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Historical perspective on von Willebrand disease

Erik E. Berntorp1 and Margareta Blombäck2

1Department of Translational Medicine, Malmö Centre for Thrombosis and Haemostasis, Lund University, Skåne University Hospital, Malmö, Sweden

2Department of Molecular Medicine and Surgery, Division of Clinical Chemistry and Blood Coagulation Reasearch, The Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

Introduction

The history of von Willebrand disease (VWD) and its causative factor, the von Willebrand factor (VWF), spans almost a century and was recently comprehensively reviewed by the late professor Birger Blombäck, who described the first publication by Erik von Willebrand [1], the gene cloning in 1985, and the discovery of the specific metalloprotease, ADAMTS13 [2], which degrades VWF. The purpose of this review is to describe the early history of the understanding of the disease and the first steps in the replacement therapy for its severe forms. Also, we describe in greater detail the findings of a group of different families investigated on the Åland Islands.

The scientist of the disease

Erik Adolf von Willebrand (Figure 1.1) was born in Vasa, Finland, in 1870. He qualified as a medical doctor in 1896 and specialized initially in physical therapy and later in internal medicine in Helsinki. Erik von Willebrand devoted much of his professional life to an interest in blood, especially its coagulation properties. In 1899, he defended a doctoral thesis that dealt with his investigation of the changes that occur in blood following a serious hemorrhage. From 1908 until his retirement in 1935, Erik von Willebrand worked at the Deaconess Institute in Helsinki, where he headed the Department of Internal Medicine between 1922 and 1931. Erik von Willebrand was known for his modesty and integrity, and in his obituary it was said that he "usually preferred to discuss his observations of nature rather than his personal achievements." He died in September 1949, at the age of 89 years.

First description of the disease: the Åland family

In 1926, Erik von Willebrand first described the inherited bleeding disorder in Finska Läkaresällskapets Handlingar (in Swedish). He identified features that suggested that this disease was distinct from classic hemophilia and other bleeding disorders known at the time, such as anaphylactoid purpura, thrombocytopenic purpura, and hereditary thrombasthenia, described by Glanzmann. What differentiated this bleeding disorder from classic hemophilia was that it was not frequently associated with muscle and joint bleeding, and it affected both women and men. He stressed that a prolonged bleeding time was its most prominent characteristic. He concluded that the condition was a previously unknown form of hemophilia, and called it "hereditary pseudohemophilia." Erik von Willebrand also discussed the pathogenesis of the condition and felt that the bleeding could best be explained by the combined effect of a functional disorder of the platelets and a systemic lesion of the vessel walls.

The original observations leading to this new disease were made in several members of a large family (identified as family S) living on the island of Föglö in the Åland archipelago in the Baltic Sea. The index case was a girl aged 5 years, named Hjördis S, who had marked and recurrent bleeding tendencies and was brought to Helsinki for consultation. Both her mother and father were from families with histories of bleeding. The girl was the ninth of 11 children, of whom 7 had experienced bleeding symptoms. Four of her sisters had died from uncontrolled bleeding at an early age. Hjördis herself had experienced several severe episodes of bleeding from the nose and lips and following tooth extractions, as well as bleeding in her ankle. At the age of 3 years, she bled for 3 days from a deep wound in her upper lip. The bleeding was so severe that she almost lost consciousness and had to be hospitalized for 10 weeks. At the age of 14 years, Hjördis bled to death during her fourth menstrual period.

Hjördis came from a large family (Figure 1.2). Intrigued by their history, Erik von Willebrand studied the family further with the help of coworkers. He published the pedigree and his clinical and laboratory evaluation in his 1926 paper. He found that 23 of the 66 family members had bleeding problems. The most prominent problem among the affected family members was mucosal bleeding: epistaxis, followed by profuse bleeding from oral lesions, easy bruising, and, in females, excessive bleeding during menstruation and childbirth. Intestinal bleeding had been the cause of death at early ages in some family members.

Figure 1.1 Erik von Willebrand.

In further studies, Erik von Willebrand found two families related to Hjördis S and one unrelated family in whom bleeding symptoms similar to those observed in Hjördis were common [3, 4]. In the 1930s, Jürgens, together with von Willebrand [5, 6], reinvestigated the patients in Åland and concluded that the disease was due to some impairment of platelet function, including platelet factor 3 deficiency. This observation led to the disease being called von Willebrand-Jürgens thrombopathy, and, although this condition is not officially recognized today, von Willebrand did not dismiss the notion that factors in blood plasma might also be important in the pathogenesis of the disease.

Other early clinical reports

In 1928, Dr. George R. Minot of Boston described five patients from two families with prolonged bleeding times and symptoms similar to the Åland family members. This may have been one of the first descriptions of VWD [7-9]. In the following years, numerous cases similar to those described by von Willebrand were reported, usually under the name of pseudohemophilia. In 1953, Alexander and Goldstein [10] found a dual defect in two patients with hereditary pseudohemophilia. They confirmed the earlier findings of prolonged bleeding time, normal platelet count and function, and abnormal nail bed capillaries. However, they also found a decreased FVIII level (5-10% of normal) and they observed a prolonged coagulation time that was normalized by normal plasma. The prolonged bleeding time, however, was not normalized and this was later explained by the fact that infusion of a restricted volume of plasma does not provide a sufficient amount of VWF [11]. Larrieu and Soulier [12] also found low FVIII activity and a prolonged bleeding time in pseudohemophilia, but otherwise normal clotting factors and platelet parameters. They proposed the name von Willebrand syndrome for the condition.

Figure 1.2 The Åland pedigree as originally described in 1926 [1]. The index case, Hjördis, is the ninth sibling in family S (Fam S). unaffected male; unaffected female; male with mild bleeding disease; female with mild bleeding disease; female with severe bleeding disease; ┼ bled to death.

The search for a new factor-the bleeding time factor

The first demonstration of the VWF was during the 1950s through a joint effort by Margareta and Birger Blombäck, working in Stockholm with the purification of fibrinogen, and Inga Marie Nilsson, who had established a clinical coagulation unit in Malmö. It was found that fibrinogen purified from Cohn fraction I of human plasma, when specifically obtained in fraction I-0 (AHF-Kabi), was heavily contaminated with an antihemophilic factor, which is plasma factor VIII (FVIII) [13].

At that time, Dr. Nilsson had a 15-year-old female patient named Birgitta who had a severe hemorrhagic diathesis. When she began to menstruate, the condition worsened and she received frequent blood transfusions. However, Birgitta developed serious side-effects from the transfusions and they were stopped. As a consequence, other treatment options had to be considered, and a hysterectomy was planned. Her coagulation evaluation had shown a prolonged bleeding time and a somewhat prolonged coagulation time but normal platelet count and function. FVIII activity was low. Since fraction I-0 had a high concentration of FVIII, it was decided that its effects should be tested in Birgitta. To the surprise of the treating physicians, not only did FVIII activity increase as expected but the bleeding time was also normalized [14]. Subsequently, a hysterectomy was successfully performed under the cover of fraction I-0. According to modern classification, this patient had type 3 VWD. She is now well and has been on regular prophylaxis with VWF concentrate for many years.

In June 1957, Inga Marie Nilsson, Erik Jorpes, Margareta Blombäck, and Stig-Arne Johansson visited Åland and studied 16 patients who had been examined 25-30 years previously by von Willebrand. No patients who had severe forms of the disease were still living. In their investigation, they found FVIII activity to be reduced in 15 of 16 cases [15]. The father of Hjördis had a normal level. The Duke bleeding time varied, with two patients having a definite prolongation and three patients having a moderate prolongation. Platelet counts were normal and, in contrast to Jürgens' earlier observation, the platelets themselves were normal with respect to...