Hemophilia and von Willebrand disease: Factor VIII and von Willebrand factor

Severe inherited bleeding disorders represent resource-sapping entities for healthcare systems worldwide. Their diagnostic workup is usually based on a precise understanding of the underlying pathogenesis, and clinical management is nearly always a multidisciplinary effort. Haemophilia A and B along with von Willebrand disease (vWD) represent the cardinal disorders of this group, and the successful management and collective health status of these patients is considered a good indicator of the general robustness of healthcare delivery in a population.

The author of this book is a clinician-investigator with a long-standing interest in haemostasis-thrombosis. This highly focussed, compact, 286-page book makes for an absorbing and insightful read. Each chapter comes with a succinct summary, and many chapters end with an interesting ‘Future Approaches’ section that presents cutting-edge information on knowledge, practice and research on the respective topic. The book is comprehensive in its coverage so much so that its back cover's claim that it will eliminate ‘the (need to) search through hundreds of journal articles’ is not incredible.

The intended readership of this book is purely scientific and not the lay community, as basic background knowledge of haemostasis is required for its comprehension. Exposure to clinical medicine would, in addition, be desirable to extract the maximum information. Haemophilia and vWD concern not just clinical and laboratory haematologists, but also geneticists, genetic counsellors, public health practitioners, policymakers and the pharmaceutical and blood product-related industries. The clinical practice sections would be of interest to some of these groups, with therapeutic products, their dosing schedules, adverse effects and alternatives receiving appropriate attention, as do indications and modalities for genetic diagnosis. The book is, however, by no means a quick reference manual, and despite a fairly detailed index, one cannot really imagine a busy resident on the ward floor reaching out for it to quickly solve an urgent problem.

The book is divided into 15 chapters. It begins with historical aspects, an overview of normal and disordered haemostasis and the anatomy, physiology and genetics of factor VIII (FVIII). The latter are conceptually heavy topics, and the author does a commendable job of keeping the reader involved even as he unravels the intricacies of the involved pathways. Often, historical snippets are interwoven that bring alive the process by which science progresses. For instance, the stories and map of Aland islands (home to the first family with vWD), the sequential discoveries of various tenase complexes and the studies on cellular/tissue sources of FVIII, all aid in the understanding of what could otherwise easily have become mundane factual descriptions.

The subsequent chapters deal with haemophilia A in detail, going through epidemiology, clinical manifestations, diagnosis and general management of the disease. Here too, the book maintains a breezy style. The author's experience shines through in statements such as ‘Pain is a fact of life for most people with hemophilia….’ and ‘Problems with adjustment to the vagaries of hemophilia can be unwittingly exacerbated by family members.’ However, scientific rigour is never compromised to sentimentality. Both of the aforementioned statements, for instance, are followed by astute clinical advice on how best to deal with these thorny problems.

An entire chapter deals with anti-FVIII antibodies. It covers recent developments in the field including the SIPPET (Survey of inhibitors in Plasma-Product Exposed Toddlers) trial that demonstrated the superiority of plasma-derived over recombinant products in terms of immunogenicity. This section also dwells on therapeutic approaches to inhibitory alloantibodies including bypassing agents and outlines the detailed monitoring and costs in managing these patients. For instance, the prohibitive cost of immune tolerance induction therapy (~1 million USD for small children) is tempered by literature cited to suggest that this may be cost-effective in the long run. Novel, recently developed agents such as ANS8 CAR (chimeric antigen receptor) T-cells that suppress the proliferation of FVIII-specific effector T-cells, emicizumab - a humanized bispecific antibody that substitutes for FVIII in the tenase complex and the frontier area of biodesigned serine protease inhibitors to regulate the natural anticoagulant protein C (and now protein Z) - are documented.

The latter half of the book deals with vWF physiology, its management in the same detail as haemophilia. The mutational landscape of vWD, however, receives less space than the corresponding section on haemophilia, possibly because capturing the heterogeneity of molecular lesions and their phenotypic correlations represents an enormous task. The management section is up-to-date although applications to Indian settings may pose obvious challenges. Non-vWD topics related to the theme are also covered, including some recent advances such as the bivalent anti-vWF humanized immunoglobulin caplicizumab that is licensed for TTP and thrombosis in the European Union.

A later chapter on acquired vWD captures the basics, but the reader in search for detail may need to supplement this from other sources. The two penultimate chapters analyze the relationship of FVIII and vWF with thrombosis, presenting a broad overview of this intriguing and evolving area. The last chapter evaluates the FVIII/vWF relationship, and while its ‘Areas for future investigation’ section makes for a compelling read, the rest of the chapter is mostly repetitive of previous content.

This book comes at an exciting time from an Indian perspective, when the situation is improving rapidly for these patients. This is contributed by increased patient advocacy, a sharper administrative focus on rare and chronic genetic diseases, the relentless march of scientific advancements and improved economic conditions of the country. The fear of getting ‘left behind’ in the goal of attaining competent and dignified care is now seen much less in Indian patients, their families and their physicians. Towards that end, this book's hope of making a positive contribution to an ultimate improvement in the quality of life and clinical outcomes of these patients by educating their caregivers is likely to be justified.