VARIABLE AND CIRCADIAN RESPONSE TO A FIXED HIGH-DOSE (12500IU TWICE-DAILY) SUBCUTANEOUS HEPARIN REGIMEN AFTER THROMBOLYTIC THERAPY FOR ACUTE MYOCARDIAL-INFARCTION

Aim: To determine the effect of a fixed high-dose (12 500 IU twice dai ly) subcutaneous heparin regimen on coagulation parameters after throm bolysis with streptokinase. Background and methods: A number of large thrombolytic trials have allocated patients to fixed high-dose (12 500 IU twice daily) subcutaneous heparin with no monitoring of coagulatio n parameters. We hypothesized that heparin's apparent lack of benefit and increased haemorrhagic complications in these trials may be the re sult of inappropriate anticoagulation. We therefore studied 11 patient s who received intravenous streptokinase and oral aspirin for acute my ocardial infarction and were subsequently started on the above heparin regimen. Blood samples were taken for activated partial thromboplasti n time (APTT) and thrombin time before streptokinase and then immediat ely before and 6 h after each heparin injection on days 1, 4, and 6, a nd 3 and 6 h after streptokinase on day 5. Plasma heparin levels were also measured on all post-streptokinase samples. Plasma fibrinogen was measured before the administration of streptokinase and once daily on the other sampling days. Results: Both the median APTT and thrombin t ime were prolonged above the normal range throughout day 1, when fibri nogen levels were depressed, with a non-significant variation between the sampling points. By day 4, however, when fibrinogen levels had ret urned to pre-streptokinase levels, the median (range) APTTs at 8 a.m. and 8 p.m. (pre-heparin) were similar, and below the therapeutic range , at 52 (38-76) and 48 (39-79) s (NS). Six hours after each heparin in jection the APTTs were elevated, but the median (range) 2 p.m. peak of 63 (46-138) s was lower than that at 2 a.m., 125 (58-178) s (P = 0.00 3). A similar peak and trough, and apparent circadian, APTT response p attern was seen on days 5 and 6. The thrombin time showed the same var iation, which was also mirrored in the plasma heparin levels, although the circadian effect was not as marked. Conclusion: There is a marked individual variation in response to fixed-dose (12 500 IU twice daily ) subcutaneous heparin, with many patients inadequately anticoagulated and an obvious circadian pattern of response. These findings have imp ortant implications when considering the benefits and haemorrhagic com plications of subcutaneous heparin therapy in general and following th rombolysis in particular.