Mechanisms of Platelet Dysfunction and Response to DDAVP in Patients with Congenital Platelet Function Defects

Summary

To examine the impact of the underlying defective platelet mechanism on the response to 1-desamino-8-D-arginine vasopressin (DDAVP, Desmopressin), we studied the effect of intravenous infusion of 0.3 μg/kg of DDAVP in a randomized double blind placebo-controlled trial with cross-over in 18 carefully characterized patients with congenital platelet defects (CPD) and BT ≥9 min. Eleven patients had normal dense granule stores and normal thromboxane A₂ (TxA₂) production (Group I), 3 patients had normal granule stores but impaired TxA₂ production (Group II), and 4 had δ-storage pool deficiency (Group III). DDAVP shortened BT at 50 min (DDAVP 14.6 ± 2.2 vs placebo 19.6 ± 2.3 min; n = 18; mean ± SE; p = 0.003) and 4h (17.0 ± 2.2 vs 19.6 ±2.1 min, p = 0.055), and raised plasma FVIIIC and von Willebrand factor (vWF). At 50 min DDAVP shortened BT by ≥5 min in 8 of 11 Group I patients (mean 9.7 ± 1.3 vs 16.3 ± 2.8 min; p <0.008), 1 of 3 Group II patients (11.9 ± 3.9 vs 17.7 ± 6.6; p = NS) and none of Group III patients (mean 30 min both arms). Ten patients (Group I or II) were managed successfully during surgical procedures with DDAVP alone. We conclude that DDAVP shortens BT in majority of CPD patients with normal dense granule stores and suggest that BT response may be dependent on the underlying platelet defect. DDAVP is a useful modality in management of selected patients, particularly those with normal dense granule stores.

• References

• 1 Rao AK. Congenital disorders of platelet function. Hematol Oncol Clin N Amer 1990; 344: 65-87
• 2 Gerritsen SW, Akkerman JW N, Sixma JJ. Correction of the BT in patients with storage pool deficiency by infusion of cryoprecipitate. Br J Haematol 1978; 40: 153-160
• 3 Kohrinsky NL, Israels ED, Gemini JM, Cheung MS, Watson CA, Bishop AJ, Schmeder ML. Shortening of BT by l-denmmo-8-D-arginine vasopressin in various bleeding disorders. Lancet 1984; 1: 1145-1148
• 4 Mamuicci PM. Desmopressin: A nonlransfusional form of treatment of congenital and acquired bleeding disorders. Blood 1988; 72: 1449-1455
• 5 Mannucci PM, Vicente V, Vianello L, Caltenaneo M, Alberca I, Coccato MP, Laioni L, Mari D. Controlled trial of desmopressin (DI)AVP) in liver cirrhosis and other conditions associated with a prolonged BT. Blood 1986; 67: 1148-1153
• 6 Nieuwenhuis HK, Sixma JJ. l-Desamino-8-d-arginine vasopressin (Desmopressin) shortens the BT in storage pool deficiency. Ann Intern Med 1988; 108: 65-67
• 7 Seluilman S, Johnson II, Lgberg N, Blombiiek M. DDAVP-induced correction of prolonged BT in patients with congenital platelet function delects. Thrombos Res 1987; 45: 165-174
• 8 Kcntro TB, Lottenberg R, Kitchens CS. Clinical efficacy of desmopressin acetate for hemostatic control in patients with primary platelet disorders undergoing surgery. Amer J Hemal 1987; 24: 215-219
• 9 DiMichelc DM, Hathaway WL. Use of DDAVP in inherited and acquired platelet dysfunction. Amer J Hemat 1990; 33: 39-45
• 10 Wijerman PW, van Dorp DB. Hcrmansky-Pudlak syndrome: Correction of BT by l-desamino-8d-arginine vasopressin. Amer J Hemat 1989; 30: 154-157
• 11 Marti GL, Rick MIT Sidbury J, Gralnick HR. DDAVP infusion in five patients with type la glycogen storage disease and associated correction of prolonged bleeding times. Blood 1986; 68 180: 184
• 12 Koike K, Rao AK, Holmsen H, Mueller PS. Platelet secretion defect in patients with the attention deficit disorder and easy bruising. Blood 1984; 63: 427-433
• 13 Holmsen H, Storm E, Day HJ. Determination of ATP and ADP in blood platelets: A modification of the firefly luciferase assay for plasma. Anal Biochem 1972; 46: 489-501
• 14 Lewy RI, Smith JB, Silver MJ, Saia J, Walinsky P, Weiner L. Detection of thromboxane B₂ in peripheral blood of patients with Prinzmetal’s angina. Prostagland Med 1979; 5: 243-250
• 15 Rao AK, Koike K, Willis J, Daniel JL, Beckett C, Hassel B, Day HJ, Smith JB, Holmsen II. Platelet secretion defect associated with impaired liberation of arachidonic acid and normal myosin light chain phosphorylation. Blood 198 64: 914-921
• 16 Rao AK, Koike K, Day HJ, Smith JB, Holmsen H. Bleeding disorder associated albumin-dependent partial deficiency in platelet thromboxane production. Effect of albumin on arachidonate metabolism in platelets Amer J Clin Path 1985; 83: 687-696
• 17 Rao AK, Willis J, Hassell B, Dangelmaier C, Holmsen H, Smith JB. Platelet activating factor is a weak platelet agonist. Evidence from normal human platelets and platelets with congenital secretion defects Amer J Hemat 1984; 17: 153-165
• 18 Rao AK, Kowalska MA, Disa J. Impaired cytoplasmic ionized calcium mobilization in inherited platelet secretion defects. Blood 1989; 74: 664-672
• 19 Rao AK, Disa J, Yang X. Concomitant defect in internal release and influx of calcium in patients with congenital platelet dysfunction and impaired agonist-induced calcium mobilization: thromboxane production is not required for internal release of calcium. J Lab Clin Med 1993; 121: 52-63
• 20 Yang X, Sun L, Ghosh S, Rao AK. Evidence of signal transduction defect in patients with inherited impaired platelet secretion. Protein kinase C (PKC) plays a major role in platelet secretion Thromb Haemost 1993; 69: 1190
• 21 Hermansky F, Pudlak P. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow: report of two cases with biochemical studies. Blood 1959; 14: 162-168
• 22 Triplett DA, Harms CS. Factor VIII or IX assay. In: Procedures for the Coagulation Laboratory. Triplet DA, Harms CS. eds. Chicago, IL: American Society of Cinical Pathologists; 1981: 38-40
• 23 Milliken GA, Johnson DE. Analyses of repeated measures experiments by using multivariate variables. In: Analysis of messy data. Vol. 1.. Milliken GA, Johnson DE. eds. New York: Van Nostrand Reinhold; 1984: 421
• 24 Kleinbaum DG, Kupper LL, Muller KE. Correlation coefficient and straight line regression analysis. In: Applied regression analysis and other multivariable methods. Kleinbaum DG, Kupper LL, Muller KE. eds Boston, MA: PWS Kent; 1988: 80
• 25 Vicente V, Alberca I, Mannucci PM. High levels of circulating von Wille- brand factor inhibit the release of this protein but not of plasminogen activator after DDAVP. Thrombos Res 1985; 38: 101-117
• 26 Vicente V, Estelles A, Laso J, Moraleda JM, Rivera J, Aznar J. Repeated infusions of DDAVP induce low response of FVIII and vWF but not of plasminogen activators. Thrombos Res 1993; 70: 117-122
• 27 Castaman G, Rodeghiero F. Failure of DDAVP to shorten the prolonged BT of two patients with congenital afibrinogenemia. Thrombos Res 1992; 68: 309-315
• 28 Yang X, Disa J, Rao AK. Effect of l-desamino-8-arginine vasopressin (DDAVP) on human platelets. Thrombos Res 1990; 59: 809-818
• 29 Ghosh S, Rao AK. Lack of effect of l-desamino-8-D-arginine vasopressin on direct adhesion of platelets to collagen. Thrombos Res 1993; 70: 417-422
• 30 Hollister AS, Onrot J, Lonce S, Nadeau JH J, Robertson D. Plasma catecholamine modulation of alpha₂ adrenoreceptor agonst affinity and sensitivity in normotensive and hypertensive human platelets. J Clin Invest 1986; 77: 1416-1421
• 31 Cattaneo M, Pared FI, Zighetti ML, Lecchi A, Lombardi R, Mannucci PM. Platelet aggregation at high shear is impaired in patients with congenital defects of platelet secretion and is corrected by DDAVP: correlation with the bleeding time. J Lab Clin Med 1995; 125: 540-547
• 32 Mannucci PM, Rota L. Plasminogen activator response after DDAVP: a clinicopharmacological study. Thromb Res 1980 20: 69-76
• 33 Prowse CV, Farrugia A, Boulton F, Tucker J, Ludlam CA, McLaren M. A comparative study using immunological and biological assays of the haemostatic responses to DDAVP infusion, venous occlusion and exercise in normal men. Thromb Haemost 1984; 51: 110-114
• 34 Cugno M, Uziel L, Marongiu F, Bottasso B, Legnani C, Palareti G. t-PA activity elicited by venous occlusion or DDAVP infusion does not produce plasmin activity in normal subjects. Thrombos Res 1990; 59: 1007-1011
• 35 Levi M, Hack CE, de Boer JP, Brandjes DP M, Biiller HR, Wouter ten Cate J. Reduction of contact activation related fibrinolytic activity in factor XIII deficient patients: Further evidence for the role of the contact system in fibrinolysis in vivo. J Clin Invest 1991; 88: 1155-1160
• 36 Levi M, de Boer JP, Roem D, Wouter ten Cate J, Hack CE. Plasminogen activation in vivo upon intravenous infusion of DDAVP: Quantitative assessment of plasmin-alpha₂-antiplasmin complex with a novel monoclonal antibody based radioimmunoassay. Thromb Haemost 1992; 67: 111-116
• 37 Weiss HJ, Lages B. Studies of thromboxane B₂, platelet factor 4, and fibrinopeptide A in bleeding time blood of patients deficient in von Wille- brand factor, platelet glycoproteins lb and IIb-IIIa, and storage granules. Blood 1993; 82: 481-490