasing the level of fvac , resulting in sustained activation of factor viii and leading to procoagulant diathesis . interestingly , an anti - factor v antibody isolated from a patient inhibited the cofactor activity of factor v during the apc / protein s complex s fviiia inactivation cascade by impairing the proper cleavage of fva by apc and inhibiting the inactivation of fva.17 this confirms that factor v inhibitors can lead to procoagulant diathesis by both direct and indirect mechanisms . given that the factor v inhibitor was undetectable in our patient , it is unlikely that it elicited the development of thrombosis during the course of treatment , but we hypothesize that the significantly elevated factor viii might have played a role . additionally , underlying hematological malignancy is another possible provoking factor . the patient presented in this case report had a unique clinical manifestation of acquired factor v inhibitor in that thrombosis occurred after factor v was no longer detectable by an assay measuring bethesda units ; however , the patient still exhibited coagulopathy with high prothrombin time and inr , suggesting the continued presence of a small amount of factor v inhibitor . at first presentation , his factor viii level was significantly higher than normal at 3.23 u / ml ( normal 0.51.5 u / ml ) which might have caused this thrombotic event . to our knowledge , this is the first report of acquired factor v inhibitor in a patient with mantle cell lymphoma simultaneously presenting with this unusual coagulopathy .
acquired factor v inhibitor is a rare hemostatic disorder that presents with hemorrhagic manifestations in the vast majority of patients . 
 factor v inhibitor may develop through a variety of mechanisms involving development of alloantibodies or autoantibodies specific to factor v. autoantibodies , in particular , have been reported in a number of conditions . in this report , we describe a case of acquired factor v inhibitor in a patient with mantle cell lymphoma who presented with hematuria . 
 seven weeks after diagnosis and successful management , the patient developed deep vein thrombosis in the right lower extremity . 
 the patient s factor v levels were normalized , and the inhibitor was successfully eradicated using corticosteroids . here 
 , we discuss this rare disorder , its unusual manifestation , and provide a mini - review of the current literature regarding factor v inhibitors .