Measurement of antifactor VIII antibody titre in the presence of emicizumab; Use of chromogenic Bethesda assays
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Chromogenic
Haemophilia B
Coagulation Disorder
In the clinical setting, patients suffering from haemophilia are classified according to the residual level of the deficient coagulation factor. Patients suffering from the severe form of haemophilia (critical factor level <0.01 IU mL-1) display some heterogeneity in their tendency to bleeding despite the uniform factor level. Utilizing a new thrombelastographic method in which coagulation is activated by very small amounts of tissue factor and where resulting data are processed with new software, we studied the whole blood coagulation profile in 11 patients with severe haemophilia A and 11 patients with moderate haemophilia. In both groups of patients, we found a considerable degree of heterogeneity in the coagulation signal. In moderate haemophilia with factor VIII (FVIII):C levels between 0.01 and 0.05 IU mL-1, variance was expected, whereas a quite substantial diversity had not been forecasted in patterns of the whole blood coagulation profiles in patients with the severe form of haemophilia A. Ex vivo substitution to patient's blood to reach various theoretical levels of recombinant factor VIII (rFVIII) revealed that the coagulation response to FVIII supplementation varied substantially. In some severely affected patients levels of FVIII:C close to 0.05 IU mL-1 was sufficient to normalize the coagulation profile, while others required a dose giving >0.50 IU mL-1 of FVIII to achieve a normal whole blood clotting profile. In conclusion, our study revealed that severe haemophilia A seems not to be a single entity, but rather several different clinical and biochemical phenotypes, and that the response to added FVIII varies amongst patients.
Haemophilia B
Clotting factor
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Introduction Assay discrepancy in factor VIII activity between the one‐stage and the chromogenic assays has been described in approximately one third of patients with non‐severe haemophilia A. Whether assay discrepancy may also occur in patients with haemophilia B remains unknown. Aim This study compared the results from the one‐stage and the chromogenic assays in patients with haemophilia B. Methods Plasma samples from patients with haemophilia B attending the haemophilia centre in Malmö, Sweden, were collected after a wash‐out period of more than 7 days and analysed with both assays. Results Fifty samples from 36 patients were analysed. No discrepancy was found in patients with severe haemophilia B. Among the 44 plasma samples from patients with non‐severe disease, 15 showed a twofold or greater difference between the results of the two methods, with the chromogenic method presenting the higher value (mean FIX :C one‐stage 0.02 vs. FIX :C chromo 0.06 IU mL −1 ). Of these 15 samples, 14 were from seven individuals from five families with the same mutated amino acid at the N‐terminal cleaving site of the activation peptide ( FIX : c.572G>A; p.Arg191His or FIX : c.571C>T; p.Arg191Cys). These mutations were not observed in any patients with non‐discrepant results. The reported bleeding frequency for these patients was low and indicative of a mild bleeding phenotype. Conclusion Our findings imply that assay discrepancy occurs for factor IX activity and that both type of assays are needed for a correct diagnosis and classification of haemophilia B. The underlying mechanism by which the mutation influences the assays remains to be determined.
Chromogenic
Haemophilia B
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Summary. In the treatment of haemophilia A and B, recombinant coagulation factors are increasingly replacing plasma‐derived factor VIII and IX concentrates. Although provided with replacement therapy, individual patients may exhibit bleeding episodes, which are difficult to control. These bleeds may be caused by von Willebrand disease (VWD) as an additional underlying coagulation disorder. We report in the present study our experience that in the collective of haemophilic patients, VWD must be anticipated at least with the same order of magnitude as it appears in a normal healthy population. Among the patients at our treatment centre, two patients (1.5%) were identified as suffering from VWD in addition to haemophilia A. In the collective of haemophilia B patients at our centre, three patients (10%) with VWD were found. Two of these patients exhibited unexpected severe bleeding episodes, which could only satisfactorily be controlled by the administration of Haemate‐P or DDAVP supplementary to the recombinant coagulation factor concentrate.
von Willebrand Disease
Haemophilia B
Factor IX
Coagulation Disorder
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von Willebrand Disease
Coagulation Disorder
Haemophilia B
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Desmopressin
von Willebrand Disease
Recombinant Factor VIIa
Platelet disorder
Haemophilia B
Factor IX
Coagulation Disorder
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Much of what is understood about specific coagulation proteins has emerged from the careful study of hereditary disorders of blood coagulation. Haemophilia is a familial X-linked disorder due to deficiency of either factor VIII (haemophilia A) or factor IX (haemophilia B), components of the intrinsic enzymatic complex that activates factor X. The severity of the disease correlates with predicted concentrations of activated factor protein, and those with activity levels below 1% are defined as having severe disease....
Coagulation Disorder
Factor IX
Haemophilia B
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Haemophilia is a group of inherited blood disorders in which blood does not clot properly. Bleeding disorders are due to defect in blood vessels, the coagulation mechanism or the blood platelets. Blood coagulation mechanism is a process which transforms blood from a liquid into solid and involves different clotting factors that generates fibrin fibers through extrinsic or intrinsic coagulation pathway which along with platelet plug stops bleeding. When coagulation factors are deficient, the blood does not clot properly and bleeding continues. An affected individual may bleed spontaneously or for longer than a healthy person after injury or surgery. Haemophilia is a X-linked recessive disorder that affects males, and females are protected by normal gene on other X-chromosome. Queen Victoria was a carrier of haemophilia and passed the mutation to her son Leopold and through her daughters to members of Royal families of Spain, Russia and Germany. JMS 2016; 19(1):32-33
Bleed
Clot formation
Coagulation Disorder
Haemophilia B
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The generation of thrombin is the key to successful haemostasis. Abnormalities in the haemostatic system may be congenital or acquired. Congenital haemophilia A is an X-linked recessive disorder of reduced or absent factor VIII activity that accounts for 80–85% of all cases of congenital haemophilia. Congenital haemophilia B is an X-linked recessive disorder of reduced or absent factor IX activity that accounts for 10–15% of all cases of congenital haemophilia. Patients with congenital haemophilia A or B can develop inhibitory antibodies against factor VIII or factor IX, respectively. Von Willebrand disease is the most common inherited bleeding disorder, affecting up to 1% of the population, and is due to a quantitative and/or qualitative defect in von Willebrand factor. Disseminated intravascular coagulation is a thrombo-haemorrhagic diathesis resulting from inappropriate activation of the haemostatic system and dysregulated thrombin generation.
Bleeding diathesis
Diathesis
Haemophilia B
Hemorrhagic diathesis
Coagulation Disorder
Factor IX
von Willebrand Disease
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Haemophilia A severity is closely correlated to the factor VIII (FVIII) activity, which can be measured in different ways. The original one-stage clotting assay is still the most widely used. The two-stage coagulation assay eliminated many of the drawbacks of the one-stage assay and was further developed into the chromogenic assay, a two-staged test with purified coagulation factors in the first stage, and a FXa-specific chromogenic substrate in the second stage. In many patients with mild or moderate haemophilia A, there is a discrepancy between the one-stage and the two-stage assays. If only the one-stage assay is used, some patients will have normal FVIII levels and not be diagnosed as having haemophilia or be considered to have a milder bleeding risk than is the case. Other patients who have normal FVIII activity will be diagnosed as haemophilia A. All haemophilia treatment centre laboratories should have access to both one-stage and chromogenic FVIII:C assays. Appropriate standards should be employed to enable accurate FVIII:C measurement. Different assays to measure inhibitor activity to infused FVIII have been developed since 1959. Inhibitor results based on the one-stage or chromogenic FVIII:C assays are well correlated, but the one-stage assay may be influenced by nonspecific inhibition.
Chromogenic
Haemophilia B
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Abstract There are three main methods used to assay factor VIII ( FVIII ) activity: the one‐stage and two‐stage clotting assays and the two‐stage chromogenic method. The most commonly used assay for the diagnosis of haemophilia A is the automated one‐stage FVIII assay. The classical two‐stage FVIII assays are less frequently used. The chromogenic FVIII :C assay is a variant of the two‐stage assay. It is easier to use and therefore used more commonly. Recently significant assay discrepancy has been recognised in the FVIII :C measurements in approximately one‐third of mild haemophilia A patients. This so‐called discrepant mild haemophilia A is characterised by a high ratio of one‐stage/two‐stage assay with one‐stage FVIII levels that are typically more than double those of the two‐stage coagulation assay. There are several mutations that destabilise the FVIII a structure that can explain this result of a more pronounced decrease of the chromogenic FVIII :C activity compared with the one‐stage activity. These mutations are clustered at the interfaces of the A1, A2 and A3 domains of the FVIII protein. The inverse discrepancy, where the one‐stage assay gives lower FVIII :C results than the chromogenic assay, seems to be associated with mutations found close to important sites for thrombin cleavage or FIX binding. We are carrying out a study of mild haemophilia A samples from the Malmö Haemophilia Centre of families with a unique F8 genotype. The activity of FVIII will be measured using a chromogenic assay and two different one‐stage assays. We hope to estimate the true size of assay discrepancy. Aim This project will review assay discrepancy in mild/moderate haemophilia A and the risk of misdiagnosis. The overall aim is to estimate the size of the problem and to learn from the literature and experiences from our centre as well as to suggest recommendations on how to avoid misdiagnosis.
Chromogenic
Haemophilia B
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