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PubMed2000

Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors.

Prothrombin complex concentrates (PCCs) and, more recently, activated prothrombin complex concentrates (APCCs), are widely used for the treatment of active bleeding in haemophiliacs with inhibitors. Myocardial infarction (MI), associated with the use of these concentrates, is a well-recognized, but uncommon, complication. We review the 14 previous cases published in the literature and describe two additional patients. MI related to the use of activated and non-activated PCCs predominantly affects young patients who often have no preceding history of, or risk factors for, MI and tends to be associated with large cumulative doses of concentrate. The most frequent pathological finding is myocardial haemorrhage, with no evidence of coronary artery atheroma or thrombosis. The management of further bleeding in these patients is difficult. We have safely used recombinant factor VIIa to treat bleeding in the immediate and long-term period following PCC-related MI.

Abdomen↗

PubMed2001

Current therapy for rare factor deficiencies.

Haemophilia A and B and von Willebrand disease account for 80-85% of all inherited bleeding disorders. The other 15% are represented by deficiencies of fibrinogen, prothrombin, or factors V, VII, X, XI, or XIII. In addition, acquired factor deficiencies are seen in a variety of conditions ranging from malignancies to autoimmune disorders. The spectrum of symptoms in these conditions varies from severe and life-threatening haemorrhage to a mild bleeding diathesis. The diagnosis depends on demonstration of decreased activity of one of the clotting factors. Due to the rarity of each of the individual factor deficiencies, purified factor concentrates are not as readily available as they are for haemophilia A and B. Treatment of rare clotting factor deficiencies consists of the most purified blood product available that contains the missing factor. Depending on which factor is deficient, either purified concentrates, prothrombin complex concentrates, cryoprecipitate, or fresh frozen plasma can be used. In addition, recombinant factor VIIa is available for treating factor VII deficient patients.

Blood Coagulation Factors↗

PubMed1988

Inactivation of lipid-enveloped viruses in labile blood derivatives by unsaturated fatty acids.

Virus sterilization of blood plasma derivatives by addition of several naturally occurring fatty acids was evaluated using vesicular stomatitis virus and Sindbis virus as markers for lipid-enveloped virus inactivation and human immunodeficiency virus (HIV). Inactivation of greater than or equal to 10(4) tissue culture infectious doses (TCID50) of marker viruses added to antihemophilic factor (AHF) concentrates, with 60-100% retention of AHF activity, was achieved with oleic, 11-eicosenoic, linoleic, linolenic, palmitoleic and arachidonic acids. Elaidic, gamma-linolenic, palmitic, and arachidic acids and another fat-soluble compound previously reported to inactivate virus, butylated hydroxytoluene, were less effective. A long chain mono- but not a di- or triglyceride also displayed virucidal properties. Evaluation of the inactivation of HIV added to an immune globulin solution on exposure to 0.033% sodium oleate for 20 min indicated inactivation of greater than or equal to 10(3.4) TCID50. The degree of virus inactivation depended on the sample composition. A favorable balance was achieved between degree of virus inactivation and retention of protein function for AHF concentrate, prothrombin complex concentrate, antithrombin III concentrate, and immune globulin solution on incubation with 0.033% (w/v) sodium oleate at 24 degrees C for 4-6 h. Virus inactivation in whole plasma and plasma cryoprecipitate was not complete despite use of higher concentrations of sodium oleate and/or incubation at 37 degrees C. Reduced virus kill in these less purified derivatives probably is a consequence of their endogenous lipid and/or albumin.

Antiviral Agents↗

PubMed2001

Acquired hemophilia A in a patient with systemic lupus erythematosus.

A patient with systemic lupus erythematosus (SLE) developed acquired hemophilia A. The patient, a 24-year-old Japanese woman, was referred to our hospital because of uncontrollable bleeding following a tooth extraction. Laboratory examination revealed prolonged APTT (116 seconds), reduced factor VIII activity (2.8 %) and the presence of factor VIII inhibitor at a titer of 46.5 Bethesda units/ml. Transfusion of prothrombin complex concentrate and activated prothrombin complex concentrate followed by administration of prednisolone and cyclophosphamide successfully arrested bleeding and reduced the factor VIII inhibitor level. Acquired hemophilia A is a rare but lethal condition. Rapid diagnosis and introduction of adequate therapies are critical.

Adult↗

PubMed2000

[A patient with life-threatening giant hematoma caused by acquired inhibitor to factor VIII].

A 66-year-old non-hemophiliac man developed widely spreaded hematoma in soft tissues around neck. On the day of admission, he was nearly choked by the giant hematoma which markedly compressed trachea. Initially, to keep air way, an intratracheal intubation using a fiber scope was carried out. Coagulation studies revealed a marked prolongation of activated partial thromboplastin time (129 seconds, control: 24.9-33.2), a diminished activity of factor VIII (less than 1%) and a significant increase of factor VIII inhibitor titer (60 Bethesda unit/ml). We thereby diagnosed coagulopathy related to acquired inhibitor against factor VIII. The general combination therapy of intravenous infusion of both prothrombin complex concentrates and activated prothrombin complex concentrates, prednisolone and plasma exchange successfully stopped expansion of the giant hematoma. However, because the titer of factor VIII inhibitor remained increased and the activity of factor VIII was continued to reduced, cyclosporin was additionally administrated. As a result, the titer of factor VIII inhibitor was markedly improved, but the reduced activity of factor VIII was continued and re-bleeding around neck was observed. We thereby administered steroid pulse therapy, which resulted in complete remission of the disease activity and recovery of factor VIII activity.

Aged↗

PubMed2007

Emergency correction of coagulation before major surgery in two elderly patients on oral anticoagulation.

Recommendations for urgent reversal of oral anticoagulation with vitamin K1 antagonists are largely derived from case series employing empirical dosing regimens with vitamin K1 and prothrombin complex concentrates. Data on the use of prothrombin complex concentrates in this indication are scarce in the elderly who are at high risk of both hemorrhagic and thrombotic complications. The two cases presented here describe patients older than 75 years who underwent rapid International Normalized Ratio (INR) reversal with prothrombin complex concentrates for surgical treatment of a bleeding ruptured spleen and for emergency surgery of a dissecting aorta. Both patients had their INRs rapidly corrected to <or= 1.6 and underwent operation without complications. Evidence on treatment of patients who present with elevated INR and who have major bleeding or need to undergo emergency surgery is based mainly on observational studies. The two elderly patients presented here underwent successful emergency surgery after their INRs had been corrected with the intravenous use of vitamin K1 in combination with prothrombin complex concentrate that was administered according to current guideline recommendations.

Journal Article↗

PubMed1995

Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada.

OBJECTIVE: To present current strategies for the treatment of hemophilia and von Willebrand's disease. OPTIONS: Prophylactic and corrective therapy with hemostatic and adjunctive agents: DDAVP (1-desamino-8-D-arginine vasopressin [desmopressin acetate]), recombinant coagulation products (human Factor VIII and human Factor VIIa) or virally inactivated plasma-derived products (high- or ultra-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity, porcine Factor VIII, high-purity human Factor IX, human prothrombin-complex concentrate, human activated prothrombin-complex concentrate), adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant. The induction of immune tolerance in patients in whom inhibitors develop should also be considered. OUTCOMES: Morbidity and quality of life associated with bleeding and treatment. EVIDENCE: Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of our reprint files, MEDLINE, citations in the articles reviewed and references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and pertinent to a predetermined outline. The availability of treatment products in Canada was also considered. VALUES: Minimizing morbidity and maximizing functional status and quality of life were given a high value. BENEFITS, HARMS AND COSTS: Proper prophylactic or early treatment with appropriate hemostatic agents minimizes morbidity and functional disability and improves quality of life. Economic gains are realized through the reduction of mortality and morbidity and their associated costs. The patient has a better opportunity to contribute to society through gainful employment and the fulfillment of social roles. Potential harms include HIV infection, hepatitis B, hepatitis C and the development of inhibitor antibodies to clotting-factor concentrates. The risk of viral transmission has been minimized through the development of procedures for the viral inactivation of plasma-derived clotting-factor concentrates and through the use of recombinant coagulation-factor concentrates and other non-plasma-derived hemostatic agents. RECOMMENDATIONS: DDAVP is the drug of choice for patients with mild hemophilia or type 1 or 2 (except 2B) von Willebrand's disease whose response to DDAVP in previous testing has been found to be adequate. Therapeutic blood components of choice include recombinant products and virally inactivated plasma-derived products. In Canada the recommended products are recombinant Factor VIII for hemophilia A, high-purity plasma-derived Factor IX for hemophilia B and plasma-derived Factor VIII concentrates containing adequate von Willebrand factor (e.g., Haemate P) for von Willebrand's disease. Dosages vary according to specific indications. Adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant are useful for the treatment of oral or dental bleeds and localized bleeds in accessible sites. In patients with inhibitor antibodies, high-dose human or porcine Factor VIII is usually effective when the inhibitor titre is less than 5 Bethesda units/mL. In nonresponsive patients, or in those whose inhibitor titre is higher, "bypassing" agents (e.g., activated prothrombin-complex concentrate and recombinant Factor VIIa) are useful. Long-term management may include immune-tolerance induction. VALIDATION: These recommendations were reviewed and approved by the Association of Hemophilia Clinic Directors of Canada (AHCDC) and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. No similar consensus statements or practice guidelines are available for comparison. SPONSORS: These recommendations were developed at the request of the Canadian Blood Agency, which funds the provision of all coagulation-factor concentrates for people with congenital bleeding disorders, and were developed and endorsed by the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society.

Antifibrinolytic Agents↗

PubMed1992

Emergency reversal of anticoagulation after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Although intracerebral hemorrhage is one of the most serious complications during oral anticoagulant therapy, there are no guidelines on emergency treatment with respect to reversal of anticoagulation effect in these patients. METHODS: We retrospectively compared laboratory data and clinical features in 17 cases of anticoagulant-related intracerebral hemorrhage treated with prothrombin complex concentrate (n = 10) or fresh-frozen plasma (n = 7). RESULTS: In the group of patients treated with prothrombin complex concentrate, the mean prothrombin time decreased from 2.83 to 1.22 International Normalized Ratio within 4.8 hours, compared with a decrease from 2.97 to 1.74 within 7.3 hours in those given fresh-frozen plasma (i.e., four to five times more rapidly after treatment with prothrombin complex concentrate) (p less than 0.001). Symptoms and signs of intracerebral hemorrhage, measured on an eight-graded Reaction Level Scale, progressed on average 0.2 grades in patients given prothrombin complex concentrate compared with 1.9 grades in those given fresh-frozen plasma (p less than 0.05). In patients with prothrombin values above 1.46, clinical progression within 12 hours occurred in five of six cases. CONCLUSIONS: Treatment with prothrombin complex concentrate reverses anticoagulation more rapidly than fresh-frozen plasma, which might be of importance for the prevention of further bleeding.

Aged↗

PubMed1998

Development of anaphylactic shock in haemophilia B patients with inhibitors.

The development of inhibitor antibody is a serious complication of haemophilia in young children. The incidence of factor IX (FIX) inhibitors in haemophilia B patients is five- to 10-times less common (1.5-3%) than the incidence of FVIII inhibitors in haemophilia A (15-30%). Inhibitors are commonly associated with the total absence of FIX antigen due to total deletions or other major derangements of the FIX gene. Unlike those with haemophilia A, patients with haemophilia B often experience anaphylactic reactions to FIX concentrates at the time of inhibitor development. Although the reasons for anaphylaxis at the time of inhibitor development are not yet clear, several hypotheses can be considered. One relates to the smaller molecular size of FIX compared with FVIII. With a molecular size of 55000, FIX diffuses into extravascular spaces more readily. Secondly, since the normal plasma FIX concentration is much higher compared with FVIII (5 microg/ml versus 0.1 microg/ml), haemophilia B patients are exposed to higher amounts of exogenous protein when a standard dose of 40-80 units/kg FIX is used. The routine exposure of haemophilia B patients to such large amounts of exogenous protein without any endogenous FIX antigen may contribute to the development of hypersensitivity. A third reason to consider is the absence of tolerance. Whether the lack of tolerance is due to the total absence of any FIX antigen or co-deletion of neighbouring genes that modulate the immune system is unknown. Management of bleeding in patients with inhibitors and anaphylaxis is complicated because the only readily available products for treatment are the FIX-containing prothrombin complex concentrates or activated prothrombin complex concentrates, the very same products that induce anaphylaxis. Recently, recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has been used effectively in several of these children, but in the USA rFVIIa is only available on a compassionate basis for the treatment of life- or limb-threatening bleeding. Eradication of the inhibitor by immune tolerance induction (ITI) has only been minimally successful in haemophilia B patients with inhibitors and anaphylaxis. Despite initial successful desensitization, the majority of these patients have had recurrent allergic reactions to FIX requiring administration of antihistamines and steroids. Recently, the development of nephrotic syndrome has been reported as a serious complication of ITI in these patients. Since inhibitor antibody is seen in association with complete gene deletions or major derangements of the FIX gene, it may be possible to select those patients with the highest risk for close monitoring during the early period of treatment by obtaining molecular diagnosis at the time of presentation.

Anaphylaxis↗

PubMed1987

Antithrombotic activity of a synthetic heparin pentasaccharide in a rabbit stasis thrombosis model using different thrombogenic challenges.

A synthetic pentasaccharide, representing the critical sequence required in heparin for binding to antithrombin III (AT III), produces strong anti-factor Xa activity in vitro in the presence of AT III and is devoid of any activity directed towards thrombin. This pentasaccharide provides a unique tool to study the question of whether an agent capable of inhibiting factor Xa but devoid of anti-factor IIa activity in vitro, has the capacity to produce an antithrombotic effect in vivo. We have previously demonstrated in a rabbit stasis thrombosis model using a human serum challenge, a significant antithrombotic effect of the pentasaccharide. This finding and discrepancies with some earlier reports on the antithrombotic actions of other oligosaccharide fragments, led us to extend these studies. Four modifications of the stasis thrombosis model were developed using the following thrombogenic challenges selected for their specified induction sites of thrombosis, thromboplastin, an activated prothrombin complex concentrate, a non-activated prothrombin complex concentrate administered simultaneously with Russell's viper venom, and factor Xa. Dose-dependent antithrombotic responses were obtained in all four systems with ED50 values between 25-43 ug/kg for pentasaccharide as compared to 16-47 ug/kg for heparin. Complete inhibition of induced thrombosis was obtained in all four systems for pentasaccharide. Ex vivo analysis revealed expected anti-factor Xa levels but no anti-factor IIa activity. It is concluded that an oligosaccharide with high anti-factor Xa activity and devoid of anti-factor IIa activity is capable of inhibiting thrombosis induced in rabbit stasis models, but that higher dosages than heparin are required for this effect.

Animals↗

PubMed1984

Development and performance characteristics of a competitive enzyme immunoassay for fibrinopeptide A.

A simple nonisotopic method for the quantitation of FPA in biologic samples has been developed utilizing a competitive enzyme immunoassay technique. The performance characteristics of these assays have been investigated in both the experimental and clinical settings and were found to be satisfactory for the routine clinical application. This method is comparable to a commercially available RIA kit (Mallinckrodt, St. Louis, MO) in both the clinical and normal samples. This assay can be used in the diagnosis of hypercoagulable states associated with various diseases. Subclinical activation of coagulation can be readily assessed when the global tests, such as the prothrombin time, partial thromboplastin time, and thrombin time, have no value. This test is of value in the monitoring of the newer antithrombotic agents, such as the low molecular weight heparin fractions that do not effect the global assays, such as the partial thromboplastin time. Similarly, the risk of thrombosis associated with the use of procoagulant therapy, such as the activated prothrombin complex concentrates, can be readily assessed using this assay. It is proposed that the FPA measurement may also provide useful information on the quality control of various plasma-based therapeutic products, such as plasma concentrates or activated prothrombin complex concentrates. FPA generation tests are currently proposed for the screening of antithrombotic and prohemostatic agents.

Blood Coagulation Tests↗

PubMed1982

The coagulant-active phospholipid content is a major determinant of in vivo thrombogenicity of prothrombin complex (Factor IX) concentrates in rabbits.

In vitro evaluation of prothrombin complex concentrates in a thrombin generation assay, using DAPA and purified components of the prothrombinase complex, demonstrated significant levels of coagulant-active "phospholipid replacing" activity. Quantification of this activity showed a significant correlation (r = 0.8747, p less than 0.01) with thrombogenicity measured in vivo in a stasis model in rabbits. Extracted lipid material retained full phospholipid replacing activity in the vitro assay. Thin-layer chromatographic characterization confirmed the presence of phospholipids with known coagulant activity in vitro. In vivo, the extracted material was nonthrombogenic but augmented the thrombogenicity of purified factor Xa. Substitution of a synthetic coagulant-active phospholipid (phosphatidylcholine-phosphatidylserine lipid vesicles) for the extracted phospholipid produced a similar augmentation of a factor-Xa-induced thrombogenicity in vivo. It is concluded that the coagulant-active phospholipid content of prothrombin complex concentrates is a major determinant of thrombogenicity but requires the presence of activated clotting factors for its expression in vivo.

Animals↗

PubMed2000

Hemophilia. Strategies for the treatment of inhibitor patients.

Symptomatic treatment of patients with hemophilia A and hemophilia B has now reached high levels of safety and efficacy. In consequence, at present the most prominent clinical complication is the development of inhibitors, which are alloantibodies directed against the coagulation factor demanded for substitution therapy in the management and prevention of bleeds. When de novo inhibitors are detected for the first time in a patient, several questions are raised. Since the clinical picture with inhibitors is dominated by an excessive tendency to bleed and reduced or lost efficacy of the usual factor concentrate, acute bleeding will often be a problem. Major questions from the patient and his next of kin are whether the inhibitors will disappear, and whether there is a therapy available that can cure this complication. Over the last 20-25 years, treatment programs have been established that seem to offer a reasonably good chance of suppressing inhibitors in hemophilia. Some protocols suggest the use of very high daily doses of factor VIII, whereas others propose much lower doses of factor VIII, seemingly with quite comparable rates of success. Therefore, controlled prospective clinical studies, focusing on the dosage aspect, are urgently required. Control of bleeding is another issue of great importance. In inhibitor patients with a low responder state, substitution with increased doses of factor VIII or IX may successfully arrest bleeding. In some hemophilia A patients with a high responder state, but with actual inhibitor titers in the lower range, a porcine factor VIII concentrate could be useful. In these cases the patient's anti-factor VIII antibody should display no major cross-reactivity towards the porcine factor VIII molecule. In patients with high-responder inhibitors, so-called bypassing agents may be used to control bleeding. There are two major classes of bypassing agents. Concentrates have been produced for more than two decades derived from plasma and characterized by a high content of vitamin K-dependent coagulation factors. Examples are the prothrombin complex concentrates (PCC), and the activated prothrombin complex concentrates (aPCC). A newly introduced recombinant activated factor VII molecule (rFVIIa) has gained approval in numerous countries based primarily on results from emergency use in a substantial number of individuals with inhibitors. Other, still experimental, products have been proposed, but no human clinical studies are available as of yet Inhibitors remain a challenge to patients and their physicians.

Factor VIII↗

PubMed1988

The prevalence of AIDS, AIDS related complex and HIV seropositivity in a large population of patients with congenital clotting disorders.

We have investigated up to the beginning of 1987 114 patients with congenital clotting disorders. 84 had received plasma and/or clotting factors concentrates. 18 out of 84 (21%) had leukopenia, thrombocytopenia, or both. 64 out of 84 (76%) had been infected by hepatitis B virus. The great majority of them (62 out 64) developed adequate immunity (anti Hbs antibodies). Despite this, 47 out 84 (57%) showed persistently elevated transaminases. 17 out of 84 (20%) had HIV-seropositivity. Among them, 7 are free of symptoms related to such a virus up to present time, 8 developed AIDS-related complex and 2 had the full-blown AIDS and died. Non significant difference in HIV seroconversion or its clinical manifestations was noted depending on the administration of factor VIII concentrates versus prothrombin complex concentrates. In contrast, plasma administration appeared to be associated with a lower risk of viral transmission. No abnormality was observed in patients who had never received haemoderivatives, except the presence of anti Hbs antibodies in 1 of them.

AIDS-Related Complex↗

PubMed2002

Concentrates containing factor IX could improve haemostasis under conditions of thrombocytopenia: studies in an in vitro model.

BACKGROUND AND OBJECTIVES: We explored the effect on haemostasis of different factor IX (FIX) concentrates under thrombocytopenic conditions using an in vitro perfusion technique. MATERIALS AND METHODS: A moderate experimental thrombocytopenia (25 000-30 000 platelets/microl) was induced by means of a filtration procedure in blood anticoagulated with low-molecular-weight heparin. The effects of three different FIX concentrates - a prothrombin complex concentrate (PCC), an intermediate-purity concentrate (FIX/X), and a high-purity concentrate (HPFIX) - on platelet deposition and fibrin formation on subendothelium were assessed at two different shear rates (600/second and 1200/second). Activation of the coagulation system was monitored through assessment of prothrombin activation fragment 1 + 2 (F1 + 2). RESULTS: Fibrin deposition increased after addition of FIX concentrates, but only showed a significant increase in experiments performed after incubation of PCC at the lower shear rate (600/second) (64.25 +/- 9.61% vs. control 31.22 +/- 8.02%; P < 0.05). Addition of FIX concentrates caused a small increase in the percentage of platelet deposition and area of those aggregates. These differences reached levels of statistical significance in the presence of FIX/X and HPFIX in experiments performed at a shear rate of 600/second. F1 + 2 baseline values in anticoagulated thrombocytopenic blood were 1.15 +/- 0.13 nm and reached levels of 2.49 +/- 0.24 and 3.60 +/- 0.33 nm at shear rates of 600 and 1200/second, respectively. Increments in F1 + 2 observed after addition of different FIX concentrates always remained in the previous ranges. CONCLUSIONS: Data from the present study provide experimental support favouring the concept that FIX concentrates containing other activated factors could improve haemostasis under conditions of moderate thrombocytopenia.

Animals↗

PubMed1999

The overdosed patient and bleedings with oral anticoagulation.

Overdose or bleeding with oral anticoagulation requires gradual antagonization of the drugs. Minor bleedings are most commonly managed by temporarily discontinuing treatment and by giving vitamin K to antagonize the coumarin derivative effects. Major bleedings, in contrast, especially intracranial hemorrhages, require immediate antagonization of anticoagulation. This is also necessary in required major surgery of anticoagulated patients. Instant normalization of hemostasis in such cases is achieved by the administration of clotting factors, in particular prothrombin complex concentrates. The use of fresh frozen plasma, instead, is less useful. The treatment with prothrombin complex concentrates requires a strict risk-benefit estimation and laboratory monitoring is recommended to optimize dosage adjustment. A 2-year follow-up of 45 out-patients receiving phenprocoumon at our center revealed a total of 11 bleeding complications (11.6/100 treatment-years, 10 minor and 1 major bleeding). Discontinuing or reducing oral anticoagulation together with vitamin K were the methods most frequently used to efficiently manage hemorrhages, whereas prothrombin complex concentrates were only used in one case with major bleeding. Oral anticoagulation appeared to be an enhancing factor for an otherwise existing bleeding diathesis rather than a genuine cause for hemorrhages.

Administration, Oral↗

PubMed2003

Control of bleeding in patients with haemophilia A with inhibitors: a systematic review.

This paper reports a systematic review of the best available evidence of clinical effectiveness in the treatment of acute bleeding in haemophilia A patients with inhibitors. Because of the lack of randomized controlled trials (RCTs) on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. Because of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. No evidence was found to support the use of high-dose factor VIII (FVIII) in bleeding episodes. However in surgery it was found to be highly successful (100%) for low-titre, low-responding inhibitors although not reliable for high-responding inhibitors. Porcine FVIII (pFVIII) was effective in the control of severe bleeding episodes with high-titre or high-responding inhibitors (100%) and in 60-90% of surgical procedures. Activated prothrombin complex concentrates (APCCs) appear to be more effective than prothrombin complex concentrates (PCCs) in the control of mild to severe bleeding episodes. There was no good evidence for the use of PCCs in surgery. APCCs controlled bleeding in approximately 90% of surgical episodes. Recombinant factor VIIa (rFVIIa) controlled 70-100% of mild to severe bleeding episodes with high-responding inhibitors, and achieved better results when used early. It was effective in 60-100% of surgical episodes. Doses varied from study to study, and side-effects from mild to infrequent but serious adverse events were reported. The quality of the evidence is variable. Limited evidence relating to other treatment options is also included in the review.

Acute Disease↗

PubMed1996

Major surgery in haemophilic patients with inhibitors using recombinant factor VIIa.

In the haemophilic patient, development of antibodies that inhibit the function of the missing coagulation factor causes several delicate problems. Most importantly, antibodies will block the function of the specific coagulation factor, and often the antibody activity is so fierce that effective substitution therapy is outruled. In consequence, alternative measures must be adopted to control bleeding. Amongst those most commonly employed, like factor IX concentrates, activated prothrombin complex concentrates, and factor VIII of porcine origin, a new recombinant activated factor VII molecule has been evaluated clinically for some years with promising results. The aim of the present paper was to present a series of patients suffering from haemophilia A or B in whom inhibitors have complicated the clinical picture, and in whom a surgical procedure was indicated. As part of a compassionate use program devised by the producer of this genetically engineered factor VIIa, 12 patients underwent life-saving or essential surgery where the recombinant factor VIIa product was used to promote haemostasis in 13 surgical procedures. Due to a short in vivo half-life of activated factor VIIa, frequent administration was scheduled, injecting factor VIIa every 2-3 h for up to 2 days after which dosage intervals were prolonged. In one case, a global evaluation of the end treatment result was not reported, but in all of the other 12 cases the end result were considered excellent (n = 11) or efficient (n = 1). In none of the cases was other types of coagulation factor treatment modalities necessary. In conclusion, recombinant factor VIIa seems a tempting alternative to traditional treatment of the haemophilic patient with inhibitors, in whom surgery is called for. With other types of haemostatic agents, surgery in haemophilic inhibitor patients has only been studied rarely, and operations have generally been restricted to life-threatening situations.

Adolescent↗