Christine A. Lee

Joint protection in haemophilia

Summary.  Haemarthroses (intra‐articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on‐demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by‐passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non‐inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor.

Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity

F . PEYVANDI ,* D . D I MICHELE , P . H . B . BO L TO N -MA GG S , C. A . LEE ,§ A . TR IPODI– and A . SR IVASTAVA** FOR THE PROJECT ON CONSENSUS D EF IN IT IONS IN RARE BLEEED ING DISORDER S O F THE FACTOR VI I I / F A C T OR I X S C IEN T I F IC A ND S T A N DA R D IS A T IO N C OM M IT T E E OF TH E I NT ERNA T I ON AL SO CIETY O N THROMBOS IS AND HAEMOSTAS I S *U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano and Luigi Villa Foundation, Milan, Italy; Department of Pediatrics, Weill Medical College of Cornell University, New York, NY, USA; Department of Clinical Haematology, University of Manchester and Manchester Royal Infirmary, Manchester, UK; §Emeritus Professor of Haemophilia, University of London, London, UK; –U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Department of Internal Medicine and Medical Specialties, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; **Department of Haematology, Christian Medical College, Vellore, India

First 20 years with recombinant FVIIa (NovoSeven).

Summary.  This review describes the background for the development of recombinant FVIIa (rFVIIa; NovoSeven) for use in haemophilic patients with inhibitors. The first proof of principle for using pharmacological doses of FVIIa as a haemostatic agent was obtained by producing small amounts of pure plasma‐derived FVIIa, which showed encouraging effect in two patients with haemophilia A and inhibitors. To make pure FVIIa available for use in a larger number of patients, rFVIIa was produced that was approved for use in patients with inhibitors against coagulation factors (congenital haemophilia and acquired haemophilia) in 1996 (EU), 1999 (USA) and 2000 (Japan). The efficacy rate in severe bleedings and in major surgery including major orthopaedic surgery has been found to be around 90% in controlled studies, and no serious safety concerns have been demonstrated. The availability of rFVIIa has facilitated the performance of elective major surgery in haemophilia patients with inhibitors. Further steps along the vision of providing a treatment for inhibitor patients similar to non‐inhibitor patients have been the efficacy of rFVIIa in home‐treatment and recently the encouraging experience in prophylaxis. The concept of using pharmacological doses of rFVIIa as a haemostatic agent is a new one, which has caused difficulties in finding the correct dose. A step forward has been the demonstration that similar efficacy can be achieved after one single dose of 270 μg kg−1 instead of three injections of a dose of 90 μg kg−1. The higher clearance rate in children suggests that higher doses may be beneficial in children. The availability of rFVIIa has made advances in the understanding of coagulation processes possible. In a cell‐based in vitro model, it has been shown that rFVIIa binds to preactivated platelets if present in concentrations of 30 nm or higher. By doing so, it activates FX into FXa and enhances the thrombin generation on the activated platelet surface in the absence of FVIII/FIX. Through the increased thrombin generation, a firm, well‐structured fibrin haemostatic plug, which is resistant to premature lysis, is formed. By exploiting this mechanism of action, rFVIIa may also be effective in situations other than haemophilia, characterized by an impaired thrombin generation.

Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an international expert panel

Acute menorrhagia is a common gynecological disorder. Prevalence is high among women with inherited bleeding disorders and recent guidance for optimal management is lacking. Following a comprehensive review of the literature, an international expert panel in obstetrics, gynecology and hematology reached consensus on recommendations regarding the management of acute menorrhagia in women without a diagnosed bleeding disorder, as well as in patients with von Willebrand disease, platelet function disorders and other rare hemostatic disorders. The causes and predictors of acute menorrhagia are discussed and special consideration is given for the treatment of women on anticoagulation therapy. This review and accompanying recommendations will provide guidance for healthcare practitioners in the emergency management of acute menorrhagia.

Prevention of haemophilic arthropathy during childhood. May common orthopaedic management be extrapolated from patients without inhibitors to patients with inhibitors

Summary.  We recommend prophylaxis in haemophilic children with an inhibitor as a way of preventing the musculoskeletal impairment that is likely to affect them. This approach has been used for children without inhibitors with excellent results. If prophylaxis is not feasible, we suggest that intensive on‐demand treatment should be given. Two agents, recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrates (aPCC), are currently used to control haemostasis either for prophylaxis or intensive on‐demand treatment. As it is recombinant, rFVIIa would seem more appropriate to be employed in children. aPCC could be used in adults, or in the event of an unsatisfactory response to rFVIIa. We recommend prophylaxis or, at least, intensive on‐demand treatment in haemophilia children with inhibitors. Both rFVIIa and aPCC are being used for this purpose. It would seem that rFVIIa might be more appropriate for children as it is a recombinant product. Nevertheless, after skeletal maturity (in adults), both agents could be used indistinctively (taking into consideration that FEIBA is a plasma‐derived product). We still need more well‐designed comparative studies in order to be able to assert that our consensus‐based conclusion is evidence based. In orthopaedic surgery, both aPCC and rFVIIa have been reported to be effective in controlling perioperative haemostasis, although in practice most centres have so far used rFVIIa for their orthopaedic procedures. We recommend rehabilitation programmes for all patients with inhibitors in order to mitigate the disabling and handicapping impact of their condition and thereby enable them to achieve social integration. Programmes for haemophilic children without inhibitors can be applied to children with inhibitors but should be individually tailored.

The 80th anniversary of von Willebrand's disease: history, management and research

Summary.  The history of von Willebrands disease (VWD) is fascinating because it demonstrates how good clinical observations, genetic studies and biochemical skills can improve basic understanding of a disease and its management. The continuous efforts of scientists and clinicians during the last 80 years have significantly improved the knowledge of von Willebrand factor (VWF) structure and function and the management of VWD. Diagnosis of phenotype and genotype is now available in many countries and treatment is becoming more specific according to the VWD type. Any therapeutic agents must correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional and low levels of factor VIII (FVIII) associated with VWF defects. Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it induces release of VWF from cellular compartments. Plasma virally inactivated VWF concentrates containing FVIII are effective and safe in patients unresponsive to DDAVP. There are advanced plans to develop a recombinant VWF but this product will require the concomitant administration of FVIII for the control of acute bleeds. Basic research studies on cellular biology, biochemistry and immunology have confirmed the role of VWF as a crucial participant in both haemostasis and thrombosis as its main biological activity is to support platelet adhesion–aggregation in the circulation. Retrospective and prospective clinical research studies, including bleeding history and laboratory markers for diagnosis as well as the use of DDAVP and VWF concentrates to manage or prevent bleeds in patients with VWD have been essential to provide general guidelines for VWD management. The large number of publications quoting VWD and VWF emphasizes the important role of VWF in medicine.

Inherited bleeding disorders in older women

Inherited bleeding disorders (IBDs) are by definition life-long. The commonest IBD is von Willebrand disease (VWD), a deficiency of von Willebrand factor (VWF), with a prevalence 1% in the general population and 13% in women with menorrhagia. Other IBDs include carriers of haemophilia A (factor VIII deficiency) and haemophilia B, (factor IX deficiency) and rare bleeding disorders (RBDs), deficiencies of factors XI, X, V, VII, II, I and inherited platelet disorders. Diagnosis is the synthesis of a bleeding history, family history and specialised laboratory tests. Women with IBDs are more likely to suffer HMB, to be symptomatic, and to present with bleeding in association with gynaecological problems. Heavy and/or abnormal menstrual bleeding increases with age due increased anovulatory cycles and gynaecological pathologies in older women. Thus, older women with IBDs are more likely to present with gynaecological bleeding symptoms, have impaired QOL and require surgical interventions. Treatment with specific clotting factor concentrates may be required and this requires an expert in haematology. Awareness of IBDs among health care providers, early diagnosis and appropriate management in a multidisciplinary approach is required to minimise the bleeding complications for women with IBDs.

Prevention of haemophilic synovitis: prophylaxis.

Summary.  It has been proven that early prophylactic therapy can prevent bleeding and arthropathy. Numerous retrospective non‐randomized cohort studies have demonstrated that prophylaxis, if started early in life, is associated with a considerable reduction of the mean number of joint bleeds and the rate of joint deterioration. It is quite extraordinary that despite the considerable evidence base it has been considered necessary by investigators to pursue the ideal of the controlled randomized trial and expose children to the risk of cerebral bleed. This questionable ethical approach is driven by the reluctance of the ‘willingness to pay’ but it is important that patients are not subjected to unnecessary investigation at either the behest of the Cochrane Database or those who control the financing of haemophilia care.

Von Willebrand Disease: Basic and Clinical Aspects

Von Willebrand Disease: Basic and Clinical Aspects provides an insight into all aspects of the condition. Since its discovery, von Willebrand disease has been extensively studied and the causative factor deficiency, the understanding of the condition and its treatment has greatly improved. This book summarizes recent research and will help to optimize the management of patients with von Willebrand disease.

Inherited Bleeding Disorders in Pregnancy: von Willebrand Disease, Factor XI Deficiency, and Hemophilia A and B Carriers

Obstetric management of women with von Willebrand Disease (VWD) and FXI deficiency, and carriers of hemophilia A and B, requires a multi-disciplinary team approach with obstetricians, midwives, hematologists, anesthetists, and neonatologists. This chapter discusses these disorders with particular emphasis on their management during pregnancy, delivery and postpartum. Diagnostic (carrier) testing before becoming pregnant in order to allow appropriate preconception counselling and timely provision of prenatal diagnosis, especially in those who could potentially carry a severely affected baby, are also addressed.