Un autre cœur qui saigne: une réévaluation de l’anticoagulation á l’héparine

Abstract

HEPARIN anticoagulation titrated by prolongation of activated clotting time (ACT) continues to be a cornerstone of surgery employing cardiopulmonary bypass (CPB). Unfractionated heparin (UH) remains the standard anticoagulant used for extracorporeal circulation in the context of CPB, while low molecular weight heparin (LMWH) is increasingly used in the management of patients with unstable angina and in the prevention of venous thrombosis. We know that patients receiving UH preoperatively are at risk of demonstrating heparin resistance, or decreased heparin responsiveness, thus it does not come as a surprise that in this issue of the Journal, Bar-Yosef et al. present evidence that preoperative treatment with LMWH is also associated with decreased heparin responsiveness as measured by celite ACT. 1 And there's the rub --is there in actuality a lesser degree of anticoagulation, or does decreased heparin responsiveness in part reflect limitations in our current clinical measures of anticoagulation?Unfractionated heparin is a linear anionic sulphated glycosaminoglycan. It is a heterogeneous compound with variability in both the length and composition of the side chain carbohydrates which explains the range of its molecular weights (MW) from 3,000 to 30,000 Da. Low molecular weight heparin consists of short chain polysaccharides, with an average molecular weight of less than 8,000 Da. The plasma half-life of LMWH is considerably longer than (two to four times) that of UH, and is prolonged even further in renal failure. The critical high affinity binding site for antithrombin (AT) are comprised of unique sequences of pentasaccharide units which occur in only about one third of heparin chains and are randomly distributed. The primary anticoagulant effect of heparins is via activation of AT producing a heparin-antithrombin (H-AT) complex which inactivates thrombin, activated factor X (fXa) and other factors. Additionally, both UH and LMWH can be shown to have non-AT dependent anticoagulant properties via direct inhibition of 'intrinsic' tenase, a phospholipid bound complex of fVIIIa and fIXa which generates fXa. Extrinsic tenase, a complex of phospholipid bound tissue factor, fX and fVIIa, also generates fXa but is not inhibited by either UH or LMWH. 2 Other, non-AT-dependent anticoagulant activity is seen at high heparin concentrations wherein activation by large MW heparin of a second plasma protein, heparin co-factor II, impairs fXa generation. Such a heparin co-factor II-mediated anticoagulant effect of heparin could be operative in severe AT deficiency. 3 Large MW H-AT inhibits thrombin through a mechanism involving non-specific binding of thrombin coincident with high affinity binding of AT, whereas inhibition of fXa requires only high affinity binding of AT. 4 Small heparin fragments (< 18 saccharides) lack ability to simultaneously bind AT and thrombin, thus LMWH has limited antithrombin activity (insensitivity of ACT) but relatively potent anti-Xa activity (antithrombotic properties). As such, the anticoagulant ...

Management and Monitoring of Anticoagulation for Children Undergoing Cardiopulmonary Bypass in Cardiac Surgery

“…The prolongation of the ACT as a measure of adequate anticoagulation does not account for factors unrelated to heparin activity, including hemodilution of contact factors and platelets as well as hypothermia of the patient and the blood sample (97,98). The reproducibility from sample to sample can be affected by the choice of activator, activation of the hemostatic activity, and operator technique (91,(99)(100)(101)(102). Furthermore, there is considerable variation between devices so results are not interchangeable from one device to another (103)(104)(105)(106).…”