Antithrombin I11 in Fresh Frozen Plasma, Cryoprecipitate, and Cryoprecipitate-depleted Plasma P. D. MINTZ,P. M. BLATT,W.J. KUHNSA N D H. R. ROBERTS From the Departments of Pathology and Medicine, University of North Carolina School of Medicine and the Department of Hospital Laboratories, North Carolina Memorial Hospital, Chapel Hill, North Carolina Antithrombin Ill (AT 111) is a plasma protein that inhlbits several activated procoagulants. Hereditary disease or acquired conditions such as severe hepatic dysfunction, nephrotic syndrome and intravascular cosgulatlon may be associated with reduced levels of AT 111. Its replacement may be essential in controlling thrombosis. In order to determine the most effective form of replacement, we compared AT Ill biological activity and antigen levels in conventionally prepared fresh frozen plasma, cryoprecipitate and cryoprecipitate depleted plasma (CDP). Both the activity and antigen levels were comparable in all three products (approximately 100%)and AT Ill was not concentrated in cryoprecipitate. These results Indicate that conventionally prepared CDP, fresh frozen plasma and cryoprecipitate contain equal quantities volume for volume of AT 111. On this basis, all products are equally effective as therapy for AT Ill deficiency, but CDP and fresh frozen plasma are recommended as convenient sources of this factor.

ANTITHROMBIN III (AT 111) is a plasma protein that inhibits several activated procoagulant^.^.' Its level has been reported to be reduced as the result of an inherited defi~iency,~ as well as in severe hepatic disease,lonephrotic syndrome6and in association with intravascular coagulation.2Heparin therapy has also been noted to lower AT I11 levels.6 The purpose of this study was to determine whether there was an advantage in the transfusion of fresh frozen plasma, conventionally prepared cryoprecipitate or cryoprecipitate depleted plasma in the replacement of AT 111. This replacement may be of benefit in controlling thrombosis.8 Methods Blood was collected in citrate phosphate d e x t r o ~ e .Plasma, ~ cryoprecipitate and cryoReceived for publication August I, 1978; accepted October 21. 1978. Supported in part by National Heart, Lung and Blood Institute grant XHL06350, RHL07149, and XHB53016; USPHS grant XCA15515-02 and XMCB370003-01-0.

precipitate-depleted plasma (CDP) were prepared by conventional blood bank technique^.^ AT 111activity was measured using a biological clotting assay (Pacific Hemostasis, Bakersfield, CA). AT I11 antigen was measured by radial immunodiffusion (Behring Diagnostics, American Hoechst Corporation, Sommerville,NJ.). Factor VIII procoagulant activity was measured using a one-stage biological clotting assay.3

Results The results are summarized in Table 1. Per cent AT I11 activity and AT 111 antigen levels were comparable in fresh frozen plasma, conventionally prepared cryoprecipitateand CDP (approximately 100%). AT I11 was not concentrated in the cryoprecipitate. The amount of AT 111 per bag of fresh frozen plasma and CDP was significantly greater than the amount per bag of cryoprecipitate.

Discussion The results of the study indicate that equal volumes of fresh frozen plasma, conventionally prepared cryoprecipitate and CDP contain comparable quantities of AT 111. In view of the greater volume per unit of fresh frozen plasma and CDP, compared with reconstituted cryoprecipitates, more AT 111 may be provided per bag with these preparations than with cryoprecipitate. Thus, because of the reduced risk of hepatitis from exposure to fewer donors and the increased convenience, we recommend fresh frozen plasma and CDP for the replacement of AT 111. However, because each milliliter of the three products contains a comparable amount of AT 111, the patient who is receiving cryoprecipitate to replenish reduced fibrinogen or factor VIII is also being provided AT 111. Because the conventionally prepared cryoprecipitate contained several milliliters of CDP in which the cryoprecipitate was re-

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MINTZ ET AL.

Table 1. Comparison of AT 111 Activity and Antigen in Fresh Frozen Plasma, Cryoprecipitate and Cryoprecipitate Depleted Plasma (COP) AT 111 Activity

Vlll Procoagulant Activity (Per Cent)

Per Cent

Ulrnl'

Ulbagt

AT 111 Antigen (Per Cent)

1. Fresh Frozen Plasma* Cryoprecipitate CDP

94 92 98

.9 .9 1.o

194 14 200

113 83 104

159 752

2. Fresh Frozen Plasma Cryoprecipitate CDP

128 102 128

1.3 1.o 1.3

280 15 260

104 94 127

155 504

3. Fresh Frozen Plasma Cryoprecipitate CDP

138 127 131

1.4 1.3 1.3

301 20 260

127 104 131

191 368

4. Fresh Frozen Plasma Cryoprecipitate CDP

100 116 108

1.o 1.2 1.1

215 18 220

117 117 113

159 188

5. Fresh Frozen Plasma Cryoprecipitate CDP

115 96 110

1.2 1.o 1.1

258 15 220

113 113 104

185 1074

*

To nearest 0.1. Arbitrarily defining 1 unit of AT 111 activity as that amount present in one ml of normal human plasma. t Assuming 215 ml plasmdbag fresh frozen plasma, 15 ml plasma derivative/bag cryoprecipitate

and 200 ml plasma derivative/bag CDP. Each number representsthe resultsobtained on one bag of fresh frozen plasma, cryoprecipitate and cryoprecipitate-depleted plasma. Thus, five different bags of each product were tested.

suspended, this study did not delineate whether the AT 111measured in this preparation was, in fact, in the supernatant plasma or in the actual cryoprecipitate. In view of the absence of a readily available AT 111 concentrate, we recommend fresh frozen plasrna or CDP for AT 111 replacement therapy.

6. Marciniak, E., and J. P. Gockerman: Heparininduced decrease in circulatory antithrombin-111. Lancet 2581, 1977. 7. Rosenberg, R. D.: Biologic actions of heparin. Semin. Hematol. 14:427, 1977. 8. Schipper, H. G., C. S. P. Jenkins, L. H. Kahle, and J. W. ten Cate: Antithrombin-III transfusion in disseminated intravascular coagulation. Lancet 19354, 1978. 9. Technical Manual of the American Association of Blood Banks, 7th ed. Washington, D.C., 1977. 10. von Kaulla, E., and K. N. von Kaulla: Antithrombin 111 and diseases. Am. J. Clin. Pathol. 48:69, 1967.

Acknowledgments The authors thank Mrs. Billie Robertson for her secretarial assistance.

References 1. Abildgaard, U.: Purification of two progressive antithrombins of human plasma. Scand. J. Clin. Lab. Invest. 19:190, 1967. 2. Bick, R. K., I. Kovacs, and L. F. Fekete: A new two-stage functional assay for antithrombin 111 (Heparin Cofactor): Clinical and laboratory evaluation. Thromb. Res. 8:745, 1976. 3. Biggs, R.: Human Blood Coagulation, Haemostasis and Thrombosis, 2nd ed. Oxford, Blackwell Scientific, 1976, p 682. 4. Egeberg, 0.: Inherited antithrombin deficiency causing thrombophilia. Thromb. Diathes. Haemorrh. 13516, 1%5. 5. Kaufman, R. H., J. de Graeff, G. B. de la Riviere, and L.A. van Es: Unilateral renal vein thrombosis and nephrotic syndrome. Am. J. Med. 60: 1048, 1976.

Paul D. Mintz, M.D., Clinical Research Fellow, Specialized Center for Thrombosis Research, Temple University Health Sciences Center, Philadelphia, Pennsylvania 19140. Philip M. Blatt, M.D., Associate Professor of Medicine and Pathology, Associate Director, Clinical Coagulation Laboratory, 601 Preclinical Educational Building 2288, University of North Carolina, Chapel Hill, North Carolina 27514. William J. Kuhns, M.D., Professor of Pathology, Director, Blood Bank, 512 Faculty Laboratory Office Building 231H, University of North Carolina, Chapel Hill, North Carolina 27514. Harold R. Roberts, M.D., Professor of Medicine and Pathology, Director, Clinical Coagulation Laboratory, 415 Clinical Sciences Building 2298, University of North Carolina, Chapel Hill, North Carolina 27514.

Antithrombin III in fresh frozen plasma, cryoprecipitate, and cryoprecipitate-depleted plasma.

Antithrombin I11 in Fresh Frozen Plasma, Cryoprecipitate, and Cryoprecipitate-depleted Plasma P. D. MINTZ,P. M. BLATT,W.J. KUHNSA N D H. R. ROBERTS Fr...
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