Biomedical subjects
Publications and source records attributed to D M Keeling.
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The revised UKHCDO factor (F) VIII/IX Inhibitor Guidelines (2000) are presented. A schema is proposed for inhibitor surveillance, which varies according to the severity of the haemophilia and the treatment type and regimen used. The methodological and pharmacokinetic approach to inhibitor surveillance in congenital haemophilia has been updated. Factor VIII/IX genotyping of patients is recommended to identify those at increased risk. All patients who develop an inhibitor should be considered for immune tolerance induction (ITI). The decision to attempt ITI for FIX inhibitors must be carefully weighed against the relatively high risk of reactions and the nephrotic syndrome and the relatively low response rate observed in this group. The start of ITI should be deferred until the inhibitor has declined below 10 Bethesda Units/ml, where possible. ITI should continue, even in resistant patients, where it is well tolerated and so long as there is a convincing downward trend in the inhibitor titre. The choice of treatment for bleeding in inhibitor patients is dictated by the severity of the bleed, the current inhibitor titre, the previous anamnestic response to FVIII/IX, the previous clinical response and the side-effect profile of the agents available. We have reviewed novel dose-regimens and modes of administration of FEIBA (factor VIII inhibitor bypassing activity) and recombinant activated FVII (rVIIa) and the extent to which these agents may be used for prophylaxis and surgery. Bleeding in acquired haemophilia is usually treated with FEIBA or rVIIa. Immunosuppressive therapy should be initiated at the time of diagnosis with Prednisolone 1 mg/kg/d +/- cyclophosphamide. In the absence of a response to these agents within 6 weeks, second-line therapy with Rituximab, Ciclosporin A, or other multiple-modality regimens may be considered.
BACKGROUND: Previous studies of the development of inhibitors and their impact on mortality have been small. OBJECTIVES: To examine the development of inhibitors in people with hemophilia in the UK and their effect on subsequent mortality. PATIENTS: 6078 males with hemophilia A and 1172 males with hemophilia B registered in the UK Haemophilia Centre Doctors' Organisation database, 1977-98. RESULTS: In severe hemophilia A inhibitors developed at rates of 34.4, 5.2 and 3.8 per 1000 years at ages <5, 5-14 and 15+years; cumulative risks at ages 5 and 75 were 16% and 36%. In hemophilia A the rate of inhibitor development decreased during 1977-90, but increased during the 1990s. In severe hemophilia B inhibitors developed at rates of 13.3 and 0.2 per 1000 years at ages <5 and 5+ and cumulative risks at ages 5 and 75 were 6% and 8%. With HIV, inhibitor development did not increase mortality. In severe hemophilia without HIV, inhibitor development doubled mortality during 1977-92, but during 1993-99 mortality was identical with and without inhibitors. In severe hemophilia without HIV but with inhibitors, mortality from causes involving bleeding decreased during 1977-99 (P = 0.001) as did mortality involving intracranial hemorrhage (P = 0.007). CONCLUSIONS: These data provide estimates of the rate of inhibitor development in hemophilia A and hemophilia B, and they show that the rate of inhibitor development has varied over time, although the reasons for this remain unclear. They also show that in severe hemophilia the substantial increase in mortality previously associated with inhibitors is no longer present.
von Willebrand disease (VWD) is the commonest inherited bleeding disorder. The aim of therapy for VWD is to correct the two defects of haemostasis in this disorder, impaired primary haemostasis because of defective platelet adhesion and aggregation and impaired coagulation as a result of low levels of factor VIII. The objective of this guideline is to inform individuals making choices about the treatment and management of VWD including the use of therapeutic products. This is the second edition of this UK Haemophilia Centre Doctors' Organization (UKHCDO) guideline and supersedes the previous edition which was published in 1994.
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Most intracranial haemorrhages in infants after the neonatal period are secondary to non-accidental injury. Occasionally brain haemorrhages in non-mobile infants are due to an inherited coagulopathy. This may often be diagnosed with a coagulation screen on admission. Little is known about the neurological outcome of infants in the latter group. Five infants are described who presented with acute spontaneous brain haemorrhage secondary to an inherited coagulopathy (n = 3) and vitamin K deficiency in alpha(1) antitrypsin deficiency (n = 1) and Alagille's syndrome (n = 1). Despite the critical clinical presentation and the severe imaging findings, these five infants made a good neurological recovery. Infants presenting with spontaneous ICH due to a significant (inherited) coagulopathy are usually easy to differentiate from non-accidental shaking injury; their bleeding pattern within the brain seems different from non-accidental shaking injury and neurodevelopment outcome appears better.
Heparin infusion may cause heparin resistance and may affect monitoring by measurement of the activated coagulation time (ACT), making the assessment of anticoagulation difficult, with the risk of over- or undertreatment, especially during cardiac surgery. We studied two groups of patients undergoing cardiopulmonary bypass (CPB): patients on heparin infusions (group H) and heparin-naive controls (group C). All patients received heparin 300 IU kg(-1) before CPB and a further dose of 5000 IU if the ACT 5 min after commencing bypass was less than 400 s. Measurements of ACT, heparin concentration, antithrombin-3, thrombin-antithrombin complex, prothrombin fragment F(1+2) and D-dimers were made before and 5 and 20 min after start of CPB. A second dose of heparin was given to eight out of 18 patients in group C and 10 out of 24 in group H. Antithrombin-3 in group H was significantly less than in group C at 5 min [59 (14) vs 52 (9)%, P<0.05]. ACT was significantly lower in group H than group C at 20 min [387 (64) vs 431 (67) s, P<0.05]. Despite ACTs of less than 400 s in both groups, no coagulation was seen, suggesting that 300 IU kg(-1) heparin is a safe dose for anticoagulation in CPB even after heparin therapy.
The recent discovery of five patients with coumarin sensitive FIX-variants due to a missense mutation in the FIX propeptide, either Ala-10Val or Ala-10Thr, has highlighted a novel type of genetic predisposition to bleeding during oral anticoagulant therapy (OAT). In the present study, we report six additional patients with such FIX variants. Haplotype analysis of FIX polymorphisms revealed a founder effect in the five German and Swiss patients with the Val-10 variant. Also, four Thr-10 variants detected in Germany, Switzerland and Great Britain derived from a common founder. Two Thr-10 variants from USA showed an independent de novo origin at a CpG dinucleotide that in general represents a mutation hotspot. These findings implicate the existence of additional subjects with corresponding variants in the populations of various countries. Even though the rare occurrence of these variants does not justify a general aPTT screening during OAT, it is recommended to monitor each bleeding event during OAT in males in order to exclude a genetic predisposition to bleeding by means of the following testing strategy: a) aPTT-testing in each bleeding complication of male patients during OAT, b) if aPTT is disproportionately prolonged, determination of FIX:C, and c) if FIX:C is disproportionately decreased as compared to FII:C, FVII:C and FX:C, sequencing of exon 2 of the FIX gene. This strategy will provide a cost-effective and safe procedure to identify patients that carry the FIX variants. Moreover, such a strategy accumulates data about the prevalence of these FIX mutations in a given population.
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The standard enzyme-linked immunosorbent assay (ELISA) test for von Willebrand factor antigen (vWF-Ag), though sensitive and specific, does not deliver the flexibility to handle single sample assessments economically or provide rapid, emergency testing capability. The present study examined the performance characteristics of an immuno-turbidimetric assay kit (STA Liatest) modified for automation on the MDA(R)180 coagulation analyser using a supplied protocol. One hundred and sixteen patient samples were assessed by both the standard and the modified method. The correlation coefficient was 0.98 across the range of values 1-487 IU/dl. Above 200 IU/dl, where specimen dilution was indicated, there was greater diversity (r = 0.86) between the techniques. Plotting the difference between methods against the mean of both showed excellent agreement between methods below 100 IU/dl vWF. The intra-assay and interassay coefficients of variation were less than 3% at both low and normal range levels. The MDA(R)180 automated vWF assay merits consideration as an alternative to ELISA testing that provides random access and result availability within 30 min.
Acquired haemophilia A due to the development of auto-antibodies directed against factor VIII (FVIII) is a rare disorder that may result in serious haemorrhagic episodes. Although in many cases no associated underlying disorders are apparent, the condition has been reported in association with autoimmune disorders, haematological malignancies, treatment with certain drugs and pregnancy. The reaction kinetics of auto-antibodies to FVIII differ from those observed with allo-antibodies in congenital haemophilia. Previous studies in congenital haemophilia have raised the possibility that inhibitory antibodies vary in their reactivity with the factor VIII molecules in different concentrates used for treatment. However, the interaction of FVIII in concentrates and inhibitors in acquired haemophilia has never been previously studied. In this study, the effect of different FVIII concentrates was studied on neutralization in vitro by performing inhibitor titres using the New Oxford inhibitor assay method. The inhibitor titre in eight patients with acquired haemophilia A was assayed against five commercially available FVIII concentrates of varying purity. The intermediate purity concentrate 8Y and the high purity concentrate that contains normal amounts of von Willebrand's Factor (vWF) (Alphanate) gave lower titres than the high purity concentrates with low (Monoclate-P) or no (Kogenate) von Willebrand content. All but one antibody had very low reactivity with porcine FVIII. Further work will be required to establish whether concentrates manifesting a low level of in vitro reactivity with the inhibitor have a better haemostatic effect in vivo.
Congenital afibrinogenaemia and hypofibrinogenaemia are rare disorders of haemostasis. In this case report the problems posed in the management of two patients with fibrinogen levels less than 0.1g L(-1) and who developed intracranial bleeding are considered. The value of fibrinogen concentrate and the role of prophylaxis is also discussed.
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In some families with mild haemophilia higher results are obtained for factor VIII activity (FVII:C) determined by one-stage assay than by two-stage or chromogenic assays. Amino-acid substitutions in the A1, A2 and A3 domains of factor VIII have been described in affected individuals with this phenotype. We describe a case of mild haemophilia A in which FVIII:C measured by one-stage assay was normal at 106%. However, FVIII:C levels measured by two-stage and chromogenic assays were 18% and 35% respectively. DNA analysis revealed a novel mutation in the A3 domain of factor VIII, His1954-->Leu. In a molecular model of the FVIII A domains, His1954 is placed in close proximity to two other mutations that have previously been shown also to be associated with one-stage/two-stage discrepancies. In this patient the diagnosis of haemophilia A would be missed if only the one-stage assay was used.
The use of D-dimer tests to exclude venous thromboembolism is an important advance in clinical practice and also has economic benefits. Ideally the test should be objective and a test that could be run on the routine coagulometer would obviate the need for additional investment in alternative hardware. A new automated latex particle immunoassay (MDA D-dimer) that can be run on a routine coagulometer was compared with a well established enzyme linked fluorescent assay (VIDAS D-dimer) on the basis of their ability to exclude venous thromboembolism. The assays were compared in 49 patients presenting to the emergency department with clinically suspected deep vein thrombosis or pulmonary embolism. After objective diagnostic imaging, 20 patients were confirmed to have venous thromboembolism. There was strong agreement between the assays in individual patients. Using a cut-off of 500 micrograms/l, both tests had a sensitivity of 100% and therefore a negative predictive value of 100%, however the MDA test would have spared more patients (20% vs. 12%) from further testing if a negative D-dimer was used to rule-out the diagnosis. It was concluded that a rapid, objective latex D-dimer test run on a routine coagulometer (MDA D-dimer) can be used to exclude the diagnosis of venous thromboembolism.
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