Successful treatment of transient acquired factor X deficiency by plasmapheresis with concomitant intravenous immunoglobulin and steroid therapy

Two patients with no history of previous bleeding diatheses presented with active bleeding from multiple body sites, declining hemoglobin levels, and markedly prolonged prothrombin times (PT) and activated partial thromboplastin times (aPTT) with incomplete correction on PT mix assays. Both patients demonstrated a severe deficiency of factor X (F.X) (<1%; reference range 60–150%). F.X levels and bleeding were refractory to multiple transfusions of fresh frozen plasma (FFP) in both patients. In contrast, daily therapeutic plasma exchange (PLEX) with concomitant administration of intravenous immunoglobulin (IV IgG) and steroids produced a rapid increase in F.X levels with cessation of bleeding, followed by stabilization and normalization of F.X levels and progressive correction of coagulation times. Neither patient has demonstrated a recurrence of the bleeding tendency following discontinuation of steroid therapy. These patients had transient acquired F.X deficiency, a rare coagulopathy, which can result in a lethal bleeding diathesis. An IgG inhibitor that selectively inhibited F.X activation in Russell's viper venom or tissue factor/F.VIIa assays was demonstrated in one patient's pretreatment plasma. Previous treatment of hemorrhage in transient acquired F.X deficiency has been prothrombin complex and/or activated clotting concentrates, which can be associated with transient hypercoagulable states. This is the first reported use of PLEX in transient acquired F.X deficiency. PLEX is safe, efficacious, and rapidly restores hemostasis in this rare acquired bleeding disorder. Am. J. Hematol. 57:245–252, 1998. © 1998 Wiley-Liss, Inc.     

Importance of pharmacokinetic studies in the management of acquired factor X deficiency

Up to 14% of individuals with systemic AL amyloidosis develop acquired factor X deficiency, which occurs due to adsorption of factor X onto amyloid fibrils. Although baseline factor X levels are not predictive of bleeding risk in these patients, serious hemorrhagic complications can occur, particularly during invasive procedures. Optimal management strategies to attenuate bleeding risk in these patients are unknown. We describe our experience in the management of acquired factor X deficiency, secondary to systemic AL amyloidosis, in a case series of three patients who received prothrombin complex concentrates (PCCs) for treatment and prevention of bleeding events. We performed a retrospective review extracting information on baseline demographics, laboratory data, pharmacokinetic (PK) studies, and clinically documented bleeding events. Our case series demonstrates that individuals with acquired factor X deficiency secondary to amyloidosis have variable laboratory and clinical responses to PCCs. This is likely due to distinct amyloid loads and fibril sequences, leading to different binding avidities for factor X. Our data emphasize the importance of performing PK testing prior to any invasive procedures to determine the dose and frequency interval to achieve adequate factor X levels for hemostasis, given the variable response between individuals.     

Hemorrhagic disorders

Patients suffering from hemorrhagic disorders often present with only minimal bleeding during surgery or injuries. However, some patients have life-threatening bleeding. Simple screening tests can be used to find the cause of the bleeding: patient and family histories provide information on whether the bleeding tendency is hereditary or acquired. Clinical examination can reveal the bleeding type. Measurement of platelet count can be used to exclude thrombocytopenia. Coagulation tests, such as prothrombin time (PT, Quick) and activated partial thromboplastin time (aPTT) can supply initial information concerning deficiency states of coagulation factors. Bleeding time is often prolonged in patients suffering from von Willebrand disease, thrombocytopenia or thrombocytopathy. If--due to the results of these screening tests-further testing of particular coagulation factors or platelet function is needed, then patients should be referred to a centre specialized in blood coagulation.     

Blutungsneigung

Patients suffering from hemorrhagic disorders often present with only minimal bleeding during surgery or injuries. However, some patients have life-threatening bleeding. Simple screening tests can be used to find the cause of the bleeding: patient and family histories provide information on whether the bleeding tendency is hereditary or acquired. Clinical examination can reveal the bleeding type. Measurement of platelet count can be used to exclude thrombocytopenia. Coagulation tests, such as prothrombin time (PT, Quick) and activated partial thromboplastin time (aPTT) can supply initial information concerning deficiency states of coagulation factors. Bleeding time is often prolonged in patients suffering from von Willebrand disease, thrombocytopenia or thrombocytopathy. If—due to the results of these screening tests—further testing of particular coagulation factors or platelet function is needed, then patients should be referred to a centre specialized in blood coagulation.     

Surreptitious bleeding in surgery: a major challenge in coagulation

Apart from inadequate surgical haemostasis, postoperative bleeding can be related to acquired disorders of platelet number, platelet function or coagulation proteins (e.g. Vitamin K deficiency, DIC or liver injury). We highlight our experience with three patients who suffered life-threatening bleeding in the postoperative setting. The three patients - a 47-year-old man and 70- and 74-year-old women -- all had negative histories for excessive bleeding with prior surgeries, and all had normal preoperative PT and aPTT tests. Surgeries were resection of ischaemic bowel, cholecystectomy and coronary artery bypass grafting. All patients experienced unexpected bleeding within the first few postoperative days requiring multiple red cell transfusions and surgical re-explorations. Evaluations within the first 4--7 days after surgery revealed that these three patients had developed prolonged aPTT due to demonstrable factor VIII antibodies initially at low titre. One patient was treated with high doses human factor VIII, corticosteroids, intravenous gammaglobulin and plasma exchanges. The inhibitor was no longer demonstrable after 6 weeks of such therapy, and he has remained in remission without therapy. The second patient was initially treated with high-dose human factor VIII infusions. Five months later, prednisone and 6-mercaptopurine were begun for worsening inhibitor titre and diffuse purpura and subcutaneous haematomas. The factor inhibitor remitted, but the patient died from liver failure related to post-transfusion hepatitis. The third patient was initially managed with high-dose human factor VIII. Two months later, worsening inhibitor titre and tongue haematoma was treated with activated prothrombin complex, corticosteroids and cyclophosphamide. Eight years later, she is on no therapy, demonstrates a mild bleeding tendency and has a stable low-titre inhibitor. There have been a few case reports of inhibitors to coagulation factors including factor VIII becoming manifest in the postoperative setting but surgery has not been widely recognized as an underlying cause for acquired haemophilia. This paper speculates on pathogenesis and reviews treatment options. This syndrome is remarkable for its abrupt onset in the first few postoperative days and for its substantial morbidity. The problem is potentially reversible with immunosuppressive therapy. Clinicians should be aware of this syndrome, considering acquired haemophilia in patients with unexpected postoperative bleeding.     

Successful total gastrectomy of gastric cancer in a congenital factor V deficient patient

Congenital factor V deficiency is a very rare hereditary coagulation disorder. Total gastrectomy in a patient with factor V deficiency has not been reported in Japan. A 71-year-old woman visited our hospital because of gastric cancer and gallbladder stone. A preoperative screening examination revealed severe anemia, prolonged prothrombin time (35.1 sec.) and activated partial thromboplastin time (109.8 sec.) The value of factor V was 8%. Her parents had a consanguineous marriage. The level of factor V in her two children and a grandchild were lower than the normal limit. We transfused fresh blood and fresh frozen plasma (FFP) preoperatively in order to improve anemia and prothrombin time and activated thromboplastin time. Operating carefully with transfused FFP and fresh blood, we performed total gastrectomy with cholecystectomy successfully. There was no serious tendency to hemorrhage during the operation and the postoperative period. Enough FFP should be transfused during the pre- and postoperative period, paying attention to pulmonary or cardiac failure in elderly patients. Postoperatively, during FFP should be used for 3-10 day with under careful observation of wound bleeding.     

以出血为首发症状的原发性系统性淀粉样变并发凝血因子X缺乏2例报告并文献复习

目的：探讨原发性系统性淀粉样变性并发凝血因子X缺乏的临床特征、发病机制及治疗方法。方法：对2例出血素质的患者进行了病史采集、体格检查、物理检查、凝血因子检查和组织活检，并结合文献就其发病机制和治疗方法进行讨论。结果：发现2例患者都有自发性肌肉血肿，心脏、肝脏、肾脏增大，血沉快，尿蛋白阳性，凝血酶原时间(PT)、活化部分凝血激酶时间(APTT)延长等特点。凝血因子检查X因子活性均明显降低，组织活检均证实为淀粉样变性。结论：目前认为原发性系统性淀粉样变性并发凝血因子X缺乏的机制是淀粉样纤维与X因子特异性结合沉积在组织中形成的。本病无特殊有效治疗，预后差。     

A case of factor V inhibitor

A 57-year-old married Chinese male without a family history of bleeding disorder was presented with severe hemorrhagic tendency and was subsequently found to be suffering from an acquired inhibitor against coagulation factor V. The prolonged prothrombin time and activated partial thromboplastin time could not be corrected by the addition of normal plasma. Subnormal value of factor V level was noted accompanied with an abnormal platelet factor III availability test. With specific antisera and staphylococcal protein A, the inhibitor was characterized as an IgG(lambda) antibody. The hemorrhagic tendency and abnormal laboratory data were corrected after treating the patient with platelet concentrate transfusion and cyclophosphamide.     

Congenital Haemorrhagic Condition Similar but Not Identical to Factor X Deficiency

A 23-year-old white male with a bleeding tendency since early childhood presented a congenital coagulation defect similar but not identical to factor X deficiency. A first and second stage defect were demonstrated, characterized by a prolonged prothrombin time, prolonged partial thromboplastin time, abnormal thromboplastin generation, abnormal prothrombin consumption. The Stypven clotting time was slightly prolonged on fresh plasma but was normal on frozen plasma. Factors I, II, V, VIII, IX, XI, and XII were all within normal limits; factor VII was at the lower limits of normally or slightly decreased. Mr. Stuart's plasma failed to correct the defect of the patients plasma; however, a known factor VII deficient plasma was able to correct the abnormality. Factor X levels showed low (3–13%) only when assayed using tissue whole thromboplastin or tissue partial thromboplastin; the factor X assay using a Stypven-cephalin mixture yielded normal or near normal values. The factor II + factor X level using a Stypven-cephalin mixture appeared normal also. The significance of the findings is discussed. The results are tentatively interpreted as being due to an abnormal factor X rather than to a real deficiency.     

Clotting alterations in primary systemic amyloidosis

BACKGROUND AND OBJECTIVE: The bleeding manifestations frequently observed in patients with immunoglobulin light chain amyloidosis (AL) have been attributed to different pathogenetic factors: amyloid deposits in several organs and systems leading to failures of these latter, the affinity of amyloid for some clotting factors, and the presence of plasma components interfering with fibrin formation could all induce alterations of clotting tests. This investigation was aimed at defining the prevalence of clotting abnormalities and their clinical manifestations in patients with AL. DESIGN AND METHODS: Thirty-six consecutive patients with biopsy proven amyloidosis and documented monoclonal gammapathy were enrolled within one year. The following clotting tests were considered in the study: activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), reptilase time (RT), Russell's viper venom time (RVTT), fibrinogen, factor X and alpha-2 antiplasmin. RESULTS: Hemorrhagic manifestations were mild to moderate in nine patients, but severe and untractable in one. The most frequent clotting anomaly was defective fibrinogen conversion to fibrin, as demonstrated by prolongation of both TT (85% of cases) and RT (90% of cases). Low levels of factor X activity were observed in about 1 out of 4 samples, while fibrinogen and alpha2 antiplasmin levels were distributed over a wide range of values. PT was prolonged in 8 and aPTT in 25 patients. The search for lupus anticoagulant was negative in samples showing a prolongation of aPTT and/or RVVT. INTERPRETATION AND CONCLUSIONS: The prolongation of TT and RT is not dependent on either the presence of a heparin-like substance in the plasma or on fibrinogen levels; furthermore, the prolongation of RVVT is not related to factor X level. The hypothesized presence in the plasma of an inhibitor of fibrin formation could also affect factor X activation by Russell viper venom. The prolongation of TT and RT represents a peculiar feature of amyloidosis. The variability in the behavior of the other clotting times and hemostatic factors studied is mirrored in the heterogeneity of the clinical features observed in this disease.     

Bedeutung von Quick,partieller Thromboplastinzeit und Co.

The Quick test and activated partial thromboplastin time (aPTT) are so-called global assays used to characterize different steps in plasmatic hemostasis. They reflect hemostasis in its classical differentiation into extrinsic and intrinsic pathways. However, they do not cover physiological aspects of cell-based hemostasis. Results are not necessarily congruent with a specific clinical situation and do not replace a complete medical history. Patients suffering from hemophilia A or B, for example, have normal Quick test results. Severe factor XII deficiency reveals an extreme aPTT prolongation without a significant bleeding tendency. In Lupus patients, aPTT is also prolonged with clinically a rather increased thrombotic risk. Fibrinogen as a substrate of coagulation discloses pathological results in both global tests in case of considerable reduction. In case of positive bleeding history and a normal global assay, disorders in platelets, von Willebrand factor and factor XIII must be considered. Reduced Quick test results may be expected in factor VII, II, V, or X deficiency. Disorders of liver synthesis of coagulation factors as well as vitamin K deficiency will be indicated by the Quick test rather than by aPTT. The most frequent hereditary reasons for a prolonged aPTT are hemophilia A and B as well as von Willebrand disease. In case of an acquired bleeding tendency, the diagnostic strategy must include autoantibodies. The sensitivity of the aPTT reagent varies widely. Low-molecular weight heparin and pentasaccharides do not influence the test. Oral direct inhibitors may reveal pathological results in a reagent-dependent manner.     

Secondary amyloidosis connected with neoplasma of urinary bladder and acquired disorders of blood coagulation. Case report

Amyloidosis is a general term encompassing a group of disorders morphologically characterized by a deposition of proteinaceous fibrillar material in the tissues. The secondary amyloidosis is associated with systemic inflammatory processes, chronic infections or neoplasm. These processes are associated with elevated levels of circulating serum amyloid protein A (SAA). We have described a unique case of led to systemic amyloidosis associated with tumor of urinary bladder with significant renal involvement and acquired disorders of blood coagulation factor IX and X deficiency. A renal biopsy specimen with Congo red stain showed diffuse deposits of amyloidosis. Immunohistochemical examination was not done. Factor IX and X was determinated and to be 10-16% of normal values. Timely patient has failed to response to fresh frozen plasma and vitamin K and favorable responded to once weekly administrated factor IX and X concentrate. Progressive deterioration of renal function required hemodialysis, but he died one year later.     

Association of acquired von Willebrand syndrome with AL amyloidosis

Acquired loss of functional von Willebrand factor (VWF) has been termed the acquired von Willebrand syndrome (AVWS). AVWS is a rare adult-onset bleeding diathesis that is clinically similar to congenital von Willebrand disease (VWD), and occurs with a variety of autoimmune, lymphoproliferative, or myeloproliferative disorders. We have identified four patients with AVWS in association with immunoglobulin light chain (AL) amyloidosis. These patients, lacking any pre-existing or family history of abnormal bleeding, developed cutaneous, mucosal, or gastrointestinal bleeding in the course of their disease without deficiency of clotting factor X or other factors; the activated partial thromboplastin time (aPTT) was prolonged in three out of the four cases. Despite normal VWF antigen levels, VWF ristocetin cofactor activity (VWF:RCo) was low. Electrophoresis patterns of high molecular weight (HMW) VWF multimers were abnormal in two of the four cases. Two of the patients were treated with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) and achieved hematologic remission. In these two patients, the bleeding diathesis improved and the coagulation parameters normalized, confirming a causal relationship between the plasma cell dyscrasia and the AVWS. AVWS should be considered in AL amyloidosis patients with hemorrhagic diatheses and normal clotting factor levels.     

Haemarthrosis after superwarfarin poisoning

INTRODUCTION: Superwarfarins are widely used as rodenticides. They are similar to warfarin, but they are more potent and act longer. In case of poisoning, they cause severe bleeding, usually from multiple sites. CASE REPORT: A 67-yr-old man was admitted with melaena, epistaxis and haemarthrosis in his left knee. PT, INR and aPTT were markedly increased. Initially, the patient was treated with blood and fresh frozen plasma (FFP) transfusions. However at the second day, PT, INR and aPTT were even worse. The combination of persistent coagulopathy, normal mixing studies, normal liver function tests and absence of hepatic failure or malabsorption syndromes lead to the suspicion of vitK dependent clotting factors deficiency due to superwarfarin poisoning. Indeed, the patient admitted a suicide attempt with rodenticide, although he had previously denied it. Psychiatric evaluation revealed a disturbed personality. Melaena stopped after 7 d. Then, the patient was administered 30 mg of vitK daily for a total period of 4 months. CONCLUSIONS: Superwarfarin poisoning leads to severe bleeding, usually from multiple sites. Prolonged treatment with high doses of vitK is necessary. Haemarthrosis, as a complication of superwarfarin poisoning, is presented here for the first time in literature.     

Control of ovulation-induced hemoperitoneum by oral contraceptives in a patient with congenital hypoprothrombinemia and in another with congenital factor V deficiency

Hemoperitoneum is a serious and often life-threatening bleeding manifestation. This is particularly true for women who carry congenital bleeding disorders. We describe here a hemoperitoneum occurring in 1 patient with congenital prothrombin deficiency and another with congenital factor V deficiency. Both patients have been followed by us for many years. The patient with prothrombin deficiency underwent laparoscopy but was treated consecutively with whole blood, plasma transfusions and 1,000 units of prothrombin complex concentrates. Response was good and she was then placed on oral contraceptives (OC) which prevented any recurrence. The patient with factor V deficiency presented several episodes of ovulation-related bleeding which required hospitalization and fresh frozen plasma transfusions. On the fifth occasion, the patient had to undergo surgery, and a left oophorectomy was carried out. After this last episode, she was also placed on OC which were very effective in preventing further recurrences. Both patients tolerated the medications very well which, in addition, were able to control menometrorrhagia with a consequent decrease over time in transfusional needs. OC are the treatment of choice in congenital bleeding disorders to control both the menorrhagia and, more importantly, ovulation-related hemoperitoneum.     

Treatment of massive cecal bleeding in a 28-Year-old patient with homozygous factor V deficiency with activated factor VII

Factor V deficiency is usually accompanied with recurrent epistaxis, menorrhagia and haemorrhages after trauma. So far, gastrointestinal bleeding has not been reported. We describe here the first case of severe cecal bleeding in a 28-year-old woman with homozygous factor V deficiency. As a reasonable alternative to large amounts of fresh frozen plasma, we indicated recombinant activated factor VII (rFVIIa), as supra-physiological concentrations directly activate factor X and prothrombin on the surface of activated platelets. With this regimen, the bleeding immediately stopped and the patient was discharged three days later. Rotation thromboelastometry studies showed a marked improvement in clot generation after rFVIIa infusion. We conclude that massive cecal mucosal bleeding is a possible manifestation of homozygous factor V deficiency and rFVIIa could be a successful therapy.     

Recombinant factor VIIa for the treatment of congenital factor VII deficiency

Factor VII deficiency is a rare autosomal bleeding disorder with a highly variable hemorrhagic predisposition. Severe bleeding, including hemarthroses, may be encountered when plasma factor VII levels are below 1%. Patients have prolonged prothrombin times, and the final diagnosis is established by quantitative factor VII assays. Some patients have true deficiencies, that is, very low factor VII activity and low factor VII antigen (cross-reacting material) levels (CRM-); others have normal antigen levels but low activity (CRM+). Still others have reduced antigen levels (CRMR). There is a rather poor correlation between clinical symptoms and factor VII activity levels in plasma. Treatment of these patients consists of fresh frozen plasma, prothrombin complex concentrates, or factor VII concentrates. Recombinant activated factor VII (rFVIIa) is a very useful alternative, and several patients have been treated successfully. Because of the short half-life of factor VIIa, repeated doses have to be administered, and continuous infusion may be even better. Antibodies to factor VII have been reported but seem to be rather rare. From the available data it appears that rFVIIa is a safe and effective treatment modality for patients with congenital factor VII deficiency.     

Acquired,non‐amyloid related factor X deficiency: review of the literature

Summary. Factor X (FX) deficiency is a rare coagulopathy due to congenital deficiency (Stuart–Prower disease) or in association with primary amyloidosis. Acquired and isolated FX deficiency occurring in the absence of a plasma cell dyscrasia has only been infrequently described. After recently diagnosing and treating a case of acquired, isolated FX deficiency, we embarked upon a review of the literature to help guide clinicians who may face this clinical situation. The literature was reviewed to identify cases of isolated, acquired FX deficiency unrelated to congenital deficiency, use of vitamin K antagonists, or amyloidosis. There were 34 cases of acquired FX deficiency identified, occurring in association with malignancy, drug exposure and infection. The majority of described cases (38%) were preceded by a non‐specific respiratory viral illness. The initial presentation was variable, ranging from no bleeding to life‐threatening haemorrhage. Twenty per cent of patients had musculoskeletal bleeding resembling patients with haemophilia. Both the prothrombin time and the activated partial thromboplastin time were markedly prolonged in nearly all patients. In 26% of patients, a specific FX inhibitor was identified. Numerous therapies have been utilized in patients with acquired FX deficiency including high‐dose glucocorticoids, plasma exchange with fresh frozen plasma and intravenous immunoglobulin. In 18% of patients, the coagulopathy resolved spontaneously. All patients achieved a complete recovery. Acquired factor X deficiency is a rare disorder, commonly associated with a preceding viral illness and a circulating FX inhibitor. Although multiple treatment modalities have been described with variable success, in many cases, it is a self‐limited condition.     

Acquired factor XIII inhibitor: clinical features,treatment, fibrin structure and epitope determination

Summary. Acquired factor XIII (FXIII) deficiency, arising from an autoantibody against factor XIII, is a rare bleeding disorder. This autoimmune disorder most commonly occurs in the elderly. Patients who develop such acquired FXIII inhibitors may present with catastrophic bleeding events and are hard to be diagnosed with the normal general coagulation tests. Though the disease is relatively rare, it is known to cause significant mortality. In this article we briefly describe a patient who presented with extensive bleeding and a normal activated partial thromboplastin time and prothrombin time (PT), but had an acquired inhibitor to FXIII; her primary disease was systemic lupus erythematosus (SLE). Also, we will focus on the clinical features, treatment modalities, fibrin structure and epitope identification for acquired factor XIII inhibitor with a review of the literature.