Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies

Abstract von Willebrand factor (VWF) is a large multimeric glycoprotein secreted from platelet α-granules and Weibel-Palade bodies of endothelial cells. VWF mediates the initial adhesion of platelets at sites of vascular injury and binds to and stabilizes blood coagulation factor VIII in the circulation to protect it from inactivation and clearance. von Willebrand disease (VWD) is the most common hereditary bleeding disorder and results from the deficiency or dysfunction of VWF leading to mucocutaneous bleeding, including epistaxis, menorrhagia, and excessive bleeding after trauma or surgery. Bleeding in patients with VWD is treated with infusion of plasma-derived VWF containing FVIII concentrates or 1-desamino-8-D-arginine vasopressin (DDAVP, desmopression). DDAVP is an analog of vasopressin antidiuretic hormone which can stimulate the exocytosis of VWF from storage sites and increase VWF and FVIII levels. DDAVP can be administrated by intravenous and intranasal routes. There are several reports of the safety and efficacy of intravenous DDAVP, but few with concentrated intranasal DDAVP (Stimate®). Here we report on the efficacy and safety of Stimate® in patients with VWD Methods Hospital records for 72 patients with VWD who received Stimate® from 1998 to 2012 were reviewed. The primary endpoint was the patients’ biological response to Stimate®, defined as at least a 3 fold increase compared to baseline of both ristocetin cofactor activity (VWF:RCo), factor VIII procoagulant activity (FVIII:C), or both VWF:RCo and FVIII:C are over 100% after Stimate®. Individuals not meeting the response criteria were deemed to be nonresponse. The adverse events were analyzed between different VWD types, response, age, gender, and race. Result Of those 72 VWD patients, 45 have type 1 (62%), 7 have type 2 (10%), and in 20 cases the subtype was unclear (28%). Responsive to Stimate® was observed in 43 (95.6%) of type 1, 4 (57.1%) of type 2, and 19 (95%) in which the diagnosis was unclear. In total, 16 patients (22.2%) had adverse events: 1 – allegoric response, 8 - mild headache, 4 - mild hyponatremia, and 4 - blood pressure (BP) reduced more than 20 mmHg. Conclusion Patients with VWD 1 have higher response rates to Stimate® than patients with VWD 2 in our test. The Stimate® is effective and safe for treatment of VWD. Disclosures: Valentino: Baxter, Bayer, Biogen Idec, GTC Biotherapeutics, Inspiration Biopharmaceuticals, Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees.

Download Full-text

Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand’s disease: a systematic review of prospective studies

Haemophilia ◽

10.1111/j.1365-2516.2011.02745.x ◽

2012 ◽

Vol 18 (3) ◽

pp. e164-e172 ◽

Cited By ~ 15

Author(s):

M. FRANCHINI ◽

M. MAKRIS ◽

E. SANTAGOSTINO ◽

A. COPPOLA ◽

P. M. MANNUCCI

Keyword(s):

Systematic Review ◽

Prospective Studies ◽

Adverse Reactions ◽

Coagulation Factor ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Coagulation Factor Concentrates

Download Full-text

Von Willebrand disease and Weibel-Palade bodies

Hämostaseologie ◽

10.1055/s-0037-1619048 ◽

2010 ◽

Vol 30 (03) ◽

pp. 150-155 ◽

Cited By ~ 9

Author(s):

J. W. Wang ◽

J. Eikenboom

Keyword(s):

Platelet Adhesion ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Inflammatory Factors ◽

Limited Data ◽

Storage Organelle ◽

And Function ◽

Von Willebrand ◽

Willebrand Factor

SummaryVon Willebrand factor (VWF) is a pivotal haemostatic protein mediating platelet adhesion to injured endothelium and carrying coagulation factor VIII (FVIII) in the circulation to protect it from premature clearance. Apart from the roles in haemostasis, VWF drives the formation of the endothelial cell specific Weibel-Palade bodies (WPBs), which serve as a regulated storage of VWF and other thrombotic and inflammatory factors. Defects in VWF could lead to the bleeding disorder von Willebrand disease (VWD).Extensive studies have shown that several mutations identified in VWD patients cause an intracellular retention of VWF. However, the effects of such mutations on the formation and function of its storage organelle are largely unknown. This review gives an overview on the role of VWF in WPB biogenesis and summarizes the limited data on the WPBs formed by VWD-causing mutant VWF.

Download Full-text

A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease

Thrombosis and Haemostasis ◽

10.1160/th10-01-0027 ◽

2010 ◽

Vol 104 (09) ◽

pp. 563-570 ◽

Cited By ~ 44

Author(s):

Petra Paulinska ◽

Petra Jilma-Stohlawetz ◽

James Gilbert ◽

Renta Hutabarat ◽

Paul Knöbl ◽

...

Keyword(s):

Pilot Trial ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Double Blind ◽

Clinical Trial Registration ◽

Maximal Increase ◽

Double Blind Design ◽

Von Willebrand

SummaryDesmopressin aggravates thrombocytopenia in type 2B von Willebrand disease (VWF type 2B) by release of large and hyper-adhesive von Wille-brand Factor (VWF) multimers. This pilot study investigated whether the anti-VWF aptamer ARC1779 can prevent desmopressin-induced thrombocytopenia and interferes with the excessive VWF turnover in patients with VWF type 2B. Concentration effect curves of ARC1779 were established for five patients in vitro and two patients with VWF type 2B were treated by infusion of ARC1779, desmopressin, or their combination in a randomised, controlled, double-blind design. ARC1779 concentrations in the range of 1–3 μg/ml blocked free A1 domain binding sites by 90% in vitro. In vivo, desmopressin alone induced a profound (-90%) drop in platelet counts in one of the patients. ARC1779 (4–5 μg/ml) completely inhibited VWF A1 domains and prevented this desmopress-in-induced platelet drop. Desmopressin alone increased VWF antigen two- to three-fold, accompanied by concordant changes in VWF Ristocetin cofactor activity (RCo) and coagulation factor VIII activity. ARC1779 substantially enhanced the desmopressin-induced maximal increase in these parameters, and improved multimer patterns. No treatment related adverse events were observed and no bleeding occurred despite marked thrombocytopenia. These data provide first proof of concept in humans and evidence that ARC1779 is a potent inhibitor of VWF. ARC1779 prevented the rapid consumption of VWF multimers together with agglutinated platelets that occurred in response to desmopressin challenge in patients with VWD type 2B.Clinical Trial registration number: NCT00632242.

Download Full-text

Clinical cases of using coagulation factor VIII with von Willebrand factor in parturient women with type III von Willebrand disease

Тромбоз, гемостаз и реология ◽

10.25555/thr.2020.3.0938 ◽

2020 ◽

Author(s):

И.В. Куртов ◽

Е.С. Фатенкова ◽

Н.А. Юдина ◽

А.М. Осадчук ◽

И.Л. Давыдкин

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Coagulation Factor Viii ◽

Vitro Fertilization ◽

Type 3 ◽

Von Willebrand ◽

Willebrand Factor

Болезнь Виллебранда (БВ) может представлять определенные трудности у рожениц с данной патологией. Приведены 2 клинических примера использования у женщин с БВ фактора VIII свертывания крови с фактором Виллебранда, показана эффективность и безопасность их применения. У одной пациентки было также показано использование фактора свертывания крови VIII с фактором Виллебранда во время экстракорпорального оплодотворения. Von Willebrand disease presents a certain hemostatic problem among parturients. This article shows the effectiveness and safety of using coagulation factor VIII with von Willebrand factor for the prevention of bleeding in childbirth in 2 patients with type 3 von Willebrand disease. In one patient, the use of coagulation factor VIII with von Willebrand factor during in vitro fertilization was also shown.

Download Full-text

Regulation der primären Hämostase durch von-Willebrand-Faktor und ADAMTS13

Hämostaseologie ◽

10.5482/ha-1167 ◽

2011 ◽

Vol 31 (04) ◽

pp. 275-280 ◽

Cited By ~ 3

Author(s):

U. Budde ◽

R. Schneppenheim

Keyword(s):

Platelet Adhesion ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Coagulation Cascade ◽

Platelet Glycoprotein ◽

Platelet Adhesion And Aggregation ◽

Hydrodynamic Shear ◽

Specific Protease ◽

Multiple Domains ◽

Von Willebrand

SummaryVon Willebrand factor (VWF) is an adhesive, multi-functional huge multimerized protein with multiple domains harboring binding sites for collagen, platelet glycoprotein receptors and coagulation factor VIII (FVIII). The functional domains enable VWF to bind to the injured vessel wall, to recruit platelets to the site of injury by adhesion and aggregation and to bind and protect FVIII, an important cofactor of the coagulation cascade. VWF function in primary haemostasis is located in particular in the arterial and micro-circulation. This environment is exposed to high shear forces with hydrodynamic shear rates ranging over several orders of magnitude from 10–1 to 105 s-1 and requires particular mechanisms to enable platelet adhesion and aggregation under these variable conditions. The respective VWF function is strictly correlating with its multimer size. Lack or reduction of large VWF multimers is seen in patients with von Willebrand disease (VWD) type 2A which correlates with reduction of both VWF:platelet GPIb-binding and VWF:collagen binding and a bleeding phenotype. To prevent unlimited platelet adhesion and aggregation which is the cause of the microangiopathic disorder thrombotic thrombocytopenic purpura (TTP), VWF function is regulated by its specific protease ADAMTS13. Whereas a particular susceptibility of VWF to ADAMTS13 proteolysis is the cause of a frequent VWD type 2A phenotype, lack or dysfunction of ADAMTS13, either acquired by ADAMTS13 antibodies or by inherited ADAMTS13 deficiency (Upshaw-Schulman Syndrome), causes TTP. Therefore VWD and TTP represent the opposite manifestations of VWF related disorders, tightly linked to each other.

Download Full-text

Testing for von Willebrand Disease in Women With Menorrhagia: A Systematic Review

Obstetrics and Gynecology ◽

10.1097/01.aog.0000133487.55682.7b ◽

2004 ◽

Vol 104 (2) ◽

pp. 381-388 ◽

Cited By ~ 36

Author(s):

Andra James ◽

David B. Matchar ◽

Evan R. Myers

Keyword(s):

Systematic Review ◽

Von Willebrand Disease ◽

Von Willebrand

Download Full-text

Hemophilia in the Peruvian Social Security System: Report of Five Centers.

Blood ◽

10.1182/blood.v114.22.4446.4446 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4446-4446

Author(s):

Gloria Chumpitaz ◽

Fernando Cauvi ◽

Juan Ramon Navarro ◽

Karina Pedraza

Keyword(s):

Conflicts Of Interest ◽

Age Groups ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Severe Illness ◽

Factor Deficiency ◽

Coagulation Factor Deficiency ◽

Receive Treatment ◽

New Diagnosis ◽

Von Willebrand

Abstract Abstract 4446 The Hemophilia Unit of the Hematology Department of the National Hospital Edgardo Rebagliatti Martins- ESSALUD, is one of the most important Hemophilia Centers through the country, that assists patients not only in its jurisdiction but also a great amount referred from other institutions due the complexity of their treatment, like acquired inhibitor disorders as well as orthopedic and mayor cardiovascular surgeries and severe hemorrhages. The Hemophilia ESSALUD system is compounded of centers in Lima (02), Callao (01) and provinces (05) (Arequipa, Chiclayo, Trujillo, Piura and Cuzco). The range of patients with new diagnosis is about 5 to 20 patients per year. The prevalence of Hemophilia in the last 5 years, accounts 83.38% patients of the global amount with coagulation disorders. Of the 331 patients in treatment, 228 (68.8%) have Hemophilia A. Considering the classification of status severity, 12.5% patients of this group belong to mild status hemophilia, 39.47% patients to moderate status, and 41.43% to severe status. In relation to Hemophilia B, we account 48 (14.5%) patients; 5.2% corresponds to mild status, 23.68% moderate status and 52.63% severe status. The rest of the patients have other disorders of coagulation such as Von Willebrand disease and rare coagulation factor deficiency (V, VII, XI and XII). According to the age group distribution for this series, a mayor proportion of 44.68%of patients belong to the group between 16 to 35 years old. The group above 35 years accounts 30%.The age groups of 6 to 15 years old and the group of 1 to 5 year old account 16.48% and 8.51%, respectively. Finally, it is important to point out that 37.76% of our hemophiliac patients are in the group of moderate illness status and 44.14% in the group of severe illness status. All the patients receive treatment with plasma-derived coagulation factor concentrates and in some cases recombinant therapy. Children receive prophylactic treatment. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

Blood ◽

10.1182/blood-2014-06-528406 ◽

2015 ◽

Vol 125 (13) ◽

pp. 2019-2028 ◽

Cited By ~ 127

Author(s):

Peter J. Lenting ◽

Olivier D. Christophe ◽

Cécile V. Denis

Keyword(s):

Life Cycle ◽

Factor Viii ◽

Von Willebrand Factor ◽

Current Knowledge ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Proinflammatory Response ◽

Wide Range ◽

Von Willebrand ◽

Willebrand Factor

Abstract To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance. von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra- and extracellular) that implicate a wide range of other proteins: its presence is required for the formation and regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), whereas VWF is also a key determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life cycle will help us gain insight into the pathogenesis of von Willebrand disease, design alternative treatment options to prolong the factor VIII half-life, and delineate the role of VWF and coresidents of the WPBs in the prothrombotic and proinflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion, and clearance is provided and we will discuss how they can be affected by the presence of protein defects.

Download Full-text