A test method for the absence of thrombogenicity in factor IX complex.
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Abstract:
Consumption coagulopathy was developed in three cases of liver cirrhosis and a case of haemophilia B upon administration of Factor IX preparations which had been tested by the manufacturers for the absence of active clotting factors according to the Japanese Minimum Requirements for Biological Products. By employing the TGT determination, however, active clotting factor(s) could be detected in some of the preparations used in these cases. Accordingly, it was found necessary to modify the current test method in the Minimum Requirements by introducing calcium ion into the test medium. There was no correlation between the clotting activitiy detected by our modified test method and the Factor IX potency of the product. Addition of heparin did not significantly influence the results in our modified method.Keywords:
Thrombogenicity
Factor IX
Clotting factor
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Factor IX
Clotting factor
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Carriers of haemophilia are known to have a wide range of clotting factor levels and bleeding symptoms. This study aimed at investigating whether carriers of severe and moderate haemophilia had an increased bleeding tendency, compared with a control group, using a condensed version of a bleeding assessment tool developed by the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD study group (MCMDM-1VWD). One hundred and twenty-six genetically verified carriers of severe and moderate haemophilia and 90 controls were interviewed regarding bleeding symptoms. A bleeding score of at least 4 was considered positive, indicating a significant bleeding tendency. Clotting factor levels were tested in the carriers.Nineteen of the women were carriers of haemophilia B, with a mean factor (F)IX:C level of 0.54 (± 0.27) kIU/l, and 107 were carriers of haemophilia A, with a mean FVIII:C level of 0.74 (± 0.32) kIU/l. The median bleeding score was 2 (-3-12) among carriers and -1 (-3-8) among controls (P < 0.001). The bleeding score was weakly correlated to clotting factor levels in carriers of haemophilia A (rs = -0.36, P < 0.001). We conclude that the bleeding tendency in our cohort of carriers differed significantly from that in the controls and that clotting factor levels might not be sufficient to predict the bleeding tendency.
Clotting factor
Factor IX
Haemophilia B
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In order to assess thrombogenicity and liver toxicity of different coagulation factor concentrates, antithrombin III, soluble fibrin, alanine aminotransferase (ALAT) and gamma-glutamyl transpeptidase (GT) were measured in samples taken before, 30 min and 24 h after the infusion. Seventy-six studies were performed in 55 patients with haemophilia A (37), B (11) or von Willebrand’s disease, type III (7). A sharp rise of soluble fibrin was observed in 2 patients with haemophilia B, indicating that modern factor IX concentrates may still be thrombogenic. A slight increase was also seen after infusion of factor VIII-von Willebrand factor concentrates of low purity. Antithrombin III, ALAT and GT did not change significantly after any of the factor concentrates. The alterations in those parameters did not correlate with the impairment of liver function.
Thrombogenicity
Factor IX
Liver toxicity
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Summary An episode of defibrination with bleeding following high dose Edinburgh Factor IX (D.E.F.IX) replacement in a patient with haemophilia B undergoing knee joint replacement is reported. We have also monitored plasma fibrinopeptide A levels in patients with haemophilia B following ten standard doses of D.E.F.IX (15–20 u/kg) and have been unable to document any change. Activation of the coagulation system, as previously noted, appears to be related to the use of Factor IX concentrates in high doses.
Thrombogenicity
Factor IX
Haemophilia B
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Haemophilia is the most common congenital disorder of coagulation and affects approximately 1 in 10,000 males around the world. Haemophilia A is due to a deficiency of factor VIII in the circulating blood whilst haemophilia B (also known as Christmas disease) is a clinically identical disorder caused by factor IX deficiency. It is less common than haemophilia A and affects 1 in about 30,000 males. Both factors VIII and IX are essential glycoproteins in the clotting cascade [1] (Fig. 1). The hallmark of severe haemophilia is recurrent and spontaneous haemarthrosis, typically affecting the hinge joints such as the ankle, knee and elbow. The severity of bleeding depends upon the level of factor in the blood.
Clotting factor
Factor IX
Haemophilia B
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Factor IX
Clotting factor
Arthropathy
Joint capsule
Hemarthrosis
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Haemophilia is an inherited bleeding disorder caused by deficiency of factors VIII or IX (FVIII/IX). Severe deficiency is associated with spontaneous bleeding into the joints and recurrent bleeding results in haemophilic arthropathy, disability and reduced quality of life. The bleeding is treated with intravenous FVIII/IX concentrate, which the majority of people with haemophilia self-administer at home. Although initially FVIII/IX was administered on demand once bleeding started, increasingly it is now being used prophylactically. In haemophilia, prophylaxis can be defined as the administration of clotting factor concentrate in anticipation of or to prevent bleeding.
Although prophylaxis is now considered the gold standard for the treatment of severe haemophilia in childhood and adolescence, its use in adulthood is more controversial but here I argue that prophylaxis should be the gold standard in haemophilia treatment for life.
Clotting factor
Haemophilia B
Arthropathy
Anticipation (artificial intelligence)
Factor IX
Gold standard (test)
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Summary In this paper, a five generation Greek family is described with haemophilia B. The disease is characterized by a normal ox-brain prothrombin time, normal levels of the vitamin-K dependent clotting factors VII and X and a proportional reduction of factor IX acttivity and antigen levels all of which is consistent with the cross-reacting material negative form of haemophilia B. However, in this family the factor IX levels in the three patients of generation V are around 1 U/dl while the three older patients in generation III have factor IX levels ranging from 28 to 44 U/dl. In the oldest patient of generation V we observed a rise of the factor IX level from 1 U/dl up to the age of 13 to 10 U/dl at age 14. In addition, the older patients have very mild bleeding symptoms or none at all, while the young ones have occasional spontaneous haemorrhages in muscles and joints, compatible with severe or moderately severe haemophilia. The disease appears to be similar to haemophilia B Leyden which has been described in a Dutch family.
Haemophilia B
Factor IX
Clotting factor
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Consumption coagulopathy was developed in three cases of liver cirrhosis and a case of haemophilia B upon administration of Factor IX preparations which had been tested by the manufacturers for the absence of active clotting factors according to the Japanese Minimum Requirements for Biological Products. By employing the TGT determination, however, active clotting factor(s) could be detected in some of the preparations used in these cases. Accordingly, it was found necessary to modify the current test method in the Minimum Requirements by introducing calcium ion into the test medium. There was no correlation between the clotting activitiy detected by our modified test method and the Factor IX potency of the product. Addition of heparin did not significantly influence the results in our modified method.
Thrombogenicity
Factor IX
Clotting factor
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The annual amount of clotting factor used by patients at the Royal Free Haemophilia Centre increased significantly from 4 million iu in 1980 to over 15 million iu by 1994 (P < 0.0001). In order to assess the reasons for this increase, data on concentrate usage over this period were retrospectively collected for patients who had haemophilia or von Willebrand's disease. Only patients who were registered exclusively at the Centre were included in the study. In total, 498 patients met the inclusion criterion. The median age of the cohort on 1 January 1980 was 21 (range < 1-69) years. During the period there were 88 births and 45 deaths. The majority of patients had haemophilia A (55%). The median follow-up period per patient was 2.1 (range 0-14.8) years. Despite adjusting for increases in the number of patients and changes in body weight, statistically significant increases in clotting factor usage were detected for some subgroups of patients, in particularly for those with severe haemophilia A and B and from the late 1980s onwards, for patients with von Willebrand's disease. Two reasons for this increase in clotting factor usage were identified as being the introduction of improved products and prophylaxis. However, the increased cost of clotting factor provision that has resulted from these changes in treatment policy should not be analysed in isolation but should be balanced off against cost decreases in other areas and against increases in the effectiveness of treatment.
Clotting factor
Haemophilia B
Factor IX
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