Immune complexes in hemophilia

Circulating immune complexes (ICs), assayed by the L1210 enzyme-linked immunoassay, were detected in 48% of patients with hemophilia. A, 50% of patients with von Willebrand's disease, and in none of our patients with hemophilia B. Eighty-five % of the hemophilia A and B patients had mild to moderate disease with only one patient demonstrating a circulating inhibitor. No correlation was found between IC levels and hepatitis B infection, SGOT, disease severity, total quantity of factor VIII or IX infused, time interval from list infusion, or rheumatoid factor positivity. Although the nature of the ICs is not known, the similarity of IC levels between hemophilia A and von Willebrand's disease is discussed with regard to antibodies generated to non-procoagulant portions of the factor VIII molecule.     

The management of hemophilia in elderly patients

After the increasing rate of deaths observed during the 1980s due to human immunodeficiency virus (HIV) infection, the health-related quality of life and life expectancy of persons with hemophilia have improved, mainly due to the progresses of replacement therapy and antiviral drugs and to the improvement of the global comprehensive care provided by specialized centers. As a consequence, an increasing number of hemophiliacs have reached an older age and nowadays physicians in hemophilia centers find that they must handle age-related clinical problems never previously observed in this population. The management of elderly persons with congenital hemophilia is discussed in the first part of this review. The second part describes the general aspects of acquired hemophilia due to anti-factor VIII autoantibodies, focusing on the clinical management of elderly patients, one of the groups most frequently affected by this acquired bleeding disorder.     

The use of continuous infusion of factor concentrates in the treatment of hemophilia

Bolus infusion of clotting factor concentrates remains the most common approach to the treatment or prevention of bleeding in patients with hemophilia. Although successful use of continuous infusion of such concentrates has been reported by several groups, this alternative treatment method has not achieved widespread popularity. We report here our experience in one hemophilia center with the use of continuous infusion of factor VIII and factor IX concentrates in 13 patients, 11 with hemophilia A, and 2 with hemophilia B. All patients were treated successfully for bleeding episodes (e.g., hemarthroses, intracranial, or gastrointestinal bleeding) or for surgical procedures (appendectomy, thoracotomy, etc.). Three patients with low titer factor VIII inhibitors were treated successfully with constant infusion therapy, requiring a mean dose of factor VIII concentrate 2.3 fold (8.20 u/kg/h) higher than that of the patients without inhibitors (3.63 u/kg/h) to maintain a circulating plasma level of factor VIII of 1 u/ml. The use of constant infusion of clotting factor concentrates is safe, efficacious, and more convenient than bolus therapy of factor concentrates and should be considered for hospitalized hemophilia patients requiring replacement therapy.     

Health status and health-related quality of life associated with hemophilia

The hemophilias are a group of disorders associated with a chronic burden of morbidity and early mortality. Improvements in these adverse features have been achieved by the use of clotting factor concentrates within comprehensive centers of specialized care providing home infusion programs. Offsetting effects from transfusion-transmitted hepatitis and HIV infection are in recent decline. The net impact of these changes merits assessment. To test the a priori hypotheses that increasing severity of factor VIII deficiency would be associated with an increasing burden or morbidity and that hepatitis and HIV positivity would impair health status further, a cross-sectional study of a population-based cohort was undertaken in a regional hemophilia program in Ontario, Canada. A survey was made of mild, moderate, and severe hemophiliacs over 13 years of age who self-reported their health status using a standard 15-item questionnaire. The responses were converted to levels in the Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3) health status classification systems to form multi-element vectors from which single-attribute morbidity and overall health-related quality of life utility scores were determined. The burden of morbidity was greater in hemophiliacs than in the general population and correlated with the category of disease (mild < moderate < severe). Hepatitis and HIV positivity conferred additional burdens of morbidity, which were mainly in the attributes of mobility (HUI2), ambulation (HUI3), and pain (HUI2/3), all of these differences reaching levels of statistical significance. Despite demonstrable improvements in the safety, effectiveness, and utilization of clotting factor concentrates, hemophiliacs continue to experience an important burden of morbidity. Measurement of this burden, as reported here, provides a basis for future economic evaluation of the costs and consequences of health care interventions provided to this population.     

Changes in coagulation parameters with exercise in patients with classic hemophilia

Vigorous exercise is known to increase VIII:C and VIIIR:Ag levels transiently in normal individuals. Although exercise programs are frequently advocated in the management of hemophilia, the effects of exercise on coagulation parameters in these patients have not been well studied. Eleven hemophiliacs were exercised on a bicycle ergometer to maximum voluntary effort as evidenced by an increase in pulse, blood pressure, and plasma catecholamine (norepinephrine and epinephrine) levels. The effects of this exercise on coagulation parameters, including functional and antigenic components of the factor VIII molecule, were determined. The entire group demonstrated a decrease in mean prothrombin time (11.7 to 11.2 sec). Four mild hemophiliacs demonstrated an increase in mean VIII:C (14.5% to 17.3%), and VIII:CAg (12% to 17.8%). Changes in VIII:C and VIII:CAg were not noted in the seven severe hemophiliacs. Both severe and mild patients demonstrated significant changes in fibrinogen, factor II, and factor VII after exercise. This study indicates that submaximal exercise modifies coagulation parameters in patients with hemophilia.     

Guidelines for the management of hemophilia

Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence‐based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion‐transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.     

Prenatal and molecular diagnosis of hemophilia B

Prenatal diagnosis was carried out on a woman who had previously given birth to a son with a spontaneous mutation of C → T transition at nt 31133 of the factor IX (F.IX) gene. The diagnosis was performed on chorionic villi sampling by the method of amplification-created restriction site (ACRS). It revealed a female fetus with a normal F.IX gene, as confirmed by DNA sequencing after delivery. Meanwhile, a survey using the ACRS method to evaluate the inheritance of 63 individuals from 8 hemophilia B families was done. A different single-point mutation in each family was proved by DNA sequencing. One individual had a mutation with a naturally-created restriction site. In each of the remaining patients, we were able to show an enzyme-cutting site in their DNA amplification product for ACRS with the designed mutagenesis primers. All patients and carriers could be diagnosed accurately by comparing ACRS results with clinical and laboratory findings. There were new novel mutations among the patients. © 1996 Wiley-Liss, Inc.     

Acquired hemophilia A: a concise review

Acquired hemophilia A is a rare but severe autoimmune bleeding disorder. It is more frequent in the elderly and results from the presence of autoantibodies directed against clotting factor VIII. In this review, we briefly report on the present state of knowledge regarding acquired hemophilia A, analyzing its epidemiology, pathogenesis, diagnostic, and clinical features. We also describe the main characteristics of this disorder according to its association with different conditions and the most important advances in the treatment of bleeding episodes and the eradication of the autoantibody.     

Pseudotumor of hemophilia in the orbit: the role of radiotherapy in management

A case of pseudotumor of hemophilia is presented that occurred in the right orbit of a boy with severe factor VIII deficiency and an inhibitor. After a period of observation and conservative management, low-dose radiotherapy (750 rads) and Proplex was used. Eighteen months after radiotherapy significant healing had occurred. The role of radiotherapy in the treatment of hemophilic pseudotumor is reviewed.     

Up-regulation of platelet activation in hemophilia A

Background

Platelets are an underappreciated factor in the classification of the bleeding tendency of patients with hemophilia. In this cross-sectional study, we investigated platelet activation status and responsiveness in relation to residual factor VIII activity and, within the group with severe hemophilia (<1% residual factor VIII activity), to annual factor VIII consumption.

Design and Methods

Twenty-one patients with mild-moderate hemophilia A, 13 with severe hemophilia A and 21 healthy controls were studied. The basal level of platelet activation and platelet responsiveness to activation and inhibition were determined by the measurement of platelet P-selectin expression and soluble platelet activation markers.

Results

Patients with severe hemophilia A had a higher percentage of activated platelets at baseline (15.9%) when compared to patients with mild-moderate hemophilia A (8.2%, P=0.014) and controls (6.4%, P<0.001). Both patients with mild-moderate hemophilia A and those with severe hemophilia A had higher levels of the soluble platelet activation markers platelet factor 4 (1.4 and 1.8 pg/10⁶ platelets), CXCL7 (65.8 and 48.2 pg/10⁶ platelets) and RANTES (12.8 and 9.5 pg/10⁶ platelets), compared to controls (platelet factor 4: 0.3 pg/10⁶ platelets, P<0.001 and <0.001; CXCL7 20.0 pg/10⁶ platelets, P<0.001 and <0.001; RANTES 4.5 pg/10⁶ platelets, P<0.001 and =0.003, respectively). In support of these observations, we found clinical evidence that higher platelet P-selectin expression correlates with lower factor VIII consumption in patients with severe hemophilia (Spearman’s r −0.65, P=0.043).

Conclusions

This study indicates that platelets from patients with severe hemophilia A are in a pre-activated state and that this pre-activated state is associated with factor VIII consumption.     

Results of secondary prophylaxis in children with severe hemophilia

In this study, 13 children with severe hemophilia were given routine replacement infusions of factor VIII or IX to treat arthropathy. The children who had a mean age of 6.9 years (range 2.0–12.5) at initiation of prophylaxis had experienced an average of 43 acute hemorrhages (range 8–127) in the year prior to prophylaxis, of which a mean of 24 (range 5–46) were into joints. Therapy was begun in five children, using factor VIII concentrate at 20 U/kg three times a week, and one boy received factor IX concentrate 40 U/kg twice a week. This dose schedule was inadequate for three factor VIII-deficient boys and for the one factor IX-deficient boy. Two of three factor VIII-deficient boys responded to an increase to 30 U/kg prior to the 3-day interval. The dose frequency was increased to three times a week for the factor IX-deficient boy, but he continued to bleed and was taken to synovectomy. One of the original five factor VIII-deficient boys plus seven other factor VIII-deficient boys were begun on factor VIII 20 U/kg every other day; 3 boys ceased bleeding. Trough factor VIII levels were measured 24 hr after an infusion in the five boys who continued to bleed. Factor VIII dosage was adjusted to achieve a trough level of >1%; 4 responded to an increase in the dose of factor VIII; 1 had an adequate trough but, due to compliance issues, was taken to synovectomy. Serial clinical and radiographic assessments determined stabilization of joint disease in more than one-half of the boys. No child showed reversal of abnormal radiographic findings. Institution of aggressive factor VIII and IX concentrate in children with established hemophilic arthropathy does not reverse joint disease but may alter the clinical course of hemophilia. Future studies to compare this intervention with primary prophylaxis instituted prior to the onset of recurrent joint hemorrhage are warranted. © 1994 Wiley-Liss, Inc.     

Acquired hemophilia: a single-center survey with emphasis on immunotherapy and treatment-related side-effects

OBJECTIVES: Acquired hemophilia is a rare disease caused by the development of autoantibodies against factor VIII. Since 1981 we have observed 17 patients with this disorder in our institution. The objective of this survey was to assess the epidemiological features, clinical course, and mortality rate of these patients, with special emphasis on therapy-related side-effects. Also, we present our results with an immunosuppressive approach based on the severity of bleeding episodes. METHODS: Clinical records of all patients with acquired hemophilia due to factor VIII inhibitor admitted or referred to our hospital between 1981 and 2001 were reviewed retrospectively. We collected each patient's sex, age, medical history, presenting symptoms, activated partial thromboplastin time, factor VIII activity, and inhibitor titre. Patient's clinical courses, including their bleeding episodes, response to therapy, and therapy-related side-effects, were also recorded. RESULTS: Complete and partial responses were achieved in 14 and one patient, respectively (overall response rate 88%) after a median time to complete response of 3.5 months (range 30 d - 25 months). The inhibitor-related and overall mortality rates were 12% and 29%, respectively. Side-effects were frequent: two patients had blood-borne infections, three patients had thrombotic complications, and nine patients had immunosuppressive therapy-related side-effects. In five patients, discontinuation of cyclophosphamide or prednisone was required. CONCLUSIONS: Although our response rates were remarkable, this survey showed that treatment-related morbidity could also be very important. Therefore, it is pertinent to bear in mind these potential side-effects in order to decide the most appropriate therapy for each particular patient.     

Detection of carriers of hemophilia by hemorrhagometry

Summary Hemorrhagometry measures bleeding time, bleeding intensity and blood loss from a small standardized skin wound. In patients with hemophilia these values are within the normal range when hemorrhagometry is performed at room temperature (24° C). However, when the wound is cooled to 17° C (cold tolerance test), bleeding time is abnormally long in hemophiliacs. Therefore we applied this test to carriers of hemophilia. The cold tolerance test was performed in 16 proven and 6 probable carriers (criteria according toNilsson). 14 proven and 4 probable carriers showed abnormal bleeding times of 15 min and more. When hemorrhagometry was performed at room temperature, the carriers could not be distinguished from normal control persons.Of 15 sisters and aunts of hemophiliacs without male offspring (potential carriers) 9 had abnormal cold tolerance test findings, in fair agreement with the probability of 0.5 to be expected theoretically. Thus the hemorrhagometry cold tolerance test seems to be helpful in detecting carriers of hemophilia.Presented at the Vth Congress of the International Society on Thrombosis and Hemostasis, Paris, July 21–26, 1975.     

Changes in longevity and causes of death among persons with hemophilia A

To examine recent changes in longevity and the causes of death among persons with hemophilia A, we evaluated death certificate data for persons who died in the United States from 1968 through 1989 and had hemophilia A or congenital Factor VIII disorder (ICD code 286.0) listed on the death certificate as one of the multiple causes of death. Multiple-cause-of-death mortality data for the United States from 1968 to 1989 were examined to compare death rates by year, focusing on death rates and causes of death for 1979-1981, 1983-1985, and 1987-1989. Gender, age group, race, geographic region, and median age at death of persons with hemophilia A and human immunodeficiency virus (HIV)-related disease listed as a cause of death were compared with those with hemophilia A without HIV-related disease. From 1968 through 1989, 2,792 hemophilia A deaths were reported. The death rate increased from 0.5 to 1.3 per 1,000,000 persons. From 1979-1981 through 1987-1989, mortality increased in all age groups above 9 years of age and age at death shifted markedly to lower ages. Median age at death decreased from 57 years in 1979-1981 to 40 years in 1987-1989. The percentage of deaths due to hemorrhage or diseases of the circulatory system decreased markedly as the result of the increase in deaths associated with HIV infection or infections other than HIV infection. Spread of HIV-1 infection in persons with hemophilia A has disrupted the reduction in mortality seen with factor replacement therapy, implementation of home care, and use of comprehensive hemophilia treatment centers. It is hoped that advances in the care of HIV-infected persons will improve survival in the hemophilia community. © 1994 Wiley-Liss, Inc.     

Pharmacokinetic dosing in prophylactic treatment of hemophilia A

Abstract: The aim of this study was to investigate individual pharmacokinetics as a tool for dosing of factor VIII (FVIII) in severe hemophilia A. It is assumed that effective prophylaxis against bleedings is maintained if the plasma FVIII:C activity is kept above 1 U/dl, and the present study is based on this assumption. A current standard dosage regimen for FVIII is 25–40 U/kg up to three times weekly. However, there is considerable individual variation in the pharmacokinetics of FVIII:C. Individual pharmacokinetic data were used to computer-simulate plasma activity curves after repeated doses in 8 patients. Going from prophylaxis regimens of normally 2–3 infusions per week to dosing every 2 days would theoretically reduce their average FVIII consumption by 43% with maintained or increased trough levels of FVIII:C. Daily dosing would reduce their mean FVIII usage by 82%. Modified dosage regimens, infusions every 2 days, were implemented in the patients, and plasma samples were drawn to verify the pharmacokinetic models. The feasibility of the method to generally raise trough levels with a decreased consumption of FVIII was confirmed. Dosing of coagulation factors according to kinetic principles can result in more cost-effective utilization of these very expensive preparations.     

Disseminated intravascular coagulation and hemorrhage in hemophilia B following elective surgery

Two patients with hemophilia B are described in whom disseminated intravascular coagulation (DIC) developed following infusion of repeated doses of Factor IX concentrate in the perioperative period. In both cases the surgery was elective, Factor IX survival studies had been done to assure proper dosing, and Factor IX levels were monitored daily. Neither patient had clinically significant liver disease. The DIC manifested itself as excessive blood loss from surgical drains without documented thrombosis and was accompanied by prolonged coagulation times, increased fibrin split products and decreased fibrinogen and platelets. In both patients the process was quickly reversed with administration of fresh frozen plasma, cryoprecipitate, and the addition of heparin to the Factor IX concentrate. These cases highlight the difficulty in managing patients with hemophilia B undergoing surgical procedures due to the potential thrombogenicity of the currently available concentrates, and the importance of differentiating the bleeding associated with DIC from underdosing with Factor IX. Furthermore, the potential complications associated with the presently available Factor IX concentrates stress the need for the development of purer, safer Factor IX concentrates.     

Hepatocellular enzyme patterns and hepatitis b virus exposure in multitransfused young and very young hemophilia patients

Thirty-eight children with severe hemophilia A, 11 years of age and under, were evaluated by initial and follow-up liver function tests (LFTs) in relation to age of onset of transfusion therapy. Each child had at least two complete evaluations within one year for a follow-up period of at least one year. The mean number of exposure days was 36 with a mean of 275 units of factor VIII per exposure day prior to initial LFTs. At initial testing, 30% of patients demonstrated antibody to HBsAg and 39–51% at least one abnormal serum enzyme level (AST, ALT, LDH). During an average follow-up period of 34.8 months, two children developed HBsAg-positive icteric hepatitis. Of those initially serologically negative for HBsAg or antibody, 44% became antibody-positive. Intermittent abnormalities of at least one serum enzyme were observed in 79% of the patient group, with 13% and 8% being persistently normal and abnormal. Eleven children born after January 1976, receiving only third-generation RIA-tested products for HBsAg, constituted a subgroup. Although only one child at first assessment had evidence of hepatitis B virus exposure, 55% had elevated ALTs, indicating considerable frequency of non-A, non-B hepatitis in this very young group.