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Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
VON WILLEBRAND'S DISEASE Lars Holmberg, MD. and Inga Marie Nilsson, MD.
.7129
1
Coagulation Laboratory, University of Lund, Allmiinna Sjukhuset, Malmo, Sweden
INTRODUCTION An abnormal bleeding tendency is often due to an inherited defect of hemostasis. One of the commonest of such defects is von Willebrand's disease (VWD), which is multifaceted but nevertheless has a typical clinical picture. Investigations of the cause of the condition have resulted in good prospects for controlling formerly life-threatening bleeding. Research in VWD also has contributed considerably to our knowledge of normal hemostasis.
HISTORY In 1926 Erik 1dolf von Willebrand (l) described an inheritable bleeding disease on the islands of Aland in the Gulf of Bothnia (Finland). Von Willebrand's description included bleeding from the gums and after tooth extraction, bleeding from the female genital tract, and bleeding from trivial wounds, but he stressed that joint bleedings, common in hemophilia, were relatively rare. Von Willebrand distinguished the disease from anaphylactoid purpura and thrombocytopenic purpura as well as from the hereditary hemorrhagic thrombas thenia described by Glanzmann. He concluded that the condition was a previously unknown form of hemophilia which affected both sexes, and he called the disease hereditary pseudohemophilia. A prolonged bleeding time was its most important characteristic. In 1928 the clinical picture was reported independently by four Americans, including Minot (2). In the 1930s Jiirgens reinvestigated the original families on Aland and concluded that the platelets, as in Glanzmann's thrombasthenia, were defective (3). Other authors were, however, unable to demonstrate either a mor phologic platelet defect or abnormal clot retraction in cases which in all respects resembled the disease described by von Willebrand (4, 5). They sought the cause of the disease in the morphology and function of the capillaries (4). In the 1950s methods were developed for measuring the various hemophilia factors. In 1953 Alexander & Goldstein (6) described two cases with a combined 'Supported by a grant from the Swedish Medical Research Council (B75-19X-87-IIA). 33
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HOLMBERG & NILSSON
defect in hemostasis, namely, a prolonged bleeding time and decreased antihemo philic factor A (AHF) activity. Similar cases were later observed by a number of other authors; Schulman et al (7) called the disease vascular hemophilia, while · Singer & Ramot (8) used the term, pseudohemophilia B. In 1957 Nilsson et al (9) found the AHF activity to be reduced in 15 cases of VWD from the original families on Aland. This finding clearly showed that the bleeding disease observed in various quarters of the world was identical to that described by von Willebrand. The same group (10) found that the platelets were normal in respect to platelet factors 1,3,and 4. The then novel AHF concentrate, plasma fraction 1-0 (II), prepared from Cohn's fraction I, corrected not only the AHF deficiency, but also the bleeding time and the capillary bleedings.
PATHOGENESIS Nilsson et al (12) later showed that patients with VWD lack a plasma factor occurring not only in normal plasma, but also in hemophilia plasma. This so-called v. Willebrand's factor (VWF) is not present in pure fibrinogen fractions or in platelets. The VWF not only corrects the prolonged bleeding time in patients with VWD, but also apparently stimulates the synthesis of AHF. The plasma fraction 1-0, prepared from hemophilia plasma and thus devoid of AHF activity, increases the AHF activity when given to patients with VWD (12). Similar results have been reported by others (13, 14). The VWF appears to be closely related to AHF and occurs in AHF-rich plasma concentrates (12, 15). It was at first not known how a plasma factor could affect primary hemostasis and shorten the bleeding time. The basis of primary hemostasis is the formation of a platelet plug. Borchgrevink (16) found decreased platelet adhesiveness in vivo in patients with VWD by comparing the platelet count in venous blood and in blood from a capillary lesion. A reliable in vitro test for measuring the interaction between platelets and a glass surface was devised by Hellem (17). Hellem's original method, which used citrated blood, did not distinguish normal persons from those with VWD (18). Salzman (19) used native blood and a quicker flow and then could demonstrate a decreased platelet adhesiveness to glass in VWD. Modifications of Salzman's method, all with a rapid blood flow, have also been diagnostically useful (20,21), although they are technically difficult and subject to methodological errors. Common to all methods of measuring platelet adhesiveness that can distinguish between persons with and without VWD is the use of a rapid flow of blood through a column of glass beads. The reduced platelet adhesiveness in VWD, like the bleeding time, can be normal ized by infusion of fresh platelet-poor plasma (19). Such normalization can be demonstrated in vitro by mixing the patient's blood with normal plasma, hemophilia plasma, or cryoprecipitate (22). The factor causing such normalization is missing in VWD plasma. Further knowledge about the pathogenesis of VWD has been obtained in recent years since the advent of highly purified AHF. The AHF, as isolated from plasma, is a very large macroglobulin. Monospecific precipitating rabbit antisera against this
Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
V. WILLEBRAND'S DISEASE
35
globulin have been prepared. Patients with hemophilia A have a cross-reacting but inactive protein in the plasma (23, 24), while the majority of patients with VWD have a low content of this so-called AHF-related antigen (23, 25). The chromato graphic pattern of normal (and hemophilia) cryoprecipitate on Sepharose 6-B ac cording to v. Mourik & Mochtar (26) shows a typical protein peak corresponding to the AHF-related plasma protein in the void volume. No such peak is seen when the starting material consists of cryoprecipitate from a patient with severe VWD. The content of AHF-related protein is thus often really decreased in VWD (27; Holmberg & Nilsson, unpublished). Bouma et al (27) showed that the AHF-related high molecular weight protein is responsible for enabling normal and hemophilic plasma to normalize the reduced platelet adhesiveness in VWD. High molecular weight AHF thus possesses not only AHF activity, but also VWF activity, and can then be called AHF-VWF protein. What is the structure of this protein? Does it consist of two components, one possessing the AHF activity and the other the VWF activity, or does it consist of a single but bifunctional molecule (27)? Much evidence suggests that the protein consists of identical or at any rate equally large protein chains, possibly connected by covalent bonds to a large molecule and by noncovalent bonds to very large aggregates, which dissociate in various salt solutions (28-30). Other investigations, however, suggest that the protein complex consists of immunologically and biologi cally separate components (31-34). Administration of AHF concentrate to a patient with severe VWD has, as pointed out abovt:, a number of effects (Figure I). It will shorten the bleeding time, and an increase in AHF activity out of proportion to the activity of the concentrate will occur. But this is not accompanied by any increase in the amount of antigenic "I.
min.
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.....
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15'30' 60' l' I 400ml AHF Figure 1 disease.
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Infusion of AHF concentrate (fraction I-D) to a patient with severe v. Willebrand's
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bleeding time.
AHF activity,
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Duke's
Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
36
HOLMBERG & NILSSON
protein,which instead decreases successively (35,36). AHF activity may thus occur in some substance, which does not react to the antiserum with any demonstrable precipitation. This AHF activity may perhaps occur in a plasma fraction of lower molecular weight (37). Judging from available experimental data,one might explain the defect in VWD as follows. The building stones of the high molecular weight AHF, i.e. protein chains with a molecular weight of 180,000---240,000 (28,29,38),are coded from an X-chromosomal AHF locus. The chains contain the sequences necessary for both AHF activity and VWF activity in the final molecule. But if the molecule is to have VWF activity,it must have a very special quarternary structure. The VWF activity seems to be labile, more labile than the ability of the protein to react with antiserum. Autosomal genes are responsible for polymerization of the chains to a large molecule with the special configuration. In the most common form of VWD with a low content of AHF antigen (25),the defect may consist of impairment of the ability to form high molecular weight AHF from the building stones-the protein chains. Since it is only the high molecular weight AHF that is precipitated with rabbit antiserum, the antigen content will be small or absent. Secondarily,a feedback inhibition of the synthesis of low molecular weight AHF occurs (Figure 2). VWD with a normal content of AHF-re1ated antigen has also been described (25). One might imagine several explanations: (a) There is X-chromosomal heredity with a defect in the sequence of the primary structure which is significant for VWF activity. Also the AHF activity is affected. The polymerization is normal (as in hemophilia A) because the autosomal genes are intact. This variant might also be regarded as a variant of hemophilia A with a prolonged bleeding time and decreased platelet adhesiveness (25), but clinically it resembles VWD rather than hemophilia A. (b) There is autosomal heredity in which polymerization may occur, but in an abnormal way, with the effect that the quaternary structure is different, resulting in reduction of both the VWF and the AHF activity. The structure is,however,so similar to normal that the molecule reacts with rabbit antiserum against AHF related protein. How and where does the VWF act in vivo? As mentioned, the factor occurs in the plasma,but with the aid of immunofluorescence it can be demonstrated also in A
1
X ---- LMW - AHF � HMW-AHF
� Figure 2
Hypothetical pathway for the synthesis of AHF and VWF. x.. X-chromosomal
gene, A: autosomal gene, LMW-AHF: low molecular weight AHF, HMW-AHF: high molecu lar weight AHF.
Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
V. WILLEBRAND'S DISEASE
37
the intima of the blood vessels (39). The protein may actually be synthesized in endothelial cells (40). Patients with severe VWD lack AHF-VWF protein not only in the plasma, but also in the vessel walls (41). In such patients infusion of cryo precipitate is followed by an increase in the AHF-VWF antigen in the plasma, while the antigen is still not demonstrable in the endothelium (Holmberg, unpublished). This finding suggests that the occurrence of AHF-VWF protein in the intima is due to a true synthesis in the vessel wall and not simply to adsorption of the protein to the endothelial surface. It is not known whether the plasma protein or the vessel protein is of greater importance in primary hemostasis. The interaction between AHF-VWF protein and platelets in primary hemostasis is still unknown. Some interesting observations have, however, been made. Purified bovine and porcine high molecular weight AHF-related proteins aggregate human platelets in vitro (42). Human AHF-VWF protein can be modified in such a way as to aggregate platelets. The antibiotic ristocetin aggregates platelets in vitro in normal persons, but generally not in patients with VWD (43). Ristocetin has no effect on isolated platelets, but requires the presence of the high molecular weight AHF-VWF protein to exert its effect (44). The effect of the enzyme neuraminidase on platelet aggregation also seems to be related to the AHF-VWF protein. Neuraminidase aggregates rabbit platelets in the presence of a plasma factor (45),and increases aggregation of human platelets with inter alia ADP (46). Vermylen et al (47) showed that human AHF-VWF protein, preincubated with neuraminidase, spontaneously aggregates human platelets in platelet-rich plasma.
GENETICS VWD seems to be one of the most common hemorrhagic diatheses. Silwer (48) estimated the frequency in Sweden at 1 :32,000 inhabitants. However, mild cases may remain undiagnosed. Most authors agree that the disease is inherited by an autosomal and dominant gene (10,49). Of 40 families with VWD, Silwer (48) found the expected pattern of autosomal dominant inheritance in 27 (Figure 3). In single published cases, however, the transmission might have been different (25, 48, 50). Some authors have shown an increased frequency of consanguineous marriages, others a high frequency of sporadic cases (51). The disease seems to be more common among women than' among men. This is probably because women with VWD so often have menorrhagia, which leads to the detection of the dis ease. Assuming that the inheritance is autosomal dominant, it is obvious that its penetrance and expressivity vary considerably (48,51,52). Yet in Silwer's material substantial differences in expressivity were uncommon. He found the penetrance to be 73-90%, and estimated the risk of a child of an affected person inheriting the disease to be 40% or less. The risk of the disease being severe was, however, regarded as 5% or less.
38
HOLMBERG & NILSSON
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Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
Figure 3
Pedigree illustrating autosomal and dominant inheritance of
Y.
Willebrand's disease.
SYMPTOMS The symptoms in VWD vary widely. In severe VWD the bleedings may be life threatening, while in mild VWD they may be so mild that the disease remains concealed. Nose bleeding is the most common symptom of VWD and occurs in 60-80% of affected patients (Silwer, 48). Bleeding from the oral cavity is also fairly common; in children, traumatic bleeding of the lips, tongue, and oral cavity are characteristic. In contrast with what is seen in hemophilia, deep subcutaneous and intramuscular
hematomas are uncommon in VWD. Very typical, however, are prolonged bleedings from trivial wounds. The most prominent bleeding symptom in women with VWD is probably menor rhagia. Menstrual disorders occur in some 50-75% of such women. The symptom is most severe during the first few years after menarche, and has occasionally been life-threatening and required hysterectomy or roentgen castration. Menorrhagia is also often a difficult problem in VWD characterized as mild by laboratory tests. Another type of bleeding from the female genital tract, which has not received much attention, is corpus luteum bleeding. Typical cases are characterized by intermen strual, more or less severe, abdominal pain and often by a low Hb because of intra-abdominal bleeding. Delivery in women with VWD is often, though not always, associated with heavy blood loss. In some women with VWD the AHF level rises during pregnancy, which lessens the risk of bleeding. The AHF, however, does not always rise, and especially not in women with an initially very low level. Even if no bleeding occurs at parturi tion, the patient must be observed for at least a week post partum because the AHF level falls after delivery. In most published series of VWD the frequency of gastrointestinal bleeding is relatively low, usually 10-15%. It is, however, striking that when such bleeding occurs it is usually very severe. In most cases the patients appear to bleed diffusely from the mucosa. Roentgen examination rarely reveals any local source of bleeding, such as gastric or duodenal ulcer. The frequency of hematuria has been given as 2-7.5%. The bleeding is rarely so severe as to require specific treatment.
V. WILLEBRANO'S DISEASE
Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
Figure 3
39
(Continued)
Joint bleedings are not very common in VWD, in contrast to hemophilia, but do occur in patients with severe disease. In a Swedish series of 32 cases of severe VWD, half of the patients had hemarthroses and seven chronic arthropathy. Postoperative bleeding is a common and serious symptom in VWD. Tooth extrac tions are often followed by prolonged oozing, unless adequate precautions have been taken. Operations in the region of the ear, nose, or throat such as tonsillectomy and adenoidectomy are often associated with prolonged serious bleeding. This is true also for abdominal operations, although it has sometimes been possible to perform an appendectomy without special precautions in patients with mild VWD. In all operations the bleedings may increase or recur several days or even weeks after the operation.
DIAGNOSIS The manifestations of bleeding, like the laboratory findings in VWD, tend to vary from time to time (1,53). The symptoms often decrease in severity with increasing age. The diagnosis of VWD must therefore be made jointly on the basis of the patient's history and several different laboratory examinations. We have used the following criteria for the diagnosis of VWD: I. bleeding in the patient's history, 2. positive heredity, 3. prolonged bleeding time, 4. decreased AHF activity (60%), 5. decreased platelet adhesiveness, and 6. decreased AHF-related antigen. We also think it possible to diagnose VWD in those cases where (a) relatives have not been examined but the patient meets the requirements given under points I and 3-6, and (b) typical disease in the family, but not all findings under points 3-6, are positive. The above-mentioned variations in the laboratory values must always be borne in mind. In patients with VWD, as in normals, the AHF activity fluctuates widely (51, 53). This applies particularly to mild and moderate cases of VWD. The AHF activity also increases with increasing age (48). The bleeding time also tends to become shorter with increasing age. Usually Duke's or Ivy's method is used. Duke's method is rather insensitive and has often been reported to fluctuate. In severe VWD, Duke's bleeding time is, however, nearly always markedly prolonged. The Ivy bleeding time, and especially the modification
Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
40
HOLMBERG
&
NILSSON
by Borchgrevink & Waaler (54), is a much more sensitive method. It is prolonged also in mild forms of the disease,where the Duke bleeding time is normal (55, 56). Measurement of platelet adhesiveness is now widely used to diagnose VWD. Salzman's method is used the most, and its value is well documented (19, 48, 51-53). Patients with VWD have, as a rule, low values, below 20%, but there is a certain overlap between normal persons and those with VWD. We therefore feel that reduced platelet adhesiveness alone cannot be taken as evidence of a symptom-free person having VWD or being a carrier of the disease, even if typical disease is known in the family. A firm diagnosis of VWD cannot be made before one has studied th� effect of an infusion of AHF concentrate (fraction 1-0 or cryoprecipitate), at least in the pro band in each family. The Duke bleeding time should become shorter, while the Ivy bleeding time is less responsive. The progressive increase in AHF activity is diagnos tic, but may sometimes be difficult to demonstrate in patients with mild VWD (51, 57, 58). Immunological determination of AHF-related antigen is often useful, especially in family investigations. The determination requires a specific antiserum. Most patients with VWD have a low level of AHF-related antigen (23, 25).
VARIANTS OF VWD Several authors have described VWD or VWD-like clinical pictures in which the content of AHF-related antigen has been normal. In such cases it must be assumed that the protein is defective both in respect to its AHF and VWF functions. Holm berg & Nilsson (25) described several VWD families in which all the affected members had a normal content of AHF-related antigen. In at least some of the families the inheritance was X-chromosomal. Similar patients with a normal content of antigen have since been described by several authors (59-62). Another variant of VWD-like disease has been observed by Nilsson & Cronberg (63). It is characterized by a prolonged bleeding time, decreased platelet adhesive ness, normal AHF activity, but decreased amount of AHF antigen (Holmberg, unpublished). Decreased ristocetin aggregation of platelets in platelet-rich plasma is typical of VWD, but not obligatory (64). There are probably many different patterns of the relation among AHF activity, AHF-related antigen, and ristocetin aggregation (62). From these variants one must separate those with simultaneous occurrence of VWD and other bleeding disorders, e.g. platelet defects (65-67) and classical hemo philia (68, 69). A so-called acquired VW syndrome has been seen, especially in systemic lupus erythematosus and myeloma (57, 70, 71).
TREATMENT The discovery that VWD is due to lack of a plasma factor opened up a new approach to treatment: administration of fresh plasma. Good therapeutic and prophylactic
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v. WILLEBRANO'S DISEASE
41
results have been achieved, but in severe VWD it has often proved to be less suitable because administration of sufficient volumes to secure hemostasis can cause a strain on the circulation. The first acceptable concentrate was the Swedish fraction 1-0 (10). This prepara tion has been used with success for almost 20 yr, and has proved capable of controlling all types of bleeding in VWD. Cryoprecipitate has also been reported to have a good effect. Experience has shown that the bleedings are controlled when the Duke bleeding time is normalized. The effect on the Duke bleeding time is shorter than that on the AHF activity level (see above), thus bleeding may occur even if the AHF level is high. The specific substitution therapy is the keystone of treatment. The most serious and common complication in the treatment with plasma concentrate is serum hepatitis. It is, however, fairly rare and only mild with fraction 1-0. Oral contraceptives have been found to have a considerable depressive effect on menorrhagia. This effect can probably be ascribed mainly to a local action of the hormone on the endometrium. Q
Therapy and prophylaxis with inhibitors of fibrinolysis, epsilon aminocaproic acid (EACA) and tranexamic acid (AMCA), have proved valuable in menorrhagia in patients who cannot use oral contraceptives. Inhibitors of fibrinolysis should also be used with specific treatment for bleeding from the ear, nose, and throat and in patients about to undergo tooth extraction (72). We recommend a large dose of AHF concentrate and AMCA intravenously before extraction of a tooth. The patient should afterwards be given AMCA orally for one week. As a rule, no further substitution therapy is necessary. Certl!in drugs are contraindicated in VWD. Acetylsalicylic acid prolongs the bleeding time and accentuates the tendency to bleed. This also holds for dextran, which reduces platelet adhesion. It should also be observed that intramuscular injections are likely to cause large hematomas.
SUMMARY Tlle common inheritable hemorrhagic disorder, von Willebrand's disease, has been
known for only about SO yr. During these years it has been well established that the
cause of the disease is a deficiency of a plasmll protein with remarkable biological properties. Future research should focus on details of the molecular structure of this protein. It is hoped that basic science will help to elucidate those aspects of von Willebrand's disease that are not yet properly understood.
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Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
Literature Cited 1. von Willebrand, E. A. 1926. Finska Liikaresiillskapets Handlingar 67(2): 7-112 2. Minot, G. R. 1928. A familial hemor rhagic condition associated with pro longation of the bleeding time. Am. 1. Med. Sci. 175:301-6 3. Jiirgens, R. 1937. Die erblichen Throm bopathien. Ergeb. Inn. Med. Kinder heilk. 53:795-826 4. Mac Farlane, R. G. 1941. Critical re view: the mechanism of haemostasis. Quart. 1. Med. 10:1-30 5. Estren, S., Sanchez Medal, L., Dame shek, W. 1946. Pseudohemophilia. Blood 1:504-33 6. Alexander, 8., Goldstein, R. 1953. Dual hemostatic defect in pseudohemo philia. 1. Clin. Invest. 32:551 (Abstr.) 7. Schulman, I., Smith, C. H., Erlandson, M., Fort, E., Lee, R. E. 1956. Vascular hemophilia. A familial hemorrhagic disease in males and females character ized by combined antihemophilic globu lin deficiency and vascular abnormality. Pediatrics 18:347-61 8. Singer, K., Ramot, B. 1956. Pseudohemophilia type B. Arch. Intern. Med. 97:715-25 9. Nilsson, I. M., Blombiick, M., Jorpes, E., Blombiick, 8., Johansson, S.-A. 1957. v. Willebrand's disease and its correction with human plasma fraction I�. Acta Med. Scand. 159:179-88 M., 10. Nilsson, I. M., Blombiick, v. Francken, I. 1957. On an inherited autosomal hemorrhagic diathesis with antihemophilic globulin (AHG) defi ciency and prolonged bleeding time. Acta Med. Scand. 159:35-57 11. Blombiick, B., Blomback, M. 1956. Pu rification of human and bovine fibrino gen. Ark. Kemi 10:415-33 12. Nilsson, I. M., B1ombiick, M., Blom back, 8. 1959. v. Willebrand's disease in Sweden. Its pathogenesis and treat ment. Acta Med. Scand. 164:263-78 13. Cornu, P., Larrieu, M.-J., Caen, J., Ber nard, J. 1960. Donnees nouvelles con cernant la maladie de Willebrand (angi oMmophilie). Rev. Fr. Etud. Clin. Biol 5:614-20 14. van Creveld, S., Mochtar, I. A. 1960. von Willebrand's disease-a plasma de ficiency cause of the prolonged bleeding time. Ann. Pediat. 194:37-46 15. Bennett, E., Dormandy, K. 1966. Pool's cryoprecipitate and exhausted plasma in the treatment of von Willebrand's
disease and factor XI-deficiency. Lancet 2:731-32 16. Borchgrevink, Chr. F. 1961. Platelet adhesion in vivo in patients with bleed ing disorders. Acta Med. Scand. 170:231-43 17. Hellem, A. J. 1960. The adhesiveness of human blood platelets in vitro. Scand. 1. Clin. Lab. Invest. Suppl. 51:\-110 18. Cronberg, S., Nilsson, I. M., Silwer, J. 1966. Studies on the platelet adhesive ness in von Willebrand's disease. Acta Med. Scand. 180:43-54 19. Salzman, E. W. 1963. Measurement of platelet adhesiveness. A simple in vitro technique demonstrating an abnormal ity in von Willebrand's disease. 1. Lab. Clin. Med. 62:724-35 20. Bowie, E. J. W., Owen, C. A., Thomp son, J. H., Didisheim, P. 1969. Platelet adhesiveness in von Willebrand's dis ease. Am. 1. Clin. Pathol. 52:69-77 21. Hellem, A. J. 1970. Platelet adhesive ness in von Willebrand's disease. Scand. 1. Haematol. 7:374-82 22. Meyer, D., Larrieu, M.-J. 1970. von Willebrand factor and platelet adhesive ness. 1. Clin. Pathol 23:228-31 23. Zimmerman, T. S., Ratnoff, O. D., Powell, A. E. 1971. Immunologic differentiation of classic hemophilia (factor VIII deficiency) and von Wille brand's disease. 1. Clin. Invest. 50: 244-54 24. Holmberg, L., Nilsson, I. M. 1973. Im munologic studies in haemophilia A. Scand. 1. Haematol. 10:12-16 25. Holmberg, L., Nilsson, I. M. 1972. Ge netic variants of von Willebrand's dis ease. Brit. Med. 1. 3:317-20 26. van Mourik, J. A., Mochtar, I. A. 1970. Purification of human antihemophilic factor (factor VIII) by gel chromatogra phy. Biochim. Biophys. Acta 221: 677-79 27. Bouma, B. N., Wiegerinck, Y., Sixma, J. J., van Mourik, J. A., Mochtar, I. A. 1972. Immunological characterization of purified anti-haemophilic factor A (factor VIII) which corrects abnormal platelet retention in von Willebrand's disease. Nature New BioI. 236:104-6 28. Shapiro, G. A., Andersen, J. C., Pizzo, S. V., McKee, P. A. 1973. The subunit structure of normal and hemophilic fac tor VIII. 1. Clin. Invest. 52:2198-2210 29. Holmberg, L., Nilsson, I. M. 1974. AHF related protein in clinical praxis. Scand. 1. Haematol 12:221-31
Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
V. WILLEBRAND'S DISEASE 30. Rick, M. E., Hoyer, L. W. 1973. Im munologic studies of antihemophilic factor (AHF, factor VIII). V. Im munologic properties of AHF subunits produced by salt dissociation. Blood 42:737-47 31. Owen, W. G., Wagner, R. H. 1972. An tihemophilic factor: separation of an ac tive fragment following dissociation by salts or detergents. Thromb. Diath. Ha emorrh. 27:502-15 32. Weiss, H. J., Hoyer, L. W. 1973. von Willebrand factor: Dissociation from antihemophilic factor procoagu1ant ac tivity. Science 182:1149-51 33. Zimmerman, T. S., Edgington, T. S. 1973. Factor VIII coagulant activity and factor VIII-like antigen: indepen dent molecular entities. J. Exp. Med. 138:1015-20 34. van Mourik, J. A., Bouma, B. N., La Bruyere, W. T., de Graaf, S., Mochtar, I. A. 1974. Factor VIII, a series of homologous oligomers and a complex of two proteins. Thromb. Res. 4:155-64 35. Bennett, B., Ratnoff, O. D., Levin, J. 1972. Immunologic studies in von Wi1lebrand's disease. J. Clin. Invest. 51: 2597-2601 36. Holmberg, L., Nilsson, I. M. 1973. Two genetic variants of von Willebrand's dis ease. N. Engl. J. Med. 288:595-98 37. Bloom, A. L., Peake, I. R., Giddings, J. C. 1973. The presence and reactions of high and lower-molecular-weight procoagulant and Factor VIII in the plasma of patients with von WiIle brand's disease after treatment: signifi cance for a structural hypothesis for Factor VIII. Thromb. Res. 3:389-404 38. Bennett, B., Forman, W. B., Ratnoff, O. D. 1973. Studies on the nature of an tihemophilic factor (factor VIII). J. Clin. Invest. 52:2191-97 39. Bloom, A. L., Giddings, J. c., Wilks, C. J. 1973. Factor VIII on the vascular intima: possible importance in haemos tasis and thrombosis. Nature New Bioi. 241:217-19 40. Jafe f , R. L. 1973. Synthesis of antihemophilic factor antigen by cultured human endo thelial cells. J. Clin. Invest. 52:2757-64 41. Holmberg, L., Mannucci, P. M., Tures son, I., Ruggeri, Z. M., Nilsson, I. M. 1974. Factor VIII antigen in the vessel wall in von Willebrand's disease and ha emophilia A. Scand. J. Haematol. 13: 33-38 42. Forbes, C. D., Prentice, C. R. M. 1973. Aggregation of human platelets by puri-
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55.
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fied porcine and bovine antihaemophilic factor. Nature New Biol 241:149-50 Howard, M. A., Firkin, B. G. 1971. Ris tocetin-A new tool in the investigation of platelet aggregation. Thromb. Diath. Haemorrh. 26:362-69 Weiss, H. J., Rogers, J., Brand, H. 1973. Defective ristocetin-induced platelet ag gregation in von Willebrand's disease and its correction by factor VIII. J. Clin. Invest. 52:2697-2707 Hovig, T. 1965. The effect of various enzymes on the ultrastructure, aggrega tion and clot retraction ability of rabbit blood platelets. Thromb. Diath. Ha emorrh. 13:84-113 Davis, J. W., Vue, K. T. N., Phillips, P. E. 1972. The effect of neuraminidase on platelet aggregation induced by ADP, norepinephrine, collagen or serotonin. Thromb. Diath. Haemorrh. 28:221-27 Vermylen, J., Donati, M. B., de Ga etano, G., Verstraete, M. 1973. Aggre gation of human platelets by bovine or h uman factor VIII: role of carbohy drate side chains. Nature 244:167-68 Silwer, J. 1973. von Willebrand's dis ease in Sweden. Acta Paediat. Scand. Suppl. 238:1-159 Barrow, E. M., Graham, 1. B. 1964. von Willebrand's disease. Progr. HematoL 4:203-21 Veltkamp, J. J., Tilburg, N. H. 1973. Detection of heterozygotes for recessive von Willebrand's disease by the assay of antihemophilic-factor-like antigen. N. Engl. J. Med. 289:882-85 Strauss, H. S., Bloom, G. E. 1965. von Willebrand's disease. Use of a platelet adhesiveness test in diagnosis and fam ily investigation. N. Engl. J. Med. 273:171-81 Larrieu, M. J. et al 1968. Congenital bleeding disorders with long bleeding time and normal platelet count. II. von Willebrand's disease (report of thirty seven patients). Am. J. Med. 45:354--72 Abildgaard, C. F. et al 1968. von Wille brand's disease: A comparative study of diagnostic tests. Pediatrics 73:355-63 Borchgrevink, Ch. F., Waaler, B. A. 1958. The secondary bleeding time. A new method for the differentiation of hemorrhagic diseases. Acta Med. Scand. 162:362-74 Nilsson, I. M., Magnusson, S., Borch grevink, C. 1963. The Duke and Ivy methods for determination of the bleed ing time. Thromb. Diath. Haemorrh. 10:223-34
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56. Silwer, J., Nilsson, I. M. 1964. On a Swedish family with 51 members affected by von Willebrand's disease. Acta Med. Scand. 175:627-43 57. Ingram, G. I. C., Kingston, P. J., Leslie, J., Bowie, E. J. W. 1971. Four cases of acquired von Willebrand's syndrome. Brit. J. Haematol. 21:189-99 58. Veltkamp, J. J., van Tilburg, N. H. 1974. "Autosomal haemophilia": a variant of von Willebrand's disease. Brit. J. Haematol 26:141-52 59. Bouma, B. et a11973. Factor-VIII anti gen and platelet retention in a glass bead column. Brit. J. Haematol. 25:645-56 60. Kernoff, P. B. A., Gruson, R., Rizza, C. R. 1974. A variant of factor VIII related antigen. Brit. J. Haematol. 26:435-40 61. Thomson, C., Forbes, C. D., Prentice, C. R. M. 1974. Abnormal factor VIII in von Willebrand's disease. Scot. Med. J. 19:58 62. Firkin, B., Koutts, J. 1974. VIII-related antigen and von Willebrand factor.
Lancet 1:803-4
63. Nilsson, I. M., Cronberg, S. 1968. A severe haemorrhagic disorder with pro longed bleeding time due to a plasma defect but with normal factor VIII. Acta Med. Scand. 184:181-86 64. Howard, M. A., Sawers, R. J., Firkin, B. G. 1973. Ristocetin: a means of differentiating von Willebrand's disease into two groups. Blood 41:687-90 65. Blackburn, E. K., Macfie, J. M., Monaghan, J. H., Page, A. P. M. 1961. Antihaemophilic factor deficiency, capillary defect of von Willebrand type,
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and idiopathic thrombocytopenia oc curring in one family. J. Clin. Pathol. 14:540-42 Quick, A. J. 1965. Hereditary throm bopathic thrombocytopenia and Minot v.Willebrand syndrome: probable co existence in a family. Am. J. Med. Set: 250:1-7 Corder, M. P., Culp, N. W., O'Neil, B. Jr. 1973. Familial occurrence of von Willebrand's disease, thrombocyto penia, and severe gastrointestinal bleed ing. Am. J. Med. Sci. 265:219-23 Quick, A. J., Adlam, R. T. 1963. Coex istence of von Willebrand's disease and hemophilia in a family. J. Am. Med. As soc. 185:635-39 Geiger, M. T., Rath, Ch. E. 1963. Oc currence of two hemorrhagic disorders with antihemophilic factor (AHF) defi ciency in the same family: classical hemophilia and von Willebrand's dis ' ease. J. Lab. Clin. Med. 61:424--36 Simone, J. V., Cornet, J. A., Abildg aard, C. F. 1968. Acquired von Wille brand's syndrome in systemic lupus ery
thematosus. Blood 31:806-12 71. Mant, M. J. et a1 1973. von Willebrand's syndrome presenting as an acquired bleeding disorder in association with a monoclonal gammopathy. Blood 42: 429-36 72. Bjoriin, G., Nilsson, I. M. 1973. Tooth extractions in hemophiliacs after ad ministration of a single dose of factor VIII or factor IX concentrate supple mented with AMCA. Oral Surg. Oral Med. Oral Path. 36:482-89
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VON WILLEBRAND'S DISEASE Lars Holmberg, MD. and Inga Marie Nilsson, MD.
.7129
1
Coagulation Laboratory, University of Lund, Allmiinna Sjukhuset, Malmo, Sweden
INTRODUCTION An abnormal bleeding tendency is often due to an inherited defect of hemostasis. One of the commonest of such defects is von Willebrand's disease (VWD), which is multifaceted but nevertheless has a typical clinical picture. Investigations of the cause of the condition have resulted in good prospects for controlling formerly life-threatening bleeding. Research in VWD also has contributed considerably to our knowledge of normal hemostasis.
HISTORY In 1926 Erik 1dolf von Willebrand (l) described an inheritable bleeding disease on the islands of Aland in the Gulf of Bothnia (Finland). Von Willebrand's description included bleeding from the gums and after tooth extraction, bleeding from the female genital tract, and bleeding from trivial wounds, but he stressed that joint bleedings, common in hemophilia, were relatively rare. Von Willebrand distinguished the disease from anaphylactoid purpura and thrombocytopenic purpura as well as from the hereditary hemorrhagic thrombas thenia described by Glanzmann. He concluded that the condition was a previously unknown form of hemophilia which affected both sexes, and he called the disease hereditary pseudohemophilia. A prolonged bleeding time was its most important characteristic. In 1928 the clinical picture was reported independently by four Americans, including Minot (2). In the 1930s Jiirgens reinvestigated the original families on Aland and concluded that the platelets, as in Glanzmann's thrombasthenia, were defective (3). Other authors were, however, unable to demonstrate either a mor phologic platelet defect or abnormal clot retraction in cases which in all respects resembled the disease described by von Willebrand (4, 5). They sought the cause of the disease in the morphology and function of the capillaries (4). In the 1950s methods were developed for measuring the various hemophilia factors. In 1953 Alexander & Goldstein (6) described two cases with a combined 'Supported by a grant from the Swedish Medical Research Council (B75-19X-87-IIA). 33
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defect in hemostasis, namely, a prolonged bleeding time and decreased antihemo philic factor A (AHF) activity. Similar cases were later observed by a number of other authors; Schulman et al (7) called the disease vascular hemophilia, while · Singer & Ramot (8) used the term, pseudohemophilia B. In 1957 Nilsson et al (9) found the AHF activity to be reduced in 15 cases of VWD from the original families on Aland. This finding clearly showed that the bleeding disease observed in various quarters of the world was identical to that described by von Willebrand. The same group (10) found that the platelets were normal in respect to platelet factors 1,3,and 4. The then novel AHF concentrate, plasma fraction 1-0 (II), prepared from Cohn's fraction I, corrected not only the AHF deficiency, but also the bleeding time and the capillary bleedings.
PATHOGENESIS Nilsson et al (12) later showed that patients with VWD lack a plasma factor occurring not only in normal plasma, but also in hemophilia plasma. This so-called v. Willebrand's factor (VWF) is not present in pure fibrinogen fractions or in platelets. The VWF not only corrects the prolonged bleeding time in patients with VWD, but also apparently stimulates the synthesis of AHF. The plasma fraction 1-0, prepared from hemophilia plasma and thus devoid of AHF activity, increases the AHF activity when given to patients with VWD (12). Similar results have been reported by others (13, 14). The VWF appears to be closely related to AHF and occurs in AHF-rich plasma concentrates (12, 15). It was at first not known how a plasma factor could affect primary hemostasis and shorten the bleeding time. The basis of primary hemostasis is the formation of a platelet plug. Borchgrevink (16) found decreased platelet adhesiveness in vivo in patients with VWD by comparing the platelet count in venous blood and in blood from a capillary lesion. A reliable in vitro test for measuring the interaction between platelets and a glass surface was devised by Hellem (17). Hellem's original method, which used citrated blood, did not distinguish normal persons from those with VWD (18). Salzman (19) used native blood and a quicker flow and then could demonstrate a decreased platelet adhesiveness to glass in VWD. Modifications of Salzman's method, all with a rapid blood flow, have also been diagnostically useful (20,21), although they are technically difficult and subject to methodological errors. Common to all methods of measuring platelet adhesiveness that can distinguish between persons with and without VWD is the use of a rapid flow of blood through a column of glass beads. The reduced platelet adhesiveness in VWD, like the bleeding time, can be normal ized by infusion of fresh platelet-poor plasma (19). Such normalization can be demonstrated in vitro by mixing the patient's blood with normal plasma, hemophilia plasma, or cryoprecipitate (22). The factor causing such normalization is missing in VWD plasma. Further knowledge about the pathogenesis of VWD has been obtained in recent years since the advent of highly purified AHF. The AHF, as isolated from plasma, is a very large macroglobulin. Monospecific precipitating rabbit antisera against this
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V. WILLEBRAND'S DISEASE
35
globulin have been prepared. Patients with hemophilia A have a cross-reacting but inactive protein in the plasma (23, 24), while the majority of patients with VWD have a low content of this so-called AHF-related antigen (23, 25). The chromato graphic pattern of normal (and hemophilia) cryoprecipitate on Sepharose 6-B ac cording to v. Mourik & Mochtar (26) shows a typical protein peak corresponding to the AHF-related plasma protein in the void volume. No such peak is seen when the starting material consists of cryoprecipitate from a patient with severe VWD. The content of AHF-related protein is thus often really decreased in VWD (27; Holmberg & Nilsson, unpublished). Bouma et al (27) showed that the AHF-related high molecular weight protein is responsible for enabling normal and hemophilic plasma to normalize the reduced platelet adhesiveness in VWD. High molecular weight AHF thus possesses not only AHF activity, but also VWF activity, and can then be called AHF-VWF protein. What is the structure of this protein? Does it consist of two components, one possessing the AHF activity and the other the VWF activity, or does it consist of a single but bifunctional molecule (27)? Much evidence suggests that the protein consists of identical or at any rate equally large protein chains, possibly connected by covalent bonds to a large molecule and by noncovalent bonds to very large aggregates, which dissociate in various salt solutions (28-30). Other investigations, however, suggest that the protein complex consists of immunologically and biologi cally separate components (31-34). Administration of AHF concentrate to a patient with severe VWD has, as pointed out abovt:, a number of effects (Figure I). It will shorten the bleeding time, and an increase in AHF activity out of proportion to the activity of the concentrate will occur. But this is not accompanied by any increase in the amount of antigenic "I.
min.
10
.....
......
I o /
.......
'0
15'30' 60' l' I 400ml AHF Figure 1 disease.
.......
........
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--.
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Infusion of AHF concentrate (fraction I-D) to a patient with severe v. Willebrand's
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bleeding time.
AHF activity,
x---x
AHF-related antigen (AHF-VWF antigen),
0- -0
Duke's
Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
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HOLMBERG & NILSSON
protein,which instead decreases successively (35,36). AHF activity may thus occur in some substance, which does not react to the antiserum with any demonstrable precipitation. This AHF activity may perhaps occur in a plasma fraction of lower molecular weight (37). Judging from available experimental data,one might explain the defect in VWD as follows. The building stones of the high molecular weight AHF, i.e. protein chains with a molecular weight of 180,000---240,000 (28,29,38),are coded from an X-chromosomal AHF locus. The chains contain the sequences necessary for both AHF activity and VWF activity in the final molecule. But if the molecule is to have VWF activity,it must have a very special quarternary structure. The VWF activity seems to be labile, more labile than the ability of the protein to react with antiserum. Autosomal genes are responsible for polymerization of the chains to a large molecule with the special configuration. In the most common form of VWD with a low content of AHF antigen (25),the defect may consist of impairment of the ability to form high molecular weight AHF from the building stones-the protein chains. Since it is only the high molecular weight AHF that is precipitated with rabbit antiserum, the antigen content will be small or absent. Secondarily,a feedback inhibition of the synthesis of low molecular weight AHF occurs (Figure 2). VWD with a normal content of AHF-re1ated antigen has also been described (25). One might imagine several explanations: (a) There is X-chromosomal heredity with a defect in the sequence of the primary structure which is significant for VWF activity. Also the AHF activity is affected. The polymerization is normal (as in hemophilia A) because the autosomal genes are intact. This variant might also be regarded as a variant of hemophilia A with a prolonged bleeding time and decreased platelet adhesiveness (25), but clinically it resembles VWD rather than hemophilia A. (b) There is autosomal heredity in which polymerization may occur, but in an abnormal way, with the effect that the quaternary structure is different, resulting in reduction of both the VWF and the AHF activity. The structure is,however,so similar to normal that the molecule reacts with rabbit antiserum against AHF related protein. How and where does the VWF act in vivo? As mentioned, the factor occurs in the plasma,but with the aid of immunofluorescence it can be demonstrated also in A
1
X ---- LMW - AHF � HMW-AHF
� Figure 2
Hypothetical pathway for the synthesis of AHF and VWF. x.. X-chromosomal
gene, A: autosomal gene, LMW-AHF: low molecular weight AHF, HMW-AHF: high molecu lar weight AHF.
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V. WILLEBRAND'S DISEASE
37
the intima of the blood vessels (39). The protein may actually be synthesized in endothelial cells (40). Patients with severe VWD lack AHF-VWF protein not only in the plasma, but also in the vessel walls (41). In such patients infusion of cryo precipitate is followed by an increase in the AHF-VWF antigen in the plasma, while the antigen is still not demonstrable in the endothelium (Holmberg, unpublished). This finding suggests that the occurrence of AHF-VWF protein in the intima is due to a true synthesis in the vessel wall and not simply to adsorption of the protein to the endothelial surface. It is not known whether the plasma protein or the vessel protein is of greater importance in primary hemostasis. The interaction between AHF-VWF protein and platelets in primary hemostasis is still unknown. Some interesting observations have, however, been made. Purified bovine and porcine high molecular weight AHF-related proteins aggregate human platelets in vitro (42). Human AHF-VWF protein can be modified in such a way as to aggregate platelets. The antibiotic ristocetin aggregates platelets in vitro in normal persons, but generally not in patients with VWD (43). Ristocetin has no effect on isolated platelets, but requires the presence of the high molecular weight AHF-VWF protein to exert its effect (44). The effect of the enzyme neuraminidase on platelet aggregation also seems to be related to the AHF-VWF protein. Neuraminidase aggregates rabbit platelets in the presence of a plasma factor (45),and increases aggregation of human platelets with inter alia ADP (46). Vermylen et al (47) showed that human AHF-VWF protein, preincubated with neuraminidase, spontaneously aggregates human platelets in platelet-rich plasma.
GENETICS VWD seems to be one of the most common hemorrhagic diatheses. Silwer (48) estimated the frequency in Sweden at 1 :32,000 inhabitants. However, mild cases may remain undiagnosed. Most authors agree that the disease is inherited by an autosomal and dominant gene (10,49). Of 40 families with VWD, Silwer (48) found the expected pattern of autosomal dominant inheritance in 27 (Figure 3). In single published cases, however, the transmission might have been different (25, 48, 50). Some authors have shown an increased frequency of consanguineous marriages, others a high frequency of sporadic cases (51). The disease seems to be more common among women than' among men. This is probably because women with VWD so often have menorrhagia, which leads to the detection of the dis ease. Assuming that the inheritance is autosomal dominant, it is obvious that its penetrance and expressivity vary considerably (48,51,52). Yet in Silwer's material substantial differences in expressivity were uncommon. He found the penetrance to be 73-90%, and estimated the risk of a child of an affected person inheriting the disease to be 40% or less. The risk of the disease being severe was, however, regarded as 5% or less.
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HOLMBERG & NILSSON
Family 42
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,
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v. WILLEBRAND'S DISEASE
Annu. Rev. Med. 1975.26:33-44. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/30/15. For personal use only.
Figure 3
Pedigree illustrating autosomal and dominant inheritance of
Y.
Willebrand's disease.
SYMPTOMS The symptoms in VWD vary widely. In severe VWD the bleedings may be life threatening, while in mild VWD they may be so mild that the disease remains concealed. Nose bleeding is the most common symptom of VWD and occurs in 60-80% of affected patients (Silwer, 48). Bleeding from the oral cavity is also fairly common; in children, traumatic bleeding of the lips, tongue, and oral cavity are characteristic. In contrast with what is seen in hemophilia, deep subcutaneous and intramuscular
hematomas are uncommon in VWD. Very typical, however, are prolonged bleedings from trivial wounds. The most prominent bleeding symptom in women with VWD is probably menor rhagia. Menstrual disorders occur in some 50-75% of such women. The symptom is most severe during the first few years after menarche, and has occasionally been life-threatening and required hysterectomy or roentgen castration. Menorrhagia is also often a difficult problem in VWD characterized as mild by laboratory tests. Another type of bleeding from the female genital tract, which has not received much attention, is corpus luteum bleeding. Typical cases are characterized by intermen strual, more or less severe, abdominal pain and often by a low Hb because of intra-abdominal bleeding. Delivery in women with VWD is often, though not always, associated with heavy blood loss. In some women with VWD the AHF level rises during pregnancy, which lessens the risk of bleeding. The AHF, however, does not always rise, and especially not in women with an initially very low level. Even if no bleeding occurs at parturi tion, the patient must be observed for at least a week post partum because the AHF level falls after delivery. In most published series of VWD the frequency of gastrointestinal bleeding is relatively low, usually 10-15%. It is, however, striking that when such bleeding occurs it is usually very severe. In most cases the patients appear to bleed diffusely from the mucosa. Roentgen examination rarely reveals any local source of bleeding, such as gastric or duodenal ulcer. The frequency of hematuria has been given as 2-7.5%. The bleeding is rarely so severe as to require specific treatment.
V. WILLEBRANO'S DISEASE
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Figure 3
39
(Continued)
Joint bleedings are not very common in VWD, in contrast to hemophilia, but do occur in patients with severe disease. In a Swedish series of 32 cases of severe VWD, half of the patients had hemarthroses and seven chronic arthropathy. Postoperative bleeding is a common and serious symptom in VWD. Tooth extrac tions are often followed by prolonged oozing, unless adequate precautions have been taken. Operations in the region of the ear, nose, or throat such as tonsillectomy and adenoidectomy are often associated with prolonged serious bleeding. This is true also for abdominal operations, although it has sometimes been possible to perform an appendectomy without special precautions in patients with mild VWD. In all operations the bleedings may increase or recur several days or even weeks after the operation.
DIAGNOSIS The manifestations of bleeding, like the laboratory findings in VWD, tend to vary from time to time (1,53). The symptoms often decrease in severity with increasing age. The diagnosis of VWD must therefore be made jointly on the basis of the patient's history and several different laboratory examinations. We have used the following criteria for the diagnosis of VWD: I. bleeding in the patient's history, 2. positive heredity, 3. prolonged bleeding time, 4. decreased AHF activity (60%), 5. decreased platelet adhesiveness, and 6. decreased AHF-related antigen. We also think it possible to diagnose VWD in those cases where (a) relatives have not been examined but the patient meets the requirements given under points I and 3-6, and (b) typical disease in the family, but not all findings under points 3-6, are positive. The above-mentioned variations in the laboratory values must always be borne in mind. In patients with VWD, as in normals, the AHF activity fluctuates widely (51, 53). This applies particularly to mild and moderate cases of VWD. The AHF activity also increases with increasing age (48). The bleeding time also tends to become shorter with increasing age. Usually Duke's or Ivy's method is used. Duke's method is rather insensitive and has often been reported to fluctuate. In severe VWD, Duke's bleeding time is, however, nearly always markedly prolonged. The Ivy bleeding time, and especially the modification
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HOLMBERG
&
NILSSON
by Borchgrevink & Waaler (54), is a much more sensitive method. It is prolonged also in mild forms of the disease,where the Duke bleeding time is normal (55, 56). Measurement of platelet adhesiveness is now widely used to diagnose VWD. Salzman's method is used the most, and its value is well documented (19, 48, 51-53). Patients with VWD have, as a rule, low values, below 20%, but there is a certain overlap between normal persons and those with VWD. We therefore feel that reduced platelet adhesiveness alone cannot be taken as evidence of a symptom-free person having VWD or being a carrier of the disease, even if typical disease is known in the family. A firm diagnosis of VWD cannot be made before one has studied th� effect of an infusion of AHF concentrate (fraction 1-0 or cryoprecipitate), at least in the pro band in each family. The Duke bleeding time should become shorter, while the Ivy bleeding time is less responsive. The progressive increase in AHF activity is diagnos tic, but may sometimes be difficult to demonstrate in patients with mild VWD (51, 57, 58). Immunological determination of AHF-related antigen is often useful, especially in family investigations. The determination requires a specific antiserum. Most patients with VWD have a low level of AHF-related antigen (23, 25).
VARIANTS OF VWD Several authors have described VWD or VWD-like clinical pictures in which the content of AHF-related antigen has been normal. In such cases it must be assumed that the protein is defective both in respect to its AHF and VWF functions. Holm berg & Nilsson (25) described several VWD families in which all the affected members had a normal content of AHF-related antigen. In at least some of the families the inheritance was X-chromosomal. Similar patients with a normal content of antigen have since been described by several authors (59-62). Another variant of VWD-like disease has been observed by Nilsson & Cronberg (63). It is characterized by a prolonged bleeding time, decreased platelet adhesive ness, normal AHF activity, but decreased amount of AHF antigen (Holmberg, unpublished). Decreased ristocetin aggregation of platelets in platelet-rich plasma is typical of VWD, but not obligatory (64). There are probably many different patterns of the relation among AHF activity, AHF-related antigen, and ristocetin aggregation (62). From these variants one must separate those with simultaneous occurrence of VWD and other bleeding disorders, e.g. platelet defects (65-67) and classical hemo philia (68, 69). A so-called acquired VW syndrome has been seen, especially in systemic lupus erythematosus and myeloma (57, 70, 71).
TREATMENT The discovery that VWD is due to lack of a plasma factor opened up a new approach to treatment: administration of fresh plasma. Good therapeutic and prophylactic
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v. WILLEBRANO'S DISEASE
41
results have been achieved, but in severe VWD it has often proved to be less suitable because administration of sufficient volumes to secure hemostasis can cause a strain on the circulation. The first acceptable concentrate was the Swedish fraction 1-0 (10). This prepara tion has been used with success for almost 20 yr, and has proved capable of controlling all types of bleeding in VWD. Cryoprecipitate has also been reported to have a good effect. Experience has shown that the bleedings are controlled when the Duke bleeding time is normalized. The effect on the Duke bleeding time is shorter than that on the AHF activity level (see above), thus bleeding may occur even if the AHF level is high. The specific substitution therapy is the keystone of treatment. The most serious and common complication in the treatment with plasma concentrate is serum hepatitis. It is, however, fairly rare and only mild with fraction 1-0. Oral contraceptives have been found to have a considerable depressive effect on menorrhagia. This effect can probably be ascribed mainly to a local action of the hormone on the endometrium. Q
Therapy and prophylaxis with inhibitors of fibrinolysis, epsilon aminocaproic acid (EACA) and tranexamic acid (AMCA), have proved valuable in menorrhagia in patients who cannot use oral contraceptives. Inhibitors of fibrinolysis should also be used with specific treatment for bleeding from the ear, nose, and throat and in patients about to undergo tooth extraction (72). We recommend a large dose of AHF concentrate and AMCA intravenously before extraction of a tooth. The patient should afterwards be given AMCA orally for one week. As a rule, no further substitution therapy is necessary. Certl!in drugs are contraindicated in VWD. Acetylsalicylic acid prolongs the bleeding time and accentuates the tendency to bleed. This also holds for dextran, which reduces platelet adhesion. It should also be observed that intramuscular injections are likely to cause large hematomas.
SUMMARY Tlle common inheritable hemorrhagic disorder, von Willebrand's disease, has been
known for only about SO yr. During these years it has been well established that the
cause of the disease is a deficiency of a plasmll protein with remarkable biological properties. Future research should focus on details of the molecular structure of this protein. It is hoped that basic science will help to elucidate those aspects of von Willebrand's disease that are not yet properly understood.
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Literature Cited 1. von Willebrand, E. A. 1926. Finska Liikaresiillskapets Handlingar 67(2): 7-112 2. Minot, G. R. 1928. A familial hemor rhagic condition associated with pro longation of the bleeding time. Am. 1. Med. Sci. 175:301-6 3. Jiirgens, R. 1937. Die erblichen Throm bopathien. Ergeb. Inn. Med. Kinder heilk. 53:795-826 4. Mac Farlane, R. G. 1941. Critical re view: the mechanism of haemostasis. Quart. 1. Med. 10:1-30 5. Estren, S., Sanchez Medal, L., Dame shek, W. 1946. Pseudohemophilia. Blood 1:504-33 6. Alexander, 8., Goldstein, R. 1953. Dual hemostatic defect in pseudohemo philia. 1. Clin. Invest. 32:551 (Abstr.) 7. Schulman, I., Smith, C. H., Erlandson, M., Fort, E., Lee, R. E. 1956. Vascular hemophilia. A familial hemorrhagic disease in males and females character ized by combined antihemophilic globu lin deficiency and vascular abnormality. Pediatrics 18:347-61 8. Singer, K., Ramot, B. 1956. Pseudohemophilia type B. Arch. Intern. Med. 97:715-25 9. Nilsson, I. M., Blombiick, M., Jorpes, E., Blombiick, 8., Johansson, S.-A. 1957. v. Willebrand's disease and its correction with human plasma fraction I�. Acta Med. Scand. 159:179-88 M., 10. Nilsson, I. M., Blombiick, v. Francken, I. 1957. On an inherited autosomal hemorrhagic diathesis with antihemophilic globulin (AHG) defi ciency and prolonged bleeding time. Acta Med. Scand. 159:35-57 11. Blombiick, B., Blomback, M. 1956. Pu rification of human and bovine fibrino gen. Ark. Kemi 10:415-33 12. Nilsson, I. M., B1ombiick, M., Blom back, 8. 1959. v. Willebrand's disease in Sweden. Its pathogenesis and treat ment. Acta Med. Scand. 164:263-78 13. Cornu, P., Larrieu, M.-J., Caen, J., Ber nard, J. 1960. Donnees nouvelles con cernant la maladie de Willebrand (angi oMmophilie). Rev. Fr. Etud. Clin. Biol 5:614-20 14. van Creveld, S., Mochtar, I. A. 1960. von Willebrand's disease-a plasma de ficiency cause of the prolonged bleeding time. Ann. Pediat. 194:37-46 15. Bennett, E., Dormandy, K. 1966. Pool's cryoprecipitate and exhausted plasma in the treatment of von Willebrand's
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