Stefan Lethagen

A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM‐1 VWD)

Summary.  Background: A quantitative description of bleeding symptoms in type 1 von Willebrand disease (VWD) has never been reported. Objectives: The aim was to quantitatively evaluate the severity of bleeding symptoms in type 1 VWD and its correlation with clinical and laboratory features. Patients and methods: Bleeding symptoms were retrospectively recorded in a European cohort of VWD type 1 families, and for each subject a quantitative bleeding score (BS) was obtained together with phenotypic tests. Results: A total of 712 subjects belonging to 144 families and 195 controls were available for analysis. The BS was higher in index cases than in affected family members (BS 9 vs. 5, P < 0.0001) and in unaffected family members than in controls (BS 0 vs. −1, P < 0.0001). There was no effect of ABO blood group. BS showed a strong significant inverse relation with either von Willebrand ristocetin cofactor (VWF:RCo), von Willebrand antigen (VWF:Ag) or factor VIII procoagulant activity (FVIII:C) measured at time of enrollment, even after adjustment for age, sex and blood group (P < 0.001 for all the four upper quintiles of BS vs. the first quintile, for either VWF:RCo, VWF:Ag or FVIII:C). Higher BS was related with increasing likelihood of VWD, and a mucocutaneous BS (computed from spontaneous, mucocutaneous symptoms) was strongly associated with bleeding after surgery or tooth extraction. Conclusions: Quantitative analysis of bleeding symptoms is potentially useful for a more accurate diagnosis of type 1 VWD and to develop guidelines for its optimal treatment.

The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study

Summary.  Objective: The aim of this study was the validation of the criteria defining a significant mucocutaneous‐bleeding history in type 1 von Willebrand disease (VWD). Subjects and methods: To avoid selection bias, 42 obligatory carriers (OC) of type 1 VWD were identified from a panel of 42 families with type 1 VWD enrolled by 10 expert centers. OC were identified by the presence of an offspring and another first degree relative with type 1 VWD (affected subjects, AFF). A standardized questionnaire was administered to evaluate hemorrhagic symptoms at the time of first examination, using a bleeding score ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion). Sensitivity, specificity, diagnostic likelihood ratios, positive and negative predictive values for the diagnosis of type 1 VWD were calculated from the data collected in OC and in 215 controls. Results: Having at least three hemorrhagic symptoms or a bleeding score of 3 in males and 5 in females was very specific (98.6%) for the bleeding history of type 1 VWD, although less sensitive (69.1%). None of the misclassified OC had life‐threatening bleeding episodes after diagnosis. Conclusions: We suggest that the use of a standardized questionnaire and bleeding score may be useful for the identification of subjects requiring laboratory evaluation for VWD.

Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD)

Summary.  Background: Type 1 von Willebrand disease (VWD) is a congenital bleeding disorder characterized by a partial quantitative deficiency of plasma von Willebrand factor (VWF) in the absence of structural and/or functional VWF defects. Accurate assessment of the quantity and quality of plasma VWF is difficult but is a prerequisite for correct classification. Objective: To evaluate the proportion of misclassification of patients historically diagnosed with type 1 VWD using detailed analysis of the VWF multimer structure. Patients and methods: Previously diagnosed type 1 VWD families and healthy controls were recruited by 12 expert centers in nine European countries. Phenotypic characterization comprised plasma VWF parameters and multimer analysis using low‐ and intermediate‐resolution gels combined with an optimized visualization system. VWF genotyping was performed in all index cases (ICs). Results: Abnormal multimers were present in 57 out of 150 ICs; however, only 29 out of these 57 (51%) had VWF ristocetin cofactor to antigen ratio below 0.7. In most cases multimer abnormalities were subtle, and only two cases had a significant loss of the largest multimers. Conclusions: Of the cases previously diagnosed as type 1 VWD, 38% showed abnormal multimers. Depending on the classification criteria used, 22 out of these 57 cases (15% of the total cohort) may be reclassified as type 2, emphasizing the requirement for multimer analysis compared with a mere ratio of VWF functional parameters and VWF:Ag. This is further supported by the finding that even slightly aberrant multimers are highly predictive for the presence of VWF mutations.

Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD (MCMDM-1VWD)

The decreased survival of von Willebrand factor (VWF) in plasma has been implicated as a mechanism in a subset of type 1 von Willebrand disease (VWD) patients. We have previously reported that the ratio of plasma levels of VWF and its propeptide (VWFpp) can be used to identify patients with reduced VWF survival. In this study, we report the assay of VWFpp and VWF:Ag in 19 individuals recruited from 6 European centers within the MCMDM-1VWD study. Eight individuals had a VWF:Ag level less than 30 IU/dL. Seven of these patients had a robust desmopressin response and significantly reduced VWF half-life that was predicted by a markedly increased steady-state plasma VWFpp/VWF:Ag ratio. VWF mutations previously associated with reduced VWF survival were identified in each of the 7 individuals. Thus, a substantially increased ratio of steady-state VWFpp/VWF:Ag predicted a reduced VWF half-life in patients with markedly decreased VWF:Ag levels. These data indicate that a reduced VWF survival is found in a subpopulation of patients with type 1 VWD. The systematic assay of both plasma VWF and the VWF propeptide in moderately severe type 1 VWD patients may identify patients with a reduced VWF survival phenotype.

On‐demand vs. prophylactic treatment for severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome

Summary.  Using an 11‐year panel of 156 Norwegian and Swedish patients with severe haemophilia, and including retrospective case‐book data from birth, we compared the differences in the haemophilia‐related resource use between on‐demand and prophylactic treatment. Patients treated on‐demand had more surgery (arthrodeses, prostheses implantations and synovectomies) and more days lost from work. Median annual factor‐concentrate consumption among adults (18+) was 211 000 IU [interquartile range (IQR) 154 000–268 000] or 3 024 IU kg−1 year−1 for patients on prophylactic treatment and 55 000 IU (IQR 28 000–91 000) for on‐demand patients (780 IU kg−1 year−1). This was partly explained by the fact that the median dose per kg body weight was twice as great 28, (IQR 24–32) for prophylaxis compared with 14 (IQR 12–16) for on‐demand. Prescribed dose per kg body weight was found to be an important factor explaining the variation in total annual factor‐concentrate consumption per patient for both types of treatment. Other variables included in the panel‐data regression analysis were the number of weeks on secondary prophylaxis for on‐demand patients and age, body weight and type of haemophilia for children (0–17 years) on prophylaxis. Differences were consistently substantial and will affect both costs and benefits of the two treatment strategies.

Tranexamic acid, given at the end of the operation, does not reduce postoperative blood loss in hip arthroplasty

We performed a randomized double-blind study on the effect of tranexamic acid on postoperative blood loss and blood transfusions in 39 primary THR operations. Tranexamic acid was given at the end of the operation and 3 hours later. Ultrasound examination 1 week later was performed to measure the occurrence of deep hematomas. In contrast to previous findings in knee arthroplasty, the administration of tranexamic acid failed to give a significant reduction in the postoperative blood loss. This lack of effect was possibly related to the fact that the drug was administered too late. In 11 of the 20 patients receiving tranexamic acid, blood transfusion was not necessary, this being the case in 4/19 in the placebo group (p = 0.05). The occurrence of postoperative deep venous thromboses was similar in the tranexamic acid and placebo groups.

von Willebrand factor/factor VIII concentrate (Haemate R P) dosing based on pharmacokinetics: a prospective multicenter trial in elective surgery

Summary.  Background: While plasma‐derived concentrates containing large amounts of von Willebrand factor (VWF) are effective in treating von Willebrand disease (VWD), optimal dosing remains to be fully characterized. Objectives: To determine the feasibility of dosing Haemate P® VWF/factor VIII (FVIII) concentrate based on pharmacokinetics (PK) in the management of surgical subjects with VWD. Methods: VWD subjects scheduled for elective surgery were enrolled in a prospective multicenter open‐label cohort study. A pre‐operative loading dose of VWF/FVIII concentrate based upon prior individual subject PK analysis was administered followed by postoperative therapeutic/maintenance infusions. Results: Twenty‐eight subjects with types 1, 2A or 3 VWD and one with type 2 M were enrolled. Median in vivo recovery of VWF ristocetin cofactor (VWF:RCo) was 1.9 IU dL−1 (IU kg−1)−1 with an interquartile range (IQR) of 1.6–2.5 IU dL−1 (IU kg−1)−1. Median response, half‐life and clearance were 74.0% (IQR, 55.5–100%), 15.6 h (IQR, 9.0–28.4 h) and 3.26 mL kg−1 h−1 (IQR, 2.29–5.21 mL kg−1 h−1), respectively. A PK‐guided median VWF:RCo loading dose of 62.4 IU kg−1 (IQR, 50.1–87.0 IU kg−1) was administered. Postoperative mean trough VWF:RCo levels of 62–73 IU dL−1 were sufficient to prevent bleeding. Investigators rated hemostasis excellent or good in 96.3% of subjects on the day of surgery and 100% on the next day and on day 14. A subject with multiple risk factors developed pulmonary embolism, which resolved without sequelae. Conclusions: Haemate P® provided effective and safe hemostasis in VWD subjects undergoing elective surgery. Selection of Haemate® P loading dose on the basis of VWF PK proved feasible.

Use of recombinant factor VIIa (NovoSeven®) in patients with Glanzmann thrombasthenia

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

THE EFFECT OF TRANEXAMIC ACID ON LOCAL AND PLASMA FIBRINOLYSIS DURING TOTAL KNEE ARTHROPLASTY

The aim of the present study was to investigate aspects of coagulation and fibrinolysis during knee arthroplasties in order to find out. 1. whether an increased fibrinolysis is correlated to an increased blood loss 2. whether there is a difference in markers for coagulation and fibrinolysis in peripheral venous blood compared to those in blood from the wounds 3. whether the administration of tranexamic acid modifies the fibrinolytic response. Twenty-four patients were included. Twelve patients were given tranexamic acid intravenously at the end of the operation. The dose was repeated three hours later. The other 12 patients were given an equivalent amount of placebo. The administration was randomised and double-blind. Levels of prothrombin fragments 1 + 2, D-dimers, plasminogen, alpha 2-antiplasmin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI-1) in venous blood were investigated just before the operation, at the end of the operation and three hours later. At the end of the operation blood for analysis was also drawn from the wound. Coagulation and fibrinolysis was activated during and after surgery. The activation was significantly higher in blood from the wounds than in peripheral venous blood. We found no direct correlation between the degree of fibrinolysis and blood loss. The administration of tranexamic acid reduced fibrinolysis in the wounds but not in peripheral venous blood. The postoperative blood loss was reduced by half.

Improved cost-effectiveness by pharmacokinetic dosing of factor VIII in prophylactic treatment of haemophilia A

The aim of the study was to investigate the feasibility of optimizing prophylactic dosing of factor VIII by the use of individual pharmacokinetic data. Twenty‐one patients were enrolled in a randomized cross‐over study on standard dosage regimens vs. dosing according to pharmacokinetic principles. The study period was 2×6 months. Using single‐dose pharmacokinetic data for each patient, plasma factor VIII procoagulant activity (FVIII:C) curves following various doses and intervals were computer‐simulated. From these calculations, a suitable dosage was chosen. FVIII:C was also repeatedly measured during study periods. Trough levels of FVIII:C, numbers of spontaneous joint bleedings and amounts of factor concentrate used during the two study periods were compared for each patient.