Coagulation and Transfusion Medicine / EFFECTS OF LOW-MOLECULAR-WEIGHT HEPARIN AND HEPARINOID ON THROMBOELASTOGRAPHIC ASSAY Effects of Unfractionated Heparin, Low-Molecular-Weight Heparin, and Heparinoid on Thromboelastographic Assay of Blood Coagulation

Thromboelastography (TEG) has been used increasingly as an intraoperative hemostasis monitoring device. Low-molecular-weight heparins are given increasingly to reduce the development of antibodies against the heparin–platelet factor 4 complex, and heparinoids are given to patients who have developed the antibody. We studied the effect of unfractionated heparin, a low-molecular-weight heparin (enoxaparin sodium [Lovenox]), and a heparinoid (danaparoid sodium [Orgaran]) on blood clotting assayed with TEG (TEG clotting) in vitro and the efficacy of protamine sulfate and heparinase for reversing the effect. Heparin, enoxaparin, and danaparoid all caused a dose-dependent inhibition of TEG clotting of normal blood. Concentrations of enoxaparin and danaparoid that totally inhibited TEG clotting only minimally prolonged the activated partial thromboplastin time. While inhibition of TEG clotting by heparin and enoxaparin was reversed by protamine sulfate and heparinase, inhibition by danaparoid was reversed only by heparinase. Abnormal TEG clotting was observed in patients receiving enoxaparin whose plasma level of the drug was more than 0.1 antiXa U/mL. However, the degree of TEG abnormality did not always coincide with plasma levels of the drug. The thromboelastograph is a device invented more than half a century ago.1 It measures the dynamic process of blood coagulation, with defined parameters reflecting integrity of specific hemostatic components.2 Thromboelastography (TEG) had not gained popularity in clinical coagulation services until it was used as an intraoperative coagulation monitoring modality during liver transplantation more than 15 years ago.3-6 Today, many liver transplantation centers use TEG in or near the operating suite to monitor coagulation changes and assist in hemostatic management during liver transplantation. During the last several years, TEG has started to gain acceptance as an intraoperative hemostatic monitoring device in coronary bypass surgery as well.7-12 Reduced blood product use has been reported during and after cardiac bypass surgery when TEG was used to assess the hemostatic condition of the patient.13,14 In bypass and heart transplant operations, the patient usually receives unfractionated heparin to prevent clotting in the extracorporeal circuit. Heparin is neutralized with protamine sulfate on completion of the procedure. When unfractionated heparin cannot be used in patients with a history of heparin-induced thrombocytopenia or thrombosis, a heparinoid15,16 often is used instead. Low-molecular-weight heparins (LMWHs) are used increasingly in a number of clinical conditions including bypass surgery.17-20 In a single patient undergoing bypass surgery and receiving a heparinoid, abnormal blood clotting assayed with TEG (TEG clotting) was recorded.10 Nadroparin, an LMWH, has been shown to inhibit TEG clotting of normal blood.21 In view of the increasing use of LMWHs and heparinoids as therapeutic agents and the thromboelastograph as a hemostatic monitoring device, we sought to further define the effect of LMWHs and heparinoids on blood coagulation assayed with TEG and the efficacy of Am J Clin Pathol 2000;113:725-731 725 © American Society of Clinical Pathologists Zmuda et al / EFFECTS OF LOW-MOLECULAR-WEIGHT HEPARIN AND HEPARINOID ON THROMBOELASTOGRAPHIC ASSAY protamine sulfate and heparinase for reversing the anticoagulant effect. The latter study, to our knowledge, has not been described. Furthermore, we performed TEG on patients receiving enoxaparin sodium (Lovenox), also an LMWH, and correlated thromboelastographic abnormalities with plasma levels of the LMWH. Materials and Methods Heparin, LMWH, and Heparinoid Unfractionated sodium heparin, 1,000 U/mL, with a mean molecular weight of 15,000 d, was extracted from porcine intestinal mucosa. Heparin was diluted to 10 U/mL with saline. Enoxaparin sodium (Lovenox) is an LMWH with a mean molecular weight of 4,500 d. According to the product insert, each milligram contains approximately 100 antiXa U. Dilutions were based on 100 anti Xa U/mg. Danaparoid sodium (Orgaran, org 10172), 750 antiXa U in 0.6 mL, is a heparinoid extracted from porcine intestinal mucosa, which is a mixture of about 84% heparan sulfate, 12% dermatan sulfate, and 4% chondroitin sulfate and has a mean molecular weight of 5,500 d.