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PubMed1980

Anti-inhibitor Coagulant Complex (Autoplex) for treatment of factor VIII inhibitors in hemophilia.

Fourteen individuals with severe hemophilia complicated by factor VIII inhibitors (1 to 132 Bethesda Units) were treated for 33 bleeding episodes with a new activated prothrombin complex concentrate, Anti-Inhibitor Coagulant Complex (Autoplex, Hyland, Glendale, Calif.). Excellent or good results were observed in 21 of 25 minor bleeding episodes treated, which included joint, soft tissue, and mucous membrane hemorrhages. Eight major bleeding problems (an epidural bleed, a puncture wound, 2 serious soft tissue hemorrhages, 2 lacerations, and 2 major surgical procedures) were treated with excellent (6) or good (2) results. No serious complications were encountered, but two children developed transient hypofibrinogenemia following Autoplex infusion. Although some shortening of the prothrombin time and activated partial thromboplastin time was noted after infusion of Autoplex, there is no useful laboratory test for monitoring therapy. Despite the unknown mechanism of action for bypassing factor VIII, Autoplex appears to be a useful and needed interim product and is safe and effective. In view of the possible potentiation of thrombosis concurrent use of fibrinolytic inhibitors should be avoided.

Adolescent↗

PubMedDate not supplied

Ultrasonic purification of Bridge anticoagulant neutralizing agent (BANA) and a study on its effect on factor VIII inhibitor.

Ether precipitation of globulins from the supernatant fraction of prothrombin complex concentrate, followed by adsorption on tricalcium phosphate and elution gives a beta2 fraction termed Bridge anticoagulant neutralizing agent (BANA). Although this is completely free of all known blood clotting factors, it improves recalcification time, PTT and thromboplastin generation of hemophilic plasma. It also counteracts the effect of factor VIII inhibitor. Ultrasonic elution produced more activity per mg N than did citrate elution. The possibility is discussed of incorporating BANA preparation in the routine fractionation of plasms without reduction in the yield of factor VIII or prothrombin comples concentrate.

Coagulants↗

PubMed2006

Basic aspects of bypassing agents.

Bypassing agents consist of activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa (rFVIIa). Their main utilization is for prevention and treatment of bleeding complications, which may occur in inhibitor-developing haemophiliacs, although new indications for rFVIIa (e.g. trauma-related and cerebral bleeds) are now under evaluation in clinical trials. The mechanisms of action for these agents are still not fully understood. The relative complexity of the composition of aPCC suggests the possibility of multiple modes of action for achieving haemostasis. Among those possibilities, the contributions of activated factor X and prothrombin have been demonstrated in recent years both in vitro and in animal models for the only aPCC which remains on the market. rFVIIa also exhibits a complex mode of action, improving coagulation through both tissue factor-dependent and -independent pathways. The various mechanisms that occur at the cellular surfaces, particularly on the outer leaflet of the platelet membrane, primarily contribute to Xase complex formation and thrombin generation. The ways in which these agents affect the complex kinetics of fibrin formation at the site of vascular damage need further clarification, although significant progress has been achieved in the last 10 years. In addition, the ex vivo monitoring that would reflect achievement of haemostasis in vivo is still not standardized, although several attempts using thromboelastography, thrombin generation and the kinetics of fibrin formation have been initiated.

Blood Coagulation↗

PubMed1984

Purified complex of factor VIII coagulant moiety and phospholipid: high factor VIII coagulant activity in factor VIII inhibitor plasma.

A complex of factor VIII coagulant moiety and phospholipid was purified by means of immunoadsorbent chromatography of factor VIII concentrate and consecutive dissociation of the immobilized factor VIII complex by human placental phospholipid (Fibraccel). The complex of factor VIII coagulant moiety and phospholipid displayed factor VIII coagulant activity (VIII C) and factor VIII coagulant antigen (VIII C:Ag), but no factor VIII related antigen (VIII R:Ag). When incubated with factor VIII inhibitor plasma, the complex of factor VIII coagulant moiety and phospholipid exerted higher factor VIII coagulant activity than native factor VIII complex, and than purified factor VIII coagulant moiety alone. Our results prove that in activated prothrombin complex concentrates a complex of factor VIII coagulant moiety and phospholipid is the active mechanism exerting procoagulant activity in factor VIII inhibitor plasma.

Blood Coagulation↗

PubMed1991

Proteolysis of factor VIII heavy chain polypeptides in plasma and concentrates.

Factor VIII heavy chain (FVIII HC) polypeptides have been studied in both normal plasma and FVIII concentrates on exposure to three coagulation proteases. FVIII samples were incubated with labelled affinity-purified anti-FVIII Fab' fragments, immunocomplexes formed were visualized by autoradiography after sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), and apparent relative molecular masses (Mr) of each band assigned. FVIII HC polypeptides were detected in all types of samples, including plasma, without further purification. Normal plasma contained a range of polypeptides with the largest dominant band at a net apparent Mr of 250-300 kD, and the smallest at 80-90 kD: the bands visualized correspond to the 90-210 kD HC species seen on conventional analysis of purified FVIII. No bands were produced from samples of haemophilic plasma. Treatment of plasma or FVIII concentrate with low concentrations (1 IU/ml) of thrombin removed the 250-300 kD and other intermediate bands, intensified then removed the 80-90 kD polypeptide and produced a band at 40-50 kD. Thrombin-associated rise and fall in FVIII clotting activity by one-stage assay correlated with intensity of the 80-90 kD polypeptide. A polypeptide of Mr 40-50 kD was also produced after incubation with activated factor X: activated factor VII plus thromboplastin had no effect on HC structure. FVIII polypeptides were visualized in prothrombin complex concentrates, with a more degraded profile seen in a deliberately 'activated' product.

Biological Products↗

PubMed1988

A combination of factor Xa and phosphatidylcholine-phosphatidylserine vesicles bypasses factor VIII in vivo.

A combination of phosphatidylcholine-phosphatidylserine lipid vesicles (PCPS), as a source of coagulant active phospholipid, when infused with factor Xa bypasses factor VIII in vivo. To demonstrate this, a reproducible model of bleeding in haemophilic dogs was used. Control studies were performed in normal dogs. In initial studies, factor Xa/PCPS at a dose of 6.5 x 10(-12) and 4.0 x 10(-7) moles/kg respectively failed to correct the abnormal bleeding in the haemophilic animals and initiated a bleeding diathesis in the normal controls. Coagulation studies and immunoblotting demonstrated activation of protein C and an anticoagulant effect resulting from significant falls in the levels of factors V and VIII. Adjustment of the dose of factor Xa/PCPS to 2.6 x 10(-11) and 4.0 x 10(-8) moles/kg respectively produced an immediate haemostatic effect in both haemophilic and normal animals with bleeding stopping within 15-30 s. Despite this observation, protein C activation was again noted. It is concluded that the presence of coagulant active phospholipid and factor Xa in prothrombin complex concentrates may explain the observed factor VIII bypassing activity of these preparations and that the use of a controlled formulation of these two components may provide a more effective approach to the management of patients with factor VIII inhibitors.

Animals↗

PubMedDate not supplied

[Treatment of patients with hemophilia A having antibodies to factor VIII].

Four haemophiliacs with antibodies to factor VIII were treated on 7 occasions with fraction FEIBA. Satisfactory clinical results were achieved in patients receiving large doses of the preparation (63-105 units/kg). The administration of fraction FEIBA produced shortening of the whole blood clotting time but there was only a slight correction in the activated partial thromboplastin time. Two patients received prothrombin complex concentrate without clinical improvement in 1 case a good haemostatic effect was achieved after the infusion of cryoprecipitate and in 1 postoperative bleeding ceased with the administration of porcine factor VIII Immunosuppressive therapy with cyclophosphamide in 3 patients failed to prevent the anamnestic rise in antibody titer.

Adolescent↗

PubMed1994

Heart transplantation under coumarin therapy: friend or foe?

Thirty-six patients were included in a retrospective study of the effect of pre-operative anticoagulant therapy on peri-operative blood loss and haemostatic changes after heart transplantation. Eleven patients (group H) had received intravenous heparin for at least 3 weeks before cardiac transplantation. Twelve patients (group P) had been transplanted when fully anticoagulated with phenprocoumon. A control group of 13 patients (group C) had undergone bypass grafting of their coronary arteries with no pre-operative anticoagulant therapy. Post-operative drainage from the chest drains was 700 ml (median) in group H, 425 ml in group P, and 360 ml in group C (group H vs. group C: P < 0.05). After heparinization for cardiopulmonary bypass, activated clotting time was 462 s (median) in group H, 1500 s in group P, and 727 s in group C (P < 0.003 vs. groups H and P). Post-operatively, patients in group P were given more units of fresh frozen plasma (median 2.5 units; P < 0.01), prothrombin complex concentrate (median 1000 I.U.; P < 0.05) and vitamin K (median 10 mg; P < 0.05) than groups H and C. Heart transplantation under full phenprocoumon therapy does not increase the likelihood of complications caused by peri-operative bleeding.

Adult↗

PubMed2002

Massive blood transfusion in the elective surgical setting.

Massive haemorrhage in elective surgery can be either anticipated (e.g. organ transplantation) or unexpected. Management requires early recognition, securing haemostasis and maintenance of normovolaemia. Transfusion management involves the transfusion of packed red cells, platelet concentrates and plasma (fresh frozen plasma and cryoprecipitate). Blood product support should be based on clinical judgment and be guided by repeated laboratory tests of coagulation. Although coagulation tests may not provide a true representation of in vivo haemostasis, they do assist in management of haemostatic factors. Below critical levels (prothrombin time or activated partial thromboplastin time >1.8; fibrinogen <1.0 g/l; platelet count < 80 x 10(9) 1(-1)) it is difficult to achieve haemostasis. Despite seemingly adequate blood component therapy there remain situations where haemorrhage is uncontrollable. In this setting, alternative approaches must be considered. These include the use of other blood products (e.g. prothrombin complex concentrates; fresh whole blood; fibrin glue) and pharmacological agents (e.g. aprotinin). Complications of massive transfusion result in significant morbidity and mortality. These may be secondary to the storage lesion of the transfused blood products, disseminated intravascular coagulation, hypothermia or hypovolaemic shock. The use of fresh blood products and leucocyte-reduced packed red cells and platelets, may minimise some of the adverse clinical sequelae.

Blood Loss, Surgical↗

PubMed1982

Pediatric transfusion: considerations by age and blood component.

Transfusion in the pediatric age group requires careful consideration of the patient's weight and age because of potential problems with intravascular volume and difficulty with administration of the blood product. Different age groups have varied disease processes that require specific blood components. A correct diagnosis is essential for their proper choice and use. Common blood components used include red blood cells, platelets, granulocytes, factor VIII preparations, and prothrombin complex concentrates. Bone marrow transplantation and apheresis are new therapeutic modalities available through immunohematology-hemotherapy units. Adverse reactions to blood components include immediate and delayed types. The choice of a blood component should be related to clinical need, with overall concern for benefit-to-risk potential for the pediatric patient.

Age Factors↗

PubMed1979

Acquired, transient factor X (Stuart factor) deficiency in patient with mycoplasma pneumonial infection.

A case of severe haemorrhagic diathesis due to acquired deficiency of factor X (both immunologically and in procoagulant activity) is presented. The clinical and serological features of this case indicated mycoplasma pneumonial infection. Factor X in the peripheral blood did not appear to be influenced by administration of vitamin K, prothrombin-complex concentrate, fresh plasma or fresh whole blood. Circulating inhibitors of blood coagulation were absent and systemic amyloidosis could not be demonstrated. After 20 d, factor X spontaneously returned to normal. In view of the absence of other known causes of factor X deficiency, a possible relationship with mycoplasma pneumonial infection is suggested.

Blood Transfusion↗

PubMed2000

Decline of factor VIII and factor IX inhibitors during long-term treatment with NovoSeven.

Recombinant factor VIIa (rFVIIa) (NovoSeveng) is used to treat bleeding episodes in hemophilia A and B patients with inhibitor antibodies against factor VIII (FVIII) and factor IX. rFVIIIa has been studied in home treatment of mild-to-moderate joint, muscle, and mucocutaneous bleeds to assess safety and efficacy. Treatment with other factor concentrates was allowed according to treating physician's judgment. Blood samples were drawn before study start and after 6 and 12 months. It has thus been possible to follow the inhibitor titres during this period. Analyses of 53 patients (49 hemophilia A, four hemophilia B) showed inhibitor levels up to 1,208 BU/ml before study start. Based on the first analysis, hemophilia A patients were divided into high responders (> 5 BU/ml; 28 patients), low responders (> 1 and < 5 BU/ml; 15 patients) and very low responders (< or = 1 BU/ml; six patients). In high responders receiving rFVIIa as only treatment, FVIII inhibitor titre decreased to one-third of the initial level. For high responders receiving other factor treatments such as FVIII or prothrombin complex concentrates, inhibitor titre remained unchanged. Titres for low responders and very low responders remained unchanged independent of treatment. Thus, when rFVIIa is used as the only coagulation factor to treat hemophilia A/B high-responder inhibitor patients, inhibitor level declines significantly.

Factor IX↗

PubMed2003

Treatment of the bleeding inhibitor patient.

The development of inhibitory antibodies to factor (F) VIII and FIX continues to be a major challenge in the treatment of patients with hemophilia. In patients with low-responding inhibitors, it is usually possible to saturate the inhibitor with the deficient factor and to achieve hemostasis, but in patients with high-responding inhibitors, two major tasks have to be considered. One is how to treat the acute bleedings and the other is how to permanently eliminate the immune response, in other words, to induce tolerance. There are several hemostatic agents available for bleeding patients with high-responding inhibitors. Nonactivated and activated prothrombin complex concentrates (PCCs) have been used for almost 30 years, and since the beginning of the 1980s, porcine FVIII has also been used. In more recent years, recombinant FVIIa has been added to the therapeutic armamentarium and has been shown to control hemostasis in most patients. Immunoadsorption may temporarily reduce the inhibitor, enabling replacement therapy for several days. Available data on these alternative regimens will be discussed with a focus on the mechanisms of action, pharmacokinetics, safety, monitoring, and clinical experience.

Animals↗

PubMed2002

Respective roles of factors II, VII, IX, and X in the procoagulant activity of FEIBA.

Activated prothrombin complex concentrates (APCCs) are effective in the therapy of bleeding episodes in hemophilic patients with inhibitors. We investigated the respective roles of factor II, factor VII, factor IX, and factor X in the procoagulant activity of the APCC FEIBA. Factor II, factor VII, factor IX, and factor X were reduced in platelet-poor plasma, and the thrombin potential (TP) was determined using a chromogenic substrate in the absence or presence of FEIBA. Reduction of factor II resulted in a significant decrease of the TP without influencing the lag phase until the onset of thrombin generation. The reduction of factor VII showed no effect on the TP, but resulted in a prolongation of the lag phase. Changes of factor IX or factor X concentrations showed neither an effect on the TP nor on lag phases. Our study demonstrates that thrombin generation in the presence of FEIBA mainly depends on prothrombin.

Blood Coagulation Factors↗

PubMed2001

[Acquired hemophilia: current diagnostic and therapeutic approaches].

PURPOSE: Acquired haemophilia is a rare disease, occurring most frequently in elderly patients, caused by the development of autoantibodies against factor VIII. CURRENT KNOWLEDGE AND KEY POINTS: The disease is characterised by spontaneous haemorrhagic complications which can be fatal in 15-20% of the patients. However spontaneous remission is possible and in fact natural evolution and aetiology are still partly unknown. Acquired haemophilia may arise in association with auto-immune diseases, lymphoproliferative malignancy, pregnancy and also as a drug reaction. The aims of the treatment are first to treat the bleeding which is the most common cause of morbidity and mortality, and second to eliminate the inhibitor by immunosuppression. However no consensus exists for these two parts of the treatment. Bleeding may be controlled by prothrombin complex concentrates, recombinant factor VIIa or porcine factor VIII. The inhibitor is abolished in up 70% of patients using prednisone and cyclophosphamide. Other combinations of prednisone with azathioprine or with cyclophosphamide and vincristine or the use of high-dose immunoglobulin or double-filtration plasmapheresis have also proven effective in some patients. FUTURE AND PROJECTS: The rare occurrence of the disease, the associated with various diseases, and lack of consensus about treatment, require multicentric prospective studies.

Aged↗

PubMed1999

Factor Xa and prothrombin: mechanism of action of FEIBA.

A complex consisting of activated factor X (FX) (enzyme) and prothrombin (substrate), both highly purified from human plasma and virus inactivated, was formulated, characterised biochemically as well as in animal studies, and given the name Partial Prothrombinase (PPT). In vitro, PPT shortened the clotting time of a high-titre human factor VIII (FVIII) inhibitor plasma in a manner similar to that of the activated prothrombin complex concentrate FEIBA and triggered coagulation in plasma samples in which factor V (FV) is present. In vivo, the ability of PPT to activate coagulation in both chimpanzees and baboons was equivalent to that of FEIBA. PPT also triggered coagulation in a von Willebrand factor(vWF)-deficient dog and controlled bleeding in rabbits with antibody-induced haemophilia A. Thus, studying the mechanism of action of PPT also explains the therapeutic principle of FEIBA.

Animals↗

PubMed1985

Long-term high dose factor VIII treatment of 3 haemophiliacs with factor VIII inhibitor.

3 patients with haemophilia A and inhibitor against Factor VIII were developing progressive haemophiliac arthropathy due to the non-feasibility of prophylactic treatment. In order to suppress inhibitor formation, long-term treatment with high-dose Factor VIII (100 units per kg body weight twice daily) was initiated. Prothrombin complex concentrate was given only for bleeding episodes. Though all 3 patients were high responders, they presented different treatment courses. 2 became low responders after 4 and 11 months' treatment, respectively. 1 patient had no demonstrable inhibitor after start of treatment. In all 3 patients, prophylactic treatment was established, in 1 case still with increased doses compared to non-inhibitor patients. The high-dose Factor VIII treatment makes in possible to provide prophylactic treatment for the high-responder inhibitor patients. However, the extremely high costs represent a serious obstacle to this treatment.

Adolescent↗

PubMed1995

The need for highly purified products to treat hemophilia B.

Thromboembolic complications of prothrombin complex concentrate (PCC) therapy were first reported by Kasper in 1973 [N Engl J Med 1973;289:160]. The following contaminants were discussed as possible contributors to the thrombogenicity risk: the presence of other zymogens in PCCs, the presence of activated factor IX or activated factor X, or the presence of phospholipids from platelets resulting from insufficient centrifugation of the donor plasma. Activated factor IX is now accepted as a major causative factor. After numerous additional reports of thromboembolic complications in patients treated with PCCs, the International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) Thrombogenicity Registry was established in 1988. Lusher collected 72 cases worldwide for the SSC/ISTH in 1988 and 1989. Thromboembolic complications and myocardial infarctions, however, continue to be serious problems associated with PCC therapy--even in the 1990s--underscoring the urgent need for high-purity factor IX products. Results from several studies by Mannucci, Bauer, and other authors demonstrated that patients treated with high-purity products developed no activation of prothrombin or thrombin, as indicated by appearance of thrombogenicity markers such as fibrinopeptide A and the amino-terminal fragments of prothrombin (F1 + 2). Other authors demonstrated that in patients at high risk for thrombotic complications, particularly those with liver disease, or postsurgery, or in those requiring repeated treatments, high-purity concentrates appear to be safe, regarding both thrombosis and risk of virus transmission.

Blood Coagulation Factors↗