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Desmopressin and hemostasis
Regulatory Peptides, 45 (1993) 311-317 © 1993 Elsevier Science Publishers B.V. All fights reserved 0167-0115/93/$06.00
311
REGPEP 01308
Desmopressin and hemostasis Jean-Louis David Unit~ Thrombose-H~mostase, CHU du Sart-Tilman, Liege (Belgium)
Key words: Desmopressin; DDAVP; Hemostatic agents
Since it has been synthetized in 1967, desmopressin (Minirin) R or DDAVP (1-desamino-8-Darginine vasopressin) was initially used for its antidiuretic properties [1]. Its capacity to induce an increase in plasma level of procoagulant factor VIII C (FVIII C), von Willebrand factor (vWF) and plasminogen activator was recognized in the following years [2,3]. In 1977, its efficiency as hemostatic agent was reported in hemophilia A and in von Willebrand disease [4]. Ever since DDAVP has been extensively used for the prevention and treatment of bleeding from several origins. This period has also been marked by a better approach to the disorders of hemostasis and an increase need for transfused blood products entailing a dramatic risk of viral contamination. DDAVP is one of the alternatives developped in response to these challenges. The originality of DDAVP is to insure hemostasis, at least in responding patients, by recruiting their own endogenous factors without any risk ofimmunogenicity. Unlike other hemostatic drugs like epsilon aminocaproic acid, tranexamic acid or aprotinin (a broad spectrum proteinase inhibitor), DDAVP does not inhibit fibrinolysis.
Correspondence to: J.-L. David, Unit6 Thrombose-H6mostase, CHU du Sart-Tilman, 4000 Liege, Belgium.
Metabolic features of vWF, FVIII C and DDAVP DDAVP induces release of vWF, a hemostatic factor which forms a link between subendothelial components and platelet GPIb and GPIIb-IIIa receptors [ 5 ]. vWF also stabilizes circulating FVIII C [6]. So, although they are linked to each other in circulation, these two factors do not exert the same hemostatic activity. They also differ in their origins: vWF is synthetized by megakaryocytes and by endothelial cells and is stored in platelet a-granules and in endothelial Weibel-Palade bodies [7,8]. FVIII C is synthetized in hepatocytes and is also stored in endothelial cells [9]. Infusion of DDAVP induces a release of both factors from their storage sites. The plasma peak values of FVIII C are reached 15 to 30 min after infusion but may be delayed in some patients [ 10]. The peak value of vWF often occurs between 30 min and 60 min after infusion but sometimes later [ 10,11]. These values correspond to an average of 3-to 5-fold increase and they are fairly reproductible in the same subject with a broad interindividual dispersion mainly observed for FVIII C [10,12]. The plasma half-life of released vWF and FVIII C are respectively around 8 h and 5 h [13]. There is no relationship between plasma concentrations of DDAVP and vWF-FVIII C complex [ 14]. This discrepancy sug-
312 gests that there is a limit to the stimulation of factor release by DDAVP. The plasma half-life of DDAVP has been evaluated at 55 min and also at 2.7 to 4.6 h probably according to the used method [15,16]. Half-life of DDAVP is prolonged in patients treated by several drugs such as chlorpropamide, clofibrate and indomethacin. It is shortened by demeclocycline, glibenclamide and carbamazepine (see review Ref. 17). DDAVP is metabolized in liver and in kidney. Its half-life is prolonged in patients with renal impairment [ 18 ].
Mechanism of action of DDAVP The mechanism by which DDAVP induces release from endothelial cells is not yet fully understood. Indeed, no release occurs when DDAVP is added to cultured endothelial cells nor when it is directly perfused through isolated human vessels [19-21]. An astute experiment has recently suggested a role of intermediate factors released from monocytes, which may be the true target cells of DDAVP [22]. The nature of vWF-endothelial releasing factor from monocytes remains hypothetical. A possible candidate is IL-1 which can induce vWF release from endothelial cells [23 ]. Hemostatic response to DDAVP seems to involve endothelial V2-1ike receptors. It is absent in patients lacking V2-receptors and suffering from nephrogenic diabetes insipidus [24]. Since it occurs in anephric patients, the response is not mediated by the kidneys [23]. DDAVP has no direct stimulatory effect on platelets [25]. By releasing vWF multimers, which may act like a plasma glue, it probably enhances platelet adhesiveness [26]. Finally, another possible mechanism of action of DDAVP seems to be independent from vWF plasma concentration. In patients with severe deficiency in vWF, an infusion of cryoprecipitate normalized the plasma level of vWF and partially shortened bleed-
ing time from 30 min to + 14 min. Although these patients did not respond to DDAVP alone, bleeding time was further shortened when DDAVP was infused following cryoprecipitate despite of any substantial modification of plasma vWF [27]. This alternative mechanism of action remains poorly understood.
Indications of DDAVP in yon Willebrand disease (VWD) and in hemophilia A DDAVP has been extensively used in various congenital or acquired disorders of hemostasis. Among these potential indications, vWD is probably one of the more commonly inherited causes of mild bleeding with a 2~o prevalence of individuals carrying a mutant gene for vWD [28]. vWD type I accounts for as many as 90~o of the cases. This type is characterized by reduced vWF plasma level with a normal multimeric structure. The patients are often asymptomatic or have minimal bleeding, although menorrhagia are frequent. Most of them are identified after unexpected per- or post-operative hemorrhage occurring even following minor surgical procedures such as tonsillectomy, dental extraction, rhinoplasty, or others, vWD type III accounts for as few as 1 subject in a million individuals [29]. Its hemorragic symptomatology is severe. The response of von Willebrand patients to DDAVP depends on the type of vWF abnormality [30]. Most of the cases of vWD type I respond to DDAVP by a correction of the quantitative plasma defect and by a shortening of bleeding time. However patients with some subtypes of type I do not respond to DDAVP. In type IIa, plasma level of functional vWF is reduced because its multimeric structure is abnormal. The response to DDAVP is beneficial in some patients but not in others. In type IIb, DDAVP releases abnormal multimers inducing platelet aggregation and consequently a deep but transient thrombocytopenia [ 31 ]. In type III, plasma vWF and FVIII C are low or absent, the bleeding time is extremely
313 Bleeding Time (min)
Fig. 1. Effect of D D A V P infusion 0.3 #g/kg on bleeding time in 20 vW patients (type I = 16, type IIA = 2, type III = 2). BT was measured before and 45 min after the end of the infusion. The upper limit of reference values was 8 min.
prolonged and DDAVP is ineffective. Therefore, it is necessary to recognize the type o f v W disease and to test each individual on his response, at least one week before any scheduled presurgical DDAVP treatment (see tachyphylaxis). The need for such a test, including the control of bleeding time appears at the examination of Fig. 1. By releasing FVIIIC, DDAVP prevents the risk of bleeding in patients with mild forms of hemophilia A [ 10]. It can be given to these patients before dental treatment or before sport practice.
Indications in other bleeding disorders Hemostatic effects of DDAVP were demonstrated in several kinds of congenital platelet dysfunction
and also in acquired dysfunctions, including those which were due to antiplatelet drugs like aspirin and ticlopidine [32,33]. Moreover, DDAVP frequently normalizes 'isolated' prolonged bleeding time [34]. However, this effect is lacking in some patients despite of plasma vWF increase. The effect of DDAVP in patients with an isolated prolonged bleeding time is shown on Fig. 2. In cirrhosis and uremia, DDAVP partially or totally corrects the defective hemostasis due to platelet abnormalities [35-37]. Its hemostatic action can be sufficient when platelet count is above 50,000//~1 [38J. In these various cases of thrombocytopenia or platelet dysfunction, the correction of bleeding tendency by DDAVP may be partially related to an increase of vWF above its normal plasma level, rendering platelets more adhesive than normal. The negative relationship between vWF concentration and
Bleeding Time (min) > 20
14
Fig. 2. Effect of D D A V P infusion 0.3 pg/kg in 25 patients with isolated prolonged bleeding time. BT was measured before and 45 min after the end of the infusion. The upper limit of reference values was 8 min.
314
bleeding time in uraemic patients tends to give credit to this possibility [39]. As for vW patients, DDAVP must be tested before every possible surgery. DDAVP has been extensively experimented in surgery, specially in cardiac surgery because cardiopulmonary bypass provokes platelet dysfunction. In patients undergoing a prolonged cardiopulmonary bypass for complex operations which entail an increased risk of bleeding, infusion of DDAVP at the end of the bypass significantly reduced blood loss and transfusions requirements [40,41]. In our practice, the most frequent applications of DDAVP in patients with documented congenital or acquired disorders of hemostasis include: excessive menstrual bleeding, preoperative preparation (tonsillectomy, adenoidectomy, dental extraction, miscellaneous...) and the prevention of abnormal bleeding after delivery. It may also be tried in emergency for any unexpected postoperative bleeding.
of tpA by the endothelium [47]. This test has permitted to evidence a defective release of tpA in patients with a past history of venous thrombosis [48].
Predonation treatment
Tachyphylaxis
When given to volunteers just before blood collection, DDAVP induced a 2 to 3-fold increase in FVIII C recovery in plasma concentrate [42]. This procedure has made it possible to limit the number of donors needed for hemophiliacs and consequently to reduce the risk of viral transmission [43].
Hemostatic efficiency of DDAVP is transient, probably because the delay for repletion o f v W F and FVIII C in their storage sites. The efficiency of DDAVP tends to disappear after repeated treatment and usually requires 3 to 4 days before being reestablished [52]. However, tachyphylaxis is not equal in all patients. Some of them respond to dally administration but unresponsiveness during 4 to 5 days may follow repeated infusions [53]. In practice, tachyphylaxis limits the use of DDAVP in operated patients with a recurrent risk of bleeding.
Profibrinolytic effects DDAVP induces the release of tissue plasminogen activator (tpA) from its endothelial storage sites [44]. However, the fibrinolytic activity of tpA is immediately blocked by plasminogen activation inhibitor (PAl-l) without causing any rise in systemic fibrinolysis [45]. The possibility of a therapeutical use of DDAVP as a prothrombolytic agent, given alone or with heparin, has been evoked but remains to be confirmed [46]. DDAVP has also been used for testing the release
Dosage and administration DDAVP can be given by intravenous infusion at the dose of 0.3 #g/kg, not exceeding 20/zg [49]. The total dose must be delivered in 50 ml of saline for 30 min. Subcutaneous injection given at the same dosage is an alternative route which seems to have a bioequivalent effect with less variability in pharmacokinetic parameters [50]. Moreover, intranasal spray of 300/~g (150 #g by puff) has approximately the same effect as an intravenous infusion of 0.2 /zg/kg and can be a convenient way for treatment in ambulatory patients [ 51 ].
Side effects Mild side effects may occur during or just after DDAVP treatment: facial flushing and feeling of facial warmth, headache, mild hypotension and tachycardia, transient gastro-intestinal complaints and slight drowsiness (see review Ref. 17). As mentioned
315
above, DDAVP has a thrombocytopenic effect in patients with vW disease type lib. Besides, rare and severe complications have also been reported. They include water intoxication with hyponatremia and seizures. Because of these sideeffects DDAVP is contraindicated in patients under circumstances of hemodilution or hyponatremia from various causes [54]. In patients with risk factors of vascular occlusion, DDAVP may be an additional contributing factor to angina pectoris, myocardial infarction, stroke and deep venous thrombosis [55]. These events may result from release of normal or abnormal multimers of vWF from atherosclerotic vessels [56]. Therefore, DDAVP must be avoided in patients with high risk factors of vascular occlusions.
Conclusions
During the last past 15 years, DDAVP has gained a prominent place among hemostatic agents. Its judicious use is safe and its efficiency has reduced the need for blood and plasma products, mainly in patients at risk of surgical bleeding. DDAVP has therefore contributed to decrease the dissemination of viral hepatitis and AIDS. In addition, DDAVP provides a pharmacological tool for investigating the mechanisms of the release of vWF, FVIII C and tpA from endothelial cells. The reader can find some excellent and recent reviews on DDAVP [17,57-61]. References 1 Zaoral, M., Kolc, J. and Sorm, F., Amino acids and peptides. LXXI. Synthesis of I-deamino-8-D-lysine vasopressin and I-deamino-D-arginine vasopressin, Coll. Czech. Chem. Commun., 32 (1967) 1250-1257. 2 Cash, J.D., Gader, A.M.A. and Da Costa, J., The release of plasminogen activator and factor VIII by LVP, AVP, DDAVP, AT III, and OT in man, Brit. J. Haematol., 27 (1974) 363. 3 Mannucci, P.M., Aberg, M., Nilsson, I.M. and Robertson, B., Mechanism of plasminogen activator and factor VIII increase after vasoaetive drugs, Brit. J. Haematol., 30 (1975) 81.
4 Mannucci, P.M., Ruggeri, Z.M., Pareti, F. L. and Capitanio, A.M., DDAVP in hemophilia, Lancet, 2 (1977) 1171-1172. 5 Sakariassen, K.S., Nievelstein, P. F. E.M., Coller, B.S. and Sixma, J.J., The role of platelet membrane glycoproteins Ib / and IIb-IIIa in platelet adherence to human artery subendothelium, Br. J. Haematol., 63 (1986) 681-691. 6 Weiss, H.J., Sussmann, I.I. and Hoyer, L.W., Stabilization of factor VIII in plasma by the von Willebrand factor, J. Clin. Invest., 60 (1977) 390-404. 7 Jaffe, E.A., Hoyer, L.W. and Nachman, R.L., Synthesis of von Willebrand factor by cultured human endothelial cells, Proc. Natl. Acad. Sci. USA, 71 (1974) 1906-1909. 8 Nachman, R., Levine, R. and Jaffe, E.A., Synthesis of factor VIII antigen by cultured guinea pig megakaryocytes, J. Clin. Invest., 60 (1977) 914-921. 9 Wion, K.L., Kelly, D., Summerfield, J.A., Tuddenham, E. G.D. and Lawn, R.M., Distribution of fator VIII messenger-RNA and antigen in human liver and other tissues, Nature, 317 (1985) 726. 10 De La Fuente, B., Kasper, C.K., Rickles, F.R. and Hoyer, L.W., Response of patients with mild and moderate hemophilia A and von Willebrand disease to treatment with desmopressin, Ann. Int. Med., 103 (1985) 6-14. 11 Andersson, K.E., Bengtsson, B. and Paulsen, O., Desamino8-D-arginine vasopressin (DDAVP): pharmacology and clinical use, Drugs Today, 24 (1988) 509-528. 12 Mannucci, P.M., Canciani, M.T., Rota, L. and Donovan, B.S., Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects, and patients with haemophilia A and von Willebrand's disease, Br. J. Haematol., 47 (1981) 283-293. 13 KOhler, M., Hellstern, P., Miyashita, C., Von Blohn, G. and Wenzel, E., Comparative study of intranasal, subcutaneous and intravenous administration of desamino-D-arginine vasopressin (DDAVP), Thromb. Haemost., 55 (1986) 108-111. 14 Mannucci, P.M., Vicente, V., Alberca, I., Sacchi, E., Longo, G., Harris, A.S. and Lindquist, A., Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses, Thromb. Haemost., 58 (1987) 1037-1039. 15 Vilhardt, H., Lundin, S. and Falch, J., Plasma kinetics of DDAVP in man, Acta Pharmacol. Toxicol., 58 (1986) 379381. 16 Krhler, M. and Harris, A., Pharmacokinetics and haematological effects of desmopressin, Eur. J. Clin. Pharmacol., 35 (1988) 281-285. 17 Richardson, D.W. and Robinson, A. G., Desmopressin, Ann. Intern. Med., 103 (1985) 228-239. 18 Aunsholt, N. A., Vilhardt, H. and Schmidt, E. B., Plasma halflife of DDAVP in uraemic patients, Acta Pharmacol. Toxicol., 59 (1986) 332-333.
316 19 Booyse, F.M., Osikowicz, G. and Feder, S., Effects of various agents on ristocetin-Willebrand factor activity in long-term cultures of von Willebrand and normal human umbilical vein endothelial cells, Thromb. Haemost., 46 (1981) 668. 20 Tuddenham, E. G. D., Lazarchick, J. and Hoyer, L.W., Synthesis and release of factor VIII by cultured human endothelial cells, Br. J. Haematol., 47 (1981) 617. 21 Barnhart, M. I., Chen, S. and Lusher, J. M., DDAVP: does the drug have a direct effect on the vessel wall?, Thromb. Res., 31 (1983) 239-253. 22 Hashemi, S., Tackaberry, E.S. and Palmer, D.S., Induced release of von Willebrand factor from endothelial cells in vitro: the effect of plasma and blood cells, Biochim. Biophys. Acta, 1052 (1990) 63-70. 23 Breit, S.N. and Green, I., Modulation of endothelial cell synthesis of von Willebrand factor by mononuclear cell products, Haemostasis, 18 (1988) 137-145. 24 Bichet, D.G., Razi, M., Lonergan, M., Arthus, M.F., Papukna, V., Kortax, C. and Barjon, J.N., Hemodynamic and coagulation responses to 1-desamino-8-D-arginine vasopressin in patients with congenital nephrogenic diabetes insipidus, N. Engl. J. Med., 318 (1988) 881-887. 25 Yang, X., Disa, J. and Rao, K., Effect of 1-desamino-8-Darginine vasopressin (DDAVP) on human platelets, Thromb. Res., 59 (1980) 809-818. 26 Sakariassen, K.S., Cattaneo, M., Berg, A., Ruggeri, Z.M., Mannucci, P.M. and Sixma, J.J., DDAVP enhances platelet adherence and platelet aggregate growth on human artery subendothelium, Blood, 64 (1984) 229-236. 27 Cattaneo, M., Moia, M., Della Valle, P., Castellan, P. and Mannucci, P.M., DDAVP shortens the prolonged bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of release ofvon Willebrand factor, Blood, 74 (1989) 1972-1975. 28 Rodeghiero, F., Castaman, G. and Dini, E., Epidemiological investigation of the prevalence of von Willebrand's disease, Blood, 69 (1987) 454-459. 29 Mannucci, P.M., Bloom, A.L., Larrieu, M.J., Nilsson, I.M. and West, R. R., Prevalence of severe von Willebrand's disease in Western Europe and Israel, Br. J. Haematol., 57 (1984) 163-169. 30 Ruggeri, Z. M., Mannucci, P. M., Lombardi, R., Federici, A. B. and Zimmerman, T.S., Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implication for pathophysiology and therapy of von Willebrand's disease subtypes, Blood, 59 (1982) 1272. 31 Holmberg, L., Nilsson, I.M., Borge, L., Gunnarson, M. and Sjorin, E , Platelet aggregation induced by l-deamino-8arginine vasopressin (DDAVP) in type liB von Willebrand's disease, N. Engl. J. Med., 309 (1983) 816-821.
32 DiMichele, D.M. and Hathaway, W.E., Use of DDAVP in inherited and acquired platelet dysfunction, Am. J. Hematol., 33 (1990) 39-45. 33 Schulman, S., Johnsson, H., Egberg, N. and Blomback, M., DDAVP-induced correction of prolonged bleeding time in patients with congenital platelet function defects, Thromb. Res, 45 (1987) 165-174. 34 Kim, H.C., Salva, K. and Fallot, P.L., Patients with prolonged bleeding time of undefined etiology, and their response to desmopressin, Thromb. Haemost., 59 (1988) 221-224. 35 Agnelli, C., Berrettini, M., De Cunto, M. and Nenci, G.G., Desmopressin-induced improvement of abnormal coagulation in chronic liver disease, Lancet, 1 (1983) 645. 36 Burroughs, A.K., Matthews, K., Qadiri, M., Thomas, N., Kernoff, P.B.A., Tuddenham, E.G.D. and Mclntyre, N., Desmpressin and bleeding time in patients with cirrhosis, Br. Med. J., 291 (1985) 1377-1381. 37 Canavese, C., Salomone, M., Pacitti, A., Mangiarotti, G. and Calitri, V., Reduced response of uremic bleeding to repeated doses of desmopressin, Lancet, 1 (1985) 867-868. 38 Kobrinsky, N.L. and Tulloch, H., Treatment of refractory thrombocytopenic bleeding with 1-desamino-8-D-arginine vasopressin (desmopressin), J. Pediatr., 112 (1988) 993-996. 39 Vigano, G.L., Mannucci, P.M., Lattuada, A., Harris, A. and Remuzzi, G., Subcutaneous desmopressin (DDAVP) shortens the bleeding time in uremia, Am. J. Hematol., 31 (1989) 32-35. 40 Salzman, E.W., Weinstein, M.J., Weintraub, R.M., Ware, J. A., Thurer, R.L., Robertson, L., Donovan, A., Gaffney, T., Bertele, V., Troll, J., Smith, M. and Chute, L.E., Treatment with desmopressin acetate to reduce blood loss after cardiac surgery, N. Engl. J. Med., 314 (1986) 1402-1406. 41 Czer, L. S.C., Bateman, T.M., Gray, R.J., Raymond, M.R., Stewart, M. E., Lee, S., Golfinger, D., Chanx, A. and Matloff, J.M., Treatment of severe platelet dysfunction and hemorrhage after cardiopulmonary bypass: reduction in blood product usage with desmopressin, J. Am. Coll. Cardiol., 9 (1987) 1139-1147. 42 Nilsson, I.M., Walter, H., Mikaelsson, M. and Vilhardt, H., Factor VIII concentrate prepared from DDAVP stimulated blood donor plasma, Scand. J. Haematol., 22 (1979) 42-46. 43 McLeod, B.C., Sassetti, R.J., Cole, E.R. and Scott, J.P., Long-term frequent plasma exchange donation of cryoprecipitate, Transfusion, 28 (1988) 307-310. 44 Prowse, C.V., Ferrugia, A., Boulton, F.E., Tucker, J., Ludlam, C.A., McLaren, M., Belch, J.J.F., Prentice, C.R.M., Dawes, J. and MacGregor, I.R., A comparative study using immunological and biological assays of the haemostatic responses to DDAVP infusion, venous occlusion and exercise in normal men, Thromb. Haemost., 51 (1984) 110-114. 45 MacGregor, I.R., Roberts, E.M., Prowse, C.V., Broomhead,
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A.F. and Ozolins, M., Fibrinolytic and haemostatic response to desamino-D-arginine vasopressin (DDAVP) administered by intravenous and subcutaneous routes in healthy individuals, Thromb. Haemost., 59 (1988) 34-39. Agnelli, G., Levi, M. and Cosmi, B., Additive effect of DDAVP and standard heparin in increasing plasma t-PA, Thromb. Haemost., 61 (1989) 507-519. Sultan, Y., Harris, A., Strauch, G., Venot, A. and De Lauture, D., A dynamic test to investigate potential tissue plasminogen activator activity. Comparison of deamino-8-D-argininevasopressin with venous occlusion in normal subjects and patients, J. Lab. Clin. Med., 111 (1988)645-653. Nilsson, I.M., Ljunger, H. and Tengborn, L., Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor, Br. Med. J., 290 (1985) 1453-1455. Mariani, H., Ciavarella, N., Mazzucconi, M. G., Antoncecchi, S., Solinas, S., Ranieri, P., Pettini, P., Agrestini, F. and Mandelli, F., Evaluation of the effectiveness of DDAVP in surgery or in bleeding episodes in haemophilia and von Willebrand's disease. A study on 43 patients, Clin. Lab. Haematol., 6 (1984) 229-238. K0hler, M., Hellstern, P. and Parrach, H., Subcutaneous injection of desmopressin (DDAVP): evaluation of a new, more concentrated preparation, Haemostasis, 1 (1989) 38-44. Lethagen, S., Harris, A.S., Sjorin, E. and Nilsson, I.M., Intranasal and intravenous administration of desmopressin: effect on FVIII/vWF, pharmacokinetics and reproducibility, Thromb. Haemost., 58 (1987) 1033-1036.
52 Theiss, W. and Schmidt, G., DDAVP in von Willebrand's disease: repeated administration and the behavior of the bleeding time, Thromb. Res., 13 (1978) 1119-1123. 53 Rodeghiero, F., Castaman, G., Di Bona, E. and Ruggeri, M., Consistency of resonses to repeated DDAVP infusions in patients with von Willebrand's disease and hemophilia A, Blood, 74 (1989) 1997-2000. 54 Shepherd, L. L., Hutchinson, R.J., Worden, E.R., Koopman, C.F. and Coran, A., Hyponatremia and seizures after intravenous administration of desmopressin acetate for surgical hemostasis, J. Pediatr., 114 (1989) 470-472. 55 Mannucci, P.M. and Lusher, J. M., Desmopressin and thrombosis, Lancet, 2 (1989) 675-676. 56 Moake, J.L., Tumer, N.A., Stathopoulos, N.A., Nolasco, L.H. and Hellum, J.D., Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear-stress induced platelet agregation, J. Clin. Invest., 78 (1986) 456. 57 Mannucci, P.M., Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders, Blood, 72 (1972) 1449-1455. 58 Vilhardt, H., Basic pharmacology of desmopressin. A review, Drug Invest., 2 (1990) 2-8. 59 Czer, L. S.C. and Capon, S.M., Clinical experience in disordes of haemostasis, Drug Invest., 2 (1990) 32-44. 60 Mannucci, P.M., Desmopressin: a nontransfusional hemostatic agent, Annu. Rev. Med., 41 (1990) 55-64. 61 Schulman, S., DDAVP-the multipotent drug in patients with coagulapathies, Trans. Med. Rev., 5 (1991) 132-144.
311
REGPEP 01308
Desmopressin and hemostasis Jean-Louis David Unit~ Thrombose-H~mostase, CHU du Sart-Tilman, Liege (Belgium)
Key words: Desmopressin; DDAVP; Hemostatic agents
Since it has been synthetized in 1967, desmopressin (Minirin) R or DDAVP (1-desamino-8-Darginine vasopressin) was initially used for its antidiuretic properties [1]. Its capacity to induce an increase in plasma level of procoagulant factor VIII C (FVIII C), von Willebrand factor (vWF) and plasminogen activator was recognized in the following years [2,3]. In 1977, its efficiency as hemostatic agent was reported in hemophilia A and in von Willebrand disease [4]. Ever since DDAVP has been extensively used for the prevention and treatment of bleeding from several origins. This period has also been marked by a better approach to the disorders of hemostasis and an increase need for transfused blood products entailing a dramatic risk of viral contamination. DDAVP is one of the alternatives developped in response to these challenges. The originality of DDAVP is to insure hemostasis, at least in responding patients, by recruiting their own endogenous factors without any risk ofimmunogenicity. Unlike other hemostatic drugs like epsilon aminocaproic acid, tranexamic acid or aprotinin (a broad spectrum proteinase inhibitor), DDAVP does not inhibit fibrinolysis.
Correspondence to: J.-L. David, Unit6 Thrombose-H6mostase, CHU du Sart-Tilman, 4000 Liege, Belgium.
Metabolic features of vWF, FVIII C and DDAVP DDAVP induces release of vWF, a hemostatic factor which forms a link between subendothelial components and platelet GPIb and GPIIb-IIIa receptors [ 5 ]. vWF also stabilizes circulating FVIII C [6]. So, although they are linked to each other in circulation, these two factors do not exert the same hemostatic activity. They also differ in their origins: vWF is synthetized by megakaryocytes and by endothelial cells and is stored in platelet a-granules and in endothelial Weibel-Palade bodies [7,8]. FVIII C is synthetized in hepatocytes and is also stored in endothelial cells [9]. Infusion of DDAVP induces a release of both factors from their storage sites. The plasma peak values of FVIII C are reached 15 to 30 min after infusion but may be delayed in some patients [ 10]. The peak value of vWF often occurs between 30 min and 60 min after infusion but sometimes later [ 10,11]. These values correspond to an average of 3-to 5-fold increase and they are fairly reproductible in the same subject with a broad interindividual dispersion mainly observed for FVIII C [10,12]. The plasma half-life of released vWF and FVIII C are respectively around 8 h and 5 h [13]. There is no relationship between plasma concentrations of DDAVP and vWF-FVIII C complex [ 14]. This discrepancy sug-
312 gests that there is a limit to the stimulation of factor release by DDAVP. The plasma half-life of DDAVP has been evaluated at 55 min and also at 2.7 to 4.6 h probably according to the used method [15,16]. Half-life of DDAVP is prolonged in patients treated by several drugs such as chlorpropamide, clofibrate and indomethacin. It is shortened by demeclocycline, glibenclamide and carbamazepine (see review Ref. 17). DDAVP is metabolized in liver and in kidney. Its half-life is prolonged in patients with renal impairment [ 18 ].
Mechanism of action of DDAVP The mechanism by which DDAVP induces release from endothelial cells is not yet fully understood. Indeed, no release occurs when DDAVP is added to cultured endothelial cells nor when it is directly perfused through isolated human vessels [19-21]. An astute experiment has recently suggested a role of intermediate factors released from monocytes, which may be the true target cells of DDAVP [22]. The nature of vWF-endothelial releasing factor from monocytes remains hypothetical. A possible candidate is IL-1 which can induce vWF release from endothelial cells [23 ]. Hemostatic response to DDAVP seems to involve endothelial V2-1ike receptors. It is absent in patients lacking V2-receptors and suffering from nephrogenic diabetes insipidus [24]. Since it occurs in anephric patients, the response is not mediated by the kidneys [23]. DDAVP has no direct stimulatory effect on platelets [25]. By releasing vWF multimers, which may act like a plasma glue, it probably enhances platelet adhesiveness [26]. Finally, another possible mechanism of action of DDAVP seems to be independent from vWF plasma concentration. In patients with severe deficiency in vWF, an infusion of cryoprecipitate normalized the plasma level of vWF and partially shortened bleed-
ing time from 30 min to + 14 min. Although these patients did not respond to DDAVP alone, bleeding time was further shortened when DDAVP was infused following cryoprecipitate despite of any substantial modification of plasma vWF [27]. This alternative mechanism of action remains poorly understood.
Indications of DDAVP in yon Willebrand disease (VWD) and in hemophilia A DDAVP has been extensively used in various congenital or acquired disorders of hemostasis. Among these potential indications, vWD is probably one of the more commonly inherited causes of mild bleeding with a 2~o prevalence of individuals carrying a mutant gene for vWD [28]. vWD type I accounts for as many as 90~o of the cases. This type is characterized by reduced vWF plasma level with a normal multimeric structure. The patients are often asymptomatic or have minimal bleeding, although menorrhagia are frequent. Most of them are identified after unexpected per- or post-operative hemorrhage occurring even following minor surgical procedures such as tonsillectomy, dental extraction, rhinoplasty, or others, vWD type III accounts for as few as 1 subject in a million individuals [29]. Its hemorragic symptomatology is severe. The response of von Willebrand patients to DDAVP depends on the type of vWF abnormality [30]. Most of the cases of vWD type I respond to DDAVP by a correction of the quantitative plasma defect and by a shortening of bleeding time. However patients with some subtypes of type I do not respond to DDAVP. In type IIa, plasma level of functional vWF is reduced because its multimeric structure is abnormal. The response to DDAVP is beneficial in some patients but not in others. In type IIb, DDAVP releases abnormal multimers inducing platelet aggregation and consequently a deep but transient thrombocytopenia [ 31 ]. In type III, plasma vWF and FVIII C are low or absent, the bleeding time is extremely
313 Bleeding Time (min)
Fig. 1. Effect of D D A V P infusion 0.3 #g/kg on bleeding time in 20 vW patients (type I = 16, type IIA = 2, type III = 2). BT was measured before and 45 min after the end of the infusion. The upper limit of reference values was 8 min.
prolonged and DDAVP is ineffective. Therefore, it is necessary to recognize the type o f v W disease and to test each individual on his response, at least one week before any scheduled presurgical DDAVP treatment (see tachyphylaxis). The need for such a test, including the control of bleeding time appears at the examination of Fig. 1. By releasing FVIIIC, DDAVP prevents the risk of bleeding in patients with mild forms of hemophilia A [ 10]. It can be given to these patients before dental treatment or before sport practice.
Indications in other bleeding disorders Hemostatic effects of DDAVP were demonstrated in several kinds of congenital platelet dysfunction
and also in acquired dysfunctions, including those which were due to antiplatelet drugs like aspirin and ticlopidine [32,33]. Moreover, DDAVP frequently normalizes 'isolated' prolonged bleeding time [34]. However, this effect is lacking in some patients despite of plasma vWF increase. The effect of DDAVP in patients with an isolated prolonged bleeding time is shown on Fig. 2. In cirrhosis and uremia, DDAVP partially or totally corrects the defective hemostasis due to platelet abnormalities [35-37]. Its hemostatic action can be sufficient when platelet count is above 50,000//~1 [38J. In these various cases of thrombocytopenia or platelet dysfunction, the correction of bleeding tendency by DDAVP may be partially related to an increase of vWF above its normal plasma level, rendering platelets more adhesive than normal. The negative relationship between vWF concentration and
Bleeding Time (min) > 20
14
Fig. 2. Effect of D D A V P infusion 0.3 pg/kg in 25 patients with isolated prolonged bleeding time. BT was measured before and 45 min after the end of the infusion. The upper limit of reference values was 8 min.
314
bleeding time in uraemic patients tends to give credit to this possibility [39]. As for vW patients, DDAVP must be tested before every possible surgery. DDAVP has been extensively experimented in surgery, specially in cardiac surgery because cardiopulmonary bypass provokes platelet dysfunction. In patients undergoing a prolonged cardiopulmonary bypass for complex operations which entail an increased risk of bleeding, infusion of DDAVP at the end of the bypass significantly reduced blood loss and transfusions requirements [40,41]. In our practice, the most frequent applications of DDAVP in patients with documented congenital or acquired disorders of hemostasis include: excessive menstrual bleeding, preoperative preparation (tonsillectomy, adenoidectomy, dental extraction, miscellaneous...) and the prevention of abnormal bleeding after delivery. It may also be tried in emergency for any unexpected postoperative bleeding.
of tpA by the endothelium [47]. This test has permitted to evidence a defective release of tpA in patients with a past history of venous thrombosis [48].
Predonation treatment
Tachyphylaxis
When given to volunteers just before blood collection, DDAVP induced a 2 to 3-fold increase in FVIII C recovery in plasma concentrate [42]. This procedure has made it possible to limit the number of donors needed for hemophiliacs and consequently to reduce the risk of viral transmission [43].
Hemostatic efficiency of DDAVP is transient, probably because the delay for repletion o f v W F and FVIII C in their storage sites. The efficiency of DDAVP tends to disappear after repeated treatment and usually requires 3 to 4 days before being reestablished [52]. However, tachyphylaxis is not equal in all patients. Some of them respond to dally administration but unresponsiveness during 4 to 5 days may follow repeated infusions [53]. In practice, tachyphylaxis limits the use of DDAVP in operated patients with a recurrent risk of bleeding.
Profibrinolytic effects DDAVP induces the release of tissue plasminogen activator (tpA) from its endothelial storage sites [44]. However, the fibrinolytic activity of tpA is immediately blocked by plasminogen activation inhibitor (PAl-l) without causing any rise in systemic fibrinolysis [45]. The possibility of a therapeutical use of DDAVP as a prothrombolytic agent, given alone or with heparin, has been evoked but remains to be confirmed [46]. DDAVP has also been used for testing the release
Dosage and administration DDAVP can be given by intravenous infusion at the dose of 0.3 #g/kg, not exceeding 20/zg [49]. The total dose must be delivered in 50 ml of saline for 30 min. Subcutaneous injection given at the same dosage is an alternative route which seems to have a bioequivalent effect with less variability in pharmacokinetic parameters [50]. Moreover, intranasal spray of 300/~g (150 #g by puff) has approximately the same effect as an intravenous infusion of 0.2 /zg/kg and can be a convenient way for treatment in ambulatory patients [ 51 ].
Side effects Mild side effects may occur during or just after DDAVP treatment: facial flushing and feeling of facial warmth, headache, mild hypotension and tachycardia, transient gastro-intestinal complaints and slight drowsiness (see review Ref. 17). As mentioned
315
above, DDAVP has a thrombocytopenic effect in patients with vW disease type lib. Besides, rare and severe complications have also been reported. They include water intoxication with hyponatremia and seizures. Because of these sideeffects DDAVP is contraindicated in patients under circumstances of hemodilution or hyponatremia from various causes [54]. In patients with risk factors of vascular occlusion, DDAVP may be an additional contributing factor to angina pectoris, myocardial infarction, stroke and deep venous thrombosis [55]. These events may result from release of normal or abnormal multimers of vWF from atherosclerotic vessels [56]. Therefore, DDAVP must be avoided in patients with high risk factors of vascular occlusions.
Conclusions
During the last past 15 years, DDAVP has gained a prominent place among hemostatic agents. Its judicious use is safe and its efficiency has reduced the need for blood and plasma products, mainly in patients at risk of surgical bleeding. DDAVP has therefore contributed to decrease the dissemination of viral hepatitis and AIDS. In addition, DDAVP provides a pharmacological tool for investigating the mechanisms of the release of vWF, FVIII C and tpA from endothelial cells. The reader can find some excellent and recent reviews on DDAVP [17,57-61]. References 1 Zaoral, M., Kolc, J. and Sorm, F., Amino acids and peptides. LXXI. Synthesis of I-deamino-8-D-lysine vasopressin and I-deamino-D-arginine vasopressin, Coll. Czech. Chem. Commun., 32 (1967) 1250-1257. 2 Cash, J.D., Gader, A.M.A. and Da Costa, J., The release of plasminogen activator and factor VIII by LVP, AVP, DDAVP, AT III, and OT in man, Brit. J. Haematol., 27 (1974) 363. 3 Mannucci, P.M., Aberg, M., Nilsson, I.M. and Robertson, B., Mechanism of plasminogen activator and factor VIII increase after vasoaetive drugs, Brit. J. Haematol., 30 (1975) 81.
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