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PubMedDate not supplied

Hemophilia in dogs, with special reference to hemophilia A among German shepherd dogs in Denmark. I: Pathophysiology, laboratory tests and genetics.

A review is given of the history and distribution of hemophilia in dogs. The current knowledge of Factor VIII relative to hemophilia A and von Willebrand's Disease is presented. The tests required for distinguishing between hemophilia A, hemophilia B, von Willebrand's Disease, and various disorders caused by other factor defects in the coagulation cascade are described. X-linked, recessive inheritance of hemophilia A is illustrated in genealogical diagrams. The precautions required in connection with blood sampling for diagnostic tests are emphasized.

Animals↗
PubMed2002

Quantifying practice effects in longitudinal research with the WISC-R and WAIS-R: a study of children and adolescents with hemophilia and male siblings without hemophilia.

OBJECTIVE: To quantify practice effects associated with annual administrations of WISC-R and WAIS-R in children and adolescents with and without hemophilia. METHODS: Participants were young men (age: 7-19; 80 with hemophilia, 30 siblings) enrolled in the Hemophilia Growth and Development Study. Participants with hemophilia completed age-appropriate Wechsler scales at baseline and at four annual follow-ups; the siblings, at baseline and one 2-year follow-up. Regression analyses were used to quantify average changes in scores, adjusting for variables related to test performance. RESULTS: Consecutive annual evaluations were free of significant practice effects for 4 years with the Verbal Scale and for 2 years with the Performance Scale. VIQ decreased, and PIQ increased over time. Baseline VIQ was related to changes in VIQ; baseline PIQ and number of test-specific retests were related to changes in PIQ. CONCLUSIONS: The findings support use of Wechsler scales for annual evaluations to monitor cognitive development in children and adolescents.

Adolescent↗
PubMedDate not supplied

Declining immune function in children and adolescents with hemophilia and HIV infection: effects on neuropsychological performance. Hemophilia Growth and Development Study.

OBJECTIVE: To determine whether declines in immune functioning are associated with changes in neuropsychological performance in children and adolescents with hemophilia who are infected with the human immunodeficiency virus (HIV). METHODS: Participants were 333 males with hemophilia, ages 6-19 years at entry. A baseline and four annual neuropsychological evaluations were given. A longitudinal growth curves analysis of data was performed to detect changes associated with declining immune function. The cohort was stratified into four groups: (1) HIV- (n = 126); (2) HIV+, average of first two and last two CD4 counts > or = 200, (n = 106; High CD4 group); (3) HIV+, average first two counts > or = 200, average last two counts < 200 (n = 41; CD4 Drop group); and (4) HIV+, average first two and last two counts < 200 (n = 60; Low CD4 group). RESULTS: There were significant differences among the four groups over time in nonverbal intelligence, perceptual/performance skills, nonverbal memory, academic achievement, and language. The Low CD4 group consistently showed the greatest decrement in performance. On measures showing a practice effect for repeated measurements, the Low CD4 group participants' scores remained stable over time, suggesting opposing effects of practice and HIV-related declines. Lowered academic performance relative to IQ was found in all groups. CONCLUSIONS: Declines in neuropsychological functioning are directly related to declines in immune functioning in HIV+ children, adolescents, and young adults with hemophilia. Hemophilia itself may be a risk factor for academic underachievement.

Adolescent↗
PubMed2000

Mortality among males with hemophilia: relations with source of medical care. The Hemophilia Surveillance System Project Investigators.

Although persons with hemophilia are known to be at increased risk of death, no studies have examined the source of medical care and other personal characteristics for associations with mortality. To determine death rates and to identify causes of death and predictors of mortality, we studied a cohort comprised of all hemophilic males identified by a six-state surveillance system. Data were obtained by medical record review of contacts with physicians, hemophilia treatment centers (HTCs), and other sources of care during 1993-1995 and from death certificates. Factors examined included age, race, state of residence, health insurance type, medical care source, hemophilia type/severity, presence of inhibitor, liver disease, HIV infection, and AIDS. A total of 2950 subjects were followed for an average of 2.6 years. Their median age was 22 years; 73% were white, 79% had hemophilia A, 42% had severe disease, and 67% had visited an HTC. During 7575 person years (PYs) of observation, 236 persons died-an age-adjusted mortality rate of 40.4 deaths/1000 PYs; 65% of deaths were HIV related. In addition to age, factors independently associated with increased risk of death (relative risk, P value) were the following: AIDS (33.5, <.001); HIV infection (4.7, <.001); liver disease (2.4, <.001); and Medicare/Medicaid insurance (1.4,. 01). Those persons who had received care in an HTC had a significantly decreased risk of death (0.6,.002). Although HIV infection and the presence of severe liver disease remain strong predictors of mortality, survival is significantly greater among hemophilics who receive medical care in HTCs. (Blood. 2000;96:437-442)

Acquired Immunodeficiency Syndrome↗
PubMed2002

Aberrant splicing and premature termination of transcription of the FVIII gene as a cause of severe canine hemophilia A: similarities with the intron 22 inversion mutation in human hemophilia.

We have identified the causative mutation in the hemophilia A dog colony at Queen's University, Canada and have observed a striking similarity with the intron 22 inversion found in approximately 45% of severely affected hemophilia A patients. The canine hemophilia A phenotype arises from aberrant splicing and premature termination of transcription of the FVIII gene, resulting in a polyadenylated transcript lacking exons distal to 22 and terminating with a novel sequence element (NSE). In dogs and other species including humans, this NSE is present in low copy number. One copy of these sequences in the canine genome is within intron 22 and reveals differences in the hybridization banding patterns between normal and hemophilic DNA, suggestive of a large genomic rearrangement. The mutation mechanism may not be uncommon, as identical mutant transcripts were isolated from two hemophilia A littermates that are unrelated to the Queen's colony and from hemophiliac dogs in the colony at Chapel Hill.

Animals↗
PubMed2006

Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study.

BACKGROUND: Prophylactic treatment for severe hemophilia A is likely to be more effective than treatment when bleeding occurs, however, prophylaxis is costly. We studied an inception cohort of 25 boys using a tailored prophylaxis approach to see if clotting factor use could be reduced with acceptable outcomes. METHODS: Ten Canadian centers enrolled subjects in this 5-year study. Children were followed every 3 months at a comprehensive care hemophilia clinic. They were initially treated with once-weekly clotting factor; the frequency was escalated in a stepwise fashion if unacceptable bleeding occurred. Bleeding frequency, target joint development, physiotherapy and radiographic outcomes, as well as resource utilization, were determined prospectively. RESULTS: The median follow-up time was 4.1 years (total 96.9 person-years). The median time to escalate to twice-weekly therapy was 3.42 years (lower 95% confidence limit 2.05 years). Nine subjects developed target joints at a rate of 0.09 per person-year. There was an average of 1.2 joint bleeds per person-year. The cohort consumed on average 3656 IU kg(-1)year(-1) of factor (F) VIII. Ten subjects required central venous catheters (three while on study); no complications of these devices were seen. One subject developed a transient FVIII inhibitor. End-of-study joint examination scores--both clinically and radiographically--were normal or near-normal. CONCLUSIONS: Most boys with severe hemophilia A will probably have little bleeding and good joint function with tailored prophylaxis, while infusing less FVIII than usually required for traditional prophylaxis.

Canada↗
PubMed1992

Carrier detection and prenatal diagnosis of hemophilia A: 5-years experience at a hemophilia center.

The identification of carriers and the prenatal diagnosis of hemophilia A have greatly improved with knowledge of the structure of the factor VIII gene. This has permitted the defect to be traced in families by using restriction fragment length polymorphisms. This study summarizes 5 years' experience at A. Bianchi Bonomi Hemophilia and Thrombosis Center and the problems encountered. One hundred and forty-four women at risk of hemophilia A from 93 families were referred to our center for DNA analysis. Carrier detection was performed in 95 women, including 11 who were pregnant. Prenatal diagnosis was performed at 7-14 weeks' gestation in 56 pregnant women. We employed two intragenic restriction fragment length polymorphisms (XbaI and BclI) and the two extragenic restriction fragment length polymorphisms (TaqI and BglII). Combining the results of intra and extragenic restriction fragment length polymorphisms with pedigree analysis, a diagnosis was reached in approximately 90% of cases. Of the 33 male fetuses, 11 were affected and 19 not affected. Two cases of recombination between extragenic restriction fragment length polymorphisms and the factor VIII locus were found.

Chorionic Villi Sampling↗
PubMed1992

Treatment of congenital and acquired hemophilia patients by extracorporeal removal of antibodies to coagulation factors: a review of US clinical studies 1987-1990. Hemophilia Study Group.

This paper reviews the use of extracorporeal immunoadsorption with immobilized Staphylococcal Protein A in attempts to lower the inhibitor titer in 22 patients with either congenital hemophilia or with acquired inhibitors. Eighty-five immunoadsorption procedures were performed at 13 locations in the United States between June, 1987 and February, 1990. In general, immunoadsorption was shown to efficiently remove IgG and, in eight congenital hemophilia patients, it also produced a clinically significant lowering of inhibitors allowing effective conventional factor replacement therapy. Three of thirteen congenital hemophilia patients treated received factor concentrate prior to immunoadsorption and were anamnestic at the time of treatment. Although they experienced substantial lowering of their inhibitor titers, it was not sufficient to allow effective factor replacement. The effectiveness of immunoadsorption therapy in the 9 patients with acquired inhibitors was more difficult to evaluate due to the wide variety of concomitant medications which were employed, although in several patients serious bleeding episodes were substantially improved (or halted) following immunoadsorption. Side effects associated with immunoadsorption were slight. These findings suggest that immunoadsorption can be a significant benefit to patients with inhibitors, particularly if it is instituted prior to factor administration.

Adolescent↗
PubMed1996

Substance use, coping, and safer sex practices among adolescents with hemophilia and human immunodeficiency virus. The Hemophilia Behavioral Intervention Evaluative Project Committee.

PURPOSE: To examine the use of alcohol and other drugs (AOD) to cope with the human immunodeficiency virus (HIV), the use of AOD before or during sex by 306 adolescent males with HIV and hemophilia, and its association with safer sex practices. METHODS: A survey instrument was administered to adolescents at 11 sites of the Hemophilia Behavioral Intervention Evaluative Project. Survey questions focused on knowledge of sexual activity, safer sex practices, AOD use, attitudinal and behavioral influences of parents, peers and sex partners, communication patterns, and perceived facilitators and barriers to practicing safer sex. RESULTS: A total of 68% of all respondents reported using condoms every time they had heterosexual sex. Respondents who did not use AOD to cope were more likely than AOD copers to report that they disclose their HIV status to all sex partners, talk to all of their sex partners about safer sex, find the use of condoms more enjoyable, and have sex partners who approved of their use of condoms. Condom use was not related to the use of AOD to cope or the use of AOD with the most recent female sex partner. CONCLUSIONS: The use of AOD to cope with HIV and its use before or during sex was negatively associated with certain safer sex attitudes and practices. AOD use may help facilitate HIV transmission among adolescents with HIV and/or hemophilia.

Adaptation, Psychological↗
PubMed2005

Efficacy of auxiliary partial orthotopic liver transplantation for cure of hemophilia in a canine hemophilia A model.

Metabolic liver disease can be cured by orthotopic liver transplantation. Some successful cases of whole or partial liver transplantation have been reported. Because liver function in these recipients is normal save for the production of the responsive metabolic factor, auxiliary partial orthotopic liver transplantation (APOLT) may produce a benefit. However, no experimental model of APOLT for metabolic liver diseases has been reported. We established a canine APOLT model to evaluate the clinical feasibility and efficacy of APOLT to cure hemophilia. The donor normal beagle dog was used to establish an APOLT model. A left lobe partial liver graft taken from the donor was orthotopically transplanted to the recipient after resection of the native left lobe preserving the native right lobe. Recipients showed no atrophy and comparable blood flow in both the graft and the native liver at the time of exploration after APOLT. Thus, APOLT was performed from a normal donor to a recipient with hemophilia A. In this recipient, blood factor VIII activity markedly increased after APOLT and was maintained for 7 weeks. No episode of bleeding was seen during the observation. In conclusion, a canine APOLT model was successfully established as evidenced by sustained production of factor VIII in a hemophilia recipient. These findings suggest the clinical feasibility and efficacy of APOLT for metabolic liver diseases.

Animals↗
PubMed1989

Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia B, and von Willebrand disease.

Recombinant factor VIIa (rF.VIIa) is a two-chain procoagulant enzyme (Mr, approximately 50,000) active only when complexed with tissue factor in the extrinsic clotting system. We administered human rF.VIIa to hemophilic and von Willebrand disease (vWD) dogs to determine its hemostatic effectiveness and survival in the circulation. Hemophilia A dogs lacking factor VIII demonstrated an immediate increase in plasma rF. VIIa and prompt stoppage of hemorrhage at bleeding time (BT) sites. In seven studies in two dogs, the range of dose of rF. VIIa was 50-220 micrograms/kg, with an apparent 7- to 11-fold increase in plasma factor VII and a mean recovery in plasma of 34%. The t1/2 was 2.8 +/- 0.5 hr. The BT was normalized except in an animal given the minimum dose. In four studies in two hemophilia B dogs lacking factor IX, BT was normalized. The elevation in plasma factor VII was by a factor of 8-30, with a mean recovery of rF.VIIa in plasma of 44%. In two studies in a homozygous vWD dog lacking von Willebrand factor, which is needed for platelet function, BT was not corrected even though large doses of rF. VIIa were given. The human rF. VIIa protein was immunogenic for dogs. These studies indicate that factor VIIa corrects the hemostatic defect in dogs with hemophilia A and B, diseases primarily of the intrinsic clotting system, but does not correct the hemostatic defect in vWD.

Animals↗
PubMed2000

HIV-associated changes in adaptive, emotional, and behavioral functioning in children and adolescents with hemophilia: results from the Hemophilia Growth and Development Study.

OBJECTIVE: To assess changes in adaptive, emotional, and behavioral functioning over four years in children and adolescents with hemophilia and with or without HIV infection and to evaluate the relationship of these changes to immune status. METHODS: Participants were 277 HIV-seropositive and 126 HIV-seronegative boys with hemophilia. Participants with HIV infection were divided into three groups based on trajectory of immune functioning (CD4+ cell counts) over the course of the study. Caregivers completed the Vineland Adaptive Behavior Scales and Pediatric Behavior Scale (PBS). RESULTS: Results showed declining Vineland Communication scores for participants with consistently poor immune functioning. These participants also started with more PBS Attention Deficit and Deviation symptoms, which then decreased more sharply than for other groups. Low CD4+ counts were consistently associated with more Health and Depression-Anxiety symptoms on the PBS. However, with few exceptions, group means remained within normal limits. CONCLUSIONS: According to their caregivers, boys with hemophilia and HIV infection showed considerable resilience with regard to adaptive behavior and emotional and behavioral problems. However, over time changes occurred in these areas that appear to be related to immune functioning.

Adaptation, Psychological↗
PubMed1999

Plasma HIV viral load in patients with hemophilia and late-stage HIV disease: a measure of current immune suppression. Multicenter Hemophilia Cohort Study.

BACKGROUND: For patients infected with HIV, plasma HIV viral load in early disease predicts long-term prognosis. However, the implications of viral load measurements late in HIV disease are uncertain. OBJECTIVE: To evaluate the relation between plasma HIV viral load and subsequent risk for disease progression in patients with late-stage HIV disease. DESIGN: Retrospective cohort study. SETTING: 16 treatment centers for patients with hemophilia. PATIENTS: 389 patients with hemophilia and late-stage HIV disease (CD4 count < 200 cells/mm3). MEASUREMENTS: Plasma HIV viral load was measured at baseline. Patients were followed for AIDS-related illnesses (primary outcome) and, specifically, Pneumocystis carinii pneumonia (secondary outcome). RESULTS: HIV viral load strongly predicted AIDS-related illness. For patients with viral loads less than 4.00 log10 copies/mL, the 1-year actuarial risk was 0% and the 5-year risk was 25%. For patients with viral loads of at least 6.00 log10 copies/mL, the 1-year actuarial risk was 42% and the 5-year risk was 78%. A linear relation existed between viral load and risk for AIDS-related illness (hazard ratio, 2.37 per 1og10 copies/mL; P < 0.001). In addition, viral load most strongly predicted risk for illness immediately after viral load testing; this predictive relation attenuated over time (P = 0.002). These findings changed little after adjustment for CD4 cell counts that were updated during follow-up. In the first year after viral load was measured, it predicted occurrence of P. carinii pneumonia (hazard ratio, 4.69 per 1og10 copies/mL; P < 0.001). CONCLUSIONS: In patients with hemophilia and late-stage HIV disease, viral load predicts disease progression independently of CD4 cell counts. Because viral load most strongly predicts progression immediately after load is measured, it seems to reflect the current level of immunosuppression.

AIDS-Related Opportunistic Infections↗
PubMed1985

Benefits of danazol treatment in patients with hemophilia A (classic hemophilia).

Danazol, an attenuated androgen, was given intermittently in three patients with hemophilia A. The rise in factor VIII activity with danazol treatment was associated with a fivefold decrease in hemorrhagic episodes and plasma concentrate product utilization when compared with similar periods without the drug. Four other patients with moderate hemophilia A who received danazol for 14 days had an increase of 400% to 850% in their factor VIII levels. Of four patients without detectable levels of factor VIII who were treated with danazol, two had elevations of the factor VIII level, to 3% and 4%, respectively. Danazol appears to be an effective treatment for patients with hemophilia A.

Adult↗
PubMed1995

HIV-infected adolescents with hemophilia: adaptation and coping. The Hemophilia Behavioral Intervention Evaluation Project.

OBJECTIVE: It is estimated that 70% of individuals with factor VIII deficiency hemophilia who received blood products before 1985 are infected with human immunodeficiency virus (HIV). The goal of the current study was to assess how adolescents with hemophilia cope with reminders of their HIV status, because adaptation is likely to have implications for these individuals' quality of life and adherence to safer sex recommendations. METHODS: Participants included 297 HIV-positive adolescents with hemophilia who were recruited from 11 sites across the United States. Adolescents reported on the use and effectiveness of strategies for coping with reminders of their HIV status. RESULTS: A significant degree of distress was reported in response to such reminders, with anger being the most commonly reported emotion. Although a wide variety of coping strategies had been tried, participants reported using resignation (80.9%), self-calming (78.8%), and distraction (76.4%) most frequently in their attempts to cope with reminders of HIV. Self-blame (3.6%), engaging in risky behaviors (22.2%), thinking about sex (25.4%), and drug/alcohol use (29.1%) were used least. These adolescents tended to rate more active cognitive and behavioral coping strategies (eg, cognitive restructuring, seeking social support, physical activity) as most effective, whereas passive strategies (eg, wishful thinking, blaming others) were reported to be least helpful. Those individuals who reported being distressed by reminders of HIV endorsed most of the coping strategies significantly more often than the nondistressed group, although ineffective strategies were commonly chosen. Sexually active adolescents were more likely than their abstinent peers to cope by thinking about sex, engaging in risky behaviors, or using alcohol and drugs. CONCLUSION: In this population of adolescents who have known their serostatus for several years, distress about everyday reminders of HIV appears to be associated with ineffective coping strategies.

Adaptation, Psychological↗
PubMed1998

Blood coagulation in hemophilia A and hemophilia C.

Tissue factor (TF)-induced coagulation was compared in contact pathway suppressed human blood from normal, factor VIII-deficient, and factor XI-deficient donors. The progress of the reaction was analyzed in quenched samples by immunoassay and immunoblotting for fibrinopeptide A (FPA), thrombin-antithrombin (TAT), factor V activation, and osteonectin. In hemophilia A blood (factor VIII:C <1%) treated with 25 pmol/L TF, clotting was significantly delayed versus normal, whereas replacement with recombinant factor VIII (1 U/mL) restored the clot time near normal values. Fibrinopeptide A release was slower over the course of the experiment than in normal blood or hemophilic blood with factor VIII replaced, but significant release was observed by the end of the experiment. Factor V activation was significantly impaired, with both the heavy and light chains presenting more slowly than in the normal or replacement cases. Differences in platelet activation (osteonectin release) between normal and factor VIII-deficient blood were small, with the midpoint of the profiles observed within 1 minute of each other. Thrombin generation during the propagation phase (subsequent to clotting) was greatly impaired in factor VIII deficiency, being depressed to less than 1/29 (<1.9 nmol TAT/L/min) the rate in normal blood (55 nmol TAT/L/min). Replacement with recombinant factor VIII normalized the rate of TAT generation. Thus, coagulation in hemophilia A blood at 25 pmol/L TF is impaired, with significantly slower thrombin generation than normal during the propagation phase; this reduced thrombin appears to affect FPA production and factor V activation more profoundly than platelet activation. At the same level of TF in factor XI-deficient blood (XI:C <2%), only minor differences in clotting or product formation (FPA, osteonectin, and factor Va) were observed. Using reduced levels of initiator (5 pmol/L TF), the reaction was more strongly influenced by factor XI deficiency. Clot formation was delayed from 11.1 to 15.7 minutes, which shortened to 9.7 minutes with factor XI replacement. The maximum thrombin generation rate observed ( approximately 37 nmol TAT/L/min) was approximately one third that for normal (110 nmol/L TAT/min) or with factor XI replacement (119 nmol TAT/L/min). FPA release, factor V activation, and release of platelet osteonectin were slower in factor XI-deficient blood than in normal blood. The data demonstrate that factor XI deficiency results in significantly delayed clot formation only at sufficiently low TF concentrations. However, even at these low TF concentrations, significant thrombin is generated in the propagation phase after formation of the initial clot in hemophilia C blood.

Adolescent↗
PubMed1992

Brain abnormalities in male children and adolescents with hemophilia: detection with MR imaging. The Hemophilia Growth and Development Study Group.

Cranial magnetic resonance (MR) imaging was performed in 124 male patients (aged 7-19 years), from 14 institutions, in whom a diagnosis of moderate to severe hemophilia was made. Blood tests in all subjects were negative for human immunodeficiency virus. Findings in MR studies were abnormal in 25 (20.2%) subjects. Six lesions in five subjects were classified as congenital. The most commonly identified congenital lesion was a posterior fossa collection of cerebrospinal fluid (five cases). Twenty-two subjects had acquired lesions that were probably related to the hemophilia or its treatment. The most commonly acquired lesions were single- or multifocal areas of high signal intensity within the white matter on T2-weighted images noted in 14 (11.3%) subjects. Two subjects had large focal areas of brain atrophy, and six had some degree of diffuse cerebral cortical atrophy. Three subjects (2.4%) had hemorrhagic lesions. To the authors' knowledge, the unexpected finding of small, focal, nonhemorrhagic white matter lesions has not previously been reported.

Adolescent↗
PubMed1995

Continuous infusion of factor concentrates: review of use in hemophilia A and demonstration of safety and efficacy in hemophilia B.

Continuous infusions of factor VIII have proved feasible in patients with hemophilia A, and the hemostatic efficacy has sometimes been superior to that of repeated bolus injections of factor VIII. Avoiding dangerously low trough levels by maintaining a constant therapeutic level not only promotes hemostasis but requires substantially less factor concentrate, which represents a considerable saving. Only limited data on continuous infusion of factor IX are available, but these data suggest similar benefits. An investigation of the stability of four prothrombin complex concentrates and three highly purified factor IX concentrates is described, as is the successful treatment of four hemophilia B patients with continuous infusions of Mononine.

Blood Coagulation Factors↗