Search

The German Institute for Quality and Efficiency in Health Care (IQWiG) conducted a rapid report to assess the therapy of hemophilia patients. Based on a systematic literature search the IQWiG identified 16 studies which show that there is now sufficient information regarding questions that previously lacked data. A benefit assessment of prophylactic and on-demand-treatment concerning different treatment outcomes shows the superiority of the prophylactic therapy regarding major bleedings for all age groups. For the group of youths and adults the analysis shows additional benefits concerning health status and pain within the preceding four weeks. The alignment of guidelines with the identified evidence shows minor correspondence between the guidelines' references and included studies. However, the guidelines' statements primarily correspond with the results of the conducted benefit assessment., Conclusion: The IQWiG's rapid report shows prophylactic therapy to be superior to on-demand therapy. These findings represent a clear indication for attending physicians and payers for prophylaxis in patients with severe hemophilia A., Competing Interests: Die Autoren erklären, dass keine Interessenkonflikte bestehen., (Schattauer GmbH.)

Unlabelled: The retrospective observational study surveys the relationship between development of inhibitors in the treatment of haemophilia patients and risk factors such as changing FVIII products. A total of 119 patients were included in this study, 198 changes of FVIII products were evaluated., Results: During the observation period of 12 months none of the patients developed an inhibitor, which was temporally associated with a change of FVIII products. A frequent change of FVIII products didn't lead to an increase in inhibitor risk. The change between plasmatic and recombinant preparations could not be confirmed as a risk factor. Furthermore, no correlation between treatment regimens, severity, patient age and comorbidities of the patients could be found.

Unlabelled: Haemophilia B (HB) was described in 1952 as a single disease for the first time. In comparison to haemophilia A (HA) the bleeding tendency seemed to be less severe. The aim of this study was to investigate this hypothesis in all patients with HA and HB treated in the haemophilia care center of the Vivantes Klinikum., Patients, Methods: All patients with severe HA and HB treated at the haemophilia care center were included. We evaluated the regimen of replacement therapy and factor concentrate consumption within the last 5 years (1/2004 to 12/2008). Intracerebral bleeds were analysed over the whole life span of the included patients., Results: 111/181 patients with HA had the severe form and 12/34 patients severe HB. 4/12 patients with severe HB had a history of intracerebral bleeding in comparison to 5/111 patients with severe HA. 2/8 adult patients with severe HB used a prophylactic treatment with factor concentrates (mean consumption 1289 IU factor IX/kg BW/year) in contrast to 60/95 adult patients with HA (mean consumption 2109 IU factor VIII /kg BW/year)., Conclusion: The data suggest a milder bleeding type of patients with severe HB in comparison to patients with severe HA but may be patients with severe HB are at higher risk for intracerebral bleeds.

Based on the documentation from patients with severe haemophilia B (FIX:C <1%) in home treatment the positive effect of continuous prophylaxis compared to on demand treatment was investigated over one year in a retrospective study from a single treatment centre (Centre for Haemostaseology Muenster). The advantage of the reduction in the number of bleeding episodes by 90% was opposed by a threefold higher consumption of FIX concentrates and a fourfold higher exposure of the patients to intravenous injections.

With early prophylactic treatment our haemophilic children grow up in good health. Nevertheless, we cannot prevent every bleeding. Those bleedings may be just subclinical but they could lead to overloading of the knee and more and more of the ankle joint in the long term. Motion analysis can help to understand this process and prevent it. A comparison of the gait function of haemophilic and healthy children of the age 3-18 years showed distinct functional differences especially in the youngest age group (3-6 years). Apparently, the coordination skill gait rhythm was significantly worse in the heamophilic group. All measured functional deficits can be treated with physiotherapy. Possible reasons for these early functional differences are overprotection and/or early subclinical bleedings.

History and Admission Findings: A 66-year-old patient presented to our clinic with extensive left arm and left flank haematomas, anaemia, a prolonged activated partial thromboplastin time (aPTT), and reduced factor IX activity 6 weeks after prosthetic mechanical aortic valve implantation., Investigation: Treatment with both vitamin K and a single injection of factor IX concentrate led to normalization of the activated partial thromboplastin time and factor IX activity, which remained constant for several days. No acquired factor IX inhibitor was detectable. Analysis of exon 2 of the factor IX gene revealed a C-->T mutation in codon 10 of the propeptide region, resulting in the substitution of alanine by valine. Echocardiography revealed a significant paravalvular leak., Treatment and Course: The substitution of valine for alanine in the factor IX propeptide leads to an impaired affinity of factor IX to the vitamin K-carboxylase complex. In this situation, treatment with coumarin derivatives can profoundly reduce factor IX activity and result in severe bleeding episodes. This patient was re-exposed to warfarin under close hematological monitoring. After 4 days factor IX activity had decreased to 15%, which was associated with an increase of the aPTT and a mild decrease of the prothrombin time. Due to rapid progression of the paravalvular leak and almost impossible long-term orale anticoagulation with coumarin derivatives, we recommended replacement of the prosthetic mechanical valve with a biological device., Conclusion: The development of severe bleeding in the context of initiating warfarin therapy raises the suspicion of a factor IX propeptide mutation. The initial screening test is the activated partial thromboplastin time, which is elevated in the presence of the mutation. If concomitantly diminished factor IX activity is found the factor IX propeptide mutation should be excluded. Use of lifelong coumarin derivatives is contraindicated in patients with this mutation. However, a general screening of the activated partial thromboplastin time after coumarin initiation is not justified by cost/benefit analysis.

Radiological and orthopaedic outcome in severe and moderate haemophilia A and B patients undergoing long-term prophylactic treatment were prospectively investigated focusing on the age of onset of prophylaxis and the number of joint bleedings prior to treatment. We report on 21 patients with severe and moderate haemophilia A and B receiving prophylactic treatment of between 3.1 and 16.1 years duration. Three patient groups were evaluated according to the age at onset of prophylaxis. In group I (n = 8) prophylactic treatment was initiated in the first 2 years of life. Patients of group II (n = 6) received prophylaxis at the age of 3-6 years. Late-onset or secondary prophylactic treatment was started at the age of 6 years and above in 7 patients (group III). All patients received virus-inactivated F VIII or F IX concentrates at dosages of 30-40 IU, in some cases up to 50 IU/kg body weight i.v. three times per week for those with haemophilia A and twice per week for those with haemophilia B. Elbow, knee and ankle joints were investigated at 3-4 yearly intervals according to the radiological and orthopaedic scores recommended by the World Federation of Haemophilia (WFH). The total number of joint bleedings before and after start of prophylaxis were recorded in all patients. In group 17 out of 8 patients had unaffected joints with constant radiological and orthopaedic scores of zero or 1, after a median of 11.25 years of prophylactic treatment. One patient in this group demonstrated mild radiological alterations (score 4). Patients of group II showed neither radiological nor orthopaedic alterations at study entry. Worsening joint scores could be detected despite ongoing prophylaxis after the 3-year interval (median orthopaedic score 4, median radiological score 8). Treatment group III already showed considerable joint damage at study entry with a median radiological score of 11 (0-33) and a median orthopaedic score of 4 (0-11). Despite prophylactic treatment both, orthopaedic (median 8, range 2-12) and radiological scores (median 19.5, range 2-47) deteriorated after 3 years. Prior to onset of prophylaxis no or only one joint bleeding occurred in treatment group I. In group II, a median of 6 joint bleeds (range 1-8) were reported before prophylaxis was started. Patients of group III usually experienced a median of more than 10 joint haemorrhages (range 6-10 or more). Under prophylactic treatment the number of joint bleedings decreased significantly in groups II and III. However, radiological and orthopaedic scores increased as a sign of progressing osteoarthropathic alterations in patients reporting more than 6 joint haemorrhages before onset of prophylaxis whereas no joint alterations could be assessed in patients with no or only one joint bleeding episode prior to prophylaxis. Even a small number of joint bleedings seems to cause irreversible osteoarthropathic alterations leading to haemophilic arthropathy. Once apparent, further progression of joint damage could not be arrested despite of prophylactic treatment (group II and III). In order to prevent haemophilic arthropathy, effective prophylaxis should be started before or at least after the first joint bleeding in severe haemophilia A and B.

Based on the results of seven ICTH-controlled PUP studies only the virus-inactivating procedures by pasteurization (60 degrees C for 10 h), tri-n-butyl-phosphate/detergent treatment, and vapor heating (60 degrees C for 10 h and 1,200 mbar) have prevented the haemophilic patients from infections with hepatitis B, C and HIV. After the disaster of the HIV infection in haemophilic patients at the beginning of the 80's the factor concentrates given today seem to be safe for virus infections during substitution therapy. To prove this high therapeutical standard there is a need for a prospective long-term pharmaco-vigilance study under the auspices of an independent body such as the Medical Advising Committee of the National Haemophilia Society or other scientific organisations.

The enormous progress made in biotechnology and purification of plasma proteins (pp) and the demands to avoid risks of transmitting HIV, hepatitis and other virus infections by these have resulted in the development of numerous recombinant human (rh) pp, which are now about to be used as replacement therapy in transfusion medicine. Human rh albumin has been used in clinical trials last year, a competition to serum albumin can be expected in the next time. During the last decade, the genes or cDNA have been cloned and characterized for all relevant pp involved in blood coagulation. Beside the rh factor VIII (rh FVIII) which has been introduced clinically in 1991, the rh FVIIa is under investigation in patients with hemophilia A and inhibitors. After establishing of rhFIX in triple transgenic mice, the industrial potential will be evaluated in terms of scale up culturing and production. The valuation of advantages and drawbacks of the current rh pp in comparison to conventional pp will have to be determined in the last decade of our century.

One of the most dramatic dangers in treating nephrolithiasis by ESWL is the development of intra- and perirenal bleeding, which requires therapeutic intervention. Even in patients whose blood parameters suggest they are healthy, hematomas are found in up to 80%. Therefore, ESWL must be regarded as contraindicated in patients with blood disorders. A case of a patient suffering from hemophilia B and from a large renal pelvic stone is reported, whom we treated by ESWL twice after sufficient substitution. X-ray revealed that the patient was stone-free on the 25th day after the first ESWL session. ESWL. A review of the literature is presented.

Paradoxical bleedings are complications occurring under replacement therapy in haemophiliacs by disturbancies of the primary haemostasis. They have been observed during treatment with factor-VIII- and prothrombin-complex concentrates of long duration and in high dosage. Clinical complications, for example delayed wound healing as well as spontaneous bleedings into the skin and from the mucous membranes, have been observed in one quarter of haemophiliacs under substitution therapy. In one third of these patients pathological parameters of primary haemostasis (prolonged bleeding time, reduced retention, retraction, ADP- and collagen-induced aggregation and the platelet factor 3 release) were found out. The following mechanisms or substances may be the cause for these disturbancies: 1. fibrinogen and factor-VIII split products 2. high content of proteins predominantly fibrinogen and factor-VIII-related antigen 3. antigen-antibody reactions 4. development of inhibitors against the Willebrand factor. For treatment of the paradoxical bleedings freshly prepared cryoprecipitate, prednison and Etamsylatum have been used.

Disturbances of haemostasis caused immunologically and non-immunologically were observed after transfusion of blood and blood derivatives. Transfusion of heparin blood increased the bleeding susceptibility only in case of pre-existing high-degree defects of haemostasis or if they were performed as massive or exchange transfusions. Massive transfusions with blood stored for a long time will induce complex defects. Under intensive substitution therapy of haemophilia A the so-called paradoxical bleeding will occur in spite of a high factor VIII level. These bleedings are supposed to be disturbances of the thrombocyte function and are caused by fibrin(ogen) derivatives. Post-transfusional thrombocytopenias may be brought to remission by repeated plasmapheresis. Factor specific inhibitory bodies will appear after substitution in a small percentage of haemophilic patients. 5 to 7 days after the onset of therapy an anamnestic reaction can be observed as a titre increase by leaps. Usually, the inhibitory titre will decrease to a mostly low basal value in the course of three to five months. The therapy with cyclophosphamide simultaneously started with the substitution will more frequently prevent the anamnestic reaction or reduce it. Titres with more than 5 units cannot be overcome at the beginning even by higher concentrations of preparations. The substitution therapy should be preceded by exchange transfusions or plasmapheresis of up to 25 units. With still higher titres only procedures of inhibitor-bypassing are possible with factor VIII preparations of animal origin or better with activated prothrombin complex preparations, such as FEIBA. Recent reports give evidence that permanent substitution with factor VIII concentrates at a highest dosage can eliminate the production of inhibitors completely.

On the basis of the indirectly established statement that activated forms of the coagulation factor are also present in PPSB fractions of own production, the activated concentrate of factor IX and of the prothrombin complex were applied in haemophilia-A patients with antibodies against factor VIII. The fraction was administered to 4 patients during 14 bleeding times, mostly during bleedings of joints an soft tissues, twice during haematuria in a dose of 40-200 E-factor IX per kg of body weight and per day. The total dose was mainly administered in a fractionized way at an interval of 8 or 12 hours. This treatment lasted for 2 to 7 days. With regard to haemostasis no fundamental improvement of global blood coagulation tests (which have pathological results in haemophilia-A patients) could be identified in the course of the treatment. However, the increase of factor II, VII, and X in the patient's plasma was striking. Contrary to exceptations, there was a less distinct increase of factor IX activity. Concluding from these findings it may be assumed that the "strengthening" of the "extrinsic system" is decisive for the haemostatic effect in the treatment mentioned.

The recognition of AIDS in several hemophiliacs in the U.S.A. in 1982 has contributed to the understanding that this disease may be transmitted by blood and blood products and that it is of infectious nature. American factor VIII and factor IX concentrates as well as the high portion of American plasma used in the production of further concentrates in Germany led to the rapid spread of this infection in German hemophiliacs. More than 50% of the patients suffering from severe hemophilia proved positive to anti-HTLV III. About 1% of these patients developed AIDS, and some of them already died. The absence of Kaposi's sarcomas in hemophiliacs remains unexplained. Virus inactivation by means of heat treatment of the concentrates by now most probably prevent further infections with the AIDS virus. probably prevent further infections with the AIDS virus.

In view of the normal present-day life expectancy of the hemophiliac, our main task is to prevent disability. The chief cause of disability is joint and muscle hemorrhages, though these are not in themselves life-threatening. Their early and proper treatment serves to avoid disability through replacement of the deficient coagulation factor, careful immobilization of the affected limb and early physical therapy. Optimum treatment calls for close cooperation between the hemophilia specialist, the general practitioner or pediatrician, and the hemophiliac.

Eight patients with severe or moderately severe haemophilia B were treated for six months, according to three schemata for two months each: 18, twice 18, or twice 9 U of factor IX per kg body-weight weekly. The sequence of the six possible treatment schemes was determined strictly at random. One patient had to be excluded because he developed hepatitis, another because allergic signs developed. In the pre-trial period the number of bleedings per two months had been about 40, as recorded by the patients. The bleedings were reduced to nine after 18 U of factor IX per kg body-weight weekly, falling to two after twice 9 and twice 18 U/kg weekly. The patients themselves considered twice 9 U/kg as the ideal dosage. It is recommended that this dosage scheme should be used initially if one decides to employ permanent substitution in haemophilia B. Once freedom from bleedings and strengthening of the motor system have been achieved one can then try 18 U per kg body-weight once a week.

This report describes a biphasic splenic rupture following trauma in a 12 1/2 years old boy with the severe form of hemophilia B. Immediately after the trauma the boy was treated with only one single dose of factor IX concentrate. He stayed free of symptoms for 9 days until finally severe abdominal bleeding occurred.

Factor IX concentrates are of paramount importance in the treatment of hemophilia B. Growing reports of thromboembolic complications and of disseminated intravascular coagulation, coupled with the danger of hepatitis transmission, suggest that the concentrates should be primarily reserved for the treatment of hemophilia B. Concise guidelines for treatment are presented.

Over the past 11 years two different plasma concentrates--Prothromblex500 (factor II, IX and X) and Prothromblex Total500 (factor II, VII, IX and X) have been used in the treatment of 246 patients with acquired coagulation disorders, in particular deficiencies of the prothrombin complex (factor II, VII, IX and X). Patients on oral anticoagulation or suffering from liver disease required substitute therapy for severe bleeding episodes, acute operations or invasive diagnostic procedures. Serial coagulation studies and analyses showed that both concentrates achieved adequate correlation of the abnormal coagulation, whereby better results were obtained in patients on oral anticoagulation than in patients with severe liver disease. All operations and diagnostic procedures were completed without haemorrhagic complications, whilst the patients admitted for a severe bleeding episode were rapidly brought under control. These plasma concentrates did not cause any side effects. No case of intravascular coagulation was observed following substitution therapy.

19 (51%) of 37 hemophiliac children and adolescents regularly treated with factor VIII and IX concentrates were positive for HTLV III antibodies. The prevalence of HTLV III antibodies was higher in patients with severe hemophilia (64%) requiring frequent administration of concentrates than in patients with mild hemophilia (17%). No patient showed signs of AIDS or AIDS related complex. Immunologic alterations (inverse ratio of helper- and suppressor lymphocytes, elevated immunoglobulins, and elevated total serum proteins) were more often observed in patients requiring frequent administration of concentrates than in patients requiring relatively infrequent administration of concentrates. Since in patients frequently treated with concentrates the prevalence of HTLV III antibodies was also higher, it was not possible to draw any conclusions whether the observed immunologic alterations are due to the HTLV III infection alone or are also induced by the frequent administration of coagulation factor concentrates. No HTLV III positive person was detected in 45 relatives of 18 HTLV III positive hemophiliac children living together in 16 households and actively participating in the care of those children. In contrast, 6 (11%) of 55 relatives living in 21 households with 23 hepatitis-B-positive hemophiliac children were positive for hepatitis B. Our results support the general impression, that the risk to contract hepatitis B seems to be greater than to contract HTLV III from seropositive patients, and should help to facilitate the social integration of HTLV III positive hemophiliac children.