Unravelling the Spectrum of von Willebrand Factor Variants in Quantitative Von Willebrand Disease: Results from a German Cohort Study.

INTRODUCTION: Von Willebrand disease (VWD), the most prevalent hereditary bleeding disorder, results from deficiency of von Willebrand factor (VWF). OBJECTIVES: This large cohort study aims to offer a comprehensive exploration of mutation spectra and laboratory features in quantitative VWF deficiencies, shedding light on genetic underpinnings and genotype-phenotype associations. PATIENTS/METHODS: Our cohort consisted of 221 Caucasian index patients with quantitative VWD, along with 47 individuals whose plasma VWF levels fell within the lower normal boundaries (50-70%). We conducted comprehensive VWF assays and genetic analyses, encompassing VWF gene sequencing, copy number variation investigations, and bioinformatic assessments. RESULTS: Following ISTH-SSC VWF guidelines, 77 index patients characterized as type 1 VWD (VWF:Ag < 30%), 111 as type 1 VWD (VWF:Ag 30-50%), and as 33 type 3 VWD. Mutation detection rates were 88%, 65%, and 92%, respectively. Notably, blood group O overrepresentation was evident in type 1 with VWF:Ag of 30-50%, particularly among mutation-negative patients, suggesting a potential causal role of blood group O. A total of 223 VWF variants, comprising 147 distinct variations, were identified in quantitative VWD patients, of which 57 were novel variants (39%). Additionally, approximately 70% of individuals with VWF levels within the lower normal boundaries (50-70%) displayed VWF variants. CONCLUSION: Our data advances our understanding of the molecular mechanisms underlying quantitative VWD, offering valuable insights for future research and clinical management. Distinct mutation patterns were observed among subgroups, particularly the contrast between type 1 VWD (VWF:Ag <30%) and type 1 (VWF:Ag 30-50%), an area with limited prior investigation.

Vascular type Ehlers-Danlos syndrome is associated with platelet dysfunction and low vitamin D serum concentration.

BACKGROUND: The vascular type represents a very rare, yet the clinically most fatal entity of Ehlers-Danlos syndrome (EDS). Patients are often admitted due to arterial bleedings and the friable tissue and the altered coagulation contribute to the challenge in treatment strategies. Until now there is little information about clotting characteristics that might influence hemostasis decisively and eventually worsen emergency situations. RESULTS: 22 vascular type EDS patients were studied for hemoglobin, platelet volume and count, Quick and activated partial thromboplastin time, fibrinogen, factor XIII, von Willebrand disease, vitamin D and platelet aggregation by modern standard laboratory methods. Results show a high prevalence of over 50 % for platelet aggregation disorders in vascular type EDS patients, especially for collagen and epinephrine induced tests, whereas the plasmatic cascade did not show any alterations. Additionally, more than half of the tested subjects showed low vitamin D serum levels, which might additionally affect vascular wall integrity. CONCLUSION: The presented data underline the importance of detailed laboratory screening methods in vascular type EDS patients in order to allow for targeted application of platelet-interacting substances that might be of decisive benefit in the emergency setting.

Prothrombotic disorders in uremic type-1 diabetics undergoing simultaneous pancreas and kidney transplantation.

BACKGROUND: Although prothrombotic disorders (PTD) are known to increase the risk of graft failure in kidney transplantation only, there are no data on PTD in simultaneous pancreas and kidney transplantation (SPK). METHODS: Forty-seven SPK performed between September 2000 and July 2002 underwent routine screening for PTD. Data were retrospectively analyzed in view of complications (relaparotomy, graft thrombosis, pancreatitis, rejection) and graft function (HbA1c, serum creatinine) 3 months posttransplantation. RESULTS: Twenty-five of forty-seven (53.2%) patients had 30 PTDs. Homozygous mutations of the MTHFR gene (C677T) were found in six, factor-V Leiden mutation (homo- or heterozygous G1691A) in seven, and prothrombin mutation (20210A) in one patient (group 1). Group 2 consists of deficiencies of protein C (n=1), of protein S (n=12), of antithrombin (n=1), and antiphospholipid syndromes (n=2). Overall, PTD had no influence on graft thrombosis (P=0.36) or rejection (P=0.56). In patients with homozygous mutations, relaparotomies were more often necessary than in patients without mutations (42.9% vs. 11.8%, P=0.046). In group 1, there was a trend toward a higher incidence of graft pancreatitis than in patients without mutations (38.5% vs. 14.7%, P=0.075). Three months posttransplantation, HbA1c was 6.0% in patients with and 5.5% in patients without PTD (P=0.023). With regard to serum creatinine, no significant differences were observed. CONCLUSION: PTD are frequent in type-1 diabetics receiving SPK and may have a role in relaparotomies, graft pancreatitis, and pancreas graft function.

Use of recombinant factor VIIa, Novo Seven, in the management of acute haemorrhage.

PURPOSE OF REVIEW: The purpose of this paper is to propose the use of factor VIIa in treating severely bleeding patients. RECENT FINDINGS: Recombinant factor VIIa was developed in 1988 to treat patients with haemophilia A or B and antibodies against factors VIII and IX, or patients with a spontaneous inhibitor against factors VIII and IX. Since then factor VIIa has been shown to be very effective in treating many other bleeding disorders, such as diverse thrombocytopathias, antibodies against other coagulation proteins like factor V, and bleeding as a result of oral anticoagulation. SUMMARY: Recombinant factor VIIa may be the universal haemostatic agent, but further studies are needed to prove this.