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I Scharrer

Publications and source records attributed to I Scharrer.

At least 19 recordsLinked to original sources
PubMed2006

High titres of IgM-antiphospholipid antibodies are unrelated to pathogenicity in patients with non-Hodgkin's lymphoma.

Heterogeneity in the mechanisms of coagulation may contribute to an increased thrombotic risk for patients with malignancies. The coincidence of malignancies and antiphospholipid antibodies (aPL) have been described in several important epidemiological studies. The pathological significance of aPL in patients with malignancies is, however, still unclear. In this study, we investigated the clinical manifestations of four patients with elevated IgM-aPL titres lying outside the region signifying 95% of normal cases and with a history of non-Hodgkin's lymphoma. The patients had elevated IgG- and IgM-anticardiolipin antibodies (aCL) and also tested positive for lupus anticoagulants. Other aPL were measured, and we found high positive results for all tested antibodies in three patients. The production of aPL, however, occurred in the absence of thrombotic complications. No thromboembolic manifestations occurred during the follow-up period either. It could also be demonstrated that the degree to which the aCL titre was elevated resembles the elevation of the non-classical antiphospholipid antibodies, but not that of beta2-GP-1 or anti-annexin antibodies. Therefore, it can be postulated that these extremely high levels of IgM-aCL antibodies do not enhance the risk of thrombosis and may be completely different from aCL antibodies in an antiphospholipid syndrome patient population without malignancies. In particular, haematological and lymphoproliferative malignancies may indeed be associated with the generation of aPL, but do not necessarily enhance the thrombophilic risk in these patients.

Aged↗
PubMed2006

Total hip replacement in patients with severe bleeding disorders. A 30 years single center experience.

Arthropathy of the hip is moderate in frequency in haemophiliac patients, but is less common than ankle, knee or elbow arthropathy. We report about our experience with total hip replacement in patients with severe bleeding disorders over a period of 30 years. Between July 1972 and 2002, 15 hips in 13 patients were replaced. The main bleeding disorders were Haemophilia A in ten patients and severe v. Willebrand disease in three patients. The mean follow-up was 132 months (range 12-363). We can demonstrate good long-term results, with only one aseptic loosening after 14 years and one septic loosening after 14 months in an HIV-positive patient. The Harris Hip Score increased from 48 points (32-66) preoperatively to 89 (76-100) postoperatively. In conclusion, total hip replacement performed in a specialised haemophiliac centre is a safe procedure, and results in pain relief and improvement of the quality of life in patients with severe bleeding disorders.

Adult↗
PubMed2006

Platelet-dependent coagulation assays for factor VIII efficacy measurement after substitution therapy in patients with haemophilia A.

FVIII therapy for haemophilia A is safe and effective, with the problem of individually sufficient efficacy unsettled. Routine one-stage clotting assays and tests employing chromogenic substrates poorly detect individual haemostatic effects of FVIII due to artificial test conditions. In particular, the use of cell-free and diluted plasma samples neglect the crucial role of platelets for thrombin and fibrin formation. To optimize FVIII substitution therapy, we measured in 40 patients with severe to mild haemophilia A before and after FVIII substitution the FVIII activity in cell-free plasma samples using a one-stage clotting assay as well a chromogenic substrate assay and compared the data with those obtained with cell-based coagulation tests, i.e. thrombin generation in platelet-rich plasma (PRP) and thromboelastography (TEG) in samples of citrated whole blood (WB). To determine the maximum ex vivo haemostatic effect we added 1 unit/ml of FVIII to samples of PRP and WB and measured the maximum thrombin generation in the thrombin generation test (TGT) and the maximum clot firmness (MCF) in TEG. After FVIII substitution we observed a nearly linear relation between the individual FVIII activities administered to the patients and the activities measured in the plasma samples. However, data obtained with TGT and TEG revealed a high inter-individual variation and a very poor correlation to the administered FVIII activity. Actually, it could be shown that FVIII substitution yielding in a FVIII plasma activity of about 30% is sufficient to get an ex vivo haemostatic effect of more that 90% as measured by maximum thrombin generation and MCF. FVIII substitution up to a plasma activity of more than 90% did not further enhance the haemostatic effect. Our data clearly demonstrate that the haemostatic effect of FVIII is not only dependent on the activity that is measured in plasma but also depends on the interplay between coagulation and blood cells, in particular with platelets. The use of cell-based coagulation tests such us TGT or TEG may help to optimize FVIII therapy by determining the individual FVIII dosage that produces a maximum haemostatic effect.

Adult↗
PubMed2005

Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT).

BACKGROUND: Reliable risk estimates for venous thrombosis in families with inherited thrombophilia are scarce but necessary for determining optimal screening and treatment policies. OBJECTIVES: In the present analysis, we determined the risk of a first venous thrombotic event in carriers of a thrombophilic defect (i.e. antithrombin-, protein C- or protein S deficiency, or factor V Leiden). PATIENTS AND METHODS: The asymptomatic carriers had been tested prior to this study in nine European thrombosis centers because of a symptomatic carrier in the family, and were followed prospectively for 5.7 years on average between March 1994 and January 2001. Annually, data were recorded on the occurrence of risk situations for venous thrombosis and events (e.g. venous thrombosis, death). RESULTS: Twenty-six of the 575 asymptomatic carriers (4.5%) and seven of the 1118 controls (0.6%) experienced a first deep venous thrombosis or pulmonary embolism during follow-up. Of these events, 58% occurred spontaneously in the carriers compared with 43% in the controls. The incidence of first events was 0.8% per year (95% CI 0.5-1.2) in the carriers compared with 0.1% per year (95% CI 0.0-0.2) in the controls. The highest incidence was associated with antithrombin deficiency or combined defects, and the lowest incidence with factor V Leiden. CONCLUSIONS: The incidence of venous events in asymptomatic individuals from thrombophilic families does not exceed the risk of bleeding associated with long-term anticoagulant treatment in the literature (1-3%).

Adolescent↗
PubMed2005

Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods.

OBJECTIVE: In order to correct the primary von Willebrand factor (VWF) defect and avoid supra-physiologic plasma levels of factor VIII, a pure VWF concentrate almost devoid of FVIII was developed and used in France since 1989. METHODS: The pharmacokinetic (PK) profile of the most recent version of this concentrate (Wilfactin; LFB, Les Ulis, France), treated with three virus-inactivation/removal methods (solvent/detergent, 35 nm filtration, dry heat treatment), was investigated in 25 patients. Seventeen patients with various types of clinically severe von Willebrand disease (VWD) were included in a crossover, randomized trial carried out in five European centers and comparing Wilfactin with concentrates containing both FVIII and VWF (FVIII/VWF). Eight type 3 VWD patients were included in another trial carried out in six French centers comparing Wilfactin with its previous version (Facteur Willebrand-LFB; LFB) that adopted one virus-inactivation method only. RESULTS: For both the measurements evaluated in this study (VWF antigen, VWF:Ag; and VWF ristocetin co-factor activity, VWF:RCo), Wilfactin had a PK profile similar to that of the FVIII/VWF concentrates and of Facteur Willebrand-LFB. VWF:RCo and VWF:Ag recoveries were 2.1 +/- 0.3 and 1.8 +/- 0.3 per IU kg(-1), respectively, and the half-lives were 12.4 +/- 1.8 and 15.9 +/- 1.5 h. The FVIII synthesis rate was 5.8 +/- 1.0 IU dL(-1) h(-1), with a half-life of 15.8 +/- 2.4 h. CONCLUSION: The PK of VWF and FVIII have not been altered by the three virus-inactivation/removal steps during the manufacturing of Wilfactin.

Adult↗
PubMed2005

Inhibitor development in patients with hemophilia A after continuous infusion of FVIII concentrates.

Continuous infusion (CI) of coagulation factor concentrates has been used since the early 1990s. Recent reports of the occurrence of an inhibitor after CI have raised concerns about this method of treatment. We conducted a retrospective study to investigate the development of inhibitors after CI of Factor VIII concentrates in Germany. So far, 13 hemophilia centers have been contacted, and data have been collected by a questionnaire. Of the 13 centers, CI had never been performed in three, no inhibitors had been detected in five, and inhibitor development after CI was recorded in 10 patients in the remaining five centers. Of these 10 patients (ages 7 months to 57 years), five were suffering from severe, one from moderate, and four from mild hemophilia. Indications for treatment were major bleeds and surgical procedures. Plasma-derived (6 cases) and recombinant (4 cases) factor concentrates were given in various infusion sets. Data concerning amount infused (4300 to > 100,000 IU), number of days of exposure to factor concentrates (1 to > 100), and inhibitor characteristics (alloantibodies, 3 LR, 7 HR) were collected. Regarding hemophilia genotype, we found missense mutations in four patients, intron-22 inversions in two, and one small deletion in one; the genotype in three was unknown. In conclusion, only 3 out of 10 patients who developed an inhibitor after CI showed the typical risk profile for inhibitor formation, which is severe hemophilia A with a severe gene defect and less than 50 days of exposure to coagulation factor concentrates. Especially striking was the finding that 50% of the patients who developed inhibitors had mild to moderate hemophilia A. Our data point to the existence of a so-far unknown factor, related to CI, that might lead to inhibitor formation.

Adult↗
PubMed2005

[Haemostaseological diseases on the intensive care units: TTP, HUS, spontaneous acquired FVIII inhibitor haemophilia and catastrophic antiphospholipid syndrome].

A minority of patients presenting with acute life threatening syndromes characterized by severe bleeding episodes or microvascular thromboses on the intensive care unit. Especially patients with TTP, HUS, acquired haemophilia and CAPS have a poor prognosis. These emergency cases require a rapid diagnosis and an immediate onset of treatment.

Antiphospholipid Syndrome↗
PubMed2005

[Liver cirrhosis and coagulopathy].

In patients with chronic liver disease profound coagulation changes and thrombocytopenia may lead to life-threatening bleeding that requires thorough diagnosis and immediate blood product replacement.

Blood Coagulation Disorders↗
PubMed2004

[The antiphospholipid syndrome].

Antiphospholipid antibody syndrome (APS) is characterised by the presence of frequently recurring venous and/or arterial thrombosis, abortions and repeated evidence of lupus anticoagulants and/or anticardiolipin (aCL)-antibodies. The presence of lupus anticoagulants and/or high levels of aCL-antibodies in particular increases the risk of thrombosis. At present there are several models for the systemic and cell-damaging pathogenesis of phospholipid-antibodies. Where there are repeated occurrences of thrombo-embolic complications long-term anticoagulant treatment is indicated. For patients who have APS in pregnancy, the use of low-molecular heparin and acetylsalicylic acid (ASS) is recommended. According to recent research, a large number of antibodies can be found in APS patients, which are directed against phospholipids and plasmaproteins, but partly also against individual genetic polymorphism, which suggests focussing in future on the genetic basis of APS as well as on influencing "auto-immune thrombosis" by modulating the immune system.

Antibodies, Anticardiolipin↗
PubMed2004

Recurrent life-threatening thromboembolism and catastrophic antiphospholipid syndrome in a patient despite sufficient oral anticoagulation.

We report on a 32-year old female patient with primary antiphospholipid syndrome (PAPS) and several thromboembolic events despite stable doses of oral anticoagulation, good patient compliance and maintained INR values of >3. Over the preceding 3 years the patient had presented a wide spectrum of manifestations of APS, including recurrent venous and arterial thromboses, cardiac, gynecological (HELLP syndrome), neurological involvements, livedo reticularis, a mild thrombocytopenia and the most feared manifestation of the catastrophic antiphospholipid syndrome (CAPS). Life-threatening bilateral subdural bleeding occurred while she was anticoagulated. The clinical features appeared to be refractory to oral anticoagulation with phenprocoumon. They were life threatening on each occasion and she developed repetitive episodes of organ damage with cardiac insufficiency (NYHA III), pulmonary hypertension and other residual defects. Even during heparinization recurrent thromboembolism supervened as well as livedo reticularis of the extremities. Lupus anticoagulants (LAC), anticardiolipin (aCL) antibodies and anti-beta(2)-glycoprotein-1 (beta(2)GPI) titers were all markedly elevated. This case report shows that recurrent episodes of thrombosis can occur despite seemingly adequate anticoagulation in patients with CAPS.

Administration, Oral↗
PubMed2004

Treatment patterns and cost-of-illness of severe haemophilia in patients with inhibitors in Germany.

To evaluate current treatment patterns and resource utilization as well as related cost in the management of severe haemophilia patients with inhibitors in Germany, a cost-of-illness study was conducted. Generally, data were generated by structured literature search. Missing data were collected by expert interviews. All data were validated by a panel of German experts in haemophilia care. In Germany, immune tolerance therapy (ITT) is first-line therapy in inhibitor management for children in the initial year after inhibitor development, particularly for high responders (HR). In adult HR patients ITT is applied but to a remarkably lower extent than in children. To treat bleeding episodes, factor VIII (FVIII) is first-line therapy in low responders (LR). For paediatric HR patients, bleeds are mainly treated with recombinant FVIIa (rFVIIa). In adult HR patients, activated prothrombin complex concentrate (aPCC) and rFVIIa are more equally distributed as treatment options. Treatment costs were calculated for paediatric patients (15 kg) and adult patients (75 kg) from third party payers' perspective. Cost for ITT ranges from Euro 70,290 (2 months; LR) to Euro 3 812,400 (24 months; with aPCC; HR) in a paediatric patient. For an adult patient ITT cost ranges from Euro 287,500 (6 months; LR) to Euro 17,253,000 (36 months; HR). For on average 12.5 acute bleeds, average annual treatment costs amount to Euro 77,000 for a child and Euro 354,000 for an adult. Assessing the results it has been taken into consideration that ITT can last longer and annual number of bleeds can be extremely higher than on average 12.5 episodes. This indicates more health care resource consumption in some patients.

Adult↗
PubMed2004

Management of haemophilic patients with inhibitors in major orthopaedic surgery by immunadsorption, substitution of factor VIII and recombinant factor VIIa (NovoSeven): a single centre experience.

Inhibitors of factor VIII or FIX in haemophilic patients are a common and serious complication associated with an increased risk of life-threatening bleeding during elective surgery. Substitution therapy fails to be effective, therefore an alternative treatment is needed. We have performed six major elective orthopaedic interventions in four patients with haemophilia A and inhibitors. A preoperative immunadsorbant therapy with Therasorb to eliminate inhibitors was successful in four cases, but during FVIII substitution inhibitors increased on day 4 to day 6 after surgery, leading to decreasing FVIII levels. Therefore, therapy was changed to recombinant FVIIa (rFVIIa; NovoSeven). Two interventions had to be covered with sole rFVIIa therapy as immunadsorbant therapy failed to be effective in one case and the need for acute intervention did not allow pretreatment in the other. We did not see increased bleeding during or after surgery when compared to our experience with non-inhibitor haemophilic patients. In conclusion, a preoperative decrease of inhibitors from immunadsorbant therapy, perioperative substitution of FVIII and changing treatment to rFVIIa when inhibitors are increased, is a safe and economic therapy for guaranteeing haemostasis in major elective orthopaedic surgery. On the contrary, sole therapy with rFVIIa allows immediate surgical intervention without a long hospital stay prior to surgery and a need for laboratory monitoring of inhibitor titres and FVIII levels. Our findings support data previously published.

Adult↗
PubMed2004

Impact of environmental and hereditary risk factors on the clinical manifestation of thrombophilia in homozygous carriers of factor V:G1691A.

BACKGROUND: Limited data exist on the clinical manifestations of homozygous factor (F)V:G1691A mutation (FV Leiden) and the impact of environmental and genetic risk factors. OBJECTIVES: To assess the contribution of these factors on the thrombophilic phenotype. PATIENTS AND METHODS: In a retrospective multicenter cohort study 165 individuals with homozygous FV:G1691A mutation, of whom 129 had previous venous thromboembolism (VTE), were included. To study the role of environmental risk factors, patients were compared by the use of a standardized questionnaire to 165 sex- and age-matched individuals (reference group A); of these, two had previous VTE. To assess the role of genetic risk factors, factor (F)II:G20210A and MTHFR:C677T were determined in individuals homozygous for FV:G1691A and in 177 healthy individuals without previous VTE (reference group B). RESULTS: The first VTE occurred significantly earlier in women (median age 25 years) than men (35.5 years). In 81% of women and 29% of men an environmental risk factor was present before first VTE. Oral contraceptives increased the risk of thrombosis 4-fold [odds ratio (OR) 4.0, 95% confidence interval (CI) 1.7, 10.4] in women with homozygous FV:G1691A. Postoperative and post-traumatic VTE as first manifestation occurred in 13% and 15% of surgical/traumatic events in patients and in 0.7% and 1.8% in reference group A, respectively (OR 19.7, 95% CI 2.5, 154 and OR 9.2, 95% CI 1.1, 79.4). Heterozygous FII:G20210A was more prevalent in symptomatic patients (11.7%) compared with reference group B (2.8%, OR 4.6, 95% CI 1.6, 13.2). The prevalence of homozygous MTHFR:C677T genotype was similar in patients and reference group B. CONCLUSIONS: Our study supports the concept of thrombophilia as a multifactorial disorder. The knowledge of coexisting factors predisposing to VTE is useful for medical advice for primary and secondary prophylaxis in these patients.

Adolescent↗
PubMed2004

Hereditary thrombophilia and fetal loss: a prospective follow-up study.

BACKGROUND: As the placental vessels are dependent on the normal balance of procoagulant and anticoagulant mechanisms, inherited thrombophilia may be associated with fetal loss. OBJECTIVES: We performed a prospective study to investigate the relation between inherited thrombophilia and fetal loss, and the influence of thromboprophylaxis on pregnancy outcome. PATIENTS AND METHODS: Women were enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). These included women with factor (F)V Leiden or a deficiency of antithrombin, protein C or protein S. Controls were partners or acquaintances of thrombophilic individuals. A total of 191 women (131 with thrombophilia, 60 controls) had a pregnancy outcome during prospective follow-up. Risk of fetal loss and effect of thromboprophylaxis were estimated by frequency calculation and Cox regression modelling. RESULTS: The risk of fetal loss appeared slightly increased in women with thrombophilia without a previous history of fetal loss who did not use any anticoagulants during pregnancy (7/39 vs. 7/51; relative risk 1.4; 95% confidence interval 0.4, 4.7). Per type of defect the relative risk varied only minimally from 1.4 for FV Leiden to 1.6 for antithrombin deficiency compared with control women. Prophylactic anticoagulant treatment during pregnancy in 83 women with thrombophilia differed greatly in type, dose and duration, precluding solid conclusions on the effect of thromboprophylaxis on fetal loss. No clear benefit of anticoagulant prophylaxis was apparent. CONCLUSIONS: Women with thrombophilia appear to have an increased risk of fetal loss, although the likelihood of a positive outcome is high in both women with thrombophilia and in controls.

Adolescent↗
PubMed2004

Familial thrombophilia and lifetime risk of venous thrombosis.

BACKGROUND: We started a large multicenter prospective follow-up study to provide reliable risk estimates of venous thrombosis in families with various thrombophilic defects. OBJECTIVES: This paper describes data collected at study entry on venous events experienced before study inclusion, i.e. the baseline data. PATIENTS/METHODS: All individuals (probands, relatives) registered in nine European thrombosis centers with the factor (F)V Leiden mutation, a deficiency of antithrombin, protein C or protein S, or a combination of these defects, were enrolled between March 1994 and September 1997. As control individuals, partners, friends or acquaintances of the thrombophilic participants were included. Incidence and relative risk of objectively confirmed venous thrombotic events (VTEs) prior to entry were calculated for the relatives with thrombophilia and the controls. RESULTS: Of the 846 relatives with thrombophilia (excluding probands), 139 (16%) had experienced a VTE with an incidence of 4.4 per 1000 person years. Of the controls, 15 of the 1212 (1%) controls had experienced a VTE with an incidence of 0.3 per 1000 person years. The risk of venous thrombosis associated with familial thrombophilia was 15.7 (95% CI 9.2-26.8) and remained similar after adjustment for regional and sex-effects (16.4; 95% CI 9.6-28.0). The highest incidence per 1000 person years was found in relatives with combined defects (8.4; 95% CI 5.6-12.2), and the lowest incidence was found in those with the FV Leiden mutation (1.5; 95% CI 0.8-2.6). CONCLUSIONS: Considerable differences in the lifetime risk of VTE were observed among individuals with different thrombophilia defects.

Adolescent↗