How I manage pregnancy in carriers of hemophilia and patients with von Willebrand disease

Abstract Women with inherited bleeding disorders, including carriers of hemophilia A and B, or with von Willebrand disease, have an increased risk of bleeding during pregnancy and delivery. The unborn child may also be affected by the bleeding disorder for which specific measures have to be considered. This requires a multidisciplinary approach, with a team that includes a hematologist, a pediatric hematologist, a clinical geneticist, an obstetrician-perinatologist, and an anesthesiologist. An optimal approach includes prepregnancy genetic counseling, prenatal diagnostic procedures, and a treatment plan for delivery for both the mother and child. Recent retrospective studies show that even if strict guidelines are followed, these women are still at risk of postpartum bleeding. This occurs even if coagulation factor levels are normalized, either due to the pregnancy-induced rise of factor levels or by infusion of coagulation factor concentrates at the time of delivery. In this article, we describe our current diagnostic and clinical management of pregnancy and delivery in women with inherited bleeding disorders. We also briefly discuss possible interventions to improve the outcome of current strategies by increasing target factor levels during and after delivery.

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Novel therapeutics for hemophilia and other bleeding disorders

Blood ◽

10.1182/blood-2017-09-743385 ◽

2018 ◽

Vol 132 (1) ◽

pp. 23-30 ◽

Cited By ~ 26

Author(s):

Michael U. Callaghan ◽

Robert Sidonio ◽

Steven W. Pipe

Keyword(s):

Factor Viii ◽

New Technologies ◽

Hemophilia A ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Bleeding Disorders ◽

Routes Of Administration ◽

New Approaches ◽

Dosing Regimens ◽

Von Willebrand

Abstract Hemophilia and von Willebrand disease are the most common congenital bleeding disorders. Treatment of these disorders has focused on replacement of the missing coagulation factor to prevent or treat bleeding. New technologies and insights into hemostasis have driven the development of many promising new therapies for hemophilia and von Willebrand disease. Emerging bypass agents including zymogen-like factor IXa and Xa molecules are in development and a bispecific antibody, emicizumab, demonstrated efficacy in a phase 3 trial in people with hemophilia A and inhibitors. Tissue factor pathway inhibitor, the protein C/S system, and antithrombin are targets of novel compounds in development to alter the hemostatic balance and new approaches using modified factor VIII molecules are being tested for prevention and eradication of inhibitor antibodies in hemophilia A. The first recombinant von Willebrand factor (VWF) product has been approved and has unique VWF multimer content and does not contain factor VIII. These new approaches may offer better routes of administration, improved dosing regimens, and better efficacy for prevention and treatment of bleeding in congenital bleeding disorders.

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Risk and Management of Intracerebral Hemorrhage in Patients with Bleeding Disorders

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0041-1740566 ◽

2022 ◽

Author(s):

Akbar Dorgalaleh ◽

Yadolah Farshi ◽

Kamand Haeri ◽

Omid Baradarian Ghanbari ◽

Abbas Ahmadi

Keyword(s):

Risk Factors ◽

Intracerebral Hemorrhage ◽

Platelet Function ◽

Hemophilia A ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Vacuum Extraction ◽

Bleeding Disorders ◽

Platelet Function Disorders ◽

Von Willebrand

AbstractIntracerebral hemorrhage (ICH) is the most dreaded complication, and the main cause of death, in patients with congenital bleeding disorders. ICH can occur in all congenital bleeding disorders, ranging from mild, like some platelet function disorders, to severe disorders such as hemophilia A, which can cause catastrophic hemorrhage. While extremely rare in mild bleeding disorders, ICH is common in severe coagulation factor (F) XIII deficiency. ICH can be spontaneous or trauma-related. Spontaneous ICH occurs more often in adults, while trauma-related ICH is more prevalent in children. Risk factors that can affect the occurrence of ICH include the type of bleeding disorder and its severity, genotype and genetic polymorphisms, type of delivery, and sports and other activities. Patients with hemophilia A; afibrinogenemia; FXIII, FX, and FVII deficiencies; and type 3 von Willebrand disease are more susceptible than those with mild platelet function disorders, FV, FXI, combined FV–FVIII deficiencies, and type 1 von Willebrand disease. Generally, the more severe the disorder, the more likely the occurrence of ICH. Contact sports and activities can provoke ICH, while safe and noncontact sports present more benefit than danger. An important risk factor is stressful delivery, whether it is prolonged or by vacuum extraction. These should be avoided in patients with congenital bleeding disorders. Familiarity with all risk factors of ICH can help prevent occurrence of this diathesis and reduce related morbidity and mortality.

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Inherited Bleeding Disorders in Iraq and Consanguineous Marriage

International Journal of Hematology-Oncology and Stem Cell Research ◽

10.18502/ijhoscr.v12i4.105 ◽

2018 ◽

Author(s):

Nidal Karim Al-Rahal

Keyword(s):

Family History ◽

Autosomal Recessive ◽

Consanguineous Marriage ◽

Von Willebrand Disease ◽

Clotting Factor ◽

Bleeding Disorders ◽

Clotting Factors ◽

Female Ratio ◽

Increased Risk ◽

Von Willebrand

Background: Consanguineous marriage is defined as inbreeding between second cousins or closer. In such families there will be a potential increase in the autosomal recessive traits with its lethal effect, with an increased risk of morbidity and mortality in the new generation. Inherited bleeding disorders (InBDs) are rare complicated diseases, difficult and expensive to treat, the defect usually due to quantitative or qualitative deficiency of clotting factors, platelets or fibrinolysis. This study attempts to assess the diversity, the frequency and the clinical features of inherited bleeding disorders (InBDs) in central part of Iraq and to determine the state of consanguineous marriage. Materials and Methods: This is a prospective cross-sectional study conducted in the National Center of Hematology NCH, Baghdad, Iraq between June2014 and June 2017. In total, 256 pediatrics and adult patients were included. Full bleeding history, family history, drug history and consanguineous marriage were recorded and followed by medical examination. First-line laboratory tests were performed and then were followed by further tests included mixing study, lupus anticoagulant testing, clotting factor activity assay, von Willebrand Antigen (VW: Ag), Ristocetin co factor vWF: RiCoF activity and platelet function test. Results: The range of age was from 1 month to 57 years, with mean age 8.424±8.623 years and median age of 6.5years. The male to female ratio was 1.1:1. The most common age group was in the range of 1-10 years (46.45%). Family history was positive in 55.07% of patients (P >0.05). The consanguinity was found in 76.95% of the families studied (P <0.0001). The most prevalent InBD was von Willebrand disease (42.98%) with majority type 3VWD (86.4%). The second most prevalent was thrombasthenia (36.71%) and the majority had Glanzmann’s thrombosthenia (86.2%). Rare bleeding disorders (RBDs) were observed in 6.25% of patients and the most common factor deficiency was FVII. Conclusion: Consanguinity is high in patients with inherited bleeding disorders in Iraq, leading to emergence of life-threatening autosomal recessive inherited diseases. Genetic counselling is recommended besides education and awareness to minimize such rare illnesses in the community.

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Cryptogenic oozers and bruisers

Hematology ◽

10.1182/hematology.2021000236 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 85-91

Author(s):

Kristi J. Smock ◽

Karen A. Moser

Keyword(s):

Platelet Function ◽

Coagulation Factor ◽

Fibrin Clot ◽

Von Willebrand Disease ◽

Bleeding Disorders ◽

Diagnostic Challenge ◽

Primary Hemostasis ◽

Platelet Function Disorders ◽

Number Of Patients ◽

Von Willebrand

Abstract Bleeding disorders with normal, borderline, or nondiagnostic coagulation tests represent a diagnostic challenge. Disorders of primary hemostasis can be further evaluated by additional platelet function testing modalities, platelet electron microscopy, repeat von Willebrand disease testing, and specialized von Willebrand factor testing beyond the usual initial panel. Secondary hemostasis is further evaluated by coagulation factor assays, and factor XIII assays are used to diagnose disorders of fibrin clot stabilization. Fibrinolytic disorders are particularly difficult to diagnose with current testing options. A significant number of patients remain unclassified after thorough testing; most unclassified patients have a clinically mild bleeding phenotype, and many may have undiagnosed platelet function disorders. High-throughput genetic testing using large gene panels for bleeding disorders may allow diagnosis of a larger number of these patients in the future, but more study is needed. A logical laboratory workup in the context of the clinical setting and with a high level of expertise regarding test interpretation and limitations facilitates a diagnosis for as many patients as possible.

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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.

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Resolving Differential Diagnostic Problems in von Willebrand Disease, in Fibrinogen Disorders, in Prekallikrein Deficiency and in Hereditary Hemorrhagic Telangiectasia by Next-Generation Sequencing

Life ◽

10.3390/life11030202 ◽

2021 ◽

Vol 11 (3) ◽

pp. 202

Author(s):

Réka Gindele ◽

Adrienne Kerényi ◽

Judit Kállai ◽

György Pfliegler ◽

Ágota Schlammadinger ◽

...

Keyword(s):

Next Generation Sequencing ◽

Hereditary Hemorrhagic Telangiectasia ◽

Von Willebrand Disease ◽

Differential Diagnostics ◽

Bleeding Disorders ◽

Next Generation ◽

Illumina Platform ◽

Clinical Patient ◽

Von Willebrand ◽

Generation Sequencing

Diagnosis of rare bleeding disorders is challenging and there are several differential diagnostics issues. Next-generation sequencing (NGS) is a useful tool to overcome these problems. The aim of this study was to demonstrate the usefulness of molecular genetic investigations by summarizing the diagnostic work on cases with certain bleeding disorders. Here we report only those, in whom NGS was indicated due to uncertainty of diagnosis or if genetic confirmation of initial diagnosis was required. Based on clinical and/or laboratory suspicion of von Willebrand disease (vWD, n = 63), hypo-or dysfibrinogenemia (n = 27), hereditary hemorrhagic telangiectasia (HHT, n = 10) and unexplained activated partial thromboplastin time (APTT) prolongation (n = 1), NGS using Illumina platform was performed. Gene panel covered 14 genes (ACVRL1, ENG, MADH4, GDF2, RASA1, F5, F8, FGA, FGB, FGG, KLKB1, ADAMTS13, GP1BA and VWF) selected on the basis of laboratory results. We identified forty-seven mutations, n = 29 (6 novel) in vWD, n = 4 mutations leading to hemophilia A, n = 10 (2 novel) in fibrinogen disorders, n = 2 novel mutations in HHT phenotype and two mutations (1 novel) leading to prekallikrein deficiency. By reporting well-characterized cases using standardized, advanced laboratory methods we add new pieces of data to the continuously developing “bleeding disorders databases”, which are excellent supports for clinical patient management.

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Coagulopathies

10.2310/em.4124 ◽

2020 ◽

Author(s):

Michael Levine

Keyword(s):

Key Words ◽

Bleeding Disorder ◽

Von Willebrand Disease ◽

Coagulation Cascade ◽

Bleeding Disorders ◽

Platelet Disorders ◽

Von Willebrand

Coagulopathy can be caused by numerous hereditary or acquired etiologies. Although some of these conditions are known and the patient is aware of the bleeding disorder, other bleeding disorders are diagnosed only after the onset of excessive hemorrhage. This review discusses both hereditary and acquired disorders of coagulopathy. Platelet disorders are discussed elsewhere. This review contains 2 figures, 7 tables, and 72 references. Key words: Coagulopathies; Coagulopathy; Bleeding disorder; Hereditary bleeding disorder; Acquired bleeding disorder; von Willebrand disease; Hemophilia; Coagulation cascade; Hemorrhage; Anticoagulant-associated hemorrhage

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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.

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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.

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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.

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