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Von Willebrand's Disease
Symposium on Hemorrhagic Disorders
Von Willebrand's Disease E. J. Walter Bowie, B.M., B.Ch.,* and Charles A. Owen, Jr., M.D., Ph.D.**
In 1924, von Willebrand reported a bleeding disease unlike any abnormality of hemostasis then known. The patients had prolongation of the bleeding time, and the bleeding affected mainly the skin and mucous membranes, as in thrombocytopenia, but depressed platelet counts were not the rule. Occasional patients had bleeding into the joints, as in hemophilia, but both males and females were affected. Blood clots retracted normally, excluding Glanzmann's disease. Similar cases had been reported although none were as well characterized clinically and genetically as von Willebrand's on the Aland Islands between Finland and Sweden. Quick has pointed out that perhaps the first case of the syndrome was described by Minot and Lee in 1920 and has suggested that the syndrome be called the "Minot-von Willebrand syndrome."36 It is now becoming clear that von Willebrand's disease is one of the commonest of the inherited bleeding disorders and, although the diagnostic criteria are still somewhat ill-defined, recent investigations have allowed the disease to be delineated more clearly.47 If the classic triad -long bleeding time, decreased factor VIII, and poor adhesiveness of platelets - is present the diagnosis is sure. It is important to be aware of the disease because mild cases can easily be overlooked if the diagnosis is not suspected. Although the disease is inherited autosomally, its exact mode of inheritance is uncertain. Most reports conclude that the inheritance is dominant. In our opinion, the difficulty of making an exact diagnosis in mild cases precludes accurate assessment of its mode of inheritance. Recently there have been reports of an acquired form of the disease which has been called "von Willebrand's syndrome."17. 41 Purpura with bleeding into the skin and mucous membranes is the commonest type of bleeding seen in these patients, and epistaxis is perhaps the commonest symptom. Menorrhagia is usual in these patients and, in some instances, menorrhagia at the menarche may be the presenting complaint. Gastrointestinal bleeding may occur spontane• Associate Professor of Internal Medicine and Clinical Pathology, Mayo Graduate School of Medicine (University of Minnesota); Consultant, Section of Clinical Pathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota "Professor of Clinical Pathology, Mayo Graduate School of Medicine (University of Minnesota); Consultant, Department of Biochemistry, Mayo Clinic, Rochester, Minnesota Medical Clinics of North America-Vol. 56, No. 1, January 1972
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OWEN, JR.
ously and appears to be commoner in males. It should be emphasized, however, that gastrointestinal bleeding should never be attributed to von Willebrand's disease or any other hemorrhagic diathesis without a careful investigation of the gastrointestinal tract. Hematuria has been described. When the factor VIII level is low, hemarthroses and hemophilic bone cysts may occur in both males and females. Bleeding often accompanies shedding of the deciduous teeth, and gingival bleeding is a common complaint. Thus, the common symptoms of von Willebrand's disease, ease of bruising, epistaxis, and menorrhagia, all may occur in women who have no abnormality of hemostasis. This emphasizes the importance of being suspicious of the disease in patients with mild bleeding problems and of carefully evaluating the clinical history. There is no question that a number of families who have been thought to have mild hemophilia may in fact be afflicted with von Willebrand's disease, the significance of epistaxis and menorrhagia being overlooked in the females. If a patient is pregnant, the test results should be interpreted with caution because, in a patient with von Willebrand's disease, pregnancy may cause the bleeding time, platelet adhesiveness, and factor VIII level to return toward normal. It is important therefore that these patients be evaluated several months after delivery before the possibility of the disease can be excluded. It is also possible that oral contraceptives may affect the tests although this has not been definitely documented. The bleeding time may be shortened by treatment with corticosteroids. In taking the history it is important to make specific inquiry about the use of aspirin because this medicament may prolong the bleeding time and impair collagen-induced platelet aggregation and the second wave of platelet aggregation with adenosine diphosphate. Quick has suggested that the bleeding time in equivocal cases is diagnostically lengthened by administration of two tablets (625 mg) of aspirin.
PROLONGATION OF BLEEDING TIME A long bleeding time was the first abnormality described in von Willebrand's disease and is one of the most important criteria for making the diagnosis. However, by the usual technique the bleeding time has a wide standard deviation, and it varies widely in the same patient. In mild cases it may at times be normal. There is general agreement 40 that the Ivy bleeding time is a more effective screening test than the Duke bleeding time because the Duke bleeding time may be normal in situations in which the Ivy bleeding time is prolonged. Geiger and Evans 12 in 1938 were able to produce shortening of the bleeding time by the administration of blood transfusions and Schulman and associates39 in 1955 obtained similar corrections by the transfusion of fresh-frozen plasma. A plasmatic fraction (1-0) of Cohn's fraction I, made from normal subjects or from patients with classic hemophilia, was shown to shorten the Duke bleeding time. If the fraction was made from a patient with von Willebrand's disease the prolonged bleeding time was not affected. It was shown that the activity producing correction of the bleeding time was
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distinct from factor VIII, fibrinogen, and platelets and on this basis it was suggested that the prolongation of the bleeding time in von Willebrand's disease was due to the absence of "vascular factor." Most of the reports in the literature deal with the Duke bleeding time which appears more easily correctable than the Ivy bleeding time. However, some workers have used the Ivy technique in their studies and correction has been produced by hemophilic plasma, a subfraction of Cohn fraction I precipitated by alcohol, and by cryoprecipitate. Weiss46 has shown that correction of the bleeding time is best produced when the fractions are made in siliconized apparatus, and it seems likely that discrepancies in the literature are often related to the method of preparation. In addition, conflicting reports may arise from the variations of the severity of the disease in the patients being studied, the amount of the preparation transfused, and the technique of performing the bleeding time test. We have found35 a great deal of variability in correction of the Duke or Ivy bleeding time by either plasma or cryoprecipitate. Although in many patients the bleeding time is not decreased to within the normal range, visual inspection of the wound has suggested that the amount of blood lost is decreased after treatment. Because of these observations we developed a new test which measures the time, intensity, and pattern of bleeding from standardized skin punctures. 43 The Mayo automatic spring-loaded lancet is used to produce an incision, in the skin of the forearm, between 1 and 2 mm deep and 1 mm wide. After the pressure in the capillaries is standardized by inflation of a blood pressure cuff on the upper arm to 40 mm Hg, a transparent plastic tube with a channel in the base is placed over the incision and distilled water is sucked through the channel of the tube by a proportioning pump. The blood entrained in the water is allowed to hemolyze completely and the hemoglobin concentration is measured in a flow-cell spectrophotometer. The absorbance is continuously recorded by a chart recorder. We have recently modified the apparatus and now measure the exuding blood volume by electrical conductance. Using these techniques we have demonstrated that, although the bleeding time may not be decreased to within the normal range, the amount of blood lost from the wound is strikingly decreased for a few hours after the transfusion of fresh-frozen plasma. The technique will permit the accurate assessment of the effect of plasma fractions and medicaments on the bleeding time in patients with von Willebrand's disease.
ABNORMALITIES OF PLATELET FUNCTION One of the obvious explanations for a long bleeding time would be that these patients have abnormalities of platelet function. Although such abnormalities have been shown in von Willebrand's disease, the relationship between the bleeding time and platelet function has not been consistent. The suspicion that platelets may be involved in the hemostatic defect was first raised by von Willebrand, and subsequent investigations, using a now-defunct instrument-the capillary throm-
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OWEN, JR.
bometer-showed a strikingly abnormal "thrombosing time." It was not until 1960 that Hellem16 developed a method for measuring the retention of platelets in glass-bead columns ("platelet adhesiveness") and showed that 5 of 15 patients with von Willebrand's disease had decreased adhesiveness. But Hellem thought that the results were spurious because four of these five patients had low hematocrit values, and erythrocytes were essential for producing maximal platelet retention. Zucker49 reported that platelet adhesiveness was indeed abnormal in von Willebrand's disease and that normal plasma corrected the abnormality. Salzman 38 used a method in which blood is drawn directly from the vein over the glass-bead column and into a Vacutainer. Some workers 42 state that the Salzman test plays an essential role in the diagnosis and Meyer and associates28 . 29 think that this is the most sensitive diagnostic test. Decreased platelet adhesiveness has not been demonstrated by all investigators, and there seems little doubt that the conflicting results are due to the different techniques used for the demonstration of platelet adhesiveness. Serious problems are inherent in the standardization of these rather complex procedures. The importance of the rate of the flow of the blood in the glass-bead column was demonstrated by O'Brien and Heywood. 33 These workers showed that, if the flow rate was too slow, platelet retention in von Willebrand's disease becomes normal. By controlling a number of variables in the test, including the flow rate, we have produced a modification of the glass-bead adhesiveness test which has proved reproducible and useful in our hands in the diagnosis of von Willebrand's disease. Blood, lightly heparinized, is pushed at a controlled rate through a glass-bead column and the percentage of platelets retained in the column is calculated for each milliliter of column effluent. Using this procedure we have shown that platelet retention in the glass-bead column is consistently decreased in severe von Willebrand's disease. The abnormal test results could be due to a platelet defect, to the absence of a factor necessary for normal "stickiness," or to an abnormal release of ADP from the erythrocytes. Our further investigations have shown that the erythrocytes are apparently normal in von Willebrand's disease and suggest that the abnormality lies not in the platelets but in the plasma.6 Meyer and Larrieu27 have reached similar conclusions.
FACTOR VIII DEFICIENCY In 1953, three independent reports1 , 22, 37 documented that the antihemophilic factor (factor VIII) level was decreased in patients with von Willebrand's disease. Subsequently, the patients in the Aland Islands were investigated and were found to have factor VIII deficiency.2o,32 Classic hemophilia is of course inherited as a sex-linked recessive characteristic, and the demonstration that factor VIII deficiency could also be inherited autosomally was of major importance and has led to many intriguing speculations regarding factor VIII inheritance and synthesis. After the documentation of factor VIII deficiency in these patients, Nilsson and colleagues30 reported a most unusual finding. One of their pa-
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tients with von Willebrand's disease was transfused with plasma fraction 1-0 of Blomback, and the patient's level of factor VIII increased higher than could be accounted for by the amount of factor VIII infused. The factor VIII remained at increased levels for 5 days in this patient. In hemophiliacs, there is a rapid decrease of infused factor VIII, the factor having an in vivo half-life of 10 to 15 hours. Even more intriguing was the demonstration by Nilsson's group that the remarkable increase in factor VIII could even be produced by plasma or fraction 1-0 made from patients with classic hemophilia who lack demonstrable plasmatic factor VIII activity. These findings have now been confirmed on numerous occasions. It also has been shown4 that the fibrinogen fraction of plasma, containing no demonstrable factor VIII activity, could cause an increase in the level of factor VIII. In addition, serum or serum absorbed with calcium phosphate can cause similar stimulation of the patient's plasmatic level of factor VIII.5. 11.42 Although the initial increase in factor VIII could be explained by the content of factor VIII in the transfused material, it was postulated that the subsequent paradoxic increase was due to new synthesis of factor VIII by the recipient. This newly synthesized factor VIII apparently is not different from ordinary factor VIII, whether plasma from a classic hemophiliac or a normal person is responsible for its production.3 It has also been reported23 that the patient's factor VIII synthetic mechanism becomes refractory after repeated transfusions. We have shown that the response of factor VIII is related to the dose of plasma given but, because of the dangers of circulatory overload occasioned by large plasma transfusions, it will be necessary to use concentrates to demonstrate the maximal response. FACTOR VIII INHERITANCE AND SYNTHESIS IN VON WILLEBRAND'S DISEASE AND HEMOPHILIA There has been a great deal of interest recently in the immunology of coagulation factors, including factor VIII. Several workers have demonstrated that a high proportion of hemophiliacs have a plasmatic material that cross-reacts with factor VIII antibodies - in other words, factor VIIIlike protein antigenically despite absence of the factor's activity biologically. In fact, Zimmerman and colleagues,48 using a rabbit antibody to factor VIII, found that cross-reacting material can be demonstrated in all hemophiliacs in amounts comparable to those in normal plasma despite the virtual absence of factor VIII clotting activity. In von Willebrand's disease, however, the amount of cross-reacting material is no greater than the amount of functionally active factor VIII. The suggestion has been made, therefore, that von Willebrand's disease represents an actual deficiency of factor VIII while classic hemophilia represents, in many instances at least, not a deficiency but an abnormality of the factor VIII molecule which renders it functionally inactive. We have a colony of pigs with a bleeding disease that has all the characteristics of human von Willebrand's disease. They provide an ideal animal model for genetic and transfusion studies. The same chro-
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OWEN, JR.
matographic fraction of plasma or serum which contains factor VIII causes the over-response of factor VIII in these animals. s In the serum fractions, no factor VIII activity can be demonstrated on functional testing. In some of our studies the fractions which cause an increase in the factor VIII level have also resulted in normalization of the bleeding time and platelet adhesiveness. However, the fractions were not pure enough so that we could be sure that all these abnormalities are due to the lack of a single factor. Von Willebrand's disease has also been described in German shepherd dogs, providing another animal model for study.9 The over-response of factor VIII to the transfusion of plasma from patients with classic hemophilia may be explained by the activation of the inactive factor VIII molecule present in the hemophiliac. There are numerous other speculative explanations for this over-response, including the possibility that normal plasma and hemophilic plasma contain a stimulating factor which causes the synthesis of factor VIII in patients with von Willebrand's disease. For example, there is the possibility that there are two different kinds of factor VIII/ one type being deficient in von Willebrand's disease and the other type being deficient in hemophilia. 34 Graham and colleagues 13- 15 ,26 have proposed several models to explain the synthesis of factor VIII. The "activator" theory suggests that an activator is produced on the locus of von Willebrand's disease and that this activates a precursor of factor VIII which is produced by the locus on the X chromosome. The "inducer" model suggests that an autosomal locus synthesizes a metabolite which acts as an inducer or regulator for the operon system on the X chromosome, which produces factor VIII. A "combining subunit" model suggests that factor VIII may be a polymer and one chain is coded by a locus on the X chromosome and the other, by an autosomal locus which would be the locus for von Willebrand's disease. 3
MISCELLANEOUS OBSERVATIONS CONCERNING BLOOD VESSELS, PLATELETS, AND COAGULATION FACTORS The possibility that an abnormality of the capillaries was responsible for the hemostatic defect was suggested by Macfarlane 24 who described distorted and bizarre capillaries in the nail beds of five patients with von Willebrand's disease, When the capillaries were punctur.ed with a glass fiber, no contraction occurred. Subsequent observations have produced many conflicting reports, one of the problems being to classify the morphology of normal capillaries. J amra and his colleagues 18 studied patients with constitutional capillaropathies and were unable to find any departure from the normal. Abnormality of platelet factor 3 activity has been reported; this is the partial thromboplastic activity of platelets. We have demonstrated5 ineffective release of factor 3 activity in two brothers with severe von Willebrand's disease but platelet procoagulant activity usually has been normal in other patients. While abnormal platelet function has been reported in another paper 5 there also are reports of normal platelet fac-
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281 tor 3 activity in this disease. 2 , 31 When the same patients Were st d' db two different groups, conflicting results were obtained, one grou: filed' y the platelet factor 3 normal31 and the other finding the activ'~ ~~ creased.19 Increased osmotic resistance to distilled water by the Pll tY I e . aee~ was demonstrated by Ulutm. In general, platelet aggregation has been found to be normal b t rapid disaggregation after aggregation by adenosine diphosphate h u been reported,21, 32 An increase in optical density can be produced by a~~ ding low concentrations of adenosine diphosphate to platelet-rich plasma from patients with von Willebrand's disease. 45 The morphology of platelets in von Willebrand's disease is also an area of controversy, both normal and abnormal features having been reported. Electron microscopic abnormalities which have been claimed include predominance of spread forms, decrease of dendritic forms deficient hyalomere, and decreased granularity. Platelet anisocytosi~ also has been reported. Several coagulation factor deficiencies, other than of factor VIII have been found to be associated with long bleeding times, notOriousl; afibrinogenemia and labile factor (factor V) deficiency. In addition there are a few reports of a prolonged bleeding time in association with deficiency of factor VII, IX, or XI. In four of the original patients from the Aland Islands, decrease of stable factor (factor VII) has been reported. 20 DIAGNOSIS OF VON WILLEBRAND'S DISEASE Of the half-dozen diagnostic criteria which are said to characterize this disease, the first to be discovered, the one easiest to test, and one of the most diagnostically significant is the bleeding time. As mentioned, the Ivy test seems to be more diagnostically precise but the Duke test is the more sensitive for evaluating efficacy of treatment. Although a factor VIII deficiency (40% of normal or less) is almost invariably found in patients with von Willebrand's disease, the low level alone is not diagnostic. The most difficult differential diagnostic problem is the patient with classic hemophilia. The hemophiliac should have a normal bleeding time, but more important is his response to the transfusion of 1 unit (250 to 300 ml) of plasma (fresh or old). There should be an increase of factor VIII in the plasma of perhaps 10% within an hour; half the increase disappears 12 hours later and virtually all, in 24 hours. By contrast, the patient with von Willebrand's disease and a factor VIII level of 20% of normal might well follow this pattern: immediately after infusion of 1 unit of plasma, the factor VIII level increases to 30% and then is 50% after 4 hours, 80% after 12 hours, 50% after 24 hours, and 25% after 2 days. Factor VIII levels may be moderately decreased in carriers of the classic hemophilia trait and may be slightly to seriously decreased in the intravascular coagul~i:ion-fibrinolysis syndrome. The latter is characterized by other clotting abnormalities and the presence of abnormal fibrinogen polymers and fibrinolytic split products in the blood. The third major diagnostic test for von Willebrand's disease is the
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OWEN, JR.
reactiveness ("adhesiveness") of platelets to glass beads. It is probably not important which test one uses so long as the laboratory has thoroughly standardized the method and can obtain· consistent results. Other abnormalities - platelet factor 3 release, capillary morphology, platelet morphology - are too controversial to be considered as giving dependable diagnostic help. When one is confronted by a patient with a Duke bleeding time of 15 minutes, a factor VIII level of 10%, and a glass-bead platelet retention of 0%, the diagnosis of von Willebrand's disease can hardly be argued. But if this patient has a brother with a bleeding tendency and only two of his three tests are abnormal and a sister also with a bleeding tendency and only one of her three tests is abnormal, can they also be said to have von Willebrand's disease? Because of the familial study one is inclined to say all three sibs have the same disease. However, when one sees a sporadic case-without family history and without an opportunity to study relatives-it is difficult to make the diagnosis of von Willebrand's disease if, for example, only the bleeding time is abnormal. Yet we suspect that these mild variants are probably by no means rare. Obviously, still more refined diagnostic criteria are needed. We have suggested5 that a broad spectrum of clinical and laboratory abnormalities will be found to be encompassed by the term "von Willebrand's disease" when more precise diagnostic techniques are developed. Such a spectrum also has been proposed by Edson.lO
TREATMENT OF VON WILLEBRAND'S DISEASE The tendency of a patient's factor VIII level to over-respond to plasma transfusion makes such treatment much more gratifying than in comparable patients with classic hemophilia. However, it is not known whether the fundamental hemostatic abnormality in von Willebrand's disease is the lack of factor VIII, the long bleeding time, or the decreased platelet-glass interaction. It is not even known whether these abnormalities reflect a deficiency of one or two or three factors ("vascular factor" for bleeding time, "stimulating factor" to increase the factor VIII synthesis, and "anti-Willebrand factor" for platelet adhesiveness). Thus, a comfortable factor VIII response to transfusion, with little or no improvement in the other two tests, may be of as much benefit to the physician as to the patient. Practically speaking, however, we have had satisfactory results in the prevention of serious bleeding with menses, dental extractions, or surgical procedures by the administration of 2 units of plasma (500 to 600 ml) at the onset of the menstrual flow or several hours before the operation. The transfusion is repeated daily in the postoperative period. Cryoprecipitate is usually as effective as plasma, but we have had one patient whose factor VIII level responded well to plasma but not at all to cryoprecipitate. The apparent decrease in menstrual bleeding in some women when they receive oral contraceptives warrants a trial of these drugs. However, one wishes the efficacy of this regimen were more firmly founded.
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It is obvious that von Willebrand's disease is still an etiologic and diagnostic problem. It remains to be shown whether the multiple hemo-
static problems are due to different defects or are the result of a single underlying abnormality. The animal models described afford an intriguing approach to this problem.
REFERENCES 1. Alexander B, Goldstein R.: Dual hemostatic defect in pseudohemophilia (abstract) J Clin Invest 32:551,1953 . 2. Bachmann F: VascuUire Hamophilie und Thrombopathie "von Willebrand-Jiirgens." Schweiz Med Wochenschr 89:1036-1039,1959 3. Barrow EM, Graham JB: Von Willebrand's disease. Progr HematoI4:203_221 1964 4. Biggs R, Matthews JM: The treatment of haemorrhage in von Willebrand's di~ease and the blood level of factor VIII (AHG). Br J HaematoI9:203-214, 1963 5. Bowie EJW, Didisheim P, Thompson JH Jr, et al: The spectrum of von Willebrand's disease. Thromb Diath Haemorrh 18:40-56, 1967 6. Bowie EJW, Owen CA Jr, Thompson JH Jr, et al: Platelet adhesiveness in von Willebrand's disease. Am J Clin PathoI52:69-77, 1969 7. Bowie EJW, Thompson JH Jr, Owen CA Jr: The stability of antihemophilic globulin and labile factor in human blood. Mayo Clin Proc 39:144-151,1964 8. Chan JYS, Owen CA Jr, Bowie EJW, et al: Von Willebrand disease "stimulating factor" in porcine plasma. Am J PhysioI214:1219-1224, 1968 9. Dodds WJ: Canine von Willebrand's disease. J Lab Clin Med 76:713-721,1970 10. Edson JR: Hemophilia, von Willebrand's disease, and related conditions: A spectrum of laboratory and clinical disorders. Hum Pathol1 :387-398, 1970 11. Fantl P, Sawers RJ: Stimulation of factor VIII (antihaemophilic) activity of transfused serum. Nature (Lond) 200:1214-1215,1963 12. Geiger AJ, Evans AG: Atypical hereditary hemorrhagic syndromes. Int Clin 2:135-157, 1938 13. Graham JB: Biochemical genetic speculations provoked by considering the enigma of von Willebrand's disease. Thromb Diath Haemorrh 9 Supplll:119-125, 1963 14. Graham JB: The genetics of hemophilia. In Hereditary Coagulation Disorders: Fibrinolysis (International SOciety of Haematology, Tenth Congress). Vo!. 7. Edited by SE Bjiirkman. Copenhagen, Ejnar Munksgaards Foriag, 1964, pp 14-28 15. Graham JB, McLester WD, Pons K, et al: Genetics of vascular hemophilia and biosynthesis of the plasma antihemophilic factor. In The Hemophilias. Edited by KM Brinkhous. Chapel Hill, University of North Carolina Press, 1964, pp 263-275 16. Hellem AJ: The adhesiveness of human blood platelets in vitro. Scand J Clin Lab Invest 12 SuppI51:1-117, 1960 17. Ingram GIC, Kingston PJ, Leslie J, et al: Four cases of acquired von Willebrand's syndrome. Br J Haematol21 :189-199.1971 18. Jamra MA, Lichtenstein R, Vieira CB, et al: Capilaropatia constitucional: forma de von Willebrand e forma capilar simples. Rev Hosp Clin Fac Med Sao Paulo 7:12-32,1952 19. Jiirgens R: Experimentelles und Klinisches zur Pathogenese der hamorrhagischen Diathesen. Dtsch Med Wochenschr 2:1727-1728,1950 20. Jiirgens R, Lehmann W., Wegelius 0., et al: Mitteilung iiber den Mangel an antihamophilem Globulin (Faktor VIII) bei der Aalandschen Thrombopathie (v. WillebrandJiirgens). Thromb Diath Haemorrh 1 :257-260, 1957 21. Larrieu M-J, Caen JP, Meyer DO, et al: Congenital bleeding disorders with long bleeding time and normal platelet count. 11. Von Willebrand's disease (report of thirty-seven patients). Am J Med 45 :354-372, 1968 22. Larrieu M-J, Soulier JP: Deficit en facteur antihemophilique a chez une fille: associe a un trouble du saignement. Rev HematoI8:361-370, 1953 23. Levine J, Jackson DP: Variable responsiveness in von Willebrand's disease (abstract). J Clin Invest 47:60a-61a, 1968 24. Macfarlane RG: Critical review: the mechanism of haemostasis. Quart J Med 10:1-29, 1941 25. Marx R: The problem of differentiating pseudohemophilias. In Hemophilia and Other Hemorrhagic States. Edited by KM Brinkhous. Chapel Hill, University of North Carolina Press, 1959, pp 108-121 26. McLester WD, Graham JB: Synthesis of plasma antihaemophilic factor. Nature (Lond) 197:708,1963 27. Meyer D, Larrieu MJ: In vivo and in vitro studies of platelet adhesiveness to glass beads in von Willebrand's disease. In Abstracts of the Simultaneous Sessions. Twelfth Congress of the International SOCiety of Hematology, New York, 1968, p 195
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28. Meyer D, Larrieu M-J, Caen J, et al: Criteres et limites du diagnostic de la maladie de Willebrand. Nouv Rev Fr Hematol 7:115-120,1967 29. Meyer D, Larrieu M-J, Maroteaux P, et al: Biological findings in von Willebrand's pedigrees: implications for inheritance. J Clin PathoI20:190-194, 1967 30. Nilsson IM, Blomback B, Blomback M, et al: Kvinnlig hamofili och dess behandling med humant antihamofiliglobulin. Nord Med 56:1654-1656,1956 31. Nilsson IM, Blomback M: Von Willebrand's disease in Sweden: occurrence, pathogenesis and treatment. Thromb Diath Haemorrh 9 Suppl11:103-118, 1963 32. Nilsson IM, Blomback M, Jorpes E, et al: V. Willebrand's disease and its correction. with human plasma fraction 1--0 Acta Med Scand. 159:179-188, 1957 33. O'Brien JR, Heywood JB: Some interactions between human platelets and glass: von Willebrand's disease compared with normal. J Clin PathoI20:56-64, 1967 34. Owen CA: Discussion. In The Hemophilias. Edited by KM Brinkhous. Chapel Hill, University of North Carolina Press, 1964, pp 300-302 35. Owen CA Jr, Bowie EJW, Didisheim P, et al: The pathophysiology of von Willebrand's disease. In Hemophilia and New Hemorrhagic States. Edited by KM Brinkhous. Chapel Hill, University of North Carolina Press, 1970, pp 187-204 36. Quick AJ: Hereditary thrombopathic thrombocytopenia and Minot-von Willebrand syndrome: probable co-existence in a family. Am J Med Sci 250:1-7,1965 37. Quick AJ, Hussey CV: Hemophilic condition in the female (abstract). J Lab Clin Med 42:929-930, 1953 38. Salzman EW: Measurement of platelet adhesiveness: a simple in vitro technique demonstrating an abnormality in von Willebrand's disease. J Lab Clin Med 62: 724- 735, 1963 39. Schulman I, Smith CH, Erlandson M, et al: Vascular hemophilia: a familial hemorrhagic disease in males and females characterized by combined antihemophilic globulin deficiency and vascular abnormality (abstract). Am J Dis Child 90:526, 1955 40. Silwer J, Nilsson IM: On a Swedish family with 51 members affected by von Willebrand's disease. Acta Med Scand 175:627-643,1964 41. Simone JV, Cornet JA, Abildgaard CF: Acquired von Willebrand's syndrome in systemic lupus erythematosus. Blood 31 :806-812, 1968 42. Strauss HS, Bloom GE: Von Willebrand's disease: use of a platelet-adhesiveness test in diagnosis and family investigation. New Eng J Med 273:171-181,1965 43. Sutor AH, Bowie EJW, Thompson JH Jr, et al: Bleeding from standardized skin punctures: automated technique for recording time, intensity, and pattern of bleeding. Am J Clin PathoI55:541-550, 1971 44. Ulutin ON: The qualitative platelet diseases. In Blood Platelets. Edited by SA Johnson, RW Monto, JW Rebuck, et aL Boston, Little, Brown & Company, 1961, pp 553-563 45. Vainer H, Caen JP, Chatelain D, et al: A useful photometric test for the diagnosis of von Willebrand's disease. J Clin PathoI17:191-193, 1964 46. Weiss HJ: The use of plasma and plasma fractions in the treatment of a patient with von Willebrand's disease. Vox Sang 7:267-280, 1962 47. Weiss HJ: Von Willebrand's disease: diagnostic criteria. Blood 32:668-679,1968 48. Zimmerman TS, Ratnoff OD, Powell AE: The immunologic differentiation of the antihemophilic factor (factor VIII) abnormalities in classic hemophilia and von Willebrand's disease (abstract). J Clin Invest 49:106a, 1970 49. Zucker MB: In vitro abnormality of the blood in von Willebrand's disease correctable by normal plasma. Nature (Lond) 197:601-602, 1963 Mayo Clinic Rochester, Minnesota 55901
Von Willebrand's Disease E. J. Walter Bowie, B.M., B.Ch.,* and Charles A. Owen, Jr., M.D., Ph.D.**
In 1924, von Willebrand reported a bleeding disease unlike any abnormality of hemostasis then known. The patients had prolongation of the bleeding time, and the bleeding affected mainly the skin and mucous membranes, as in thrombocytopenia, but depressed platelet counts were not the rule. Occasional patients had bleeding into the joints, as in hemophilia, but both males and females were affected. Blood clots retracted normally, excluding Glanzmann's disease. Similar cases had been reported although none were as well characterized clinically and genetically as von Willebrand's on the Aland Islands between Finland and Sweden. Quick has pointed out that perhaps the first case of the syndrome was described by Minot and Lee in 1920 and has suggested that the syndrome be called the "Minot-von Willebrand syndrome."36 It is now becoming clear that von Willebrand's disease is one of the commonest of the inherited bleeding disorders and, although the diagnostic criteria are still somewhat ill-defined, recent investigations have allowed the disease to be delineated more clearly.47 If the classic triad -long bleeding time, decreased factor VIII, and poor adhesiveness of platelets - is present the diagnosis is sure. It is important to be aware of the disease because mild cases can easily be overlooked if the diagnosis is not suspected. Although the disease is inherited autosomally, its exact mode of inheritance is uncertain. Most reports conclude that the inheritance is dominant. In our opinion, the difficulty of making an exact diagnosis in mild cases precludes accurate assessment of its mode of inheritance. Recently there have been reports of an acquired form of the disease which has been called "von Willebrand's syndrome."17. 41 Purpura with bleeding into the skin and mucous membranes is the commonest type of bleeding seen in these patients, and epistaxis is perhaps the commonest symptom. Menorrhagia is usual in these patients and, in some instances, menorrhagia at the menarche may be the presenting complaint. Gastrointestinal bleeding may occur spontane• Associate Professor of Internal Medicine and Clinical Pathology, Mayo Graduate School of Medicine (University of Minnesota); Consultant, Section of Clinical Pathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota "Professor of Clinical Pathology, Mayo Graduate School of Medicine (University of Minnesota); Consultant, Department of Biochemistry, Mayo Clinic, Rochester, Minnesota Medical Clinics of North America-Vol. 56, No. 1, January 1972
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ously and appears to be commoner in males. It should be emphasized, however, that gastrointestinal bleeding should never be attributed to von Willebrand's disease or any other hemorrhagic diathesis without a careful investigation of the gastrointestinal tract. Hematuria has been described. When the factor VIII level is low, hemarthroses and hemophilic bone cysts may occur in both males and females. Bleeding often accompanies shedding of the deciduous teeth, and gingival bleeding is a common complaint. Thus, the common symptoms of von Willebrand's disease, ease of bruising, epistaxis, and menorrhagia, all may occur in women who have no abnormality of hemostasis. This emphasizes the importance of being suspicious of the disease in patients with mild bleeding problems and of carefully evaluating the clinical history. There is no question that a number of families who have been thought to have mild hemophilia may in fact be afflicted with von Willebrand's disease, the significance of epistaxis and menorrhagia being overlooked in the females. If a patient is pregnant, the test results should be interpreted with caution because, in a patient with von Willebrand's disease, pregnancy may cause the bleeding time, platelet adhesiveness, and factor VIII level to return toward normal. It is important therefore that these patients be evaluated several months after delivery before the possibility of the disease can be excluded. It is also possible that oral contraceptives may affect the tests although this has not been definitely documented. The bleeding time may be shortened by treatment with corticosteroids. In taking the history it is important to make specific inquiry about the use of aspirin because this medicament may prolong the bleeding time and impair collagen-induced platelet aggregation and the second wave of platelet aggregation with adenosine diphosphate. Quick has suggested that the bleeding time in equivocal cases is diagnostically lengthened by administration of two tablets (625 mg) of aspirin.
PROLONGATION OF BLEEDING TIME A long bleeding time was the first abnormality described in von Willebrand's disease and is one of the most important criteria for making the diagnosis. However, by the usual technique the bleeding time has a wide standard deviation, and it varies widely in the same patient. In mild cases it may at times be normal. There is general agreement 40 that the Ivy bleeding time is a more effective screening test than the Duke bleeding time because the Duke bleeding time may be normal in situations in which the Ivy bleeding time is prolonged. Geiger and Evans 12 in 1938 were able to produce shortening of the bleeding time by the administration of blood transfusions and Schulman and associates39 in 1955 obtained similar corrections by the transfusion of fresh-frozen plasma. A plasmatic fraction (1-0) of Cohn's fraction I, made from normal subjects or from patients with classic hemophilia, was shown to shorten the Duke bleeding time. If the fraction was made from a patient with von Willebrand's disease the prolonged bleeding time was not affected. It was shown that the activity producing correction of the bleeding time was
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distinct from factor VIII, fibrinogen, and platelets and on this basis it was suggested that the prolongation of the bleeding time in von Willebrand's disease was due to the absence of "vascular factor." Most of the reports in the literature deal with the Duke bleeding time which appears more easily correctable than the Ivy bleeding time. However, some workers have used the Ivy technique in their studies and correction has been produced by hemophilic plasma, a subfraction of Cohn fraction I precipitated by alcohol, and by cryoprecipitate. Weiss46 has shown that correction of the bleeding time is best produced when the fractions are made in siliconized apparatus, and it seems likely that discrepancies in the literature are often related to the method of preparation. In addition, conflicting reports may arise from the variations of the severity of the disease in the patients being studied, the amount of the preparation transfused, and the technique of performing the bleeding time test. We have found35 a great deal of variability in correction of the Duke or Ivy bleeding time by either plasma or cryoprecipitate. Although in many patients the bleeding time is not decreased to within the normal range, visual inspection of the wound has suggested that the amount of blood lost is decreased after treatment. Because of these observations we developed a new test which measures the time, intensity, and pattern of bleeding from standardized skin punctures. 43 The Mayo automatic spring-loaded lancet is used to produce an incision, in the skin of the forearm, between 1 and 2 mm deep and 1 mm wide. After the pressure in the capillaries is standardized by inflation of a blood pressure cuff on the upper arm to 40 mm Hg, a transparent plastic tube with a channel in the base is placed over the incision and distilled water is sucked through the channel of the tube by a proportioning pump. The blood entrained in the water is allowed to hemolyze completely and the hemoglobin concentration is measured in a flow-cell spectrophotometer. The absorbance is continuously recorded by a chart recorder. We have recently modified the apparatus and now measure the exuding blood volume by electrical conductance. Using these techniques we have demonstrated that, although the bleeding time may not be decreased to within the normal range, the amount of blood lost from the wound is strikingly decreased for a few hours after the transfusion of fresh-frozen plasma. The technique will permit the accurate assessment of the effect of plasma fractions and medicaments on the bleeding time in patients with von Willebrand's disease.
ABNORMALITIES OF PLATELET FUNCTION One of the obvious explanations for a long bleeding time would be that these patients have abnormalities of platelet function. Although such abnormalities have been shown in von Willebrand's disease, the relationship between the bleeding time and platelet function has not been consistent. The suspicion that platelets may be involved in the hemostatic defect was first raised by von Willebrand, and subsequent investigations, using a now-defunct instrument-the capillary throm-
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OWEN, JR.
bometer-showed a strikingly abnormal "thrombosing time." It was not until 1960 that Hellem16 developed a method for measuring the retention of platelets in glass-bead columns ("platelet adhesiveness") and showed that 5 of 15 patients with von Willebrand's disease had decreased adhesiveness. But Hellem thought that the results were spurious because four of these five patients had low hematocrit values, and erythrocytes were essential for producing maximal platelet retention. Zucker49 reported that platelet adhesiveness was indeed abnormal in von Willebrand's disease and that normal plasma corrected the abnormality. Salzman 38 used a method in which blood is drawn directly from the vein over the glass-bead column and into a Vacutainer. Some workers 42 state that the Salzman test plays an essential role in the diagnosis and Meyer and associates28 . 29 think that this is the most sensitive diagnostic test. Decreased platelet adhesiveness has not been demonstrated by all investigators, and there seems little doubt that the conflicting results are due to the different techniques used for the demonstration of platelet adhesiveness. Serious problems are inherent in the standardization of these rather complex procedures. The importance of the rate of the flow of the blood in the glass-bead column was demonstrated by O'Brien and Heywood. 33 These workers showed that, if the flow rate was too slow, platelet retention in von Willebrand's disease becomes normal. By controlling a number of variables in the test, including the flow rate, we have produced a modification of the glass-bead adhesiveness test which has proved reproducible and useful in our hands in the diagnosis of von Willebrand's disease. Blood, lightly heparinized, is pushed at a controlled rate through a glass-bead column and the percentage of platelets retained in the column is calculated for each milliliter of column effluent. Using this procedure we have shown that platelet retention in the glass-bead column is consistently decreased in severe von Willebrand's disease. The abnormal test results could be due to a platelet defect, to the absence of a factor necessary for normal "stickiness," or to an abnormal release of ADP from the erythrocytes. Our further investigations have shown that the erythrocytes are apparently normal in von Willebrand's disease and suggest that the abnormality lies not in the platelets but in the plasma.6 Meyer and Larrieu27 have reached similar conclusions.
FACTOR VIII DEFICIENCY In 1953, three independent reports1 , 22, 37 documented that the antihemophilic factor (factor VIII) level was decreased in patients with von Willebrand's disease. Subsequently, the patients in the Aland Islands were investigated and were found to have factor VIII deficiency.2o,32 Classic hemophilia is of course inherited as a sex-linked recessive characteristic, and the demonstration that factor VIII deficiency could also be inherited autosomally was of major importance and has led to many intriguing speculations regarding factor VIII inheritance and synthesis. After the documentation of factor VIII deficiency in these patients, Nilsson and colleagues30 reported a most unusual finding. One of their pa-
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tients with von Willebrand's disease was transfused with plasma fraction 1-0 of Blomback, and the patient's level of factor VIII increased higher than could be accounted for by the amount of factor VIII infused. The factor VIII remained at increased levels for 5 days in this patient. In hemophiliacs, there is a rapid decrease of infused factor VIII, the factor having an in vivo half-life of 10 to 15 hours. Even more intriguing was the demonstration by Nilsson's group that the remarkable increase in factor VIII could even be produced by plasma or fraction 1-0 made from patients with classic hemophilia who lack demonstrable plasmatic factor VIII activity. These findings have now been confirmed on numerous occasions. It also has been shown4 that the fibrinogen fraction of plasma, containing no demonstrable factor VIII activity, could cause an increase in the level of factor VIII. In addition, serum or serum absorbed with calcium phosphate can cause similar stimulation of the patient's plasmatic level of factor VIII.5. 11.42 Although the initial increase in factor VIII could be explained by the content of factor VIII in the transfused material, it was postulated that the subsequent paradoxic increase was due to new synthesis of factor VIII by the recipient. This newly synthesized factor VIII apparently is not different from ordinary factor VIII, whether plasma from a classic hemophiliac or a normal person is responsible for its production.3 It has also been reported23 that the patient's factor VIII synthetic mechanism becomes refractory after repeated transfusions. We have shown that the response of factor VIII is related to the dose of plasma given but, because of the dangers of circulatory overload occasioned by large plasma transfusions, it will be necessary to use concentrates to demonstrate the maximal response. FACTOR VIII INHERITANCE AND SYNTHESIS IN VON WILLEBRAND'S DISEASE AND HEMOPHILIA There has been a great deal of interest recently in the immunology of coagulation factors, including factor VIII. Several workers have demonstrated that a high proportion of hemophiliacs have a plasmatic material that cross-reacts with factor VIII antibodies - in other words, factor VIIIlike protein antigenically despite absence of the factor's activity biologically. In fact, Zimmerman and colleagues,48 using a rabbit antibody to factor VIII, found that cross-reacting material can be demonstrated in all hemophiliacs in amounts comparable to those in normal plasma despite the virtual absence of factor VIII clotting activity. In von Willebrand's disease, however, the amount of cross-reacting material is no greater than the amount of functionally active factor VIII. The suggestion has been made, therefore, that von Willebrand's disease represents an actual deficiency of factor VIII while classic hemophilia represents, in many instances at least, not a deficiency but an abnormality of the factor VIII molecule which renders it functionally inactive. We have a colony of pigs with a bleeding disease that has all the characteristics of human von Willebrand's disease. They provide an ideal animal model for genetic and transfusion studies. The same chro-
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OWEN, JR.
matographic fraction of plasma or serum which contains factor VIII causes the over-response of factor VIII in these animals. s In the serum fractions, no factor VIII activity can be demonstrated on functional testing. In some of our studies the fractions which cause an increase in the factor VIII level have also resulted in normalization of the bleeding time and platelet adhesiveness. However, the fractions were not pure enough so that we could be sure that all these abnormalities are due to the lack of a single factor. Von Willebrand's disease has also been described in German shepherd dogs, providing another animal model for study.9 The over-response of factor VIII to the transfusion of plasma from patients with classic hemophilia may be explained by the activation of the inactive factor VIII molecule present in the hemophiliac. There are numerous other speculative explanations for this over-response, including the possibility that normal plasma and hemophilic plasma contain a stimulating factor which causes the synthesis of factor VIII in patients with von Willebrand's disease. For example, there is the possibility that there are two different kinds of factor VIII/ one type being deficient in von Willebrand's disease and the other type being deficient in hemophilia. 34 Graham and colleagues 13- 15 ,26 have proposed several models to explain the synthesis of factor VIII. The "activator" theory suggests that an activator is produced on the locus of von Willebrand's disease and that this activates a precursor of factor VIII which is produced by the locus on the X chromosome. The "inducer" model suggests that an autosomal locus synthesizes a metabolite which acts as an inducer or regulator for the operon system on the X chromosome, which produces factor VIII. A "combining subunit" model suggests that factor VIII may be a polymer and one chain is coded by a locus on the X chromosome and the other, by an autosomal locus which would be the locus for von Willebrand's disease. 3
MISCELLANEOUS OBSERVATIONS CONCERNING BLOOD VESSELS, PLATELETS, AND COAGULATION FACTORS The possibility that an abnormality of the capillaries was responsible for the hemostatic defect was suggested by Macfarlane 24 who described distorted and bizarre capillaries in the nail beds of five patients with von Willebrand's disease, When the capillaries were punctur.ed with a glass fiber, no contraction occurred. Subsequent observations have produced many conflicting reports, one of the problems being to classify the morphology of normal capillaries. J amra and his colleagues 18 studied patients with constitutional capillaropathies and were unable to find any departure from the normal. Abnormality of platelet factor 3 activity has been reported; this is the partial thromboplastic activity of platelets. We have demonstrated5 ineffective release of factor 3 activity in two brothers with severe von Willebrand's disease but platelet procoagulant activity usually has been normal in other patients. While abnormal platelet function has been reported in another paper 5 there also are reports of normal platelet fac-
VON WILLEBRAND'S DISEASE
281 tor 3 activity in this disease. 2 , 31 When the same patients Were st d' db two different groups, conflicting results were obtained, one grou: filed' y the platelet factor 3 normal31 and the other finding the activ'~ ~~ creased.19 Increased osmotic resistance to distilled water by the Pll tY I e . aee~ was demonstrated by Ulutm. In general, platelet aggregation has been found to be normal b t rapid disaggregation after aggregation by adenosine diphosphate h u been reported,21, 32 An increase in optical density can be produced by a~~ ding low concentrations of adenosine diphosphate to platelet-rich plasma from patients with von Willebrand's disease. 45 The morphology of platelets in von Willebrand's disease is also an area of controversy, both normal and abnormal features having been reported. Electron microscopic abnormalities which have been claimed include predominance of spread forms, decrease of dendritic forms deficient hyalomere, and decreased granularity. Platelet anisocytosi~ also has been reported. Several coagulation factor deficiencies, other than of factor VIII have been found to be associated with long bleeding times, notOriousl; afibrinogenemia and labile factor (factor V) deficiency. In addition there are a few reports of a prolonged bleeding time in association with deficiency of factor VII, IX, or XI. In four of the original patients from the Aland Islands, decrease of stable factor (factor VII) has been reported. 20 DIAGNOSIS OF VON WILLEBRAND'S DISEASE Of the half-dozen diagnostic criteria which are said to characterize this disease, the first to be discovered, the one easiest to test, and one of the most diagnostically significant is the bleeding time. As mentioned, the Ivy test seems to be more diagnostically precise but the Duke test is the more sensitive for evaluating efficacy of treatment. Although a factor VIII deficiency (40% of normal or less) is almost invariably found in patients with von Willebrand's disease, the low level alone is not diagnostic. The most difficult differential diagnostic problem is the patient with classic hemophilia. The hemophiliac should have a normal bleeding time, but more important is his response to the transfusion of 1 unit (250 to 300 ml) of plasma (fresh or old). There should be an increase of factor VIII in the plasma of perhaps 10% within an hour; half the increase disappears 12 hours later and virtually all, in 24 hours. By contrast, the patient with von Willebrand's disease and a factor VIII level of 20% of normal might well follow this pattern: immediately after infusion of 1 unit of plasma, the factor VIII level increases to 30% and then is 50% after 4 hours, 80% after 12 hours, 50% after 24 hours, and 25% after 2 days. Factor VIII levels may be moderately decreased in carriers of the classic hemophilia trait and may be slightly to seriously decreased in the intravascular coagul~i:ion-fibrinolysis syndrome. The latter is characterized by other clotting abnormalities and the presence of abnormal fibrinogen polymers and fibrinolytic split products in the blood. The third major diagnostic test for von Willebrand's disease is the
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OWEN, JR.
reactiveness ("adhesiveness") of platelets to glass beads. It is probably not important which test one uses so long as the laboratory has thoroughly standardized the method and can obtain· consistent results. Other abnormalities - platelet factor 3 release, capillary morphology, platelet morphology - are too controversial to be considered as giving dependable diagnostic help. When one is confronted by a patient with a Duke bleeding time of 15 minutes, a factor VIII level of 10%, and a glass-bead platelet retention of 0%, the diagnosis of von Willebrand's disease can hardly be argued. But if this patient has a brother with a bleeding tendency and only two of his three tests are abnormal and a sister also with a bleeding tendency and only one of her three tests is abnormal, can they also be said to have von Willebrand's disease? Because of the familial study one is inclined to say all three sibs have the same disease. However, when one sees a sporadic case-without family history and without an opportunity to study relatives-it is difficult to make the diagnosis of von Willebrand's disease if, for example, only the bleeding time is abnormal. Yet we suspect that these mild variants are probably by no means rare. Obviously, still more refined diagnostic criteria are needed. We have suggested5 that a broad spectrum of clinical and laboratory abnormalities will be found to be encompassed by the term "von Willebrand's disease" when more precise diagnostic techniques are developed. Such a spectrum also has been proposed by Edson.lO
TREATMENT OF VON WILLEBRAND'S DISEASE The tendency of a patient's factor VIII level to over-respond to plasma transfusion makes such treatment much more gratifying than in comparable patients with classic hemophilia. However, it is not known whether the fundamental hemostatic abnormality in von Willebrand's disease is the lack of factor VIII, the long bleeding time, or the decreased platelet-glass interaction. It is not even known whether these abnormalities reflect a deficiency of one or two or three factors ("vascular factor" for bleeding time, "stimulating factor" to increase the factor VIII synthesis, and "anti-Willebrand factor" for platelet adhesiveness). Thus, a comfortable factor VIII response to transfusion, with little or no improvement in the other two tests, may be of as much benefit to the physician as to the patient. Practically speaking, however, we have had satisfactory results in the prevention of serious bleeding with menses, dental extractions, or surgical procedures by the administration of 2 units of plasma (500 to 600 ml) at the onset of the menstrual flow or several hours before the operation. The transfusion is repeated daily in the postoperative period. Cryoprecipitate is usually as effective as plasma, but we have had one patient whose factor VIII level responded well to plasma but not at all to cryoprecipitate. The apparent decrease in menstrual bleeding in some women when they receive oral contraceptives warrants a trial of these drugs. However, one wishes the efficacy of this regimen were more firmly founded.
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It is obvious that von Willebrand's disease is still an etiologic and diagnostic problem. It remains to be shown whether the multiple hemo-
static problems are due to different defects or are the result of a single underlying abnormality. The animal models described afford an intriguing approach to this problem.
REFERENCES 1. Alexander B, Goldstein R.: Dual hemostatic defect in pseudohemophilia (abstract) J Clin Invest 32:551,1953 . 2. Bachmann F: VascuUire Hamophilie und Thrombopathie "von Willebrand-Jiirgens." Schweiz Med Wochenschr 89:1036-1039,1959 3. Barrow EM, Graham JB: Von Willebrand's disease. Progr HematoI4:203_221 1964 4. Biggs R, Matthews JM: The treatment of haemorrhage in von Willebrand's di~ease and the blood level of factor VIII (AHG). Br J HaematoI9:203-214, 1963 5. Bowie EJW, Didisheim P, Thompson JH Jr, et al: The spectrum of von Willebrand's disease. Thromb Diath Haemorrh 18:40-56, 1967 6. Bowie EJW, Owen CA Jr, Thompson JH Jr, et al: Platelet adhesiveness in von Willebrand's disease. Am J Clin PathoI52:69-77, 1969 7. Bowie EJW, Thompson JH Jr, Owen CA Jr: The stability of antihemophilic globulin and labile factor in human blood. Mayo Clin Proc 39:144-151,1964 8. Chan JYS, Owen CA Jr, Bowie EJW, et al: Von Willebrand disease "stimulating factor" in porcine plasma. Am J PhysioI214:1219-1224, 1968 9. Dodds WJ: Canine von Willebrand's disease. J Lab Clin Med 76:713-721,1970 10. Edson JR: Hemophilia, von Willebrand's disease, and related conditions: A spectrum of laboratory and clinical disorders. Hum Pathol1 :387-398, 1970 11. Fantl P, Sawers RJ: Stimulation of factor VIII (antihaemophilic) activity of transfused serum. Nature (Lond) 200:1214-1215,1963 12. Geiger AJ, Evans AG: Atypical hereditary hemorrhagic syndromes. Int Clin 2:135-157, 1938 13. Graham JB: Biochemical genetic speculations provoked by considering the enigma of von Willebrand's disease. Thromb Diath Haemorrh 9 Supplll:119-125, 1963 14. Graham JB: The genetics of hemophilia. In Hereditary Coagulation Disorders: Fibrinolysis (International SOciety of Haematology, Tenth Congress). Vo!. 7. Edited by SE Bjiirkman. Copenhagen, Ejnar Munksgaards Foriag, 1964, pp 14-28 15. Graham JB, McLester WD, Pons K, et al: Genetics of vascular hemophilia and biosynthesis of the plasma antihemophilic factor. In The Hemophilias. Edited by KM Brinkhous. Chapel Hill, University of North Carolina Press, 1964, pp 263-275 16. Hellem AJ: The adhesiveness of human blood platelets in vitro. Scand J Clin Lab Invest 12 SuppI51:1-117, 1960 17. Ingram GIC, Kingston PJ, Leslie J, et al: Four cases of acquired von Willebrand's syndrome. Br J Haematol21 :189-199.1971 18. Jamra MA, Lichtenstein R, Vieira CB, et al: Capilaropatia constitucional: forma de von Willebrand e forma capilar simples. Rev Hosp Clin Fac Med Sao Paulo 7:12-32,1952 19. Jiirgens R: Experimentelles und Klinisches zur Pathogenese der hamorrhagischen Diathesen. Dtsch Med Wochenschr 2:1727-1728,1950 20. Jiirgens R, Lehmann W., Wegelius 0., et al: Mitteilung iiber den Mangel an antihamophilem Globulin (Faktor VIII) bei der Aalandschen Thrombopathie (v. WillebrandJiirgens). Thromb Diath Haemorrh 1 :257-260, 1957 21. Larrieu M-J, Caen JP, Meyer DO, et al: Congenital bleeding disorders with long bleeding time and normal platelet count. 11. Von Willebrand's disease (report of thirty-seven patients). Am J Med 45 :354-372, 1968 22. Larrieu M-J, Soulier JP: Deficit en facteur antihemophilique a chez une fille: associe a un trouble du saignement. Rev HematoI8:361-370, 1953 23. Levine J, Jackson DP: Variable responsiveness in von Willebrand's disease (abstract). J Clin Invest 47:60a-61a, 1968 24. Macfarlane RG: Critical review: the mechanism of haemostasis. Quart J Med 10:1-29, 1941 25. Marx R: The problem of differentiating pseudohemophilias. In Hemophilia and Other Hemorrhagic States. Edited by KM Brinkhous. Chapel Hill, University of North Carolina Press, 1959, pp 108-121 26. McLester WD, Graham JB: Synthesis of plasma antihaemophilic factor. Nature (Lond) 197:708,1963 27. Meyer D, Larrieu MJ: In vivo and in vitro studies of platelet adhesiveness to glass beads in von Willebrand's disease. In Abstracts of the Simultaneous Sessions. Twelfth Congress of the International SOCiety of Hematology, New York, 1968, p 195
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OWEN, JR.
28. Meyer D, Larrieu M-J, Caen J, et al: Criteres et limites du diagnostic de la maladie de Willebrand. Nouv Rev Fr Hematol 7:115-120,1967 29. Meyer D, Larrieu M-J, Maroteaux P, et al: Biological findings in von Willebrand's pedigrees: implications for inheritance. J Clin PathoI20:190-194, 1967 30. Nilsson IM, Blomback B, Blomback M, et al: Kvinnlig hamofili och dess behandling med humant antihamofiliglobulin. Nord Med 56:1654-1656,1956 31. Nilsson IM, Blomback M: Von Willebrand's disease in Sweden: occurrence, pathogenesis and treatment. Thromb Diath Haemorrh 9 Suppl11:103-118, 1963 32. Nilsson IM, Blomback M, Jorpes E, et al: V. Willebrand's disease and its correction. with human plasma fraction 1--0 Acta Med Scand. 159:179-188, 1957 33. O'Brien JR, Heywood JB: Some interactions between human platelets and glass: von Willebrand's disease compared with normal. J Clin PathoI20:56-64, 1967 34. Owen CA: Discussion. In The Hemophilias. Edited by KM Brinkhous. Chapel Hill, University of North Carolina Press, 1964, pp 300-302 35. Owen CA Jr, Bowie EJW, Didisheim P, et al: The pathophysiology of von Willebrand's disease. In Hemophilia and New Hemorrhagic States. Edited by KM Brinkhous. Chapel Hill, University of North Carolina Press, 1970, pp 187-204 36. Quick AJ: Hereditary thrombopathic thrombocytopenia and Minot-von Willebrand syndrome: probable co-existence in a family. Am J Med Sci 250:1-7,1965 37. Quick AJ, Hussey CV: Hemophilic condition in the female (abstract). J Lab Clin Med 42:929-930, 1953 38. Salzman EW: Measurement of platelet adhesiveness: a simple in vitro technique demonstrating an abnormality in von Willebrand's disease. J Lab Clin Med 62: 724- 735, 1963 39. Schulman I, Smith CH, Erlandson M, et al: Vascular hemophilia: a familial hemorrhagic disease in males and females characterized by combined antihemophilic globulin deficiency and vascular abnormality (abstract). Am J Dis Child 90:526, 1955 40. Silwer J, Nilsson IM: On a Swedish family with 51 members affected by von Willebrand's disease. Acta Med Scand 175:627-643,1964 41. Simone JV, Cornet JA, Abildgaard CF: Acquired von Willebrand's syndrome in systemic lupus erythematosus. Blood 31 :806-812, 1968 42. Strauss HS, Bloom GE: Von Willebrand's disease: use of a platelet-adhesiveness test in diagnosis and family investigation. New Eng J Med 273:171-181,1965 43. Sutor AH, Bowie EJW, Thompson JH Jr, et al: Bleeding from standardized skin punctures: automated technique for recording time, intensity, and pattern of bleeding. Am J Clin PathoI55:541-550, 1971 44. Ulutin ON: The qualitative platelet diseases. In Blood Platelets. Edited by SA Johnson, RW Monto, JW Rebuck, et aL Boston, Little, Brown & Company, 1961, pp 553-563 45. Vainer H, Caen JP, Chatelain D, et al: A useful photometric test for the diagnosis of von Willebrand's disease. J Clin PathoI17:191-193, 1964 46. Weiss HJ: The use of plasma and plasma fractions in the treatment of a patient with von Willebrand's disease. Vox Sang 7:267-280, 1962 47. Weiss HJ: Von Willebrand's disease: diagnostic criteria. Blood 32:668-679,1968 48. Zimmerman TS, Ratnoff OD, Powell AE: The immunologic differentiation of the antihemophilic factor (factor VIII) abnormalities in classic hemophilia and von Willebrand's disease (abstract). J Clin Invest 49:106a, 1970 49. Zucker MB: In vitro abnormality of the blood in von Willebrand's disease correctable by normal plasma. Nature (Lond) 197:601-602, 1963 Mayo Clinic Rochester, Minnesota 55901