Late onset and pregnancy-induced congenital thrombotic thrombocytopenic purpura.

UNLABELLED: We report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode. DIAGNOSIS: In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity. CONCLUSION: Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.

Correlation between endogenous VWF:Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three-times-weekly prophylaxis with rFVIII-FS.

Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor (VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen (VWF:Ag) levels are correlated with FVIII pharmacokinetic (PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non-inhibitor patients in a multinational, randomized, double-blind, Ph II study received prophylaxis with once-weekly BAY 79-4980 (35 IU kg(-1)) or thrice-weekly recombinant sucrose-formulated FVIII (rFVIII-FS; 25 IU kg(-1)). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13-64 years; BAY 79-4980, n = 63; rFVIII-FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age (P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUC(norm) and T1/2 significantly increased with increased VWF:Ag (P < 0.001); clearance significantly decreased with increased VWF:Ag (P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII-FS significantly correlated with VWF:Ag and age (P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK.

Long term outcome and sequelae in patients after acute thrombotic thrombocytopenic purpura episodes.

UNLABELLED: We report on 21 patients with idiopathic thrombotic thrombocytopenic purpura (TTP) whose courses of disease have been followed from the respective diagnosis until now. They had a documented ADAMTS13 activity below 5%, a high autoantibody titer and detectable ultralarge von Willebrand factor (VWF) multimers during their episodes. The initial diagnosis was based on clinical symptoms and on laboratory parameters: thrombocytopenia, haemolytic anaemia, schistocytes and an increased LDH level. 103 acute clinical episodes of 21 TTP-patients during a time period of 30 years are described. Case histories, comorbidities and sequelae were retrospectively documented. RESULTS, CONCLUSION: Although patients are consistently in a prothrombotic status, clinical acute manifestations only occur after triggering. Most common trigger factors are gastrointestinal infections and pregnancy. The relapse risk per month is 0.026; men have a higher risk for relapses (0.044) than women (0.021). Patients recover physically well, except for renal insufficiency in four cases. Nevertheless, major portion of patients suffers persistently from depression, anxiety disorders and persistent neurocognitive impairments.

[Haemophilia treatment centres in Germany]. / Register von Hämophilie-Zentren in Deutschland.

UNLABELLED: An adequate number of qualified haemophilia centres is an essential requirement for effective and cost-efficient haemophilia care. During a reassessment of the delivery of haemophilia care in Germany a broad range of criteria relating to structure and quality of the centres were defined and a questionnaire was developed. RESULTS: Of 137 doctors who received the questionnaire, 113 (82%) replied. Based on data related to diagnostic and treatment services, together with voluntary information from PEI forms (Paul Ehrlich Institut, Germany), 72 haemophilia centres were established. Three levels of haemophilia care were defined by the Medical Advisory Council of the German Haemophilia Society. This is in accordance with criteria defined by European working parties. 17 haemophilia centres were designated CCC (Comprehensive Care Centre), 24 were designated HTC (Haemophilia Treatment Centre) and 31 smallest centres were allocated the status HTR (Haemophilia Treatment Regional). In comparison to the survey in 2007, there was only slight variance in the CCC centres (+ 2 centres/-1 centre). From the previous HTC centres, 7 have withdrawn from this treatment level: 4 maintain treatment on the lower level HTR, and 3 centres had ceased treatment. On the HTR level of treatment, 6 of 29 (21%) had ceased to offer treatment. 9 had been able to increase the number of patients and were designated HTC. 5404 patients with haemophilia and 3047 with the severe form of haemophilia were reported. 67% were treated in CCC, 25% in haemophilia treatment centres and 8% in the 31 smallest centres. 13 of the adult CCC are situated in the department of internal medicine and 4 in the section of transfusion medicine. CONCLUSIONS: The survey and analysis of the haemophilia treatment centres in Germany show that the delivery of haemophilia care through 17 CCC, 24 HCT and 31 HTR appears to be adequately structured. But it is noticeable and alarming, however, that on both HTC and HTR levels of treatment, 32% and 21%, respectively, have left their treatment level. 9 centres (12.5%) have finished working in haemophilia care in the last four years. On the strength of these results, endeavours to maintain haemophilia centres must be intensified. A high level of effective care can be guaranteed only through continued existence of the centres.

Autoimmune disorders in patients with idiopathic thrombotic thrombocytopenic purpura.

UNLABELLED: 76 German patients suffering from thrombotic thrombocytopenic purpura (TTP) were interrogated about the prevalence of co-occurring autoimmune disorders. In order to analyze a possible association of TTP with the questioned diseases, a comparison of prevalence rates between the patient group and the general population has been made for each disease. RESULTS: Compared to the estimated prevalence rates, the statistical analysis revealed an unexpected high occurrence of the following disorders within the patient group: Hashimoto's thyroiditis (23.5% within the patients compared to 0.7% within the general population, p<0.001), systemic lupus erythematosus (SLE) (6.5% in patients to 0.025% in the general population, p<0.001), immune thrombocytopenic purpura (ITP) (6.3% in patients to 0.02% in the general population, p<0.001), psoriasis (9.4% in patients to 2.5% in the general population, p=0.005) and celiac disease (3.1% in patients to 0.2% in the general population, p=0.007). CONCLUSION: These findings confirm the mentioned tendency of autoimmune diseases to co-occur in one individual and argue once more for a genetic susceptibility in idiopathic TTP as well as in autoimmune disorders.

[Massive subretinal hemorrhage and anticoagulants. An unfortunate combination?]. / Submakuläre Massenblutung und Gerinnungshemmer. Eine unglückliche Kombination?

Exudative age-related macular degeneration (ARMD) is one of the conditions which has been shown to be associated with a risk of massive subretinal hemorrhage. Patients with thick submacular hemorrhage complicating ARMD typically have a poor visual prognosis. Antiplatelet therapy with aspirin, clopidogrel or ticlopidine has significant benefits in the secondary prevention of fatal and non-fatal coronary and cerebrovascular events. Anticoagulation is frequently used in this elderly age group for a variety of other comorbidities including prosthetic heart valves, atrial fibrillation, ischemic heart disease, cerebrovascular disease and venous thromboembolism. However, it is a well established observation that the longer patients remain on anticoagulant therapy, the higher the cumulative risk of bleeding. Over the past years, there has been a rapidly growing body of literature concerning the risk of hemorrhagic ocular complications with ophthalmic surgery in patients receiving anticoagulant therapy. By contrast, there are still little data on the relationship between anticoagulation or antiplatelet therapy and spontaneous ocular hemorrhages and only few reports have focused on patients with ARMD. Just recently, several authors reported a strong association of anticoagulants and antiplatelet agents with the development of large subretinal hemorrhages in ARMD patients. Moreover, arterial hypertension is a high risk factor for large subretinal hemorrhages in ARMD patients receiving anticoagulants or antiplatelet agents. Physicians should be aware of an increased risk of extensive subretinal hemorrhage in ARMD patients when deciding on the initiation and duration of anticoagulant and antiplatelet therapy.

[Bleeding and coagulation disorders in tonsillectomies]. / Nachblutungen und Gerinnungsstörungen bei Tonsillektomien.

BACKGROUND: The aim of our prospective analysis was to show the incidence of bleeding disorders among a tonsillectomy patient population and in case of bleeding disorders. PATIENTS AND METHODS: This study comprised 92 consecutive patients who underwent tonsillectomies from 1 January 2007 to 31 December 2007 at the Department of Otorhinolaryngology, University Medical Center Mainz. In addition to gender, age, date of bleeding, Quick, aPTT and platelet count, the following blood values were determined: vWF:AG, vWF:RCo, vWF:RCo/vWF:AG, factor XIII, factor VIII:C, PFA 100™ ADP and PFA 100™ epinephrine (special coagulation analysis). RESULTS: Twelve of 92 patients (13%) showed evidence of coagulopathy. Four of these 12 patients had a postoperative hemorrhage. In eight patients a factor XIII deficiency was diagnosed, with two of them suffering a hemorrhage. In four patients, von Willebrand disease was diagnosed; two of them bled. No correlation between the presence of a coagulopathy and the bleeding rate could be determined. CONCLUSION: Routine preoperative performance of special coagulation analysis in all patients does not significantly contribute to the detection of increased postoperative hemorrhage risk.

[The significance of bleeding disorders in patients with epistaxis]. / Stellenwert von Gerinnungsstörungen bei Patienten mit Epistaxis.

BACKGROUND: Epistaxis can have a variety of different local or systemic causes. It is the cardinal symptom of von Willebrand disease (VWD), the most frequent congenital bleeding disorder with a prevalence of approximately 1%. The usual routine coagulation screening tests (PT, APTT, platelet count) are not sufficient to diagnose VWD, factor XIII (FXIII)-deficiency or platelet dysfunction. METHOD: A prospective study was conducted implementing enhanced coagulation screening for bleeding disorders in a total of 100 inpatients admitted for epistaxis. RESULTS: A bleeding disorder was found in 13%. In eight patients VWD was diagnosed, in six patients FXIII-deficiency was found, and in one patient both. CONCLUSION: The prevalence of bleeding disorders in patients with epistaxis is higher than in the general population. Epistaxis can be the primary symptom of chronic inflammatory disease or malignant disease. A thorough anamnesis is necessary and in cases of doubt additional testing for underlying disorders is recommended.

[Thrombophilic and systemic risk factors in patients with retinal vein occlusion]. / Thrombophiliediagnostik und Abklärung systemischer Risikofaktoren bei Patienten mit venösen retinalen Gefässverschlüssen.

Over the past years there has been a dramatic increase in the number of identifiable causes of thrombophilia. However, as retinal vein occlusions (RVO) have a strong pathogenic correlation with the presence of hypertension or arteriosclerosis and the average age of affected patients is usually within the sixth or seventh decade of life, thrombophilia screening of RVO patients poses a particularly difficult diagnostic challenge. It is clear that to use medical resources appropriately and improve the level of interdisciplinary patient care in RVO, subgroup analysis is required. Just recently, some studies have demonstrated the significant role of coagulation disorders in specific subgroups of RVO patients and have provided recommendations for clinical practice. These results indicate that thrombophilic risk factors are significantly more prevalent among patients equal or less than 45 years of age at the time of RVO or a previous thromboembolic event, among patients with a remarkable family history of thromboembolism prior to the age of 45 years, or among patients without cardiovascular risk factors. According to these data, thrombophilia screening should be considered in these selected subgroups.

[Thrombotic-thrombocytopenic purpura]. / Thrombotisch-thrombozytopenische Purpura.

Thrombotic-thrombocytopenic purpura (TTP) is a microangiopathic disorder characterized by multiple von Willebrand-Factor (vWF) rich microthrombi affecting the arterioles and capillary vessels of several organs. Ultra large von Willebrand multimers cause the blood clotting process by linking to platelets due to a lack of a plasma metalloprotease named ADAMTS13. Deficiency of this vWF-cleaving enzyme is caused by an inborn mutation in the gene coding or, more often, by acquired autoantibodies that inhibit ADAMTS13. TTP is a life-threatening disease which requires urgent admission to a hematological centre. Plasmapheresis therapy should be started immediately when diagnosis of primary TTP is likely. Patients typically present with schistozytes, hemolysis, thrombocytopenia and neurological abnormalities such as headache, focal deficits or coma. The monoclonal CD20 antibody rituximab targets ADAMTS13 antibody production and has the potential to be an effective therapy for relapsed TTP or initial treatment to shorten duration of plasma exchange.

HLA genotype in patients with acquired haemophilia A.

Acquired haemophilia A (AH) is a rare bleeding disorder caused by an auto-antibody to coagulation factor VIII. It is associated with various autoimmune diseases, pregnancy, cancer or drug ingestion; however, in 50% of patients, no underlying disorder is found. In the present study, we investigated the association of HLA class I (A, B and Cw) and class II (DRB1 and DQB1) alleles with AH in a cohort of 57 patients. While no association with any class I allele was detected, a significantly higher frequency of DRB1*16 [odds ratio (OR) 10.2, 95%CI: 5.32-19.57, P < 0.0001] and DQB1*0502 (OR 2.2, 95%CI: 1.12-4.54, P < 0.05) was observed. In contrast, the frequency of DRB1*15 and DQB1*0602 alleles was found to be decreased in patients with AH corresponding to an OR of 0.4 for both HLA loci. Upon comparing the frequencies of these alleles with those of patients with congenital haemophilia A with inhibitors, the data demonstrate that the high risk alleles in patients with AH DRB1*16 and DQB1*0502 are found to be low risk alleles in patients with congenital haemophilia A with inhibitors (OR 1.1 and 1.5 respectively). Conversely, the alleles that exhibit low risk in AH DRB1*15 and DQB1*0602 are found to be high risk for haemophilia A inhibitor patients (OR 2.2 and 3.7 respectively). The pathophysiological reason for this finding remains unknown. It might be speculated that the presence or absence of the FVIII antigen and the various ability of HLA molecules to present the FVIII antigen to the T-cell receptor contribute to these findings.

The influence of preoperative anticoagulation on outcome and quality of life after surgical treatment of chronic subdural hematoma.

The main aim of this study was to investigate the influence of perioperative anticoagulation on the clinical course and outcome of 144 patients who underwent surgery for chronic subdural hematoma (CSDH). The outcome was categorized according to the modified Rankin Scale (mRS), Barthel Index and postoperative quality of life (QoL) scale. There was a significant correlation between preoperative aspirin medication and reoperation (Mann-Whitney U-test, p<0.05). Moreover, dosage and duration of postoperative low-molecular-weight heparin (LMWH) administration were associated with a higher risk of reoperation (Mann-Whitney U-test, p<0.01) and a worse outcome on the mRS (Mann-Whitney U-test, p<0.05). Intraoperative treatment with prothrombin complex concentrate led to a poor outcome on the mRS (Craddock-Flood test, p<0.05). Reoperation is the strongest predictive factor of a poor QoL after surgical treatment of CSDH. Both preoperative and postoperative anticoagulation treatment may affect reoperation rate and, thus, postoperative QoL.

Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency.

Severe factor XIII (FXIII) deficiency is a rare autosomal recessive coagulation disorder affecting one in two million individuals. The aim of the present study was to screen for and analyse F13B gene defects in the German population. A total of 150 patients presenting with suspected FXIII deficiency and one patient with severe (homozygous) FXIII deficiency were screened for mutations in F13A and F13B genes. Twenty-five individuals presented with detectable heterozygous mutations, 12 of them in the F13A gene and 13 of them in the F13B gene. We report on the genotype-phenotype correlations of the individuals showing defects in the F13B gene. Direct sequencing revealed 12 unique mutations including seven missense mutations (Cys5Arg, Ile81Asn, Leu116Phe, Val217Ile, Cys316Phe, Val401Glu, Pro428Ser), two splice site mutations (IVS2-1G>C, IVS3-1G>C), two insertions (c.1155_1158dupACTT, c.1959insT) and one in-frame deletion (c.471-473delATT). Two of the missense mutations (Cys5Arg, Cys316Phe) eliminated disulphide bonds (Cys5-Cys56, Cys316-Cys358). Another three missense mutations, (Leu116Phe, Val401Glu, Pro428Ser) were located proximal to other cysteine disulphide bonds, therefore indicating that the region in and around these disulphide bonds is prone to functionally relevant mutations in the FXIII-B subunit. The present study reports on a fairly common prevalence of F13B gene defects in the German population. The regions in and around the cysteine disulphide bonds in the FXIII-B protein may be regions prone to frequent mutations.

Coagulation disorders and the risk of retinal vein occlusion.

Over the past years, there has been a dramatic increase in the number of identifiable causes of thrombophilia. However, to date, there are no large, prospective studies to assess an optimal, cost-effective approach with regard to screening and case finding for thrombophilic risk factors in patients presenting with retinal vessel occlusion. Two hundred twenty-eight patients with retinal vein occlusion (RVO) and 130 age-matched healthy controls were prospectively screened for thrombophilic risk factors. Both cohorts were divided into three subgroups, depending on the patients' age at the time of the RVO or a previous thromboembolic event. Patient age < or =45 years was associated with a high prevalence of coagulation disorders (p<0.0001). Among patients < or =45 years and >45 to < or =60 years, a family history of thromboembolism was strongly associated with the presence of thrombophilic disorders. The absence of cardiovascular risk factors was found to be a strong predictor for the presence of coagulation disorders in all patient groups (< or =45 years, p=0.003; >45 to < or =60 years, p=0.0008; >60 years, p=0.001). Multivariate analysis revealed the presence of resistance to activated protein C (p=0.014), antiphospholipid antibodies (p=0.022), and deficiency of the anticoagulant proteins (p=0.05) as independent risk factors for the development of RVO among patients < or =45 years. Our results indicate that thrombophilic disorders are associated with the development of retinal vein occlusion in patients < or =45 years by the time of the RVO or a previous thromboembolic event, in patients with a family history of thromboembolism, or in patients without cardiovascular risk factors.

[Selective thrombophilia screening of young patients with retinal vein occlusion]. / Selektives Thrombophiliescreening junger Patienten mit venösen retinalen Gefässverschlüssen.

BACKGROUND: The potential impact of coagulation abnormalities on retinal vascular occlusive diseases, individually and in combination with cardiovascular risk factors, remains unclear. PATIENTS AND METHODS: In a prospective case-control study a cohort of 74 young patients with central, hemicentral or branch retinal vein occlusion (RVO) (

[Thrombophilic disorders associated with non-arteritic anterior ischaemic optic neuropathy in patients < 60 years of age]. / Thrombophile Gerinnungsstörungen bei unter 60-jährigen Patienten mit nichtarteriitischer anteriorer ischämischer Optikusneuropathie.

BACKGROUND: The potential impact of coagulation abnormalities on non-arteritic ischaemic optic neuropathy (NAION), individually and in combination with cardiovascular risk factors, remains unclear. PATIENTS AND METHODS: In a prospective case-control study a cohort of 26 NAION patients < 60 years at the time of the NAION or a previous thromboembolic event and 50 subjects matched for age and sex were prospectively screened for thrombophilic risk factors. RESULTS: Overall, thrombophilic defects were found to be present in 12 of 26 patients (46.2 %) and in 9 of 50 (18 %) controls (p = 0.01). The most frequent coagulation disorders were high levels of factor VIII (p = 0.04) and lipoprotein (a) (p = 0.03). Moreover, we identified two patients with homozygous resistance to activated protein C, which is the first description of this coagulation disorder associated with NAION. Patients without cardiovascular risk factors had a statistically significant higher frequency of coagulation disorders than patients with these risk factors (p = 0.038). CONCLUSIONS: Our results indicate that thrombophilic disorders are associated with the development of non-arteriitic ischaemic optic neuropathy in patients < 60 years of age at the time of a first thromboembolic event. Selective screening of young patients and patients without cardiovascular risk factors may be helpful in identifying NAION patients with thrombophilic defects.

Cross-cultural development and psychometric evaluation of a patient-reported health-related quality of life questionnaire for adults with haemophilia.

Co-morbidities of haemophilia, such as arthropathy and blood-borne infections, can adversely affect the quality of life of adult patients with haemophilia. The purpose of this study was to develop and validate a haemophilia-specific health-related quality of life questionnaire for adults (HAEMO-QoL-A). Subjects with varying severities of haemophilia completed the HAEMO-QoL-A at baseline and 4 weeks. Other assessments included the SF-36 and Health Assessment Questionnaire - Functional Disability Index (HAQ-FDI). Two-hundred and twenty-one participants completed the 41-item HAEMO-QoL-A covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns) and four independent items. Internal consistency was good-to-excellent (Cronbach's alpha-range: 0.75-0.95). Test-retest reproducibility was good, with intraclass correlation coefficients >0.80 except for the Emotional Impact domain (0.79). Concurrent validity between the HAEMO-QoL-A total and subscale scores and all SF-36 subscale scores were generally good (correlations range: 0.13-0.87). Significant correlations between the HAEMO-QoL-A and the HAQ-FDI ranged from -0.14 to -0.69. There were non-significant correlations with the Treatment Concerns subscale and with the Worry subscale. The HAEMO-QoL-A discriminated significantly between adults with haemophilia by severity and HIV status. The Physical Functioning subscale discriminated between patients receiving prophylactic or on-demand therapy. The HAEMO-QoL-A is a valid and reliable instrument for assessing quality of life in haemophilia patients.

Increased frequency of the CTLA-4 49 A/G polymorphism in patients with acquired haemophilia A compared to healthy controls.

Acquired haemophilia (AH) is an autoimmune disorder characterized by autoantibodies against endogenous factor VIII (FVIII). Half of the patients present with an underlying disease known to cause the FVIII autoantibodies whereas in the other half the disease is of idiopathic nature. Recently, it has been shown that variants of the polymorphic cytotoxic T lymphocyte antigen-4 (CTLA-4) gene are associated with autoimmune diseases and also represent a risk factor for inhibitor formation in inherited haemophilia A. In the present study, we investigated whether CTLA-4 variants also play a role in the pathogenesis of AH. Therefore, we analyzed three single nucleotide polymorphisms (SNPs) of the CTLA-4 gene (-318 C/T, +49 A/G and CT60 A/G) in 57 AH patients and 98 controls. The CTLA-4 + 49 G allele occurred with a significantly higher frequency in patients with AH compared with controls [odds ratio (OR) = 2.17, 95% confidence interval (CI): 1.36-3.48, P = 0.001]. This effect was mainly caused by a higher frequency of the 49 G allele in female patients (OR = 5.1, 95% CI: 1.76-15.02, P = 0.002), whereas in males the frequencies were not significantly different (OR = 1.4, P = 0.5). A higher frequency of the G allele was also observed in the subcohort with AH and underlying autoimmune disease (OR = 3.1, P = 0.04). Our observations of a higher frequency of the CTLA-4 + 49 A/G SNP in AH patients are in concordance with findings in other autoimmune disorders. In conclusion, on the background of the CTLA-4 gene polymorphism, further genetic and/or environmental factors might contribute to and finally trigger the clinical manifestation of AH.

Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin): a prospective study of 50 patients.

BACKGROUND AND OBJECTIVES: A plasma-derived von Willebrand factor (VWF) concentrate with low factor VIII (FVIII) content was specifically developed to treat von Willebrand disease (VWD). Efficacy and safety were investigated by merging the results of two comparable protocols conducted prospectively in 5 European and 12 French centers. METHODS AND RESULTS: Fifty patients with clinically severe VWD (72% had VWF ristocetin cofactor activity less than 10 IU dL(-1) and 46% had FVIII < 20 IU dL(-1)) were treated with the concentrate as the only therapy, except for clinical situations requiring a priming dose of FVIII to rapidly correct an intrinsic coagulation defect. A total of 139 spontaneous bleeding episodes were treated; only 53 (38%) needed a concomitant FVIII dose. Outcome was excellent or good in 89% of the episodes. Forty-four patients underwent 108 surgical or invasive procedures. Outcome was excellent or good in 95 scheduled procedures (only VWF was infused) and 13 emergency procedures (a priming FVIII dose was co-administered with the first VWF infusion). There were no thrombotic complications and none of the 18 patients with type 3 VWD developed anti-VWF or anti-FVIII antibodies. CONCLUSIONS: This concentrate safely and effectively provides hemostasis in patients with clinically severe VWD.