History of von Willebrand Disease
In 1926, Erik von Willebrand first described a hereditary hematologic disease in the Finska Läkaresällskapets Handlingar (1). He described features of the disease that were different from classic hemophilia or other diseases known at that time, such as thrombocytic purpura or Glanzman’s disease. The different features von Willebrand observed compared to classic hemophilia were the fact that muscle and joint bleeding were not frequently seen, and the disease affected both men and women. A prolonged bleeding time was most frequently associated with the disease. With his knowledge, he proposed that this clinical manifestation was a previously unknown form of hemophilia and called it ‘hereditary pseudohemophilia’. Although there were few methods of analyzing his theories, he proposed that the prolonged bleeding could best be explained by a combination of a functional disorder of the platelets and lesions of the vessel walls.
His primary observations were made in several family members living in the Swedish province of Aland. The primary case was a five-year-old girl named Hjordis, who was seen by von Willebrand for recurrent bleeding tendencies. Both her mother and father had histories of bleeding. Hjordis was the ninth of eleven children, of whom seven showed bleeding symptoms. Four of her sisters had died at an early age of uncontrolled bleeding. Hjordis herself had experienced different severe episodes of bleeding; both form her nose and lips, as well as following tooth extractions. At the age of 14 years, she bled to death during her fourth menstrual period.
As Hjordis came from a large family, von Willebrand used the opportunity to study the family more extensively. He published a pedigree of the family in the previously mentioned paper of 1926 (fig 1). He found that 23 of the 66 members of the family had a history of bleeding problems. The most distinctive problem was mucosal bleeding: epistaxis, bleeding from oral lesions, easy bruising and in females excessive bleeding during menstrual periods and at childbirth.
In the 1930’s, von Willebrand together with Jürgens reinvestigated the patients in Aland and found that the disease was due to a platelet dysfunction, including platelet factor 3 deficiency. This led to the disease being called von Willebrand-Jürgens thrombopathy, however this condition is not recognized anymore at this time. However, Von Willebrand did not dismiss the notion that blood factors may be responsible for the pathogenesis of this disease.
Other descriptions of patients with similar symptoms have been described in the following years, amongst others by Dr. George Minot of Boston (2). In 1953, Alexander and Goldstein described two patients with similar symptoms (3). However, they also found that antihemophilic factor (Factor VIII, FVIII) was lowered to 5-10% of normal concentrations, and found a clotting time that was prolonged. This prolongation had been found to be corrected by infusion of normal plasma. However, the bleeding time did not normalize, a finding that was later explained to be due to the fact that the infusion of a little amount of plasma does not provide sufficient Von Willebrand Factor (VWF) (4). The same year, Larrieu and Soulier found similar results in a girl, with low FVIII and prolonged bleeding time, but with normal clotting factors and platelet parameters. They subsequently proposed the name of von Willebrand syndrome for the condition.
The causing factor: VWF
Even though von Willebrand proposed in 1926 that a combined effect of a functional disorder of the platelets and a systemic lesion of the vessel wall, he could not find any definitive proof that a causing factor was present in the blood. It took until 1950 before the first demonstration of the presence of such a factor was done. Blombäck and collegues were trying to purify fibrinogen from Cohn fraction I of human plasma. They found that when this fibrinogen was obtained from fraction I-0 (AHF-Kabi), it was heavily contaminated with an antihemophilic factor, FVIII (5). At the same time, Dr. Nilsson from Malmö had a patient that had a severe bleeding diathesis. Due to severe adverse reactions to recurrent transfusions, treating options were poor. The patient had been found to have low FVIII concentrations, thus posing the option to use the fraction I-0 in treating the low FVIII. To the surprise of the physicians, not only did the FVIII activity increase, but the bleeding time normalized as well (6). This observation was later confirmed to be found in patients with von Willebrand Disease (VWD), but not in hemophilia, proving that VWD is a clearly distinctive disease (7). To discriminate whether this effect was from FVIII alone, or that other factor were in play, fraction I-0 was prepared from patients with severe hemophilia A. This fraction did not only correct the bleeding time in patients with VWD, but stimulated the FVIII-production as well . Fraction I-0 from VWD-patients had no effect. Still, there was the possibility that platelets had a significant role in this process. To assess this possibility, Blombäck et al. used a platelet suspension from a normal donor, as well as a fraction I-0 from a patient with thrombocytopenia. Neither one of those increased FVIII or decreased bleeding time. This suggested that a previously undiscovered plasma factor must be responsible for these findings. It was called bleeding time correcting factor, now known as VWF.
At first it was not understood how this factor could affect the primary hemostasis and shorten the bleeding time. This was solved by different experiments conducted by Borchgrevink (8) , Salzman (9), and Jörgensen (10). They showed that the platelet adhesiveness was decreased in VWD. Salzman also showed that discrimination between normal patients and VWD patients was only shown in high flow. It was also shown that normal plasma and hemophilic plasma could normalize the adhesiveness. Jörgensen and Borchgrevink (10) demonstrated a decreased adhesiveness of platelets to disrupted endothelium in VWD. This indicates that the factor lacking in VWD is responsible for enhancing adhesiveness of platelets to vessel walls and thereby influencing primary hemostasis.
After the first publication of Von Willebrand, it took nearly 30 years before it was clear that a previously unknown plasma factor was responsible for the hemostatic impairment seen in VWD. In that time, a treatment (fraction I-0) had already been shown to be an effective replacement of VWF. This discovery made it possible for the detection of a plasma factor that was clearly lacking in VWD, differentiating VWD from other hemostatic diseases. VWF has been detected immunologically as a distinctive entity from FVIII in 1971 (11). After that it has been cloned (12-14), and the amino-acid sequence has been determined (15). This has made it possible for clinicians to differentiate VWD into different types, which will be explained in a next chapter.
von Willebrand Factor structure and function
VWF is the largest multimeric plasma protein and is synthesized primarily in endothelial cells. Both decreased levels as defective functioning of VWF cause the most prevalent bleeding disorder, VWD. Some estimations say that 1% of the human population may have some form of VWD (16, 17).
It was not known that FVIII and VWF were two different proteins and had different functions until the 1970s. This is for instance shown by Weiss et al (18), who pose the theory in 1973 that FVIII and VWF are in fact the same protein. However, Bennett et al found an incongruent relation between pro-coagulant activity of FVIII and the concentration of VWF. This observation led Zimmerman and Edgington to try to investigate whether VWF and FVIII are in fact different molecules (19). They have proven that after depletion of plasma of FVIII, they could still find VWF. This result can be correlated to the fact that FVIII and VWF are closely correlated to each other, but have distinct functions. VWF acts as a carrier protein for FVIII in plasma, thus making it possible for the two proteins to be isolated together. This explains the former terminology of VWF, namely FVIII-related antigen.
A second antigen has been found to be absent from plasma in patients with severe VWD (20). At first this antigen was called von Willebrand antigen II (VW-agII), but is now known as von Willebrand Factor propeptide (VWF-pp) (21). It has been found to be a part of pro-VWF, and is cleaved from the mature protein during processing in the Golgi apparatus.
Several groups have identified the entire coding sequence of VWF in 1985 (12-14). The VWF mRNA has been shown to be approximately 9kb in size. After identifying the coding sequence, the entire VWF gene has been cloned and localized to chromosome 12 (14, 22, 23).
Different types of VWD
VWD type 2N
Fig 1. The pedigree of the Family S. The index case (Hjordis S) is number 16 on the fourth row, the ninth sibling in family S.
References
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