Search PubMed⌕ Search

Biomedical subjects

C R Hay

Publications and source records attributed to C R Hay.

At least 19 recordsLinked to original sources
PubMed2001

Continuous infusion of porcine factor VIII in patients with haemophilia A and high-responding inhibitors: stability and clinical experience.

A multicentre retrospective survey was conducted to assess the efficacy and side-effect profile of porcine factor VIII (pFVIII:C) given by continuous infusion (CI) to patients with congenital haemophilia A and inhibitors. Twenty-nine episodes in 18 patients were treated by CI of pFVIII:C. Efficacy was graded as good in 79% of infusions and fair in 17%. There was a failed response in only one episode. Fourteen percent of patients experienced transfusion reactions with bolus doses, but no reactions were observed in patients given CI. There were no severe reactions. All the reactions resolved following interruption of the infusion and administration of steroids. Premedication did not prevent reactions. In this series the median decrease in platelet count after bolus injection of pFVIII:C was -67 X 10(9) L(-1) compared with a median decrease of -2 x 109 L(-1) during the course of CI, thus, continuous infusion of pFVIII:C appears to have less effect on platelet count than bolus injection. An anamnestic response was associated with 77% of infusions. This high rate of anamnesis reflects patient selection, in that they were all known to have high-level high-responding FVIII inhibitors with cross-reactivity to pFVIII. After reconstitution, the pFVIII:C showed little loss in factor VIII activity in solution over a 24-h period. We conclude that pFVIII:C may be effectively administered by CI to patients with haemophilia A and high-responding FVIII inhibitors. CI is the probably the mode of administration of choice for intensive replacement therapy with pFVIII.

Adolescent↗
PubMed2001

Elective surgery on factor VIII inhibitor patients using continuous infusion of recombinant activated factor VII: plasma factor VII activity of 10 IU/ml is associated with an increased incidence of bleeding.

We examined recombinant activated factor VII (rVIIa) administered by continuous infusion to eight patients with inhibitors to factor VIII, undergoing elective surgery. rVIIa was infused at a fixed rate of 16.5 microg/kg/h for a median of 13.5 days (range 1-26). There was effective haemostasis at this infusion rate in only one of two minor procedures and two of six major operations. Three patients experienced excessive bleeding despite plasma factor VII activity around 10 IU/ml. Serious bleeding occurred in two other patients caused by procedural errors unrelated to rVIIa and required re-operation. The median rVIIa clearance on day 1 was 57 ml/h/kg (range 18-100) and on day 3 was 100 ml/h/kg (range 61-200). Clearance on the final infusion day was not significantly different from day 3. The infusion did not induce pathological activation of the coagulation mechanism. The only thrombotic adverse events were two episodes of superficial thrombophlebitis of the infused vein in one subject. In conclusion, the 16.5 microg/kg/h infusion rate reliably achieves plasma factor VII activity levels of 10 IU/ml, but this level does not provide reliable haemostasis.

Adult↗
PubMed2000

The treatment of bleeding in hemophilic patients with inhibitors with recombinant factor VIIa.

Recombinant factor VIIa (rFVIIa) has proven efficacy in the treatment of patients with alloantibodies and autoantibodies to factors VIII and IX. More than 80% of over 2,000 reported bleeding episodes treated with rFVIIa have been controlled in a variety of clinical circumstances. Its theoretical lack of activation of the coagulation system prompted many clinicians to undertake elective surgical procedures using rFVIIa in addition to on-demand treatment of minor bleeding episodes. Hemostatic efficacy has been good for most of these surgical procedures, without serious adverse events. rFVIIa is considered a useful, safe, and effective treatment for bleeding in patients with anti-factor VIII (FVIII) and anti-factor IX (FIX) inhibitors. However, the optimal dose for various clinical situations has yet to be established and requires further investigation. Laboratory monitoring of treatment using plasma FVIIa measurements should be better standardized. Despite the relatively high cost of this new drug, rFVIIa represents a major therapeutic advance in the treatment of hemophilic patients with inhibitors.

Autoantibodies↗
PubMed2000

Porcine factor VIII: past, present and future.

Porcine factor VIII concentrate is effective in up to 90% of bleeds. Its use is, however, sometimes associated with reactions and a fall in platelet count Furthermore, it is not virally attenuated, although no viral transmission from this product to humans has ever been demonstrated. A third-generation porcine factor VIII is currently being developed. This is purified from parvovirus-free porcine plasma using immunoaffinity and ion-exchange chromatography. It is virally attenuated using the solvent detergent method. It should have a very high specific activity and be virtually free of porcine von Willebrand factor. These product characteristics should confer greater product safety and a greatly reduced risk of treatment side effects.

Animals↗
PubMed2000

Hemophilia treatment. Immune tolerance induction: prospective clinical trials.

Successful immune tolerance induction (ITI) relates significantly to the starting inhibitor titer but not the peak historical inhibitor titer. Below a starting titer of 10 BU/mL success appears to be unrelated to the dose of factor VIII (FVIII) used for ITI. Above this starting titer, larger doses of FVIII may be associated with a better outcome from ITI. Opinion on the importance of the dose of FVIII used for ITI is polarized and there is no agreement on the optimal regimen for ITI. A prospective randomized clinical trial is proposed in which patients will initially be treated on demand with bypass therapy until the inhibitor titer has fallen below 10 BU/mL. Patients will then be randomized to receive a high or low-dose regime. Efficacy, cost-effectiveness and morbidity will be compared.

Cost-Benefit Analysis↗
PubMed1999

The methylenetetrahydrofolate reductase gene C677T polymorphism in patients with homozygous sickle cell disease and stroke.

Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism may cause hyperhomocysteinaemia, a recognized risk factor for stroke, in individuals with folate deficiency. Homozygous sickle cell (SS) disease is associated both with increased demands for folic acid and a tendency to develop stroke. We therefore investigated a possible role of the MTHFR C677T polymorphism in SS disease patients with stroke. Investigation of the frequency of the polymorphism in 48 patients with stroke and in 48 age-, sex- and racially-matched SS controls without stroke failed to reveal a difference between the groups (Fisher exact test, P = 0.99). Homozygosity for the MTHFR C677T polymorphism is unlikely to be a risk factor for stroke in this population with SS disease.

Adolescent↗
PubMed1998

Acquired haemophilia.

Acquired haemophilia is a rare but life-threatening acquired bleeding diathesis caused by autoimmune depletion of factor VIII. This occurs most frequently in elderly patients who lack disease associations. Acquired haemophilia may also arise in association with SLE rheumatoid arthritis, Sjögren's syndrome, other autoimmune conditions, lymphoproliferative malignancy, pregnancy and as a drug reaction. Acquired haemophilia has an equal sex distribution. The aims of treatment are to eliminate the inhibitor by immunosuppression and to treat the bleeding, which is the most common cause of death in patients with acquired haemophilia. The inhibitor is abolished in up to 70% of patients using prednisolone and cyclophosphamide, although other immunosuppressive regimens may also be used. These include azathioprine, vincristine and other cytotoxic agents, high-dose immunoglobulin and cyclosporin A. Bleeding may be controlled using porcine factor VIII or recombinant factor VIIa, although human factor VIII and prothrombin complex concentrates also have a limited role as haemostatic agents in this condition.

Age Factors↗
PubMed1998

The effect of monoclonal or ion-exchange purified factor VIII concentrate on HIV disease progression: a prospective cohort comparison.

The CD4 count has been reported to decline less rapidly in HIV-infected haemophiliacs treated with monoclonally purified factor VIII concentrates than in those using intermediate-purity concentrates. No survival advantage has been demonstrated for this effect, and it is unclear whether this effect occurs with all high-purity concentrates. Two cohorts of patients with severe haemophilia A and HIV treated with either ion-exchange-purified or monoclonally-purified concentrates were compared. The CD4 count, survival, AIDS-defining illnesses, CDC category and anti-retroviral therapy were recorded at 6-monthly intervals for 3 years following the change from intermediate to high-purity factor VIII. 116 patients were recruited, 37 of whom were treated with an ion-exchange purified factor VIII concentrate at three centres, mean (SD) age 31.1 (12.2) years, and 79 were treated with monoclonally purified factor VIII concentrate at two centres, mean (SD) age 29.8 (11.2) years. At the start of the study the median CD4 count was (monoclonal v ion-exchange) 0.30 v 0.16 x 10(9)/l. The CD4 count declined in both arms to a median of (monoclonal v ion-exchange) 0.16 v 0.08 x 10(9)/l at the final visit. Analysis of the (CD4 count)(1/2) over time, using a random coefficients model, found that the mean (SE) rates of decline were not statistically significantly different in the two treatment groups (monoclonal v ion exchange: -0.050 (0.008) v -0.034 (0.011) (CD4 count)(1/2) per year, P = 0.24). No statistically significant difference in survival (log-rank test: P = 0.33) was found. There was no difference in the proportion of individuals experiencing one or more AIDS-defining illnesses (P = 0.32) or in the proportion progressing to CDC category IV (P = 0.28) during the study. The CD4 count declined during the study at a rate similar to that previously reported in patients treated with intermediate-purity factor VIII concentrate, and there was no evidence of any difference between the two treatment groups.

Blood Component Transfusion↗
PubMed1998

Increased bleeding in HIV-positive haemophiliacs treated with antiretroviral protease inhibitors.

Seventeen HIV-positive patients with congenital haemophilia, one with von Willebrand's disease, and one with acquired haemophilia in remission, were treated with antiretroviral protease inhibitors. Clear increases in the frequency of bleeds or changes in the bleeding pattern were documented in 10 individuals taking HIV protease inhibitors. Blood product requirements were increased in eight individuals with severe haemophilia over the 6 months after starting HIV protease inhibitors. Therapy with the HIV protease inhibitor was discontinued in two patients in whom the increased bleeding was severe. No haemostatic cause for the increased bleeding tendency could be identified. Patients with bleeding disorders should be warned about this potential complication of HIV protease inhibitor therapy, and should be closely monitored.

Adult↗
PubMed1998

Factor VIII inhibitors in mild and moderate-severity haemophilia A.

Inhibitors are an uncommon complication of mild haemophilia, occurring in 3-13% of patients and usually arising during adulthood. The risk of inhibitor development in this group appears to be associated with relatively few high-risk factor VIII genotypes clustered in the A2 and C2 domains, especially the Arg593-Cys and the Trp2229-Cys mutations. Kindreds with these mutations have an inhibitor incidence of up to 40%. These mutations may induce a stable conformational change in the factor VIII molecule rendering it antigenically distinct from wild-type factor VIII. Inhibitors in mild haemophilia usually cross-react with endogenous factor VIII reducing the basal VIIIC to < 0.01 IU/ml, and causing spontaneous bleeding. This bleeding is sometimes severe and life-threatening, two-thirds of patients developing a pattern of soft tissue, gastrointestinal (GI) and urinogenital bleeding reminiscent of acquired haemophilia. Bleeding has been treated with human and porcine factor VIII, bypass therapy and DDAVP. Recombinant factor VIIa and DDAVP have the advantage that they do not induce an anamnestic rise in inhibitor titre. About 60% of these inhibitors disappear in the remainder over a median of 9 months. Few of these inhibitors recur, suggesting that most such patients have become tolerant. The inhibitors persist long-term and remain troublesome in about 40% of patients. The limited data available on immune tolerance induction in this group indicate a generally poor response to this approach. Two of nine achieved tolerance, with a partial response in a further four. Inhibitors are an uncommon but life-threatening complication of haemophilia. This complication should be considered when selecting the treatment modality for patients with a family history of inhibitors, and DDAVP used whenever possible.

Antibodies↗
PubMed1998

Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation.

Twenty six patients with mild or moderate haemophilia A and inhibitors are described. The inhibitor was detected at a median age of 33 years, after a median of 5.5 bleeding episodes. This usually following intensive replacement therapy. The median presenting inhibitor titre was antihuman 11.6 BU/ml, antiporcine 1.45 BU/ml. Plasma basal factor VIII level declined from a median of 0.08 IU/ml to 0.01 IU/ml following the inhibitor development. This caused spontaneous bleeding in 22 and a bleeding pattern similar to acquired haemophilia in 17. Bleeding was often severe and caused two deaths. The inhibitor disappeared spontaneously, or following immune tolerance induction, in 16 cases after a median of 9 months (range 0.5-46), with a return to the original baseline VIIIC level and bleeding pattern accompanied inhibitor loss. The inhibitor persisted in the remainder of the cases over a median period of 99 months (range 17-433 months) of follow-up. Inhibitors are an uncommon complication of mild haemophilia which frequently persist and may be associated with severe, life-threatening, haemorrhage. Forty-one percent of treated haemophilic family members had a history of factor VIII inhibitors, suggesting a familial predisposition to develop inhibitors in these kindreds. Sixteen patients from 11 families were genotyped. Seven different missense mutations affecting the light chain were detected and two in the A2 domain. Five patients from three families had a mutation causing a substitution of Trp2229 by Cys in the C2 domain which appears to predispose to inhibitor formation since 7 of the 18 affected individuals have a history of inhibitor development.

Adolescent↗
PubMed1998

Plasma thrombomodulin in renal disease: effects of renal function and proteinuria.

Plasma thrombomodulin (PTM) may be a marker of vascular endothelial damage and is increased in active vasculitis. However, since PTM is a mixture of glycoproteins (MW between 28 to 105 kD), some may be variably excreted by the kidney. PTM level thus may be affected both renal impairment and proteinuria. This study examines patients with varied renal pathology and relates PTM levels to renal function and proteinuria. PTM levels were measured in eighty nine renal patients with varied renal pathology: 23 patients on hemodialysis (HD), 66 with variable renal function (from normal to severe renal impairment), and proteinuria from insignificant to nephrotic range. PTM levels rose as renal function declined and were highest in HD patients. PTM levels also seemed to rise with increasing proteinuria. Indeed, this relationship appeared to be exaggerated in patients with hypertensive and diabetic nephropathy compared to those with primary glomerulonephritis. Measurements of PTM are clearly affected both by renal function and proteinuria. Thus the confidence limits above which an abnormal level is recognised should be increased as renal function declines.

Adult↗
PubMed1997

The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population.

We have investigated the prevalence of a recently reported genetic variation in the prothrombin gene (G20210A) in patients with an objectively confirmed history of venous thrombosis, 12/219 patients (5.5%) were found to be heterozygous carriers of the 20210A allele. The incidence of the 20210A allele in a group of 164 healthy controls was 1.2% (allele frequency 0.61%, 95% CI 0.08-2.19). When patients with a known alternative hereditary risk factor for venous thrombosis (factor V Leiden mutation or deficiency of antithrombin, protein C or protein S) were excluded, the G20210A variant was found to increase the risk for venous thrombosis by approximately 5-fold (odds ratio 5.4, 95% CI 1.16-25.0). This prothrombin gene sequence variation adds further to the list of recognized genetic risk factors for thrombophilia.

Adult↗
PubMed1997

HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party.

The risk of developing factor VIII inhibitor antibodies in haemophilia A may relate both to factor VIII genotype and genes within the HLA complex known to influence immune response. We investigated a cohort of 176 patients with severe haemophilia A and with either high-level inhibitors (> 10BU/ml) or with no history of an inhibitor, stratified according to the presence or absence of the factor VIII gene intron 22 inversion. HLA DRB1, DQA1 and DQB1 polymorphisms were determined by PCR. HLA frequencies form 137 United Kingdom controls were used for comparison. HLA phenotype frequency differences, expressed as odds ratios with 95% confidence intervals were as follows: HLA-DRB*1501, DQB1*0602 and DQA1*0102 were all increased in frequency in patients with inhibitors, only DQA1*0102 reaching statistical significance (OR 2.7, 1.2-5.9). These alleles form part of an established HLA haplotype. The frequencies of HLA-DRB1*1501, DQB1*0602 and DQA1*0102 were particularly raised in patients with inhibitors and a factor VIII gene intron 22 inversion, although again only DQA1*0102 achieved significance (OR 3.1, 1.0-10.1). The frequency of DRB1*01, DQB1*0501, DQA1*0101 were also increased in inhibitor patients lacking the intron 22 inversion although this failed to achieve statistical significance. This data suggests that HLA class II profile constitutes a weak risk factor for developing inhibitor antibodies to factor VIII. This may be more pronounced in patients with an intron 22 inversion.

Chromosome Inversion↗