Hemophilia and Von Willebrand Disease

Factor VIII and Von Willebrand Factor

David Green

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128129555
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Hemophilia and Von Willebrand Disease: Factor VIII and Von Willebrand Factor serves as a must-have reference on the important role these essential blood-clotting proteins play in research and clinical medicine. Clinicians and researchers face the daily challenge of staying current on the vast amounts of research that is now generated. The reference to Janus in the title refers to the two roles of the Factor VIII/Von Willebrand Factor Complex: initiation of coagulation and propagation of clot formation. The complex prevents bleeding in hemophilia and Von Willebrand disease but also augments arterial and venous thrombosis.

• Presents one source of information on Hemophilia and Von Willebrand Disease, as well as Factor VIII and Von Willebrand Factor, eliminating the search through hundreds of journal articles
• Combines the multi-disciplinary research that is generated from Factor VIII/Von Willebrand Factor – hematology, drug discovery, genetics, cell biology, and oncology
• Delves into unanswered questions and future directions of this important blood-clotting complex

Chapter 1

Historical Background of Blood Coagulation

Abstract

The protein missing from individuals with hemophilia A (classical hemophilia) was first identified in 1937 and called antihemophilic globulin (AHG). It became known as factor VIII (FVIII) in the 1950s, when a Committee of the International Society of Thrombosis and Haemostasis assigned Roman numerals to all the known clotting factors. In 1964, investigators in the United States and United Kingdom described the clotting of blood as a sequence of enzyme-substrate reactions in which each clotting factor was a proenzyme converted to an enzyme by the preceding factor. The concept of a coagulation cascade held sway for many years until it was modified by contemporary molecular studies that provided more precise information about clotting protein interactions. By the end of the 1970s, scientists had purified FVIII 10,000-fold, activated it with thrombin, and demonstrated that it played a key role in the activation of FX. The high-molecular-weight complex circulating in plasma could be dissociated into two components, FVIII and Von Willebrand Factor (VWF). Exercise and hormones such as epinephrine and thyroxine were shown to raise the plasma concentrations of the proteins, and a vasopressin analogue, desmopressin (DDAVP), was found to promote the release of FVIII/VWF from endothelial cells. This observation led to the use of desmopressin for the diagnosis and treatment of hemophilia A and Von Willebrand Disease (VWD), and had a significant impact on the study of these and other bleeding disorders.

Keywords

Hemophilia a factor VIII (FVIII); Von Willebrand disease; Von Willebrand Factor (VWF)

It's such a wonderful trick, isn’t it? You tilt a tube and the contents fall out and then you do it again and it doesn’t fall out. It's so sudden, and it's so easy to see.

- Rosemary Biggs

Blood spurts from a wound when a vessel is severed, and the formation of a clot at the site of the injury prevents further blood loss. Blood flow is not compromised because the clot covers the wound and does not extend very far into the injured vessel. As long as the clot remains in place, bleeding does not resume and eventually new tissue growth permanently seals the punctured vessel. This seemingly miraculous healing process has inspired many scientists to study how blood coagulates. The history of clotting discoveries has been ably summarized by Oscar Ratnoff [1]. He writes that as long ago as 1686, Malphighi described a network of white fibrous strands that remained after a blood clot was washed free of red cells. However, it was not until 1830 that Babington [2] noted that these strands, subsequently called fibrin, were not found in blood prior to clotting, and suggested that they arose from a precursor, subsequently named fibrinogen by Virchow in 1856 [3]. A major step forward was Schmidt's observation at the end of the 19th century that fibrinogen underwent conversion to fibrin through the action of an enzyme he called thrombin, and this occurred only when blood clotted [4]. Thrombin arose from a precursor, prothrombin, which was present in unclotted blood, but how prothrombin was converted to thrombin was unclear.

An important conceptual advance was the formulation of a blood coagulation scheme by Paul Morawitz in 1905 [5]. He proposed that it was a two-step process: first, injured tissues released a factor, termed thromboplastin, which converted prothrombin to thrombin, and second, thrombin converted fibrinogen to fibrin. He also recognized that calcium was required for thromboplastin to be active. This theory accounted for how blood forms clots when tissues are injured, but did not explain how blood coagulates when drawn into a test tube, since no tissue thromboplastin is present in the tube. An even more relevant clinical problem is that fibrinogen, prothrombin, and calcium are all present in normal amounts in people with hemophilia, who nonetheless have a severe bleeding problem.

Factor VIII and Hemophilia A

The conundrum posed by hemophilia was addressed by Arthur Patek, Jr. and his coworkers in the 1930s. They observed that a substance was present in normal blood that shortened the clotting time of hemophilic blood [6,7]. On investigation, this substance had the characteristics of a protein—it contained nitrogen, it was too large to pass through a membrane filter, and it lost its ability to shorten the clotting time if it was heated. A precipitate formed if the putative clotting factor was mixed with acidified water, a characteristic of globular proteins. When the precipitate was dissolved in saline solution and infused intravenously into people with hemophilia, it shortened the clotting time of their blood, suggesting it might have a potential role in the treatment of this disorder. Patek and colleagues wrote: “The fact that a normal globulin substance reduces the clotting time in vivo, we believe changes the complexion of the disease from an abnormality that was immutably fixed to one that is amenable to change.” This assertion might have been the first time that scientists suggested that an inherited disorder could be mitigated by a medical intervention.

Patek and coworkers called their protein antihemophilic globulin (AHG) because it accelerated the clotting time of hemophilic blood [7]. At the time of their discovery, hemophilia was defined as a bleeding disorder that affected boys and men; although their mothers and sisters could pass the trait on to some of their male children, the sons of hemophiliacs were normal. The defects in other bleeding disorders that affected women as well as men were also eventually characterized. As the factor deficient in each type of hemorrhagic disorder was elucidated, researchers named the involved proteins after the individuals in whom the condition was discovered, giving origin to names such as Christmas Factor and Hageman Factor. Stuart-Prower factor was named after the two patients with the same defect studied by different workers. Other investigators selected names that described how the factor functioned in coagulation; some of these unwieldy monikers were serum prothrombin conversion accelerator, plasma thromboplastic component, and proaccelerin. Each worker selected the name that best fit his or her experimental studies, and one influential researcher, Walter Seegers, created an entirely distinct set of names for the clotting factors he examined [8]. Eventually, there were several designations for each clotting protein; the appellations given to the protein deficient in classical hemophilia are shown in Table 1.1.

Table 1.1

Synonyms Used for Factor VIII Prior to 1960

Antihemophilic globulin

Antihemophilic globulin A

Antihemophilic factor (AHF)

Plasma thromboplastic factor (PTF)

Plasma thromboplastic factor A

Thromboplastic plasma component (TPC)

Facteur antihemophilique A

Thromboplastinogen

Prothrombokinase

Platelet cofactor

Plasmokinin

Thrombokatilysin

Modified from Wright IS. Nomenclature of blood clotting factors. Can Med Assoc J 1959;80:659–61.

By the 1950s, it was apparent that the profusion of names was causing a great deal of confusion and hampering research. The International Society of Thrombosis and Haemostasis (ISTH) was founded in 1954; its mission was to advance the understanding, prevention, diagnosis, and treatment of thrombotic and bleeding disorders. As one of its first tasks, the ISTH organized a committee, the International Committee for the Standardization of the Nomenclature of Blood Clotting Factors, to bring order to the cacophony of clotting factors [9]. The Committee met between 1954 and 1959, and decided to take a rigorous approach to the identification and naming of clotting factors; it recommended that Roman numerals be assigned only to those factors that had data on the effects of pH, storage, absorbance, and inactivation by heating. In addition, there needed to be a clinical disorder associated with a deficiency or excess of the factor, and a reproducible method of assay. They adopted this rigorous approach because a presumed clotting activity had been previously designated factor VI, but its existence could not be confirmed by further study; this number was never assigned to any other factor. Table 1.2 lists the clotting factors that were assigned Roman numerals; it includes Von Willebrand Factor, which has not been assigned a Roman numeral.

Table 1.2

Clotting Factors and Their Physiologic Concentrations in Plasma

Clotting factor	Physiologic concentration (μg/mL)
Factor I: fibrinogen	2000–4000
Factor II: prothrombin	100–150
Factor III: tissue factor	–
Factor IV: calcium	90–105
Factor V: proaccelerin	5–10
Factor VII: proconvertin	0.5
Factor VIII: antihemophilic globulin	0.1–0.2
Von Willebrand Factor	10
Factor IX: Christmas factor	4–5
Factor X: Stuart-Prower factor	8–10
Factor XI: Plasma thromboplastin antecedent	5
Factor XII: Hageman factor	30
Factor XIII: Fibrin-stabilizing factor	10

Modified from Roberts HR, Monroe III DM, Hoffman M. Molecular biology and biochemistry of the coagulation factors and pathways of hemostasis. In: Williams Hematology. 7th ed. New York: McGraw-Hill; 2006. p. 1666 [chapter 106].

Other proteins that participate tangentially in coagulation, such as prekallikrein and high-molecular-weight kininogen, as well as anticoagulants and fibrinolytic factors, have not been assigned Roman numerals.

Progress in advancing the field of blood coagulation was dependent on the development of broadly accessible methods to assay the putative clotting factors. An early clotting test that was simple and reproducible was the pro...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Author Biography
• Preface
• Acknowledgments
• Introduction
• Chapter 1: Historical Background of Blood Coagulation
• Chapter 2: Hemostasis and FVIII
• Chapter 3: FVIII Anatomy and Physiology
• Chapter 4: FVIII Genetics
• Chapter 5: Congenital Deficiency of Factor VIII: Hemophilia A
• Chapter 6: FVIII Concentrates
• Chapter 7: General Management of Hemophilia
• Chapter 8: Antibodies to FVIII
• Chapter 9: The Von Willebrand Factor
• Chapter 10: Von Willebrand Disease: Classification and Diagnosis
• Chapter 11: Treatment of Von Willebrand Disease
• Chapter 12: Acquired Von Willebrand Syndrome
• Chapter 13: Factor VIII and Thrombosis
• Chapter 14: Von Willebrand Factor and Thrombosis
• Chapter 15: Factor VIII/Von Willebrand Factor: The Janus of Coagulation
• Index