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Management of inherited von Willebrand disease
Best Practice & Research Clinical Haematology Vol. 14, No. 2, pp. 455±462, 2001
doi:10.1053/beha.2001.0143, available online at http://www.idealibrary.com on
13 Management of inherited von Willebrand disease Pier Mannuccio Mannucci Augusto B. Federici
MD
MD
Angelo Bianchi Bonomi Haemophilia and Thrombosis Center and Department of Internal Medicine, IRCCS Maggiore Hospital, University of Milan, Italy
von Willebrand disease is a bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor. The diagnosis is based on measurements of plasma and platelet von Willebrand factor, the ability of von Willebrand factor to interact with its platelet receptor and the analysis of the multimeric composition of von Willebrand factor. Owing to the heterogeneity of von Willebrand factor defects, a correct diagnosis of types and subtypes may be sometimes dicult but is very important for an appropriate therapy. The aim of treatment is to correct the dual defects of haemostasis, i. e. abnormal coagulation, expressed by a low level of factor VIII, and abnormal platelet adhesion, expressed by a prolonged bleeding time. Desmopressin is the treatment of choice in patients with type 1 von Willebrand disease, who account for approximately 70% of cases, because it corrects the factor VIII/von Willebrand factor level and the prolonged bleeding time in most of these patients. In type 3 and in the majority of type 2 von Willebrand disease patients, desmopressin is not eective and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are eective and currently safe, but they do not always correct the bleeding time defect. Platelet concentrates or desmopressin can be used as adjunctive treatments when a poor correction of the bleeding time after concentrates is associated with continued bleeding. Studies are in progress, ®rst to better characterize patients with type 1 von Willebrand disease and to determine their response to desmopressin, and second, to evaluate the pharmacokinetios of factor VIII following factor VIII/von Willebrand factor concentrates and to establish the indication for concentrates. Key words: von Willebrand factor; congenital von Willebrand disease; desmopressin; factor VIII/von Willebrand factor concentrates.
von Willebrand disease (VWD) is the bleeding disorder most frequently encountered and is caused by a quantitative (types 1 and 3) or a qualitative (type 2) defect of von Willebrand factor (VWF). von Willebrand factor is the high molecular weight glycoprotein that plays an essential role in the early phases of haemostasis by promoting platelet adhesion to the subendothelium and platelet aggregation under high shear conditions.1 Since von Willebrand factor is also the carrier of factor VIII in plasma, a de®ciency of von Willebrand factor results in an impairment of both the primary phase of haemostasis and blood coagulation. 1521±6926/01/02045508 $35.00/00
c 2001 Harcourt Publishers Ltd. *
456 P. M. Mannucci and A. B. Federici
In most cases, VWD is congenital, inherited in an autosomal dominant fashion; an autosomal recessive pattern is also described in some cases. Patients with VWD may have had a mild, moderate or severe bleeding tendency since their early childhood, usually proportional to the degree of the von Willebrand factor defect. Inherited VWD has been subdivided into three categories that re¯ect the underlying pathophysiology. Types 1 and 3 VWD re¯ect, respectively, the partial and virtually complete de®ciency of von Willebrand factor, whereas type 2 VWD re¯ects a qualitative de®ciency of von Willebrand factor.2 The revised classi®cation introduced in 1994 by Sadler3 recommends the subdivision of type 2 VWD into four variants (2A, 2B, 2M, and 2N) according to speci®c details of their phenotypic features (Table 1). This classi®cation also addresses the problems of compound heterozygosity and of disorders related to VWD that are not caused by a defect in the von Willebrand factor gene, such as `platelet-type pseudo-VWD' and the acquired von Willebrand syndrome.2,3 In patients with VWD, the goal of therapy is to correct the dual defect of haemostasis, i.e. the prolonged bleeding time caused by abnormal platelet adhesion, and the abnormal intrinsic coagulation pathway resulting from low levels of factor VIII. There are two treatments of choice in VWD: desmopressin and transfusional therapy with plasma-derived factor VIII/VWF concentrates. Other forms of treatment can be considered as being adjunctive or alternative to these (Table 2). Table 1. Classi®cation of von Willebrand disease. 1. VWD is caused by mutation of the VWF locus 2. Type 1 VWD refers to partial quantitative de®ciency of VWF Type 2 VWD refers to qualitative de®ciency of VWF Type 3 VWD refers to virtually complete de®ciency of VWF 3. Type 2 A VWD refers to qualitative variants with decreased platelet-dependent function that is associated with the absence of high-molecular-weight multimers 4. Type 2 B VWD refers to qualitative variants with increased anity for platelet GPIb 5. Type 2 M VWD refers to qualitative variants with decreased platelet-dependent function not caused by the absence of high-molecular-weight multimers 6. Type 2 N VWD refers to qualitative variants with markedly decreased anity for factor VIII 7. When recognized, a mixed phenotype caused by compound heterozygosity is indicated by separate classi®cation of each allele separated by a slash (/) 8. For the description of mutations, numbering systems are suggested for aminoacids and nucleotides VWF von Willebrand factor; GpIb glycoprotein Ib. From an updated version by Sadler.3
Table 2. Management of dierent types and subtypes of von Willebrand disease.
Type Type Type Type Type Type Type
1 2A 2B 2M 2N 3 3 with alloantibodies
VWF=von Willebrand factor.
Treatment of choice
Alternative and adjunctive therapy
Desmopressin Factor VIII/VWF concentrates Factor VIII/VWF concentrates Factor VIII/VWF concentrates Desmopressin Factor VIII/VWF concentrates Recombinant factor VIII
Anti-®brinolytics, oestrogens
Desmopressin, platelet concentrates
Inherited von Willebrand disease 457
DESMOPRESSIN Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of vasopressin originally designed for the treatment of diabetes insipidus. DDAVP increases the factor VIII and von Willebrand factor plasma concentration without important side-eects when administered to healthy volunteers or patients with mild haemophilia and VWD.4 The mode of action of DDAVP is not completely understood. The addition of DDAVP to cultured endothelial cells has no eect on von Willebrand factor synthesis or secretion, so the agent is presumed to act through an as yet unidenti®ed second messenger.5 The ®rst clinical trial of DDAVP was successfully performed in 1977, with the aim of avoiding the use of blood products in cases of mild haemophilia and VWD patients who needed dental extractions and other surgical procedures.6 Following these early observations, DDAVP has become widely used for the treatment of these conditions.7 The obvious advantages of DDAVP are that it is relatively inexpensive and carries no risk of transmitting blood-borne viruses. DDAVP is usually administered intravenously at a dose of 0.3 mg/kg diluted in 50 ml saline infused over 30 minutes. This treatment increases the plasma factor VIII and von Willebrand factor to 3±5 times above the basal level within 30 minutes. In general, the high factor VIII/von Willebrand factor concentrations last for 6±8 hours. Since the responses in a given patient are consistent on dierent occasions, a test dose of DDAVP administered at the time of diagnosis helps to establish the individual response pattern. Infusions can be repeated every 12±24 hours depending on the type and severity of the bleeding episode. Some patients treated repeatedly with DDAVP become, however, less responsive to therapy.8 The drug is also available in concentrated forms for subcutaneous and intranasal administration, which can be convenient for home treatment. The side-eects of DDAVP treatment are usually mild tachycardia, headache and ¯ushing; these symptoms are attributed to the vasomotor eects of the drug and can often be attenuated by slowing the rate of infusion. Hyponatraemia and volume overload caused by the anti-diuretic eects of DDAVP are relatively rare: a few cases have been described, mostly in young children who have received closely repeated infusions.9 Even though no thrombotic episodes have been reported in VWD patients treated with DDAVP, this drug should be used with caution in elderly patients with atherosclerotic disease because a few cases of myocardial infarction and stroke have occurred in haemophiliacs and uraemic patients given DDAVP.10,11 DDAVP is most eective in patients with type 1 VWD, especially those who have a normal von Willebrand factor level in the storage sites (type 1, `platelet normal'); in these patients factor VIII, von Willebrand factor and bleeding time are usually corrected within 30 minutes and remain normal for 6±8 hours. In other VWD subtypes, responsiveness to DDAVP is variable: a poor and short-lasting response is observed in type 1 `platelet low'.12 In type 2A disease, the factor VIII level is usually increased by DDAVP but the bleeding time is shortened in only a minority of cases. Desmopressin is contra-indicated in type 2B von Willebrand factor because of the transient appearance of thrombocytopenia.13 There have, however, been reports on the clinical usefulness of DDAVP in some cases of 2B.14,15 In type 2N VWD relatively high levels of factor VIII are observed following DDAVP infusion, but the released factor VIII circulates for a shorter time period in patient plasma because the stabilizing eect of the von Willebrand factor is impaired.16
458 P. M. Mannucci and A. B. Federici
Patients with type 3 VWD are usually unresponsive to DDAVP. A subgroup of these patients has, however, recently been identi®ed in whom the factor VIII level becomes normal after DDAVP even though the bleeding time remains markedly prolonged.17
OTHER NON-TRANSFUSIONAL THERAPIES FOR VON WILLEBRAND DISEASE Two other types of non-transfusional therapy are used in the management of VWD: anti-®brinolytic amino acids and oestrogens. Anti-®brinolytic amino acids are synthetic drugs that interfere with the lysis of newly formed clots by saturating the binding sites on plasminogen, thereby preventing its attachment to ®brin and making the plasminogen unavailable within the forming clot. Epsilon aminocaproic acid (50 mg/kg four times a day) and tranexamic acid (25 mg/ kg three times a day) are the most used anti-®brinolytic amino acids. Both medications can be administered orally, intravenously or topically and are useful as adjuncts in the management of oral cavity bleeding, epistaxis, gastrointestinal bleeding and menorrhagia. As drugs that inhibit the ®brinolytic system, they carry a potential risk of thrombosis in patients with an underlying pre-thrombotic state. They are also contra-indicated in the management of urinary tract bleeding. Oestrogens increase the plasma von Willebrand factor level, but the response is so variable and unpredictable that they are not widely used for therapeutic purposes. It is common clinical experience that the continued use of oral contraceptives is very useful in reducing the severity of menorrhagia in women with VWD, even in those with type 3 disease, despite the fact that the factor/VIII/von Willebrand factor level is not modi®ed.
TRANSFUSIONAL THERAPIES Transfusional therapy with blood products containing factor VIII/von Willebrand factor is the treatment of choice in the patients who are unresponsive to DDAVP. Early studies indicated that cryoprecipite administered every 12±24 hours normalized the plasma factor VIII level, shortened the bleeding time and stopped or prevented clinical bleeding in VWD.18 Based on these observations, cryoprecipitate has been the mainstay of VWD therapy for many years. A recent analysis of previously published reports has, however, pointed out that the bleeding time is not always corrected following cryoprecipitate administration.19 Virucidal methods cannot be applied to cryoprecipitate, so this product also carries a small but de®nite risk of transmitting blood-borne infections. Therefore, virusinactivated concentrates, originally developed for the treatment of haemophilia A, play an important role in the current management of VWD patients unresponsive to DDAVP. Concentrates obtained by immunoanity chromatography on monoclonal antibodies (factor VIII 4 2 000 IU/mg) contain a very small amount of von Willebrand factor and are therefore unsuitable for VWD management. A chromatography-puri®ed concentrate particularly rich in von Willebrand factor and with a low content of factor VIII ± very-high purity von Willebrand factor concentrate ± has also recently been produced.20 This concentrate was eective when tested in a small cohort of type 3
Inherited von Willebrand disease 459 Table 3. Doses of factor VIII/von Willebrand factor concentrates recommended in von Willebrand disease patients unresponsive to desmopressin. Type of bleeding
Dose(IU/kg)
Number of infusions
Objective
Major surgery
50
Once a day or every other day
Maintain factor VIII 4 50 IU/dl until healing is complete
Minor surgery
30
Once a day or every other day
Factor VIII 4 30 IU/dl until healing is complete
Dental extractions
20
Single
Factor VIII 4 30 IU/dl for up to 6 hours
Spontaneous or posttraumatic bleeding
20
Single
VWD cases21, and its ecacy and safety are now under evaluation in a larger number of patients. The dosages of concentrates recommended for the control of bleeding episodes are summarised in Table 3. Since commercially available intermediate and high-purity factor VIII/von Willebrand factor concentrates contain a large amount of factor VIII and von Willebrand factor, high post-infusion levels of these moieties are consistently obtained. There is, moreover, a sustained rise in factor VIII, higher than would be predicted from the doses infused, lasting for up to 24 hours. This pattern is caused by the stabilizing eect of exogenous von Willebrand factor on endogenous factor VIII, which is synthesized at a normal rate in these patients.22 Therefore, all products are able to correct FVIII de®ciency even though they are not always eective in correcting the bleeding time.19 There are probably multiple reasons for the inconsistent eects on the bleeding time. So far, no concentrate contains a completely functional von Willebrand factor, as tested in vitro by evaluating the multimeric pattern and using several functional assays, because von Willebrand factor proteolysis occurs during puri®cation as a result of the action of platelet and leukocyte proteases contaminating the plasma used for fractionation.23 Despite their limited and inconsistent eect on the bleeding time, factor VIII/von Willebrand factor concentrates are successfully used for the treatment of VWD patients unresponsive to DDAVP, especially for soft tissue and post-operative bleeding.19 The results of a large international study by the Alphanate Study Group on the clinical use of a plasma-derived factor VIII/von Willebrand factor concentrate have been reported: according to these data, 73% of bleeding episodes were resolved by a single infusion of concentrate, and haemostatic control during surgery was obtained even in the absence of bleeding time correction.24 When bleeding persists despite replacement therapy, other therapeutic options are available. DDAVP, given after cryoprecipitate, further shortened or normalized the bleeding time in patients with type 3 VWD in whom cryoprecipitate failed to correct the bleeding time.25 Platelet concentrates (given before or after cryoprecipitate, at a dose of 4±5 1011 platelets) achieved a similar eect in patients unresponsive to cryoprecipitate alone, in terms of both bleeding time correction and bleeding control.26,27 These data emphasize the important role of platelet von Willebrand factor in establishing and maintaining primary haemostasis.
460 P. M. Mannucci and A. B. Federici
TREATMENT OF VON WILLEBRAND DISEASE DURING PREGNANCY AND DELIVERY During pregnancy, the von Willebrand factor and factor VIII levels tend to rise in type 1 and 2 VWD, but this rise does not occur until the 10±11th week of gestation. No signi®cant changes occur in patients with type 3 VWD. Since the improvement in von Willebrand factor and factor VIII level during pregnancy is variable, patients should be monitored during pregnancy and for several weeks after delivery, when the levels fall rapidly and may cause late bleeding.28 In type 1 VWD, the factor VIII level is the best predictor of the risk of bleeding at delivery: the risk of bleeding is minimal when the factor VIII level is over 50 U/dL but can be signi®cant when it is lower than 20 U/ dL.28 Careful surgical haemostasis along with eective uterine contraction usually compensates for a prolonged bleeding time. In type 3 VWD, characterized by a prolonged bleeding time and a low FVIII level, replacement therapy with concentrates is necessary. Patients with type 2B VWD may develop or show an aggravation of their thrombocytopenia during pregnancy29,30, but it is not clear whether thrombocytopenia exacerbates clinical bleeding. TREATMENT OF PATIENTS WITH TYPE 3 VON WILLEBRAND DISEASE AND ALLO ANTIBODIES For the rare patients with type 3 VWD who develop anti-von Willebrand factor alloantibodies after multiple transfusion, the infusion of von Willebrand factor concentrates is not only ineective, but may also cause post-infusion anaphylaxis as a result of the formation of immune complexes.31±35 These reactions may be lifethreatening.34 To overcome this reaction, one patient undergoing emergency abdominal surgery was treated with recombinant factor VIII because this product, being completely devoid of von Willebrand factor, did not cause anaphylactic reactions. Because of the very short half-life of factor VIII devoid of its von Willebrand factor carrier, recombinant factor VIII had to be administered by continuous intravenous infusion in very large doses sucient to maintain the factor VIII level above 50 U/dL for 10 days following surgery.35 FUTURE EXPECTATIONS OF THE MANAGEMENT OF VON WILLEBRAND DISEASE Several topics related to the management of VWD must be addressed in the near future. First, a better characterization of type 1 VWD is needed, along with an identi®cation of those patients who are responsive to DDAVP. This aim might be achieved by the 3 year international project Molecular and Clinical Markers for Diagnosis and Management of type 1 VWD that is currently being sponsored by the European Community: in this project, 12 European haemophilia centres will enrol 200 families with type 1 VWD and will correlate the phenotypic data with molecular abnormalities, inheritance pattern and response to DDAVP. Second, a better evaluation of the pharmacokinetics of factor VIII:C following the administraton of factor VIII/von Willebrand factor concentrates in VWD will establish whether or not there are indications for using pure factor VIII/von Willebrand factor products devoid of factor VIII:C; the data from the co-operative study Optimizing Orphan Drug
Inherited von Willebrand disease 461
Therapy in Severe Forms of VWD, initiated in 1997 and sponsored by the European Community, will be available in 2002. Third, multicentre clinical studies on the ecacy of factor VIII/von Willebrand factor concentrates in VWD management are required: the results of one of the largest international studies (the Alphanate Study Group) are already available and will soon be published. REFERENCES 1. Ruggeri ZM, Ware JL & Ginsburg D. von Willebrand factor. In Loscalzo J & Schafer AI (eds). Thrombosis and Hemorrhage, pp 305±329. New York: Blackwell Scienti®c Publications, 1993. 2. Sadler JE. von Willebrand disease. In Bloom A & Thomas DP (eds). Haemostasis and Thrombosis, pp 843±857. London: Churchill Livingstone, 1993. * 3. Sadler JE. A revised classi®cation of von Willebrand disease. Thrombosis and Haemostasis 1994; 71: 520±525. 4. Cash JD, Garder AMA & Da Costa J. The release of plasminogen activator and factor VIII by LVP, AVP, DDAVP, ATIII and OT in man. British Journal of Haematology 1974; 27: 363±364. 5. Hashemi S, Palmer DS, Aye MT & Ganz PR. Platelet-activating factor secreted by DDAVP-treated monocytes mediates von Willebrand factor release from endothelial cells. Journal of Cell Physiology 1993; 154: 496±505. * 6. Mannucci PM, Ruggeri ZM, Pareti FI & Capitanio A. A new pharmacological approach to the management of hemophilia and von Willebrand disease. Lancet 1977; 1: 869±872. 7. Rodeghiero F, Castaman G & Mannucci PM. Clinical indications for desmopressin (DDAVP) in congenital and acquired von Willebrand disease. Blood Reviews 1991; 5: 155±161. * 8. Mannucci PM, Bettega D & Cattaneo M. Consistency of responses to repeated DDAVP infusions in patients with von Willebrand disease and haemophilia A. British Journal of Haematology 1992; 82: 87±93. 9. Smith TJ, Gill JC, Ambroso DR & Hathaway WE. Hyponatremia and seizures in young children given DDAVP. American Journal of Hematology 1989; 31: 199±202. 10. Bond L & Bevin D. Myocardial infarction in a patient with hemophilia A treated with DDAVP. New England Journal of Medicine 1988; 318: 121. 11. Byrnes JJ, Larcada A & Moake JL. Thrombosis following desmopressin for uremic bleeding. American Journal of Hematology 1988; 28: 63±65. *12. Mannucci PM, Lombardi R, Bader R et al. Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor. Blood 1985; 66: 796±802. *13. Holmberg L, Nilsson I, Borge L et al. Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in type II B von Willebrand disease. New England Journal of Medicine 1983; 309: 816±821. 14. Fowler WE, Berkowitz LR & Roberts HR. DDAVP for type IIB von Willebrand disease. Blood 1989; 74: 1859±1860. 15. Casonato A, Fabris F & Girolami A. Platelet aggregation and pseudothrombocytopenia induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in type II B von Willebrand disease. European Journal of Haematology 1990; 45: 36±42. 16. Mazurier C, Gaucher C, Jorieux S et al. Biological eect of desmopressin in eight patients with type 2 N (`Normandy') von Willebrand disease. British Journal of Haematology 1994; 88: 849±854. 17. Castaman G, Lattuada A, Mannucci PM & Rodeghiero F. Factor VIII:C increases after desmopressin in a subgroup of patients with autosomal recessive severe von Willebrand disease. British Journal of Haematology 1995; 89: 849±854. 18. Perkins HA. Correction of the hemostatic defects in von Willebrand disease. Blood 1967; 30: 375±380. 19. Rodeghiero F, Castaman G, Meyer D & Mannucci PM. Replacement therapy with virus-inactivated plasma concentrates in von Willebrand disease. Vox Sanguinis 1992; 62: 193±199. 20. Burnouf-Radosevich M & Burnouf T. Chromatographic preparation of a therapeutic highly puri®ed von Willebrand factor concentrate from human cryoprecipitate. Vox Sanguinis 1992; 62: 1±11. 21. Meriane F, Zerhouni L, Djeha N et al. Biological eects of a S/D-treated, very high purity, von Willebrand factor concentrate in ®ve patients with severe von Willebrand disease. Blood Coagulation and Fibrinolysis 1993; 4: 1023±1029. 22. Cornu P, Larrieu MJ, Caen J & Bernard J. Transfusion studies in von Willebrand disease: eect on bleeding time and factor VIII. British Journal of Haematology 1963; 9: 189±202. *23. Mannucci PM, Lattuada A & Ruggeri ZM. Proteolysis of von Willebrand factor in therapeutic plasma concentrates. Blood 1994; 83: 3018±3027.
462 P. M. Mannucci and A. B. Federici 24. Mannucci PM, Chediak J, Byrnes JJ et al. A high purity factor VIII concentrate in the treatment of von Willebrand's disease. Thrombosis and Haemostasis 1999; (supplement): 559. Abstract. 25. Cattaneo M, Moia M, Della Valle P et al. DDAVP shortens the prolonged bleeding time of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of released von Willebrand factor. Blood 1989; 74: 1972±1975. *26. Castillo R, Monteagudo J, Escolar G et al. Hemostatic eect of normal platelet transfusion in severe von Willebrand disease. Blood 1991; 77: 1901±1905. 27. Castillo R, Escolar G, Monteagudo J et al. Hemostasis in patients with severe von Willebrand disease improves after normal platelet transfusion and normalizes with further correction of the plasma defect. Transfusion 1987; 37: 785±790. 28. Conti M, Mari D, Conti E et al. Pregnancy in women with dierent types of von Willebrand disease. Obstetrics and Gynecology 1986; 68: 282±285. 29. Rick ME, Williams SB, Sacher RA & McKeon PL. Thrombocytopenia associated with pregnancy in a patient with type II B vWD. Blood 1987; 69: 786±789. 30. Pareti FI, Federici AB, Cattaneo M & Mannucci PM. Spontaneous platelet aggregation during pregnancy in a patient with vWD type II B can be blocked by monoclonal antibodies to both platelet glycoproteins Ib and IIb/IIIa. British Journal of Haematology 1990; 75: 86±91. *31. Mannucci PM & Federici AB. Antibodies to von Willebrand factor in von Willebrand disease. In Aledort LM, Hoyer LW, Lusher JM et al (eds) Inhibitors to Coagulation Factors, pp 87±92. New York: Plenum Press, 1995. 32. Shelton-Inloes BB, Chebab FF, Mannucci PM et al. Gene deletion correlates with the development of alloantibodies in von Willebrand disease. Journal of Clinical Investigation 1987; 79: 1459±1465. *33. Mannucci PM, Ruggeri ZM, Ciavarella N et al. Precipitating antibodies to FVIII/von Willebrand factor in von Willebrand disease: eects on replacement therapy. Blood 1981; 57: 25±31. 34. Mannucci PM, Tamaro G, Narchi G et al. Life-threatening reaction to FVIII concentrate in a patient with severe vWD and alloantibodies to von Willebrand factor. European Journal of Haematology 1987; 39: 467±470. 35. Bergamaschini L, Mannucci PM, Federici AB et al. Posttransfusion anaphylactic reaction in a patient with severe von Willebrand disease: role of complement and alloantibodies to von Willebrand factor. Journal of Laboratory and Clinical Medicine 1995; 125: 348±355.
doi:10.1053/beha.2001.0143, available online at http://www.idealibrary.com on
13 Management of inherited von Willebrand disease Pier Mannuccio Mannucci Augusto B. Federici
MD
MD
Angelo Bianchi Bonomi Haemophilia and Thrombosis Center and Department of Internal Medicine, IRCCS Maggiore Hospital, University of Milan, Italy
von Willebrand disease is a bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor. The diagnosis is based on measurements of plasma and platelet von Willebrand factor, the ability of von Willebrand factor to interact with its platelet receptor and the analysis of the multimeric composition of von Willebrand factor. Owing to the heterogeneity of von Willebrand factor defects, a correct diagnosis of types and subtypes may be sometimes dicult but is very important for an appropriate therapy. The aim of treatment is to correct the dual defects of haemostasis, i. e. abnormal coagulation, expressed by a low level of factor VIII, and abnormal platelet adhesion, expressed by a prolonged bleeding time. Desmopressin is the treatment of choice in patients with type 1 von Willebrand disease, who account for approximately 70% of cases, because it corrects the factor VIII/von Willebrand factor level and the prolonged bleeding time in most of these patients. In type 3 and in the majority of type 2 von Willebrand disease patients, desmopressin is not eective and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are eective and currently safe, but they do not always correct the bleeding time defect. Platelet concentrates or desmopressin can be used as adjunctive treatments when a poor correction of the bleeding time after concentrates is associated with continued bleeding. Studies are in progress, ®rst to better characterize patients with type 1 von Willebrand disease and to determine their response to desmopressin, and second, to evaluate the pharmacokinetios of factor VIII following factor VIII/von Willebrand factor concentrates and to establish the indication for concentrates. Key words: von Willebrand factor; congenital von Willebrand disease; desmopressin; factor VIII/von Willebrand factor concentrates.
von Willebrand disease (VWD) is the bleeding disorder most frequently encountered and is caused by a quantitative (types 1 and 3) or a qualitative (type 2) defect of von Willebrand factor (VWF). von Willebrand factor is the high molecular weight glycoprotein that plays an essential role in the early phases of haemostasis by promoting platelet adhesion to the subendothelium and platelet aggregation under high shear conditions.1 Since von Willebrand factor is also the carrier of factor VIII in plasma, a de®ciency of von Willebrand factor results in an impairment of both the primary phase of haemostasis and blood coagulation. 1521±6926/01/02045508 $35.00/00
c 2001 Harcourt Publishers Ltd. *
456 P. M. Mannucci and A. B. Federici
In most cases, VWD is congenital, inherited in an autosomal dominant fashion; an autosomal recessive pattern is also described in some cases. Patients with VWD may have had a mild, moderate or severe bleeding tendency since their early childhood, usually proportional to the degree of the von Willebrand factor defect. Inherited VWD has been subdivided into three categories that re¯ect the underlying pathophysiology. Types 1 and 3 VWD re¯ect, respectively, the partial and virtually complete de®ciency of von Willebrand factor, whereas type 2 VWD re¯ects a qualitative de®ciency of von Willebrand factor.2 The revised classi®cation introduced in 1994 by Sadler3 recommends the subdivision of type 2 VWD into four variants (2A, 2B, 2M, and 2N) according to speci®c details of their phenotypic features (Table 1). This classi®cation also addresses the problems of compound heterozygosity and of disorders related to VWD that are not caused by a defect in the von Willebrand factor gene, such as `platelet-type pseudo-VWD' and the acquired von Willebrand syndrome.2,3 In patients with VWD, the goal of therapy is to correct the dual defect of haemostasis, i.e. the prolonged bleeding time caused by abnormal platelet adhesion, and the abnormal intrinsic coagulation pathway resulting from low levels of factor VIII. There are two treatments of choice in VWD: desmopressin and transfusional therapy with plasma-derived factor VIII/VWF concentrates. Other forms of treatment can be considered as being adjunctive or alternative to these (Table 2). Table 1. Classi®cation of von Willebrand disease. 1. VWD is caused by mutation of the VWF locus 2. Type 1 VWD refers to partial quantitative de®ciency of VWF Type 2 VWD refers to qualitative de®ciency of VWF Type 3 VWD refers to virtually complete de®ciency of VWF 3. Type 2 A VWD refers to qualitative variants with decreased platelet-dependent function that is associated with the absence of high-molecular-weight multimers 4. Type 2 B VWD refers to qualitative variants with increased anity for platelet GPIb 5. Type 2 M VWD refers to qualitative variants with decreased platelet-dependent function not caused by the absence of high-molecular-weight multimers 6. Type 2 N VWD refers to qualitative variants with markedly decreased anity for factor VIII 7. When recognized, a mixed phenotype caused by compound heterozygosity is indicated by separate classi®cation of each allele separated by a slash (/) 8. For the description of mutations, numbering systems are suggested for aminoacids and nucleotides VWF von Willebrand factor; GpIb glycoprotein Ib. From an updated version by Sadler.3
Table 2. Management of dierent types and subtypes of von Willebrand disease.
Type Type Type Type Type Type Type
1 2A 2B 2M 2N 3 3 with alloantibodies
VWF=von Willebrand factor.
Treatment of choice
Alternative and adjunctive therapy
Desmopressin Factor VIII/VWF concentrates Factor VIII/VWF concentrates Factor VIII/VWF concentrates Desmopressin Factor VIII/VWF concentrates Recombinant factor VIII
Anti-®brinolytics, oestrogens
Desmopressin, platelet concentrates
Inherited von Willebrand disease 457
DESMOPRESSIN Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of vasopressin originally designed for the treatment of diabetes insipidus. DDAVP increases the factor VIII and von Willebrand factor plasma concentration without important side-eects when administered to healthy volunteers or patients with mild haemophilia and VWD.4 The mode of action of DDAVP is not completely understood. The addition of DDAVP to cultured endothelial cells has no eect on von Willebrand factor synthesis or secretion, so the agent is presumed to act through an as yet unidenti®ed second messenger.5 The ®rst clinical trial of DDAVP was successfully performed in 1977, with the aim of avoiding the use of blood products in cases of mild haemophilia and VWD patients who needed dental extractions and other surgical procedures.6 Following these early observations, DDAVP has become widely used for the treatment of these conditions.7 The obvious advantages of DDAVP are that it is relatively inexpensive and carries no risk of transmitting blood-borne viruses. DDAVP is usually administered intravenously at a dose of 0.3 mg/kg diluted in 50 ml saline infused over 30 minutes. This treatment increases the plasma factor VIII and von Willebrand factor to 3±5 times above the basal level within 30 minutes. In general, the high factor VIII/von Willebrand factor concentrations last for 6±8 hours. Since the responses in a given patient are consistent on dierent occasions, a test dose of DDAVP administered at the time of diagnosis helps to establish the individual response pattern. Infusions can be repeated every 12±24 hours depending on the type and severity of the bleeding episode. Some patients treated repeatedly with DDAVP become, however, less responsive to therapy.8 The drug is also available in concentrated forms for subcutaneous and intranasal administration, which can be convenient for home treatment. The side-eects of DDAVP treatment are usually mild tachycardia, headache and ¯ushing; these symptoms are attributed to the vasomotor eects of the drug and can often be attenuated by slowing the rate of infusion. Hyponatraemia and volume overload caused by the anti-diuretic eects of DDAVP are relatively rare: a few cases have been described, mostly in young children who have received closely repeated infusions.9 Even though no thrombotic episodes have been reported in VWD patients treated with DDAVP, this drug should be used with caution in elderly patients with atherosclerotic disease because a few cases of myocardial infarction and stroke have occurred in haemophiliacs and uraemic patients given DDAVP.10,11 DDAVP is most eective in patients with type 1 VWD, especially those who have a normal von Willebrand factor level in the storage sites (type 1, `platelet normal'); in these patients factor VIII, von Willebrand factor and bleeding time are usually corrected within 30 minutes and remain normal for 6±8 hours. In other VWD subtypes, responsiveness to DDAVP is variable: a poor and short-lasting response is observed in type 1 `platelet low'.12 In type 2A disease, the factor VIII level is usually increased by DDAVP but the bleeding time is shortened in only a minority of cases. Desmopressin is contra-indicated in type 2B von Willebrand factor because of the transient appearance of thrombocytopenia.13 There have, however, been reports on the clinical usefulness of DDAVP in some cases of 2B.14,15 In type 2N VWD relatively high levels of factor VIII are observed following DDAVP infusion, but the released factor VIII circulates for a shorter time period in patient plasma because the stabilizing eect of the von Willebrand factor is impaired.16
458 P. M. Mannucci and A. B. Federici
Patients with type 3 VWD are usually unresponsive to DDAVP. A subgroup of these patients has, however, recently been identi®ed in whom the factor VIII level becomes normal after DDAVP even though the bleeding time remains markedly prolonged.17
OTHER NON-TRANSFUSIONAL THERAPIES FOR VON WILLEBRAND DISEASE Two other types of non-transfusional therapy are used in the management of VWD: anti-®brinolytic amino acids and oestrogens. Anti-®brinolytic amino acids are synthetic drugs that interfere with the lysis of newly formed clots by saturating the binding sites on plasminogen, thereby preventing its attachment to ®brin and making the plasminogen unavailable within the forming clot. Epsilon aminocaproic acid (50 mg/kg four times a day) and tranexamic acid (25 mg/ kg three times a day) are the most used anti-®brinolytic amino acids. Both medications can be administered orally, intravenously or topically and are useful as adjuncts in the management of oral cavity bleeding, epistaxis, gastrointestinal bleeding and menorrhagia. As drugs that inhibit the ®brinolytic system, they carry a potential risk of thrombosis in patients with an underlying pre-thrombotic state. They are also contra-indicated in the management of urinary tract bleeding. Oestrogens increase the plasma von Willebrand factor level, but the response is so variable and unpredictable that they are not widely used for therapeutic purposes. It is common clinical experience that the continued use of oral contraceptives is very useful in reducing the severity of menorrhagia in women with VWD, even in those with type 3 disease, despite the fact that the factor/VIII/von Willebrand factor level is not modi®ed.
TRANSFUSIONAL THERAPIES Transfusional therapy with blood products containing factor VIII/von Willebrand factor is the treatment of choice in the patients who are unresponsive to DDAVP. Early studies indicated that cryoprecipite administered every 12±24 hours normalized the plasma factor VIII level, shortened the bleeding time and stopped or prevented clinical bleeding in VWD.18 Based on these observations, cryoprecipitate has been the mainstay of VWD therapy for many years. A recent analysis of previously published reports has, however, pointed out that the bleeding time is not always corrected following cryoprecipitate administration.19 Virucidal methods cannot be applied to cryoprecipitate, so this product also carries a small but de®nite risk of transmitting blood-borne infections. Therefore, virusinactivated concentrates, originally developed for the treatment of haemophilia A, play an important role in the current management of VWD patients unresponsive to DDAVP. Concentrates obtained by immunoanity chromatography on monoclonal antibodies (factor VIII 4 2 000 IU/mg) contain a very small amount of von Willebrand factor and are therefore unsuitable for VWD management. A chromatography-puri®ed concentrate particularly rich in von Willebrand factor and with a low content of factor VIII ± very-high purity von Willebrand factor concentrate ± has also recently been produced.20 This concentrate was eective when tested in a small cohort of type 3
Inherited von Willebrand disease 459 Table 3. Doses of factor VIII/von Willebrand factor concentrates recommended in von Willebrand disease patients unresponsive to desmopressin. Type of bleeding
Dose(IU/kg)
Number of infusions
Objective
Major surgery
50
Once a day or every other day
Maintain factor VIII 4 50 IU/dl until healing is complete
Minor surgery
30
Once a day or every other day
Factor VIII 4 30 IU/dl until healing is complete
Dental extractions
20
Single
Factor VIII 4 30 IU/dl for up to 6 hours
Spontaneous or posttraumatic bleeding
20
Single
VWD cases21, and its ecacy and safety are now under evaluation in a larger number of patients. The dosages of concentrates recommended for the control of bleeding episodes are summarised in Table 3. Since commercially available intermediate and high-purity factor VIII/von Willebrand factor concentrates contain a large amount of factor VIII and von Willebrand factor, high post-infusion levels of these moieties are consistently obtained. There is, moreover, a sustained rise in factor VIII, higher than would be predicted from the doses infused, lasting for up to 24 hours. This pattern is caused by the stabilizing eect of exogenous von Willebrand factor on endogenous factor VIII, which is synthesized at a normal rate in these patients.22 Therefore, all products are able to correct FVIII de®ciency even though they are not always eective in correcting the bleeding time.19 There are probably multiple reasons for the inconsistent eects on the bleeding time. So far, no concentrate contains a completely functional von Willebrand factor, as tested in vitro by evaluating the multimeric pattern and using several functional assays, because von Willebrand factor proteolysis occurs during puri®cation as a result of the action of platelet and leukocyte proteases contaminating the plasma used for fractionation.23 Despite their limited and inconsistent eect on the bleeding time, factor VIII/von Willebrand factor concentrates are successfully used for the treatment of VWD patients unresponsive to DDAVP, especially for soft tissue and post-operative bleeding.19 The results of a large international study by the Alphanate Study Group on the clinical use of a plasma-derived factor VIII/von Willebrand factor concentrate have been reported: according to these data, 73% of bleeding episodes were resolved by a single infusion of concentrate, and haemostatic control during surgery was obtained even in the absence of bleeding time correction.24 When bleeding persists despite replacement therapy, other therapeutic options are available. DDAVP, given after cryoprecipitate, further shortened or normalized the bleeding time in patients with type 3 VWD in whom cryoprecipitate failed to correct the bleeding time.25 Platelet concentrates (given before or after cryoprecipitate, at a dose of 4±5 1011 platelets) achieved a similar eect in patients unresponsive to cryoprecipitate alone, in terms of both bleeding time correction and bleeding control.26,27 These data emphasize the important role of platelet von Willebrand factor in establishing and maintaining primary haemostasis.
460 P. M. Mannucci and A. B. Federici
TREATMENT OF VON WILLEBRAND DISEASE DURING PREGNANCY AND DELIVERY During pregnancy, the von Willebrand factor and factor VIII levels tend to rise in type 1 and 2 VWD, but this rise does not occur until the 10±11th week of gestation. No signi®cant changes occur in patients with type 3 VWD. Since the improvement in von Willebrand factor and factor VIII level during pregnancy is variable, patients should be monitored during pregnancy and for several weeks after delivery, when the levels fall rapidly and may cause late bleeding.28 In type 1 VWD, the factor VIII level is the best predictor of the risk of bleeding at delivery: the risk of bleeding is minimal when the factor VIII level is over 50 U/dL but can be signi®cant when it is lower than 20 U/ dL.28 Careful surgical haemostasis along with eective uterine contraction usually compensates for a prolonged bleeding time. In type 3 VWD, characterized by a prolonged bleeding time and a low FVIII level, replacement therapy with concentrates is necessary. Patients with type 2B VWD may develop or show an aggravation of their thrombocytopenia during pregnancy29,30, but it is not clear whether thrombocytopenia exacerbates clinical bleeding. TREATMENT OF PATIENTS WITH TYPE 3 VON WILLEBRAND DISEASE AND ALLO ANTIBODIES For the rare patients with type 3 VWD who develop anti-von Willebrand factor alloantibodies after multiple transfusion, the infusion of von Willebrand factor concentrates is not only ineective, but may also cause post-infusion anaphylaxis as a result of the formation of immune complexes.31±35 These reactions may be lifethreatening.34 To overcome this reaction, one patient undergoing emergency abdominal surgery was treated with recombinant factor VIII because this product, being completely devoid of von Willebrand factor, did not cause anaphylactic reactions. Because of the very short half-life of factor VIII devoid of its von Willebrand factor carrier, recombinant factor VIII had to be administered by continuous intravenous infusion in very large doses sucient to maintain the factor VIII level above 50 U/dL for 10 days following surgery.35 FUTURE EXPECTATIONS OF THE MANAGEMENT OF VON WILLEBRAND DISEASE Several topics related to the management of VWD must be addressed in the near future. First, a better characterization of type 1 VWD is needed, along with an identi®cation of those patients who are responsive to DDAVP. This aim might be achieved by the 3 year international project Molecular and Clinical Markers for Diagnosis and Management of type 1 VWD that is currently being sponsored by the European Community: in this project, 12 European haemophilia centres will enrol 200 families with type 1 VWD and will correlate the phenotypic data with molecular abnormalities, inheritance pattern and response to DDAVP. Second, a better evaluation of the pharmacokinetics of factor VIII:C following the administraton of factor VIII/von Willebrand factor concentrates in VWD will establish whether or not there are indications for using pure factor VIII/von Willebrand factor products devoid of factor VIII:C; the data from the co-operative study Optimizing Orphan Drug
Inherited von Willebrand disease 461
Therapy in Severe Forms of VWD, initiated in 1997 and sponsored by the European Community, will be available in 2002. Third, multicentre clinical studies on the ecacy of factor VIII/von Willebrand factor concentrates in VWD management are required: the results of one of the largest international studies (the Alphanate Study Group) are already available and will soon be published. REFERENCES 1. Ruggeri ZM, Ware JL & Ginsburg D. von Willebrand factor. In Loscalzo J & Schafer AI (eds). Thrombosis and Hemorrhage, pp 305±329. New York: Blackwell Scienti®c Publications, 1993. 2. Sadler JE. von Willebrand disease. In Bloom A & Thomas DP (eds). Haemostasis and Thrombosis, pp 843±857. London: Churchill Livingstone, 1993. * 3. Sadler JE. A revised classi®cation of von Willebrand disease. Thrombosis and Haemostasis 1994; 71: 520±525. 4. Cash JD, Garder AMA & Da Costa J. The release of plasminogen activator and factor VIII by LVP, AVP, DDAVP, ATIII and OT in man. British Journal of Haematology 1974; 27: 363±364. 5. Hashemi S, Palmer DS, Aye MT & Ganz PR. Platelet-activating factor secreted by DDAVP-treated monocytes mediates von Willebrand factor release from endothelial cells. Journal of Cell Physiology 1993; 154: 496±505. * 6. Mannucci PM, Ruggeri ZM, Pareti FI & Capitanio A. A new pharmacological approach to the management of hemophilia and von Willebrand disease. Lancet 1977; 1: 869±872. 7. Rodeghiero F, Castaman G & Mannucci PM. Clinical indications for desmopressin (DDAVP) in congenital and acquired von Willebrand disease. Blood Reviews 1991; 5: 155±161. * 8. Mannucci PM, Bettega D & Cattaneo M. Consistency of responses to repeated DDAVP infusions in patients with von Willebrand disease and haemophilia A. British Journal of Haematology 1992; 82: 87±93. 9. Smith TJ, Gill JC, Ambroso DR & Hathaway WE. Hyponatremia and seizures in young children given DDAVP. American Journal of Hematology 1989; 31: 199±202. 10. Bond L & Bevin D. Myocardial infarction in a patient with hemophilia A treated with DDAVP. New England Journal of Medicine 1988; 318: 121. 11. Byrnes JJ, Larcada A & Moake JL. Thrombosis following desmopressin for uremic bleeding. American Journal of Hematology 1988; 28: 63±65. *12. Mannucci PM, Lombardi R, Bader R et al. Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor. Blood 1985; 66: 796±802. *13. Holmberg L, Nilsson I, Borge L et al. Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in type II B von Willebrand disease. New England Journal of Medicine 1983; 309: 816±821. 14. Fowler WE, Berkowitz LR & Roberts HR. DDAVP for type IIB von Willebrand disease. Blood 1989; 74: 1859±1860. 15. Casonato A, Fabris F & Girolami A. Platelet aggregation and pseudothrombocytopenia induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in type II B von Willebrand disease. European Journal of Haematology 1990; 45: 36±42. 16. Mazurier C, Gaucher C, Jorieux S et al. Biological eect of desmopressin in eight patients with type 2 N (`Normandy') von Willebrand disease. British Journal of Haematology 1994; 88: 849±854. 17. Castaman G, Lattuada A, Mannucci PM & Rodeghiero F. Factor VIII:C increases after desmopressin in a subgroup of patients with autosomal recessive severe von Willebrand disease. British Journal of Haematology 1995; 89: 849±854. 18. Perkins HA. Correction of the hemostatic defects in von Willebrand disease. Blood 1967; 30: 375±380. 19. Rodeghiero F, Castaman G, Meyer D & Mannucci PM. Replacement therapy with virus-inactivated plasma concentrates in von Willebrand disease. Vox Sanguinis 1992; 62: 193±199. 20. Burnouf-Radosevich M & Burnouf T. Chromatographic preparation of a therapeutic highly puri®ed von Willebrand factor concentrate from human cryoprecipitate. Vox Sanguinis 1992; 62: 1±11. 21. Meriane F, Zerhouni L, Djeha N et al. Biological eects of a S/D-treated, very high purity, von Willebrand factor concentrate in ®ve patients with severe von Willebrand disease. Blood Coagulation and Fibrinolysis 1993; 4: 1023±1029. 22. Cornu P, Larrieu MJ, Caen J & Bernard J. Transfusion studies in von Willebrand disease: eect on bleeding time and factor VIII. British Journal of Haematology 1963; 9: 189±202. *23. Mannucci PM, Lattuada A & Ruggeri ZM. Proteolysis of von Willebrand factor in therapeutic plasma concentrates. Blood 1994; 83: 3018±3027.
462 P. M. Mannucci and A. B. Federici 24. Mannucci PM, Chediak J, Byrnes JJ et al. A high purity factor VIII concentrate in the treatment of von Willebrand's disease. Thrombosis and Haemostasis 1999; (supplement): 559. Abstract. 25. Cattaneo M, Moia M, Della Valle P et al. DDAVP shortens the prolonged bleeding time of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of released von Willebrand factor. Blood 1989; 74: 1972±1975. *26. Castillo R, Monteagudo J, Escolar G et al. Hemostatic eect of normal platelet transfusion in severe von Willebrand disease. Blood 1991; 77: 1901±1905. 27. Castillo R, Escolar G, Monteagudo J et al. Hemostasis in patients with severe von Willebrand disease improves after normal platelet transfusion and normalizes with further correction of the plasma defect. Transfusion 1987; 37: 785±790. 28. Conti M, Mari D, Conti E et al. Pregnancy in women with dierent types of von Willebrand disease. Obstetrics and Gynecology 1986; 68: 282±285. 29. Rick ME, Williams SB, Sacher RA & McKeon PL. Thrombocytopenia associated with pregnancy in a patient with type II B vWD. Blood 1987; 69: 786±789. 30. Pareti FI, Federici AB, Cattaneo M & Mannucci PM. Spontaneous platelet aggregation during pregnancy in a patient with vWD type II B can be blocked by monoclonal antibodies to both platelet glycoproteins Ib and IIb/IIIa. British Journal of Haematology 1990; 75: 86±91. *31. Mannucci PM & Federici AB. Antibodies to von Willebrand factor in von Willebrand disease. In Aledort LM, Hoyer LW, Lusher JM et al (eds) Inhibitors to Coagulation Factors, pp 87±92. New York: Plenum Press, 1995. 32. Shelton-Inloes BB, Chebab FF, Mannucci PM et al. Gene deletion correlates with the development of alloantibodies in von Willebrand disease. Journal of Clinical Investigation 1987; 79: 1459±1465. *33. Mannucci PM, Ruggeri ZM, Ciavarella N et al. Precipitating antibodies to FVIII/von Willebrand factor in von Willebrand disease: eects on replacement therapy. Blood 1981; 57: 25±31. 34. Mannucci PM, Tamaro G, Narchi G et al. Life-threatening reaction to FVIII concentrate in a patient with severe vWD and alloantibodies to von Willebrand factor. European Journal of Haematology 1987; 39: 467±470. 35. Bergamaschini L, Mannucci PM, Federici AB et al. Posttransfusion anaphylactic reaction in a patient with severe von Willebrand disease: role of complement and alloantibodies to von Willebrand factor. Journal of Laboratory and Clinical Medicine 1995; 125: 348±355.