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PubMed1999

A protease isolated from human plasma activating factor VII independent of tissue factor.

An activity detected in a prothrombin complex concentrate, termed 'thrombin-like' due to its amidolytic properties, was recently reported by another working group. This serine-protease revealed partial structural homology with a 'hepatocyte growth factor activator'. An impact of this protease on coagulation has not yet been described. The protease was isolated from plasma fractions by ion exchange chromatography and adsorption to immobilized heparin and/or aprotinin. Clotting tests including the FVIIa-rTF assay were performed employing coagulometry. A monoclonal antibody-derived F(ab')2 to FVIII was used to investigate the FVIII bypassing activity (FEIBA). The identity of the-protease with the so-called 'thrombin-like' protease was supported by sequencing of the amino-termini. Its amidolytic activity was significantly enhanced in the presence of calcium and/or heparin. Incubation with purified FVII revealed the generation of FVIIa, but was prevented by pre-incubation of the protease with aprotinin. In contrast, purified FV and FVIII were inactivated. Studying coagulation parameters, clotting times like plasma recalcification times and the prothrombin times were found to be shortened by addition of the protease. Employing a FVIII-inhibitory F(ab')2 and enhancing clotting times significantly, FEIBA of the protease was found. We demonstrated that the isolated protease activates FVII independent of tissue factor. Net acceleration of coagulation was found in several global clotting assays resulting in an in vitro FEIBA. The physiological relevance of these findings deserves further investigation.

Amidohydrolases↗

PubMed2002

Parvovirus B19 transmission by heat-treated clotting factor concentrates.

BACKGROUND: Human parvovirus B19 (B19) DNA can be frequently detected in plasma-derived coagulation factor concentrates. The production of some clotting factor products includes heat treatment steps for virus inactivation, but the effectiveness of such steps for B19 inactivation is unclear. Moreover, detailed transmission case reports including DNA sequence analysis and quantification of B19 DNA from contaminated heat-treated blood components have not been provided so far. Therefore, the correlation between B19 DNA in blood components and infectivity remains unclear. STUDY DESIGN AND METHODS: Asymptomatic B19 infections of two patients with hemophilia A were detected by anti-B19 seroconversion after administration of B19-contaminated heat-treated clotting factors. The suitability of nucleic acid sequence analysis for confirmation of B19 transmission was investigated. Furthermore, the B19 DNA level in blood components was determined and the drug administration was reviewed to calculate the amount of inoculated B19 DNA. RESULTS: Both B19 transmissions from clotting factor products could be confirmed by identical nucleic acid sequences of virus DNA from patients and blood components while sequences from unrelated controls could be differentiated. One patient received, for 4 days, a total of 180 mL vapor heat-treated prothrombin complex concentrate containing 8.6 x 10(6) genome equivalents per mL of B19 DNA. The other patient received 966 mL of low-contamination (4.0 x 10(3) genome equivalents/mL) dry heat-treated FVIII concentrate over a period of 52 days. CONCLUSION: B19 transmissions can be confirmed by nucleic acid sequencing. However, due to the low variability of the B19 genome, a large part of the B19 genome must be analyzed. The transmissions show that the applied heat treatment procedures were not sufficient to inactivate B19 completely.

Child, Preschool↗

PubMed2006

New approaches in the management of inhibitor patients.

The most serious current complication of factor replacement therapy for hemophilia patients is the development of neutralizing antibodies to the factor termed inhibitors. Patients with high-titer inhibitors frequently develop serious bleeding complications which do not respond to standard factor replacement therapy. Therefore, they must be treated with the so-called bypassing agents, recombinant factor VIIa and activated prothrombin complex concentrates, neither of which is as effective as standard factor replacement in patients without inhibitors. Immune tolerance therapy aimed at eradicating inhibitors is successful in a majority of patients; however, a sizable minority will have life-long inhibitors and often develop debilitating joint disease. The ultimate goal is to develop strategies aimed at preventing inhibitor development though these have not been realized yet. Until this is achieved, additional novel approaches are needed to improve the treatment of bleeding episodes and to better treat arthropathy once it develops. Finally, there is no laboratory monitoring device which can predict the clinical response of patients to bypassing agents. Thus another goal of current research is to develop such a tool which will enable the individualization of bypassing agent.

Blood Coagulation Factor Inhibitors↗

PubMed1979

A new treatment strategy for hemophilia B: incorporation of factor IX into red cell ghosts.

Although patients with severe hemophilia B have lifelong spontaneous hemorrhage and crippling hemarthroses, patients with 0.01--0.03 U/ml Factor IX activity have a milder disease state. The clinical condition of severely affected individuals could potentially be improved by prolonging the half-life of transfused Factor IX. The feasibility of incorporating Factor IX into red cell ghosts was suggested by resealing experiments with similar sized molecules such as albumin. We have prepared resealed red cell ghosts containing human Factor IX and X. Human red cells were subjected to hypotonic lysis at 0 degrees C, pH 6.0. Commercial prothrombin complex concentrate was dissolved in the lysing medium immediately prior to the addition of the red cells. After being returned to isotonicity, the red cell ghosts were annealed at 37 degrees C for 30 minutes and then washed extensively. When intact red cell ghosts were tested, no Factor IX or X activity could be demonstrated. After disruption of the red cell ghost membranes with 3M urea or 2% Triton X-100, the procoagulants could be quantitatively recovered. Similar recovery of the clotting factors could be demonstrated from the lysate and the early wash samples. Red cells from Factor IX and X deficient patients served equally well as those from normal subjects. Red cell ghosts prepared in similar fashion but not exposed to the procoagulants had negligible clotting activity. We have demonstrated that human clotting factors can be incorporated into red cell ghosts. The ability of this system to prolong the biological half-life of Factor IX is under investigation.

Erythrocyte Membrane↗

PubMed1997

Assessment of bleeding for the evaluation of therapeutic preparations in small animal models of antibody-induced hemophilia and von Willebrand disease.

Three small animal models of bleeding are described and used to evaluate the effects of preparations intended for therapy of human bleeding disorders. We modified techniques for the assessment of bleeding to be able to reproducibly quantify blood loss and rate of blood flow in addition to the measurement of bleeding time. Temporary hemophilia was induced in a rabbit model by injection of high titer human inhibitor plasma [> or = 1000 Bethesda units (BU)/ml]. A decrease in rabbit FVIII from normal values to below the limit of detection was observed within 30 min, cuticle bleeding time changed from normal (approx. 10 min) to steady state bleeding (> 30 min), and the rate of blood flow increased from 4 to > 30 microliters blood/min. Infusion of an activated prothrombin complex concentrate, (FEIBA STIM4, Immuno) at doses between 75 and 150 U/kg normalized the rate of blood flow, while infusion of FVIII/vWF concentrate resulted in partial correction. Administration of FVIIa, both recombinant and plasma-derived, failed to correct bleeding, however. In an analogous murine model, FVIII/ vWF inhibitor plasma was obtained by immunizing goats with a purified human FVIII/vWF complex. This plasma cross-reacted with mouse vWF in vitro. Injection of the anti-FVIII/vWF inhibitor plasma into mice caused a decrease in vWF antigen, in some animals with a complete loss of vWF multimers comparable to severe von Willebrand disease. A specific anti-vWF inhibitor plasma obtained by immunization of goats with recombinant vWF was used in a further murine model, resulting in a gradual but substantial decrease in FVIII as well as in intensive bleeding. The infusion of a FVIII/vWF concentrate (IMMUNATE, IMMUNO) normalized the rate of blood flow in both murine models. The same assessment methods were used to characterize bleeding in a natural mouse model of von Willebrand disease (strain RIIIS/J). The use of quantitative techniques of assessment of blood loss and rate of blood flow appears to be a helpful tool for characterizing hemorrhagic situations and evaluating the capacity of therapeutic preparations to correct hemostatic defects.

Animals↗

PubMed2007

Current use of by-passing agents in Europe in the management of acute bleeds in patients with haemophilia and inhibitors.

The ultimate goal of treatment for patients with inhibitory antibodies should be to permanently eradicate the inhibitor by immune tolerance induction therapy (ITI). However, ITI procedures fail in a substantial number of patients and in many countries ITI is not even offered owing to its high cost. How patients with inhibitors are managed in different European countries is evaluated with a special focus on the use of by-passing agents, i.e. recombinant FVIIa (rFVIIa) and activated prothrombin complex concentrates (aPCC), as well as the type of monitoring performed. Investigators from 22 large haemophilia centres participating within the network of the European Haemophilia Therapy Standardisation Board (EHTSB) were asked to complete a questionnaire. rFVIIa was routinely used in all centres for both children and adults at dosages ranging from 90 to 250 mug kg(-1) at an interval of 2-4 h. aPCC was used in 85% of the centres in adults and in 25% of the centres in children with haemophilia A at dosages of 50-100 IU kg(-1) every 6-12 h. The corresponding figures for children and adults with haemophilia B were 40% and 15% of the centres, respectively. Higher dosages of both agents were considered in the case of life-threatening bleeds. General recommendations were developed, based on the information provided by the survey. The results clearly indicate the need for well-designed comparative studies to optimize the use of by-passing agents.

Acute Disease↗

PubMed1998

Measurement of active coagulation factors in Autoplex-T with colorimetric active site-specific assay technology.

Autoplex-T is a partially activated prothrombin complex concentrate used primarily for the treatment of patients expressing factor VIII inhibitors. While Autoplex-T has a demonstrated record of clinical effectiveness, the procoagulant composition of this material has not been reported. This absence of composition data is a reflection of the lack of techniques appropriate for accurately measuring an individual protease such as factor IXa in complex mixtures of similar proteases. The development of Colorimetric Active Site-Specific ImmunoAssay technology (CASSIA) has permitted the accurate analysis of the coagulant enzymes present in Autoplex-T. Ten lots of Autoplex-T were reacted with both biotinylated phenylalanylprolylarginine chloromethylketone and biotinylated glutamylglycylarginine chloromethylketone. Only activated forms of the clotting factors present in Autoplex-T react with the peptide chloromethylketones and were thus separated from the other proteins present in Autoplex-T by adsorption onto streptavidin. The individual proteins bound to streptavidin were then detected with specific antibodies. Mean results from the analysis of ten lots of Autoplex-T (mean values) are as follows: factor Xla, 5.9 nM or 0.8 microg/ml; factor Xa, 46.5 nM or 2.1 microg/ml; factor IXa, 177.8 nM or 11.7 microg/ml; factor VIIa, 68.6 nM or 3.3 microg/ml and factor IIa, 5.3 nM or 0.2 microg/ml. These results are discussed with respect to the mechanism of action of Autoplex-T in the treatment of factor VIII inhibitor patients.

Amino Acid Chloromethyl Ketones↗

PubMed1985

A primate model (Macaca mulatta) to study the pharmacokinetics of heparin and its fractions.

We have extensively studied the hemostatic parameters and the responses to the anticoagulant action of heparin and its fractions in the primate model (M. mulatta) and found these to be identical to those obtained in humans. The functional properties of antithrombin III, alpha 2-antiplasmin, and platelet factor 4 were also identical to humans in amidolytic and coagulant assays. Human antibodies against FPA, B beta 15-42 peptide, platelet factor 4, and thromboxane B2 reacted with the primate antigen, and assays were developed to measure these parameters in primates. Infusion of activated prothrombin complex concentrates (more than 100 U/kg/day) on a continual basis up to 3 days resulted in a hypercoagulable state manifested by an elevation of FPA, thromboxane B2, and changes in the thrombelastographic patterns. Similarly, infusion of homologous primate serum also resulted in a hypercoagulable state, as was evident by a sharp increase in the FPA levels. The antithrombotic effects of intravenous and subcutaneous administration of heparin, its low molecular fraction, and their constituents were studied after intravenous and subcutaneous injections. The low molecular weight fractions showed the most effective antithrombotic effects, whereas somewhat milder protection was observed with the starting material and highly anionic fraction. The prolongation of global tests, such as the APTT, TT, and changes in the thromboelastogram did not correlate with the reduction in the blood markers of hypercoagulable state. A modified simplate bleeding time method was used to study the effect of heparin and its fractions on the bleeding profile of heparin fractions. The components of fibrinolytic systems were also measurable in both the clot-based and amidolytic methods to predict the profibrinolytic actions of heparin fractions in its mode. These studies suggest that plasma markers, such as the platelet release proteins, products of thrombin activation, and prostaglandin metabolites, may provide better indices in the monitoring of the antithrombotic actions of newer heparins and antithrombotic drugs. Studies suggest that the pathophysiologic responses after a thrombogenic trigger in the primate model are close to humans, and drug modulation of these may provide relevant clinical information. This model provides the most similar preclinical model to study the actions of heparin fractions.

Animals↗

PubMed1982

Surgery for scoliosis in congenital factor VII deficiency.

A patient with severe congenital factor VII deficiency had an anterior and posterior spine fusion for severe scoliosis. For both operations, hemostatic management was 50 units of prothrombin complex concentrate (Konyne) per kilogram of body weight before surgery and every eight hours after surgery for the first 24 hours. Subsequently, 10 mL/kg of fresh frozen plasma was given daily for five days. No bleeding problems were encountered. A treatment protocol is outlined for replacement therapy management during surgery for patients with severe factor VII deficiency. Managing hemostatic control during surgery in patients with severe factor VII deficiency is relatively easy.

Adolescent↗

PubMed1998

Postpartum acquired factor VIII inhibitors: results of a survey.

Postpartum factor VIII inhibitors are rare; thus, collecting clinical and treatment data may provide valuable information in guiding patient management. This paper reports the results of a survey of United States and Canadian hemophilia centers on 14 patients with postpartum acquired factor VIII inhibitors. Patients ranged in age from 23 to 40 years. Parity at diagnosis was most frequently the first gestation. Two patients were diagnosed prepartum, but two patients only up to one year postpartum. Initial inhibitor titers ranged from two to 550 Bethesda units (BU), and rose to five to 885 BU. The median duration of the inhibitor was 27 months, with two of the 14 inhibitors unresolved at the time of the survey. A total of 80 bleeding episodes occurred, five of which were life or limb threatening. Three patients received no blood products and were not hospitalized. Of those treated for hemostasis, activated prothrombin complex concentrates and porcine factor VIII were most often reported to be effective. For immunosuppression, all patients received steroids and most received additional treatment. Steroids were reported ineffective more frequently than cyclophosphamide. No adverse fetal events were noted and there was no maternal mortality. These results underline the clinical heterogeneity of the severity of postpartum factor VIII inhibitors, and provide treatment guidelines in the absence of prospective studies.

Adult↗

PubMed2001

Therapeutic choices for patients with hemophilia and high-titer inhibitors.

Effective treatment of bleeding episodes in hemophilia with high titer inhibitors (HTI) remains a challenge, despite the fact that the therapeutic armamentarium has expanded considerably over the past few years. Treatment safety has improved with the availability of porcine factor VIII (FVIII) and bypassing products such as recombinant factor VIIa (rFVIIa), and plasma-derived activated Prothrombin Complex Concentrates (aPCCs) that are virally inactivated. The major drawbacks of rFVIIa and aPCCs are their unpredictable hemostatic effect, lack of laboratory assays to monitor efficacy and dosing frequency, and the risk of thrombosis. The proceedings of a one-day workshop of physicians who specialized in treating patients with hemophilia held in Vienna on May 13, 2000 have been summarized. In making a decision regarding the choice of product, physicians often consider the type of bleeding episode (life or limb threatening), age of the patient, volume of the reconstituted product, previous exposure to plasma derived products, cost, efficacy, and safety. For plasma naïve patients, to achieve rapid hemostasis a majority of the panelists used porcine FVIII (for patients who lack porcine inhibitory antibodies) or rFVIIa. For patients previously treated with plasma derived factors, in addition to the above concentrates, aPCCs were recommended. Although no data exists regarding safety and efficacy, switching products was routinely practiced either because of availability or cost. Furthermore, the panelists were uncertain about the efficacy of bypassing agents in the prevention of joint disease in inhibitor patients. The workshop participants felt that future research offers the best solution to resolve some of the dilemmas faced by clinicians and may help individualise treatment in a hemophilia patient with a high titer inhibitor.

Animals↗

PubMed2004

Prevention of bleeds in hemophilia patients with inhibitors: emerging data and clinical direction.

In patients with hemophilia, the development of high-responding inhibitors to factor VIII prevents adequate replacement therapy and results in increased risk of serious bleeding episodes, poor control of joint bleeding, and progressive, debilitating joint disease. Immune tolerance therapy can eradicate inhibitors, but it is not uniformly successful. Emerging data suggest that prophylaxis using activated prothrombin complex concentrates may be effective and safe in reducing the incidence of joint bleeding during immune tolerance therapy and for patients in whom immune tolerance induction fails. However, only controlled clinical trials will ultimately demonstrate whether prophylaxis can prevent joint bleeding and damage, and improve quality of life in patients with inhibitors.

Blood Coagulation Factors↗

PubMed1989

Use of recombinant activated factor VII for treatment of a retropharyngeal hemorrhage in a hemophilic patient with a high titer inhibitor.

Treatment options during an acute hemorrhage for a hemophilic patient who has an inhibitor (antibody) to factor VIII (FVIII) are limited. If the inhibitor titer is high, even massive doses of FVIII are not sufficient to neutralize the antibody. Likewise, immunoadsorption techniques or plasmapheresis cannot remove enough antibody to permit treatment with FVIII. Allergic reactions and cross-reacting inhibitors complicate therapy with porcine FVIII. Prothrombin complex concentrates (PCC) may be effective but the mechanism is unclear. The theory that activated factor VII (FVIIa) is the active principle in PCC prompted our treatment of a patient with a recombinant FVIIa (rFVIIa) product (NOVO Industries). The patient presented with a large retropharyngeal hemorrhage and an initial inhibitor titer of 129 Bethesda units (BU). Despite Autoplex therapy (100U/kg), tracheal compression by the hematoma increased and asphyxiation was imminent. RFVIIa therapy (60 micrograms/kg) was substituted for Autoplex and nine doses were given without complication. The hemorrhage was controlled. By 18 hr breathing was normal and swallowing and speech were greatly improved. Clinically, the patient dramatically responded to rFVIIa. In addition, the purity, the lack of known infectious agents, and the ease of administration make rFVIIa a potentially attractive new therapy. Use of this product also promises to further our understanding of in vivo hemostasis.

Adult↗

PubMed1990

Orthotopic liver transplantation in a patient with combined hemophilia A and B.

A 38-year-old man with severe factor IX and mild factor VIII deficiencies complicated by cirrhosis secondary to chronic non-A non-B hepatitis underwent orthotopic liver transplantation as treatment for both the cirrhosis and his congenital coagulopathy. Intraoperative hemostasis was obtained with factor VII-depleted prothrombin complex concentrate and fresh frozen plasma. Factor VIII and factor IX levels were assayed frequently in the perioperative period, and both returned to normal within 24 hr and remained normal postoperatively. Liver transplantation can be considered as definitive therapy for hemophilia A and/or B with transfusion-related liver disease.

Adolescent↗

PubMed1991

Skin necrosis following prolonged administration of coumarin in a patient with inherited protein S deficiency.

Depression of the vitamin K-dependent modulators of coagulation during the initial phase of oral anticoagulant therapy may lead to a transient hypercoagulable state and skin necrosis. We report a case of skin necrosis associated with inherited protein S deficiency following prolonged coumarin therapy. As a result of a stasis ulceration causing a rise in c4b binding protein and concurrent treatment with topical sulfonamide, we hypothesize that a precipitous decrease in free protein S led to skin necrosis. Progression of the necrosis was halted with unactivated prothrombin complex concentrate. This case confirms the rare association between coumarin induced skin necrosis and protein S deficiency and emphasizes potential drug interactions.

Adult↗

PubMed1992

Protein C survival during replacement therapy in homozygous protein C deficiency.

Homozygous protein C (PC) deficiency is a rare genetic defect that usually results in fatal thrombotic complications (purpura fulminans and DIC), but it can be successfully managed with oral anticoagulants or PC replacement. The successful use of PC replacement for two individuals is described. The activity and antigen levels of PC in fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC) are also reported. The concentration of PC in FFP is 87 +/- 15 units/dl. PC is present in all PCC analyzed; however, a ten-fold difference between the various brands and/or lots is noted. The PC activity and antigen correlates well with no significant levels of APC. Upon infusion of FFP into two homozygous PC-deficient children, the PC levels obtained were less than or equal to 30 units/dl post-infusion and undetectable after 12-18 hr. With infusions of PCC, plasma levels of PC obtained were 100-145 units/dl and less than 10 units/dl after 48 hr. The percent recovery and half-lives of PC from FFP and PCC were 49.8% and 7.8 hr, and 84% and 7.4 hr, respectively. One infant was treated every 48 hr for 2 years without significant purpura fulminans or DIC complications. The levels of the other PC system components did not change during the infusion of the PC-rich material. Based on this information, a specific replacement protocol has been developed using a PC-rich concentrate. However, several problems may arise with the "less pure" PC-rich concentrates: catheter-tip thrombosis, related large vessel thrombosis and blood-transmitted diseases. With a specific PC concentrate, replacement therapy is a viable alternative for the long-term management/treatment of homozygous PC deficiency.

Antigens↗

PubMed2007

Prophylactic treatment of a small child with severe factor VII deficiency using repeat dosing from a single vial of recombinant activated factor VII.

We report our experience with a small child with severe factor VII deficiency and a history of frequent and spontaneous life-threatening hemorrhage. The patient has received several years of successful prophylactic treatment with an every 3-day infusion program in which she receives recombinant activated factor VII (rVIIa) using multiple doses from a single reconstituted vial over a 72-hr period. Comparison is made to prophylactic treatment in this same patient using plasma-derived factor VII (PDVII) using a prothrombin complex concentrate (PCC).

Blood Coagulation Factors↗

PubMed1983

Factors XI and XII are low in subjects with liver disease.

We prospectively measured levels of factors XI and XII in parallel with other coagulation factors in 39 unselected patients with liver disease and in 20 control subjects. Mean levels of factors XI and XII in subjects with liver disease were significantly reduced, being 58% and 61%, respectively, compared with 100% and 94% in controls. Reductions in levels of factors XI and XII were most pronounced in those subjects with low serum albumin. The partial thromboplastin time (APTT) reflected low levels of either factor XI or XII and was most prolonged when both were low, but cause and effect was not demonstrated. Low levels of these factors may explain previous reports of poor response of APTT to infusions of prothrombin complex concentrates. Finally, these low levels strongly suggest that factors XI and XII are produced in the liver.

Blood Coagulation Factors↗