The von Willebrand Factor A-1 domain binding aptamer BT200 elevates plasma levels of VWF and Factor VIII: a first-in-human trial
Haematologica. 2021 Nov 25. doi: 10.3324/haematol.2021.279948. Online ahead of print.ABSTRACTVon Willebrand Factor (VWF) and Factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary haemostasis and clotting respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomised, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favourable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: Single ascending dose of BT200 (0.18-48mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterised, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin induced aggregation, platelet function under high shear rates, and thrombin generation. Mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dosedependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagenadenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (p.PMID:34818873 | DOI:10.3324/haematol.2021.279948
In this study we investigated and characterized the molecular and pathogenic mechanisms through which a novel cysteine variant p.(Cys1084Tyr) causes an unusual, mixed phenotype form of von Willebrand disease (VWD). Phenotypic data including bleeding scores, laboratory values, VWF multimer distribution and desmopressin response kinetics were investigated in 5 members (2 parents and 3 daughters) of a consanguineous family. VWF synthesis and secretion were also assessed in a heterologous expression system and in a transient transgenic mouse model. Heterozygosity for p.(Cys1084Tyr) was associated with variable expressivity of ...
CONCLUSIONS: Release of VWF from endothelial cells opens the platelet-binding site, irrespective of the presence of flow. However, not all available platelet-binding sites are being occupied, suggesting some extent of regulation. Part of this regulation involves endothelial proteins that are co-secreted with VWF, like osteoprotegerin. This regulatory mechanism may be of more relevance under inflammatory conditions.PMID:34816579 | DOI:10.1111/jth.15598
Hematol Oncol Clin North Am. 2021 Aug 13:S0889-8588(21)00083-6. doi: 10.1016/j.hoc.2021.07.004. Online ahead of print.ABSTRACTVon Willebrand disease (VWD) is a common bleeding disorder, affecting male and female individuals equally, that often manifests in mucosal bleeding. VWD can be secondary to a quantitative (Type 1 and Type 3) or qualitative (Type 2) defects in Von Willebrand factor (VWF). Initial testing includes VWF antigen, as well as a platelet binding assay to differentiate between qualitative and quantitative defects. Further subtyping requires additional testing and is needed to ensure appropriate treatment. De...
Von Willebrand disease (VWD) is a common bleeding disorder, affecting male and female individuals equally, that often manifests in mucosal bleeding. VWD can be secondary to a quantitative (Type 1 and Type 3) or qualitative (Type 2) defects in Von Willebrand factor (VWF). Initial testing includes VWF antigen, as well as a platelet binding assay to differentiate between qualitative and quantitative defects. Further subtyping requires additional testing and is needed to ensure appropriate treatment. Desmopressin, antifibrinolytics, hormonal treatments for heavy menstrual bleeding, and VWF concentrates are commonly used in the treatment of VWD.
In patients presenting with a suspect hereditary bleeding disorder a detailed bleeding history is first obtained. Testing proceeds in a tiered manner with platelet count, platelet morphology, platelet histogram, PFA-100, fibrinogen, prothrombin time, and activated partial thromboplastin time. More detailed testing includes von Willebrand factor, individual clotting factor assays, and platelet function testing. Next, testing for a dysfibrinogenemia, FXIII, or a fibrinolytic defect is considered. Hemostatic abnormality is not demonstrated in a fraction of patients. An approach to management in these patients, such as desmopr...
ConclusionsThe use of desmopressin in intracranial hemorrhage does not appear to negatively impact the ability for patients to reach goal sodium of 145 –155 mEq/L. However, in patients with higher sodium goals, desmopressin may decrease hypertonic saline effectiveness.
CONCLUSIONS: In this large case series, the majority of vWD patients received neuraxial anesthesia for labor and delivery, with no noted adverse events. This suggests that neuraxial anesthesia can be safely performed with the peripartum management that we describe. Pretreatment was dictated by the type and severity of vWD. Multidisciplinary planning is important to optimize the coagulation status of patients with vWD and facilitate options for analgesia and anesthesia.PMID:33913917 | DOI:10.1213/ANE.0000000000005502
(IBDs) encompass a large number of different but rare conditions that can lead to increased risk of bleeding. The most common IBDs are von Willebrand disease, haemophilia A and haemophilia B. The diagnosis of IBDs requires a detailed history of the bleeding and specialized coagulation testing. The management of bleeding episodes in patients with IBDs can include the use of coagulation factor concentrate, desmopressin and antifibrinolytics such as tranexamic acid. This brief review focuses on the more common IBDs.
Conclusions: The LC-MS/MS method presented enables quantification of desmopressin in human plasma, and it is sensitive, specific, efficient, accurate, and precise. This analytical technique is a valuable and useful tool to study the interpatient variability of pharmacokinetics.
CONCLUSIONS: Both the prospective and retrospective cohorts demonstrated consistent variation in subjects whose diagnosis changed between 2A, 2B, and 2M. The importance of accurately diagnosing type 2 VWD may be most significant in the 2B subtype given potential concerns with the use of desmopressin in type 2B VWD. Some genetic variants appear in multiple types of VWD, making specific diagnoses challenging. PMID: 33049112 [PubMed - as supplied by publisher]