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Clinical indications for desmopressin (DDAVP) in congenital and acquired von Willebrand disease
Clinical Indications for Desmopressin (DDAVP) in Congenital and Acquired von Willebrand Disease
F. Rodeghiero, G. Castaman, P. Mannuccio Mannucci SUMMA R Y. In the majority of patients with congenital and acquired van Willebrand disease (vWD), desmopressin (DDAVP) is able to increase circulating factor VIII coagulant (VIII : C) to levels sufllcient to secure satisfactory hemostasis. The bleeding time (BT) is also often normalized. In this review, all cases of vWD treated with DDAVP for the prevention or control of hemorrhage and reported in the literature for whom at least basal and peak values of VIII : C were available have been analysed. When reported, the effect on the BT was also considered. It appears that, in keeping with clinical experience gaiued with blood products, the correction of VIII : C defect is often sufllcient to secure normal hemostasis. The only significant exception is mucosal bleeding, for which the correction of BT also appears to be necessary. Several patients (mainly with type I vWD) with basal VIII : C levels of 5-10% have been successfully treated to prevent bleeding after tooth extractions and minor surgery and to control spontaneous and post-traumatic bleeding. Experience with DDAVP in major surgery is still limited, so that the compound cannot be recommended for routine use. In acquired vWD, a trial with DDAVP is advised before resorting to substitutive therapy with blood derivatives. Since side effects to DDAVP treatment are limited and uo major complications have been consistently demonstrated, DDAVP can be proposed as the treatment of first choice for most patients with vWD. The recent availabllity of concentrated preparations of DDAVP for intranasal administration and the demonstration that the subcutaneous route is an effective and simpler alternative to the intravenous route should further facilitate its use and make home-therapy feasible.
Von Willebrand’s disease (vWD) is a bleeding disorder due to deficiency and/or abnormality of von Willebrand factor (vWF).’ The congenital disease has a prevalence of at least 1% .’ Acquired abnormalities of vWF, often associated with bleeding diatheses of variable severity, are also being recognized with increasing frequency, especially in association with lympho- and myeloproliferative disorders. vWF plays a major role in primary hemostasis by promoting the adhesion of platelets to exposed subenF. Ro&ghko, G. Castaman, P. Msmmccio Manmcci, Department of Hematology and Hemophilia and Thrombosis Center, San Bortolo Hospital, Vicenza; and A. Bianchi Bonomi Hemophilia and Thrombosis Center and Institute of Internal Medicine, IRCCS Maggiore Hospital and University, Milan, Italy. Correspondence to: Dr F. Rodeghiero, Department of Hematology, San Bortolo Hospital, I-36100 Vicenza, Italy. B/oodRevkws (1991) 5, 155-161 :C 1991 Longman Group UK Ltd
dothelium, with subsequent formation of a platelet plug at the site of vascular injuries.’ In addition, vWF circulates as a non-covalent complex with coagulant factor VIII (VIII : C) and is required for the stabilization of this protein in circulation.3 As a consequence, patients with congenital or acquired deficiency or abnormality of vWF often have both prolonged bleeding times (BT) and reduced VIII : C. In this disorder the goals of treatment should be to correct VIII: C deficiency and the impairment of primary hemostasis, as reflected by the prolonged BT. Ristocetin cofactor (RiCof) measurement (a functional assay of the ability of vWF to interact with glycoprotein Ib on platelet membranes), widely used for the diagnosis of the disease along with the assay of vWF antigen (vWF: Ag), should not be
1%
BLOOD
REVIEWS
considered valid substitute for BT for evaluating primary hemostasis, since results of the two tests often diverge in individual patients.4 Until recently, substitutive therapy with blood products (fresh frozen plasma, cryoprecipitate or commercial factor VIII concentrates, containing also large amounts of vWF) has been the mainstay of therapy and has been demonstrated to be able to fully correct VIII: C deficiency, although BT was only partially, transiently and not always corrected. In the late 1970’s, desmopressin (l-desamino-&darginine vasopressin, DDAVP),’ a synthetic analogue of antidiuretic hormone that releases vWF from endogenous stores,697 rapidly emerged as an effective, less costly and safer treatment than substitutive therapy. However, the effects of DDAVP differ in the different types and subtypes of the disease and not all clinical situations can be effectively managed with this agent. Three principal types of vWD have been recognized.’ Type I, the most frequent, in which vWF is reduced quantitatively but is structurally normal; type II, in which there is a structural abnormality of vWF, as reflected by the abnormally low levels of RiCof in comparison to vWF: Ag; and type III, recessively transmitted, in which the patients have very low or undetectable levels in all VIII/vWF measurements.’ Type I appears to be the most frequent subtype, accounting for 70-80% of cases,8*g whereas type III is very rare, with a prevalence of about 1 case per million inhabitants.” Although several reviews about DDAVP6 and its biological effects in vWD and various disorders of hemostasis’,” have been published, a review of the literature focussed on the safety, efficacy and limitations of this agent in the different types and subtypes of vWD should be especially valuable in order to make recommendations about its best use in the disease. Biological Effects of DDAVP VIII: C does usually increase in both type I and II vWD after DDAVP.‘2-32 vWF: Ag and RiCof increase in type I platelet-normal patients (with normal platelet vWF content)‘* but increase poorly in type I platelet-low patients (with reduced platelet vWF content).‘* RiCof does not increase in type I plateletdiscordant patients (with normal platelet vWF : Ag and low RiCof)‘* and in most type II patients.20-32 The BT is almost invariably normalized in type I platelet-normal patients,” type I Vicenza patients” and in those with the recently described variant with defective vWF-VIII : C binding.lg It remains substantially unchanged in the other type I subtypes.‘* BT has a heterogeneous pattern of behaviour in type II A”-** being partially or completely corrected in rare patients and remaining prolonged in all the other cases.26-32 In type II B, it has been demonstrated that, although VIII : C increases, thrombocytopenia occurs after DDAVP due to the release of abnormal vWF and BT is rarely modified.23 Hence, the majority
of investigators suggest that DDAVP is contraindicated for type II B. However, others have recently demonstrated benefit from DDAVP infusion for this subtype also.24,25 Tables 1 and 2 summarize biological responses to DDAVP in subjects with the various types and subtypes of vWD. VIII/vWF measurements and BT are not modified by DDAVP in type III patients,33 who are considered poor candidates for use of the compound. Infusions of DDAVP, given mainly to type I vWD subjects (usually not further sub-classified), have consistently shown median increases of VIII : C to 3.1-8.8 times above the basal level (an increment similar to that observed in hemophiliacs), with a wide range (1.2-20 times).7,34-37 Hyper-responsiveness to DDAVP has been found in type I platelet-normal patients, with a median increment of VIII: C to 8.8 times basal level (range 6.4-20). 35 Large increments have also been observed in patients with type II A.34 Disappearance of VIII : C released by DDAVP can either be rapid, with return to the basal level 4-6 h after infusion,34 or slower, with levels above twice the basal value for longer than 5 h. 34*38Rapid return to baseline has invariably been observed in type I platelet-normal patients and type I Vicenza.ls3’ In these studies the BT was shown to be consistently corrected in type I patients, with rare exceptions.5’34-36*3g*40The pattern for type II A patients was variable, with BT rarely normalized or shortened in some patients.20-22~34 From these data, it appears that DDAVP responsiveness in the various types and subtypes of the disease can usually be predicted. However, in view of the several possible exceptions and the heterogeneity of vWD, the best way to anticipate DDAVP responsiveness is to do a test infusion.’ It has been demonstrated that the responses to DDAVP in a given patient (and within-family) on different occasions are reasonably consistent.7*37 Hence, a testinfusion, 1 or 2 weeks before any elective treatment, is recommended for a new patient.
Clinical Effectiveness For the purpose of the present review, only cases treated with DDAVP for whom at least basal and peak levels of VIII: C were available have been considered. When reported, data for BT were also analyzed.
Spontaneous or Traumatic Bleeding
Several patients with vWD (mainly of type I) have been treated with DDAVP for spontaneous or posttraumatic bleeding (epistaxis, menorrhagia, muscle hematomas).5~34*36~3gIn the majority of these cases, basal VIII : C was already above 15%. Successful control of hemostasis was invariably reported even in cases in whom the BT was not corrected.34 Substi-
CLINICAL INDICATIONS
FOR DESMOPRESSIN
IN CONGENITAL AND ACQUIRED VON WILLEBRAND
DISEASE
157
Table 1 Subtype of type I vWD and their biological responses to DDAVP
Designation
VIII : c
After DDAVP RiCof vWF: Ag
Subtype platelet normal* (12) Subtype platelet low” (12) Subtype platelet discordant# (12) Type Ic (15) Type I New York (16) Type I Malmoe (17) Type I Vicenza (18) Type I with defective VIII-vWF binding (19)
tt
tt
Tt
N
T
c-1
++
S or U
Tt
tt
+-+
U
t
T
r
N
Bleeding Time
Responsiveness to DDAVP not reported t
t
t
N or S
tt
tt
Tt
N
t
tt
tt
N
*also called 1-2 (13) or IA (14) “also called I-l (13) or IA (14) #also called IB (10) t = increase; tt = marked increase; c* = little or no increase N = normalized; S = shortened; U = unchanged Table 2 Subtypes of type II vWD and their biological responses to DDAVP
Designation
VIII:C
vWF:Ag
Table 3 Surgery with DDAVP in 44 patients with vWD. Cases divided according to basal and peak VIII : C
After DDAVP RiCof Bleeding Time Basal VIII : C (%)
Type II A 20-22 Type II B* 23-25 Type II C, 11D, II F, II H 26-29, 32 Type II E, II G 30, 31
tt
tt
++ variable
TT
It
T or t*
LJ (rarely S or N)
tt
It
++
U (rarely S)
Responsiveness to DDAVP not reported
_ 2 7 10 25
Bleeding complications _ None After thyroidectomy None After knee surgery
Data from (refs. 5, 34, 36, 39, 40, 42, 44-46 and personal unpublished observations)
*Thrombocytopenia after DDAVP t = increase; tt = marked increase; ++ = little or not increase N = normalized; S = shortened; U = unchanged
tutive therapy was required only exceptionally achieve complete control of bleeding symptoms.
2-5 6-10 II-15 16-30 >30
Peak post-DDAVP VIII : c (%) < 30 30-49 > 50
to
Dental Extractions Dental extractions were done for about 60 patients with DDAVP, those with basal levels of VIII : C from 5 to above 50%, but usually higher than or equal to 20°~.34-36,3g-43 The majority of these patients were of type I and the BT was almost invariably corrected by DDAVP.34>40,42,43 Multiple dental extractions were safely done with DDAVP alone in a homogeneous group of 14 patients with type I plateletnormal vWD and more severely reduced VIII: C (mean 13%, range 8-20).35 Surgery Our survey of published cases and our own unpublished cases indicates that surgery has been carried out with DDAVP in 44 instances, most frequently in type I vWD (Table 3). In 42 cases, all with basal
VIII: C levels above 6%, there was no excessive bleeding during and after surgery. In all patients peak VIII : C levels were well above 50% postDDAVP5*34*36~3g,40*42-44 (Table 3). Two or more DDAVP infusions, at intervals of 8-24 h, were usually given. BT was usually normalized.34*36*3g*40*42-44 An impressive example of the usefulness of DDAVP in major surgery is the case reported by Isola et a1,46 who demonstrated that a patient with type I vWD was successfully treated with DDAVP for 12 days for major orthopedic surgery, with VIII : C levels consistently higher than 50% and BT shortened. The experience with type II vWD is more limited. In the original series reported by Mannucci et al,’ a cholecystectomy was carried out without mishap in a patient with type II A and a basal level of VIII: C of 44% (postDDAVP peak level were above lOO%), despite the fact that the BT was not corrected by DDAVP. Hysterectomy was safely carried out by Mannucci et a145 in a patient with type II B and a basal VIII: C level of 27%.45 DDAVP was administered 3 times on the day of operation and 48 h later and was able to induce an increase of 3-4 times the VIII: C basal level; BT was not normalized.45 One of our patients with type II B vWD had a cholecystectomy without
158 BLOOD REVIEWS mishap, despite the fact that the ET was not corrected. There are only two instances of failure with DDAVP reported (Table 3). Knee surgery was performed in a type I patient and bleeding ensued, so that cryoprecipitate was required to achieve good hemostasis.34 One of our patients with type I platelet-normal (unpublished) bled severely 2 days after thyroidectomy and cryoprecipitate had to be infused to stop bleeding. BT were normalized in both cases. Conclusions In summary, several patients with moderate to mild type I vWD have been treated with DDAVP for spontaneous or traumatic bleeding or for prevention of hemorrhage after tooth extraction. Bleeding complications were seldom observed and were of minor importance despite the fact that in some cases the BT remained prolonged. The limited experience available with patients with type II A and type II B vWD seems to indicate a similar favourable response to DDAVP in terms of clinical effectiveness. Clinical experience with DDAVP in surgery, albeit limited, seems to indicate that the compound can be safely used in some cases, whether or not the BT defect is corrected. In all patients VIII : C was 50% or higher after DDAVP. The only two reported bleeding episodes ensued despite the fact that VIII: C was above 50%, a level that should be compatible with satisfactory hemostasis (Table 3). Perhaps in those cases bleeding occurred for surgical reasons. DDAVP in Acquired von Willebrand’s Disease An acquired von Willebrand syndrome has been reported in several disorders, including lympho- and myeloproliferative syndromes, congenital heart disease and, recently, uremia.47-50 Mannucci et a148 have shown that VIII/vWF measurements and BT were normalized in 7 patients with lymphoproliferative disorders or benign monoclonal gammopathies and an intact basal multimeric pattern. This normalization was short-lived in comparison to that observed in patients with congenital type I platelet-normal vWD, probably because of an accelerated clearance of VIII/vWF from plasma. On the contrary, in patients with multimer defects, DDAVP has little or no biological and clinical effect.47q51 DDAVP has been used for at least 6 cases of acquired von Willebrand syndrome in a clinical setting to prevent or stop bleeding, but clinical effectiveness was obtained in only 3 cases, in association with a substantial increase of VIII/vWF measurements and BT normalization.47~52’53
DDAVP given subcutaneously is bioequivalent in terms of both pharmacokinetics and VIII : C responses to intravenously administered DDAVP54 and is effective in controlling bleeding symptoms.40*55 The availability of commercial concentrated preparations should make home therapy feasible. Significant and reproducible VIII : C and vWF responses (2-2.5 times the basal levels) are elicited by intranasally administered DDAVP at a dosage ten times greater than that recommended for intravenous dosage.38*56*57 This approach has been suggested for self-administered emergency aid. I1 Tachyphylaxis Some patients treated repeatedly with DDAVP at closely spaced intervals become progressively less responsive.5s45 Although poor responsiveness is by no means a constant phenomenon, clinical use of DDAVP should be reserved for those situations in which only a short term enhancement of hemostasis is required and basal levels of VIII/vWF measurements are able to sustain sufficient hemostasis thereafter. Some cases require additional therapy with blood products. DDAVP and the Fibrinolytic System Plasminogen activator is released from endothelial stores after DDAVP infusion.41*55,58A rapid increase in fibrinolytic activity is observed, peaking 30 min after infusion and decaying with a half-time of about 30 min.41 The magnitude of the response is far less than that observed in pathological hyperfibrinolysis. 41 Although, at least in theory, release of plasminogen activator is a potential drawback to the use of DDAVP, there is no clinical evidence of increased risk of bleeding due to hyperfibrinolysis after DDAVP. Nevertheless, concurrent administration of antifibrinolytic agents (epsilon-aminocaproic or tranexamic acid) has been suggested by some. Conventional doses of these agents are effective in preventing hyperfibrinolysis after DDAVP.41 Their concomitant administration in conjunction with DDAVP seems advisable for dental extractions, because antifibrinolytic agents given in conjunction with factor VIII or IX have been demonstrated to be effective in reducing blood loss in hemophilia A and B.59s60 The addition of antifibrinolytic agents for treatment of spontaneous bleeding and surgery remains questionable. In addition, some concern has been expressed that these agents might, at least potentially, precipitate thrombotic episodes61v’j2 Side-effects
Dosage and Route of Administration The recommended dosage of DDAVP is 0.3 ug/kg intravenously and subcutaneously, because larger doses do not elicit larger VIII: C responses.36
Occasional reports have claimed a thrombogenic effect for DDAVP.63-67 A review of cases conducted within the framework of the Factor VIII-Factor IX Subcommittee of International Society on Throm-
CLINICAL INDICATIONS FOR DESMOPRESSIN
IN CONGENITAL AND ACQUIRED VON WILLEBRAND
bosis and Hemostasi@* has however demonstrated the very low incidence of these episodes (10 cases among the estimated 433 000 treated individuals, including those without vWD, during the period 1985-1988). Some caution seems, nevertheless, to be advisable when DDAVP is used in patients of advanced age or with heart disease or vascular atherosclerosis. secondary to water retention Hyponatremia, caused by the antidiuretic action of DDAVP, seems not to be a real problem in adult patients. Only one hemophiliac has been reported to have had hyponatremfa after 6 closely spaced infusions of high doses of DDAVP (0.5 ug/kg). 6g However, hyponatremia and seizures have been described in children under the age of 2 years after even a single infusion.” A recent report described 4 additional patients (2 younger and 2 older children) with severe hyponatremia after closely repeated DDAVP infusions (up to 22 doses during 7 days). 71 Fluid restriction, avoidance of hyponatremic solutions and close monitoring of serum electrolytes and urine output should be done for at least 24 h after DDAVP administration to young children.
Therapeutic Recommendations DDAVP should be the treatment of first choice for spontaneous and traumatic bleeding, dental extractions and minor surgery for the majority of patients with vWD who have basal VIII : C levels higher than 4-5%, provided that a test infusion has shown a clinically useful increase of VIII : C (above 50%). The majority of investigators suggest that DDAVP is contraindicated for patients with type II B disease7*23 and it is not effective for those with severe homozygous type III. 33 A second infusion can be administered after 8-l 2 h. Tranexamic acid, 15 mg/kg, three times a day, should be administered before and for 7 days after dental extractions. Its usefulness for surgery is less clear. DDAVP can be used successfully for such spontaneous bleedings as epistaxis, hematomas, severe menorrhagia: a single infusion is usually sufficient. Menorrhagia is easily controlled in vWD by tranexamic acid or hormonal therapy and these agents should be the first-choice treatments. Since the experience with DDAVP in major surgery is very limited, this treatment should be reserved for patients with milder disease and for those for whom close monitoring with repeated assays of VIII : C is available, since replacement therapy with factor VIII concentrate could become necessary. Some types of bleeding, such as mucosal bleeding (e.g., gastrointestinal bleeding) require normalization of BT for correction.72,73 Accordingly, the BT should be measured in these situations and, if not corrected by DDAVP, VIII/vWF concentrates able to shorten BT74*75 are mandatory, if the bleeding is still in progress.
DISEASE
I59
Acknowledgements This review was written within the frame of activities of the von Willebrand Disease Committee of the World Federation of Hemophilia, chaired by Professor Dominique Meyer.
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Clinical evaluation of subcutaneously administered DDAVP. Thrombosis Research 49: 363-372 Warrier I, Lusher J M 1983 DDAVP: a useful alternative to blood components in moderate hemophilia A and von Willebrand’s disease. Journal of Pediatrics 102: 228-232 Ludlam C A, Peake I R, Allen N, Davies B L, Furlong R A, Bloom A L 1980 Factor VIII and fibrinolytic response to deamino-8-D-argenine vasopressin in normal subjects and dissociate response in some patients with haemophilia and von Willebrand’s disease. British Journal of Haematology 45: 499-511 Gckelford P A, Menon N C, Berry E W 1980 Clinical experience with arginine vasopressin (DDAVP) in von Willebrand’s disease and mild haemophilia. New Zealand Medical Journal 92: 375-378 Menon C, Berry E W, Gckelford P 1978 Beneficial effect of DDAVP on bleeding time in von Willebrand’s disease. Lancet ii: 143-744 Theiss W, Schmidt G 1978 DDAVP in von Willebrand’s disease: repeated administration and the behaviour of the bleeding time. Thrombosis Research 13: 1119-l 123 Mannucci P M. Ruaeeri Z M. Pareti F I. Caoitanio A 1977 DDAVP in hemophza. Lan&t ii: 1171-1172’ Isola L, Forster A, Aledort L M 1984 DDAVP and bleeding time in von Willebrand’s disease. Annals of Internal Medicine 101: 719-720 Budde U, Schaefer G, Mueller N, Egli H, Ruggeri Z M, Zimmerman T S 1984 Acquired von Willebrand’s disease in the myeloproliferative syndrome. Blood 64: 981-985 Mannucci P M, Lombardi R, Bader R et al 1984 Studies of the pathophysiology of acquired von Willebrand’s disease in seven patients with lymphoproliferative disorders or benign monoclonal gammopathies. Blood 64: 614-621 Gill J C, Wilson A D, Endres-Brooks J, Montgomery R R 1986 Loss of the largest von Willebrand factor multimers from the plasma of patients with congenital cardiac defects. Blood 67: 758-761 Rodeghiero F, Castaman G, Lombardi R, Mannucci P M 1988 von Willebrand factor abnormalities in two patients with uraemia. Lancet ii: 1016-1017 Lopez-Femandez M F, Lopez-Berges C, Martin R et al 1986 Unique multimeric pattern of von Willebrand factor in a patient with a benign monoclonal gammopathy. Scandinavian Journal of Haematology 36 302-308 Takahashi H, Nagayama R, Tanabe Y et al 1986 DDAVP in acquired von Willebrand syndrome associated with multiple myeloma. American Journal of Hematology 22: 421-429 Castaman G, Rodeghiero F, Di Bona E, Ruggeri M 1989 Clinical effectiveness of desmopressin in a case of acquired von Willebrand’s syndrome associated with benign monoclonal gammopathy. Blut 52I:21 I-213 Mannucci P M, Vicente V, Alberta I et al 1987 Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses. Thrombosis and Haemostasis 58: 1037-1039 Gader A M A, Clarkson A R, Cash J D 1973 The plasminogen activator and coagulation factor VIII responses to adrenaline, noradrenaline, soprenaline and salbutamol in man. Thrombosis Research 3: 51-57 Nilsson I M, Vilhardt H, Holmberg L, Astedt B 1982 Association between factor VIII related antigen and plasminogen activator. Acta Medica Scandinavica 211: 1051-1059 Lethagen S, Harris A S, Sjorin E, Nilsson I M 1987 Intranasal and intravenous administration of desmopressin: Effect on FVIIIjVWF pharmacokinetics and reproducibility. Thrombosis and Haemostasis 58: 1033-1037 Mannucci P M, Aberg M, Nilsson I M, Robertson B 1975 Mechanism of plasminogen activator and factor VIII increase after vasoactive drugs. British Journal of Haematology 30: 81-93 Forbes C D, Barr R D, Reid G et al 1972 Tranexamic acid in control of hemorrhage after dental extraction in hemophilia and Christmas disease. British Medical Journal 2: 311 Walsh P N, R&a C R, Matthews J M et al 1971 Epsilonaminocaproic acid therapy for dental extractions in haemophilia and Christmas disease: a double-bind controlled trial. British Journal of Haematology 20: 463
CLINICAL INDICATIONS
FOR DESMOPRESSIN
IN CONGENITAL AND ACQUIRED VON WILLEBRAND DISEASE
61.
161
70.
62. thrombosis. Lancet’i: 49 63. O’Brien J R, Green P J, Salmon G et al 1989 Desmopressin and myocardial infarction. Lancet i: 664 64. van Dar&zig J M, Duren D R, ten Cate J W 1989 Desmopressin and myocardial infarction. Lancet i: 664 65. Bond L, Bevan D 1988 Myocardial infarction in a patient with hemophilia treated with DDAVP. New England Journal of Medicine 318: 121 66. Viron B, Michel C, Serrato T, Verdy E 1987 Risque thrombogene du DDAVP dans l’insuffisance renal chronique. Nephrologie 8: 225 61. Bymes J J, Larcada A, Moake J L 1988 Thrombosis following desmopressin for uremic bleeding. American Journal of Hematology 28: 63-64 68. Mannucci P M, Lusher J M 1989 Desmopressin and thrombosis. Lancet ii: 675-676 69. Lowe J, Pettigrew A, MiddIeton S, Forbes C D, Prentice C R M 1977 DDAVP in hemophilia. Lancet ii: 614
71.
72. 73.
74.
75.
hyponatremia after repeated intravenous administration of desmopressin. American Journal of Hematology 32: 258-261 Perkins H A 1967 Correction of the hemostatic defects in von Willebrand’s disease. Blood 30: 375-380 Blait P M, Brinkhous K M, Culp H R, Krauss J S, Roberts H R 1976 Antihemophilic factor concentrate therapy in van Willebrand disease. Dissociation of the bleeding-time factor and ristocetin-cofactor activities. Journal of the American Medical Association 236: 2770-2772 Czapek E E, Gadarowski J J, Ontiveros J D, Pedraza J L 1988 Humate- P for treatment of von Willebrand disease. Blood 72: 1100 Fukui H, Nishino M, Terada S et al 1988 Hemostatic effect of a heat-treated factor VIII concentrate (Haemate P) in von Willebrand’s disease. Blut 56: 17I- 178
F. Rodeghiero, G. Castaman, P. Mannuccio Mannucci SUMMA R Y. In the majority of patients with congenital and acquired van Willebrand disease (vWD), desmopressin (DDAVP) is able to increase circulating factor VIII coagulant (VIII : C) to levels sufllcient to secure satisfactory hemostasis. The bleeding time (BT) is also often normalized. In this review, all cases of vWD treated with DDAVP for the prevention or control of hemorrhage and reported in the literature for whom at least basal and peak values of VIII : C were available have been analysed. When reported, the effect on the BT was also considered. It appears that, in keeping with clinical experience gaiued with blood products, the correction of VIII : C defect is often sufllcient to secure normal hemostasis. The only significant exception is mucosal bleeding, for which the correction of BT also appears to be necessary. Several patients (mainly with type I vWD) with basal VIII : C levels of 5-10% have been successfully treated to prevent bleeding after tooth extractions and minor surgery and to control spontaneous and post-traumatic bleeding. Experience with DDAVP in major surgery is still limited, so that the compound cannot be recommended for routine use. In acquired vWD, a trial with DDAVP is advised before resorting to substitutive therapy with blood derivatives. Since side effects to DDAVP treatment are limited and uo major complications have been consistently demonstrated, DDAVP can be proposed as the treatment of first choice for most patients with vWD. The recent availabllity of concentrated preparations of DDAVP for intranasal administration and the demonstration that the subcutaneous route is an effective and simpler alternative to the intravenous route should further facilitate its use and make home-therapy feasible.
Von Willebrand’s disease (vWD) is a bleeding disorder due to deficiency and/or abnormality of von Willebrand factor (vWF).’ The congenital disease has a prevalence of at least 1% .’ Acquired abnormalities of vWF, often associated with bleeding diatheses of variable severity, are also being recognized with increasing frequency, especially in association with lympho- and myeloproliferative disorders. vWF plays a major role in primary hemostasis by promoting the adhesion of platelets to exposed subenF. Ro&ghko, G. Castaman, P. Msmmccio Manmcci, Department of Hematology and Hemophilia and Thrombosis Center, San Bortolo Hospital, Vicenza; and A. Bianchi Bonomi Hemophilia and Thrombosis Center and Institute of Internal Medicine, IRCCS Maggiore Hospital and University, Milan, Italy. Correspondence to: Dr F. Rodeghiero, Department of Hematology, San Bortolo Hospital, I-36100 Vicenza, Italy. B/oodRevkws (1991) 5, 155-161 :C 1991 Longman Group UK Ltd
dothelium, with subsequent formation of a platelet plug at the site of vascular injuries.’ In addition, vWF circulates as a non-covalent complex with coagulant factor VIII (VIII : C) and is required for the stabilization of this protein in circulation.3 As a consequence, patients with congenital or acquired deficiency or abnormality of vWF often have both prolonged bleeding times (BT) and reduced VIII : C. In this disorder the goals of treatment should be to correct VIII: C deficiency and the impairment of primary hemostasis, as reflected by the prolonged BT. Ristocetin cofactor (RiCof) measurement (a functional assay of the ability of vWF to interact with glycoprotein Ib on platelet membranes), widely used for the diagnosis of the disease along with the assay of vWF antigen (vWF: Ag), should not be
1%
BLOOD
REVIEWS
considered valid substitute for BT for evaluating primary hemostasis, since results of the two tests often diverge in individual patients.4 Until recently, substitutive therapy with blood products (fresh frozen plasma, cryoprecipitate or commercial factor VIII concentrates, containing also large amounts of vWF) has been the mainstay of therapy and has been demonstrated to be able to fully correct VIII: C deficiency, although BT was only partially, transiently and not always corrected. In the late 1970’s, desmopressin (l-desamino-&darginine vasopressin, DDAVP),’ a synthetic analogue of antidiuretic hormone that releases vWF from endogenous stores,697 rapidly emerged as an effective, less costly and safer treatment than substitutive therapy. However, the effects of DDAVP differ in the different types and subtypes of the disease and not all clinical situations can be effectively managed with this agent. Three principal types of vWD have been recognized.’ Type I, the most frequent, in which vWF is reduced quantitatively but is structurally normal; type II, in which there is a structural abnormality of vWF, as reflected by the abnormally low levels of RiCof in comparison to vWF: Ag; and type III, recessively transmitted, in which the patients have very low or undetectable levels in all VIII/vWF measurements.’ Type I appears to be the most frequent subtype, accounting for 70-80% of cases,8*g whereas type III is very rare, with a prevalence of about 1 case per million inhabitants.” Although several reviews about DDAVP6 and its biological effects in vWD and various disorders of hemostasis’,” have been published, a review of the literature focussed on the safety, efficacy and limitations of this agent in the different types and subtypes of vWD should be especially valuable in order to make recommendations about its best use in the disease. Biological Effects of DDAVP VIII: C does usually increase in both type I and II vWD after DDAVP.‘2-32 vWF: Ag and RiCof increase in type I platelet-normal patients (with normal platelet vWF content)‘* but increase poorly in type I platelet-low patients (with reduced platelet vWF content).‘* RiCof does not increase in type I plateletdiscordant patients (with normal platelet vWF : Ag and low RiCof)‘* and in most type II patients.20-32 The BT is almost invariably normalized in type I platelet-normal patients,” type I Vicenza patients” and in those with the recently described variant with defective vWF-VIII : C binding.lg It remains substantially unchanged in the other type I subtypes.‘* BT has a heterogeneous pattern of behaviour in type II A”-** being partially or completely corrected in rare patients and remaining prolonged in all the other cases.26-32 In type II B, it has been demonstrated that, although VIII : C increases, thrombocytopenia occurs after DDAVP due to the release of abnormal vWF and BT is rarely modified.23 Hence, the majority
of investigators suggest that DDAVP is contraindicated for type II B. However, others have recently demonstrated benefit from DDAVP infusion for this subtype also.24,25 Tables 1 and 2 summarize biological responses to DDAVP in subjects with the various types and subtypes of vWD. VIII/vWF measurements and BT are not modified by DDAVP in type III patients,33 who are considered poor candidates for use of the compound. Infusions of DDAVP, given mainly to type I vWD subjects (usually not further sub-classified), have consistently shown median increases of VIII : C to 3.1-8.8 times above the basal level (an increment similar to that observed in hemophiliacs), with a wide range (1.2-20 times).7,34-37 Hyper-responsiveness to DDAVP has been found in type I platelet-normal patients, with a median increment of VIII: C to 8.8 times basal level (range 6.4-20). 35 Large increments have also been observed in patients with type II A.34 Disappearance of VIII : C released by DDAVP can either be rapid, with return to the basal level 4-6 h after infusion,34 or slower, with levels above twice the basal value for longer than 5 h. 34*38Rapid return to baseline has invariably been observed in type I platelet-normal patients and type I Vicenza.ls3’ In these studies the BT was shown to be consistently corrected in type I patients, with rare exceptions.5’34-36*3g*40The pattern for type II A patients was variable, with BT rarely normalized or shortened in some patients.20-22~34 From these data, it appears that DDAVP responsiveness in the various types and subtypes of the disease can usually be predicted. However, in view of the several possible exceptions and the heterogeneity of vWD, the best way to anticipate DDAVP responsiveness is to do a test infusion.’ It has been demonstrated that the responses to DDAVP in a given patient (and within-family) on different occasions are reasonably consistent.7*37 Hence, a testinfusion, 1 or 2 weeks before any elective treatment, is recommended for a new patient.
Clinical Effectiveness For the purpose of the present review, only cases treated with DDAVP for whom at least basal and peak levels of VIII: C were available have been considered. When reported, data for BT were also analyzed.
Spontaneous or Traumatic Bleeding
Several patients with vWD (mainly of type I) have been treated with DDAVP for spontaneous or posttraumatic bleeding (epistaxis, menorrhagia, muscle hematomas).5~34*36~3gIn the majority of these cases, basal VIII : C was already above 15%. Successful control of hemostasis was invariably reported even in cases in whom the BT was not corrected.34 Substi-
CLINICAL INDICATIONS
FOR DESMOPRESSIN
IN CONGENITAL AND ACQUIRED VON WILLEBRAND
DISEASE
157
Table 1 Subtype of type I vWD and their biological responses to DDAVP
Designation
VIII : c
After DDAVP RiCof vWF: Ag
Subtype platelet normal* (12) Subtype platelet low” (12) Subtype platelet discordant# (12) Type Ic (15) Type I New York (16) Type I Malmoe (17) Type I Vicenza (18) Type I with defective VIII-vWF binding (19)
tt
tt
Tt
N
T
c-1
++
S or U
Tt
tt
+-+
U
t
T
r
N
Bleeding Time
Responsiveness to DDAVP not reported t
t
t
N or S
tt
tt
Tt
N
t
tt
tt
N
*also called 1-2 (13) or IA (14) “also called I-l (13) or IA (14) #also called IB (10) t = increase; tt = marked increase; c* = little or no increase N = normalized; S = shortened; U = unchanged Table 2 Subtypes of type II vWD and their biological responses to DDAVP
Designation
VIII:C
vWF:Ag
Table 3 Surgery with DDAVP in 44 patients with vWD. Cases divided according to basal and peak VIII : C
After DDAVP RiCof Bleeding Time Basal VIII : C (%)
Type II A 20-22 Type II B* 23-25 Type II C, 11D, II F, II H 26-29, 32 Type II E, II G 30, 31
tt
tt
++ variable
TT
It
T or t*
LJ (rarely S or N)
tt
It
++
U (rarely S)
Responsiveness to DDAVP not reported
_ 2 7 10 25
Bleeding complications _ None After thyroidectomy None After knee surgery
Data from (refs. 5, 34, 36, 39, 40, 42, 44-46 and personal unpublished observations)
*Thrombocytopenia after DDAVP t = increase; tt = marked increase; ++ = little or not increase N = normalized; S = shortened; U = unchanged
tutive therapy was required only exceptionally achieve complete control of bleeding symptoms.
2-5 6-10 II-15 16-30 >30
Peak post-DDAVP VIII : c (%) < 30 30-49 > 50
to
Dental Extractions Dental extractions were done for about 60 patients with DDAVP, those with basal levels of VIII : C from 5 to above 50%, but usually higher than or equal to 20°~.34-36,3g-43 The majority of these patients were of type I and the BT was almost invariably corrected by DDAVP.34>40,42,43 Multiple dental extractions were safely done with DDAVP alone in a homogeneous group of 14 patients with type I plateletnormal vWD and more severely reduced VIII: C (mean 13%, range 8-20).35 Surgery Our survey of published cases and our own unpublished cases indicates that surgery has been carried out with DDAVP in 44 instances, most frequently in type I vWD (Table 3). In 42 cases, all with basal
VIII: C levels above 6%, there was no excessive bleeding during and after surgery. In all patients peak VIII : C levels were well above 50% postDDAVP5*34*36~3g,40*42-44 (Table 3). Two or more DDAVP infusions, at intervals of 8-24 h, were usually given. BT was usually normalized.34*36*3g*40*42-44 An impressive example of the usefulness of DDAVP in major surgery is the case reported by Isola et a1,46 who demonstrated that a patient with type I vWD was successfully treated with DDAVP for 12 days for major orthopedic surgery, with VIII : C levels consistently higher than 50% and BT shortened. The experience with type II vWD is more limited. In the original series reported by Mannucci et al,’ a cholecystectomy was carried out without mishap in a patient with type II A and a basal level of VIII: C of 44% (postDDAVP peak level were above lOO%), despite the fact that the BT was not corrected by DDAVP. Hysterectomy was safely carried out by Mannucci et a145 in a patient with type II B and a basal VIII: C level of 27%.45 DDAVP was administered 3 times on the day of operation and 48 h later and was able to induce an increase of 3-4 times the VIII: C basal level; BT was not normalized.45 One of our patients with type II B vWD had a cholecystectomy without
158 BLOOD REVIEWS mishap, despite the fact that the ET was not corrected. There are only two instances of failure with DDAVP reported (Table 3). Knee surgery was performed in a type I patient and bleeding ensued, so that cryoprecipitate was required to achieve good hemostasis.34 One of our patients with type I platelet-normal (unpublished) bled severely 2 days after thyroidectomy and cryoprecipitate had to be infused to stop bleeding. BT were normalized in both cases. Conclusions In summary, several patients with moderate to mild type I vWD have been treated with DDAVP for spontaneous or traumatic bleeding or for prevention of hemorrhage after tooth extraction. Bleeding complications were seldom observed and were of minor importance despite the fact that in some cases the BT remained prolonged. The limited experience available with patients with type II A and type II B vWD seems to indicate a similar favourable response to DDAVP in terms of clinical effectiveness. Clinical experience with DDAVP in surgery, albeit limited, seems to indicate that the compound can be safely used in some cases, whether or not the BT defect is corrected. In all patients VIII : C was 50% or higher after DDAVP. The only two reported bleeding episodes ensued despite the fact that VIII: C was above 50%, a level that should be compatible with satisfactory hemostasis (Table 3). Perhaps in those cases bleeding occurred for surgical reasons. DDAVP in Acquired von Willebrand’s Disease An acquired von Willebrand syndrome has been reported in several disorders, including lympho- and myeloproliferative syndromes, congenital heart disease and, recently, uremia.47-50 Mannucci et a148 have shown that VIII/vWF measurements and BT were normalized in 7 patients with lymphoproliferative disorders or benign monoclonal gammopathies and an intact basal multimeric pattern. This normalization was short-lived in comparison to that observed in patients with congenital type I platelet-normal vWD, probably because of an accelerated clearance of VIII/vWF from plasma. On the contrary, in patients with multimer defects, DDAVP has little or no biological and clinical effect.47q51 DDAVP has been used for at least 6 cases of acquired von Willebrand syndrome in a clinical setting to prevent or stop bleeding, but clinical effectiveness was obtained in only 3 cases, in association with a substantial increase of VIII/vWF measurements and BT normalization.47~52’53
DDAVP given subcutaneously is bioequivalent in terms of both pharmacokinetics and VIII : C responses to intravenously administered DDAVP54 and is effective in controlling bleeding symptoms.40*55 The availability of commercial concentrated preparations should make home therapy feasible. Significant and reproducible VIII : C and vWF responses (2-2.5 times the basal levels) are elicited by intranasally administered DDAVP at a dosage ten times greater than that recommended for intravenous dosage.38*56*57 This approach has been suggested for self-administered emergency aid. I1 Tachyphylaxis Some patients treated repeatedly with DDAVP at closely spaced intervals become progressively less responsive.5s45 Although poor responsiveness is by no means a constant phenomenon, clinical use of DDAVP should be reserved for those situations in which only a short term enhancement of hemostasis is required and basal levels of VIII/vWF measurements are able to sustain sufficient hemostasis thereafter. Some cases require additional therapy with blood products. DDAVP and the Fibrinolytic System Plasminogen activator is released from endothelial stores after DDAVP infusion.41*55,58A rapid increase in fibrinolytic activity is observed, peaking 30 min after infusion and decaying with a half-time of about 30 min.41 The magnitude of the response is far less than that observed in pathological hyperfibrinolysis. 41 Although, at least in theory, release of plasminogen activator is a potential drawback to the use of DDAVP, there is no clinical evidence of increased risk of bleeding due to hyperfibrinolysis after DDAVP. Nevertheless, concurrent administration of antifibrinolytic agents (epsilon-aminocaproic or tranexamic acid) has been suggested by some. Conventional doses of these agents are effective in preventing hyperfibrinolysis after DDAVP.41 Their concomitant administration in conjunction with DDAVP seems advisable for dental extractions, because antifibrinolytic agents given in conjunction with factor VIII or IX have been demonstrated to be effective in reducing blood loss in hemophilia A and B.59s60 The addition of antifibrinolytic agents for treatment of spontaneous bleeding and surgery remains questionable. In addition, some concern has been expressed that these agents might, at least potentially, precipitate thrombotic episodes61v’j2 Side-effects
Dosage and Route of Administration The recommended dosage of DDAVP is 0.3 ug/kg intravenously and subcutaneously, because larger doses do not elicit larger VIII: C responses.36
Occasional reports have claimed a thrombogenic effect for DDAVP.63-67 A review of cases conducted within the framework of the Factor VIII-Factor IX Subcommittee of International Society on Throm-
CLINICAL INDICATIONS FOR DESMOPRESSIN
IN CONGENITAL AND ACQUIRED VON WILLEBRAND
bosis and Hemostasi@* has however demonstrated the very low incidence of these episodes (10 cases among the estimated 433 000 treated individuals, including those without vWD, during the period 1985-1988). Some caution seems, nevertheless, to be advisable when DDAVP is used in patients of advanced age or with heart disease or vascular atherosclerosis. secondary to water retention Hyponatremia, caused by the antidiuretic action of DDAVP, seems not to be a real problem in adult patients. Only one hemophiliac has been reported to have had hyponatremfa after 6 closely spaced infusions of high doses of DDAVP (0.5 ug/kg). 6g However, hyponatremia and seizures have been described in children under the age of 2 years after even a single infusion.” A recent report described 4 additional patients (2 younger and 2 older children) with severe hyponatremia after closely repeated DDAVP infusions (up to 22 doses during 7 days). 71 Fluid restriction, avoidance of hyponatremic solutions and close monitoring of serum electrolytes and urine output should be done for at least 24 h after DDAVP administration to young children.
Therapeutic Recommendations DDAVP should be the treatment of first choice for spontaneous and traumatic bleeding, dental extractions and minor surgery for the majority of patients with vWD who have basal VIII : C levels higher than 4-5%, provided that a test infusion has shown a clinically useful increase of VIII : C (above 50%). The majority of investigators suggest that DDAVP is contraindicated for patients with type II B disease7*23 and it is not effective for those with severe homozygous type III. 33 A second infusion can be administered after 8-l 2 h. Tranexamic acid, 15 mg/kg, three times a day, should be administered before and for 7 days after dental extractions. Its usefulness for surgery is less clear. DDAVP can be used successfully for such spontaneous bleedings as epistaxis, hematomas, severe menorrhagia: a single infusion is usually sufficient. Menorrhagia is easily controlled in vWD by tranexamic acid or hormonal therapy and these agents should be the first-choice treatments. Since the experience with DDAVP in major surgery is very limited, this treatment should be reserved for patients with milder disease and for those for whom close monitoring with repeated assays of VIII : C is available, since replacement therapy with factor VIII concentrate could become necessary. Some types of bleeding, such as mucosal bleeding (e.g., gastrointestinal bleeding) require normalization of BT for correction.72,73 Accordingly, the BT should be measured in these situations and, if not corrected by DDAVP, VIII/vWF concentrates able to shorten BT74*75 are mandatory, if the bleeding is still in progress.
DISEASE
I59
Acknowledgements This review was written within the frame of activities of the von Willebrand Disease Committee of the World Federation of Hemophilia, chaired by Professor Dominique Meyer.
References 1. Ruggeri Z M, Zimmerman T S 1987 von Willebrand factor and von Willebrand disease. Blood 70: 895-907 2. Rodeghiero F, Castaman G, Dini E 1987 Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 69: 454-459 3. Weiss H J, Sussman I I, Hoyer L W 1977 Stabilization of factor VIII in olasma bv von Willebrand factor. Journal of Clinical Investigation 6t?: 390-401 4. Abildgaard C F, Suzuki Z, Harrison J, Jeffcoate K, Zimmerman T S 1980 Serial studies in von Willebrand’s disease: variability versus ‘variants’. Blood 56: 712-716 5. Mannucci P M, Ruggeri Z M, Pareti F I, Capitanio A 1977 DDAVP: a new pharmacological approach to the management of haemophilia and von Willebrand’s disease. Lancet I: 689-872 6. Richardson D W, Robinson A G 1985 Desmopressin. Annals of Internal Medicine 103: 228-239 7. Mannucci P M 1986 Desmopressin (DDAVP) for treatment of disorders of hemostasis. Progress in Hemostasis and Thrombosis 8: 19-45 8. Nilsson I M 1984 von Willebrand’s disease from 1926- 1983 Stand J Haematol (Suppl) 33: 21-43 9. Colvin B T, O’Callaghan U, Thomas N et al 1986 A survey of von Willebrand’s disease in North London. Research in Clinical Laboratories 16: 236 (abstract) 10. Mannucci P M. Bloom A L. Larrieu M J. Nilsson I M. West R R 1984 Atherosclerosis and von Willebrand factor. 1: Prevalence of severe von Willebrand’s disease in Western Europe and Israel. British Journal of Haematology 57: 163-169 11. Mannucci P M 1988 Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders. Blood 7t: 1449-1455 12. Mannucci P M, Lombardi R, Bader R, et al 1985 Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor. Blood 66: 796-802 13. Weiss H L, Pietu G, Rabinowitz R, Girma J P, Rogers J, Meyer D 1983 Heterogeneous abnormalities in the multimeric structure, antigenic properties and plasma-platelet content of factor VIII-von Willebrand factor in subtypes of classic (type I) and variant (type IIA) von Willebrand’s disease. Journal of Laboratory and Clinical Medicine 101: 411-421 14. Hoyer L W, Rizza C R, Tuddenham E G D, Carta C A, Armitage H, Rotblat F 1983 von Willebrand factor multimer patterns in von Willebrand’s disease. British Journal of Haematology 55: 493-507 15. Ciavarella G, Ciavarella N, Antoncecchi S et al 1985 Highresolution analysis of von Willebrand factor multimeric composition defines a new variant of type I von Willebrand disease with aberrant structure but presence of all size multimers (Type IC). Blood 66: 1423-1429 16. Weiss H J. Sussman I I 1986 A new von Willebrand variant (type I, New York): increased ristocetin-induced platelet aggregation and plasma von Willebrand factor containing the full range of multimers. Blood 68: 149-156 17. Holmberg L, Berntorp E, Donner M, Nilsson I M 1986 von Willebrand’s disease characterized by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers in plasma. Blood 68: 668-672 18. Mannucci P M, Lombardi R, Castaman G et al 1988 von Willebrand disease ‘Vicenza’ with larger-than-normal (supranormal) von Wiilebrand factor multimers. Blood 71: 65-70 19. Nishino M, Girma J P, Rothschild C, Fressinaud E, Meyer D 1989 New variant of von Willebrand disease with defective binding to factor VIII. Blood 74: 1591-1599 20. Gralnick H R, Williams S B, McKeown L P et al 1986
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21.
22.
23.
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26.
21.
28.
29.
30.
31.
32.
33.
34.
35.
36.
31.
38.
39.
BLOOD REVIEWS DDAVP in type IIA von Willebrand’s disease. Blood 67: 465-468 Ruggeri Z M, Mannucci P M, Lombardi R, Federici A B, Zimmermann T S 1982 Multimeric composition of factor VIII/van Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand’s disease subtypes. Blood59: 1272-1278 Batlle J. Lonez Fernandez M F. Cameos M et al 1986 The heterogeneiiy of type IIA von Willebr&l’s disease: studies with protease inhibitors. Blood 68: 1207-1212 Holmberg L, Nilsson I M, Borge L, Gunnarsson M, Sjorin E 1983 Platelet aggregation induced by Idesamino-B-Dareinine vasopressin (DDAVP) in tvoe IIB von Willebrand’s disease. New England Journal of Mdicine 309 8 16-821 Fowler W E, Berkowitz L R, Roberts H R 1989 DDAVP for type II B von Willebrand disease. Blood 74: 1859-1860 Connaghan D G, Gralnick H R 1990 Beneficial response to desmopressin in type II B von Willebrand’s disease. Blood 76: 417 (abstract) Ruggeri Z M, Nilsson I M, Lombardi R, Holmberg L, Zimmermann T S 1982 Aberrant multimeric structure of von Willebrand factor in a new variant of von Willebrand’s disease (Type IX). Journal of Clinical Investigation 70: 1124-l 127 Mannucci P M, Lombardi R, Pareti F I, Solinas S, Mazzucconi M G, Mariani G 1983 A variant of von Willebrand’s disease characterized by recessive inheritance and missing triplet structure of von Willebrand factor multimers. Blood 62: 1000-1005 Thomas N D, O’Callaghan U, Lowe G D 0 et al 1989 Response to DDAVP in type IID von Willebrand’s disease. Clinical and Laboratory Haematology 11: 189-197 Mannucci P M, Lombardi R, Federici A B, Dent J A, Zimmermann T S, Ruggeri Z M 1986 A new variant of type II von Willebrand disease with aberrant multimeric structure of plasma but not platelet von Willebrand factor (Type IIF). Blood 68: 269-274 Zimmermann T S, Dent J A, Ruggeri 2 M, Nannini L H 1986 Subunit composition of plasma von Willebrand factor. Journal of Clinical Investigation 77: 947-951 Gralnick H R, Williams S B, McKeown L P, Maisonneuve P, Jenneau C, Sultan Y 1987 A variant of type II von Willebrand disease with an abnormal triplet structure and discordant effects of protease inhibitors on plasma and platelet von Willebrand factor structure. American Journal of Hematology 24: 259-266 Federici A B, Mannucci P M, Lombardi R et al 1989 Type II H von Willebrand disease: new structural abnormality of plasma and platelet von Willebrand factor in a patient with prolonged bleeding time and borderline levels of ristocetin cofactor activity. American Journal of Hematology 32: 287-293 Mannucci P M, Pareti F I, Holmberg L, Nilsson I M, Ruggeri Z M 1976 Studies on the prolonged bleeding time in von Willebrand’s disease. Journal of Laboratory and Clinical Medicine 88: 662-671 De La Fuente B, Kasper C K, Rickles F R, Hoyer L W 1985 Response of patients with mild and moderate hemophilia A and von Willebrand’s disease to treatment with desmopressin. Annals of Internal Medicine 103: 6-14 Rodeghiero F, Castaman G, Di Bona E, Ruggeri M, Lombardi R, Mannucci P M 1988 Hyper-responsiveness to DDAVP for patients with type I von Willebrand’s disease and normal intra-platelet von Willebrand factor. European Journal of Haematology 40: 163-167 Mariani G, Ciavarella N, Mazzucconi M G et al 1984 Evaluation of the effectiveness of DDAVP in surgery and bleeding episodes in haemophilia and von Willebrand’s disease. A study on 43 patients. Clinical and Laboratory Haematology 6: 229-238 Rodeahiero F. Castaman G. Di Bona E. Rueeeri M 1989 Con&tency of responses to repeated DDAVP-infusions in patients with von Willebrand’s disease and hemophilia A. Blood 74: 1997-2000 Mannucci P M, Canciani M T, Rota L, Donovan B S 1981 Response of factor VIII/van Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand’s disease. British Journal of Haematology 4T: 283-293 Ghirardini A, Chistolini A, Tirindelli M C et al 1988
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Clinical evaluation of subcutaneously administered DDAVP. Thrombosis Research 49: 363-372 Warrier I, Lusher J M 1983 DDAVP: a useful alternative to blood components in moderate hemophilia A and von Willebrand’s disease. Journal of Pediatrics 102: 228-232 Ludlam C A, Peake I R, Allen N, Davies B L, Furlong R A, Bloom A L 1980 Factor VIII and fibrinolytic response to deamino-8-D-argenine vasopressin in normal subjects and dissociate response in some patients with haemophilia and von Willebrand’s disease. British Journal of Haematology 45: 499-511 Gckelford P A, Menon N C, Berry E W 1980 Clinical experience with arginine vasopressin (DDAVP) in von Willebrand’s disease and mild haemophilia. New Zealand Medical Journal 92: 375-378 Menon C, Berry E W, Gckelford P 1978 Beneficial effect of DDAVP on bleeding time in von Willebrand’s disease. Lancet ii: 143-744 Theiss W, Schmidt G 1978 DDAVP in von Willebrand’s disease: repeated administration and the behaviour of the bleeding time. Thrombosis Research 13: 1119-l 123 Mannucci P M. Ruaeeri Z M. Pareti F I. Caoitanio A 1977 DDAVP in hemophza. Lan&t ii: 1171-1172’ Isola L, Forster A, Aledort L M 1984 DDAVP and bleeding time in von Willebrand’s disease. Annals of Internal Medicine 101: 719-720 Budde U, Schaefer G, Mueller N, Egli H, Ruggeri Z M, Zimmerman T S 1984 Acquired von Willebrand’s disease in the myeloproliferative syndrome. Blood 64: 981-985 Mannucci P M, Lombardi R, Bader R et al 1984 Studies of the pathophysiology of acquired von Willebrand’s disease in seven patients with lymphoproliferative disorders or benign monoclonal gammopathies. Blood 64: 614-621 Gill J C, Wilson A D, Endres-Brooks J, Montgomery R R 1986 Loss of the largest von Willebrand factor multimers from the plasma of patients with congenital cardiac defects. Blood 67: 758-761 Rodeghiero F, Castaman G, Lombardi R, Mannucci P M 1988 von Willebrand factor abnormalities in two patients with uraemia. Lancet ii: 1016-1017 Lopez-Femandez M F, Lopez-Berges C, Martin R et al 1986 Unique multimeric pattern of von Willebrand factor in a patient with a benign monoclonal gammopathy. Scandinavian Journal of Haematology 36 302-308 Takahashi H, Nagayama R, Tanabe Y et al 1986 DDAVP in acquired von Willebrand syndrome associated with multiple myeloma. American Journal of Hematology 22: 421-429 Castaman G, Rodeghiero F, Di Bona E, Ruggeri M 1989 Clinical effectiveness of desmopressin in a case of acquired von Willebrand’s syndrome associated with benign monoclonal gammopathy. Blut 52I:21 I-213 Mannucci P M, Vicente V, Alberta I et al 1987 Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses. Thrombosis and Haemostasis 58: 1037-1039 Gader A M A, Clarkson A R, Cash J D 1973 The plasminogen activator and coagulation factor VIII responses to adrenaline, noradrenaline, soprenaline and salbutamol in man. Thrombosis Research 3: 51-57 Nilsson I M, Vilhardt H, Holmberg L, Astedt B 1982 Association between factor VIII related antigen and plasminogen activator. Acta Medica Scandinavica 211: 1051-1059 Lethagen S, Harris A S, Sjorin E, Nilsson I M 1987 Intranasal and intravenous administration of desmopressin: Effect on FVIIIjVWF pharmacokinetics and reproducibility. Thrombosis and Haemostasis 58: 1033-1037 Mannucci P M, Aberg M, Nilsson I M, Robertson B 1975 Mechanism of plasminogen activator and factor VIII increase after vasoactive drugs. British Journal of Haematology 30: 81-93 Forbes C D, Barr R D, Reid G et al 1972 Tranexamic acid in control of hemorrhage after dental extraction in hemophilia and Christmas disease. British Medical Journal 2: 311 Walsh P N, R&a C R, Matthews J M et al 1971 Epsilonaminocaproic acid therapy for dental extractions in haemophilia and Christmas disease: a double-bind controlled trial. British Journal of Haematology 20: 463
CLINICAL INDICATIONS
FOR DESMOPRESSIN
IN CONGENITAL AND ACQUIRED VON WILLEBRAND DISEASE
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62. thrombosis. Lancet’i: 49 63. O’Brien J R, Green P J, Salmon G et al 1989 Desmopressin and myocardial infarction. Lancet i: 664 64. van Dar&zig J M, Duren D R, ten Cate J W 1989 Desmopressin and myocardial infarction. Lancet i: 664 65. Bond L, Bevan D 1988 Myocardial infarction in a patient with hemophilia treated with DDAVP. New England Journal of Medicine 318: 121 66. Viron B, Michel C, Serrato T, Verdy E 1987 Risque thrombogene du DDAVP dans l’insuffisance renal chronique. Nephrologie 8: 225 61. Bymes J J, Larcada A, Moake J L 1988 Thrombosis following desmopressin for uremic bleeding. American Journal of Hematology 28: 63-64 68. Mannucci P M, Lusher J M 1989 Desmopressin and thrombosis. Lancet ii: 675-676 69. Lowe J, Pettigrew A, MiddIeton S, Forbes C D, Prentice C R M 1977 DDAVP in hemophilia. Lancet ii: 614
71.
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hyponatremia after repeated intravenous administration of desmopressin. American Journal of Hematology 32: 258-261 Perkins H A 1967 Correction of the hemostatic defects in von Willebrand’s disease. Blood 30: 375-380 Blait P M, Brinkhous K M, Culp H R, Krauss J S, Roberts H R 1976 Antihemophilic factor concentrate therapy in van Willebrand disease. Dissociation of the bleeding-time factor and ristocetin-cofactor activities. Journal of the American Medical Association 236: 2770-2772 Czapek E E, Gadarowski J J, Ontiveros J D, Pedraza J L 1988 Humate- P for treatment of von Willebrand disease. Blood 72: 1100 Fukui H, Nishino M, Terada S et al 1988 Hemostatic effect of a heat-treated factor VIII concentrate (Haemate P) in von Willebrand’s disease. Blut 56: 17I- 178