Variable and circadian response to a fixed high-dose (12 500IU twice daily) subcutaneous heparin regimen after thrombolytic therapy for acute myocardial infarction

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Abstract
To determine the effect of a fixed high-dose (12 500 IU twice daily) subcutaneous heparin regimen on coagulation parameters after thrombolysis with streptokinase. A number of large thrombolytic trials have allocated patients to fixed high-dose (12 500 IU twice daily) subcutaneous heparin with no monitoring of coagulation parameters. We hypothesized that heparin's apparent lack of benefit and increased haemorrhagic complications in these trials may be the result of inappropriate anticoagulation. We therefore studied 11 patients who received intravenous streptokinase and oral aspirin for acute myocardial infarction and were subsequently started on the above heparin regimen. Blood samples were taken for activated partial thromboplastin time (APTT) and thrombin time before streptokinase and then immediately before and 6 h after each heparin injection on days 1,4, and 6, and 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. Both the median APTT and thrombin time were prolonged above the normal range throughout day 1, when fibrinogen levels were depressed, with a non-significant variation between the sampling points. By day 4, however, when fibrinogen levels had returned 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 injection 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 = 0.003). A similar peak and trough, and apparent circadian, APTT response pattern was seen on days 5 and 6. The thrombin time showed the same variation, which was also mirrored in the plasma heparin levels, although the circadian effect was not as marked. 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 important implications when considering the benefits and haemorrhagic complications of subcutaneous heparin therapy in general and following thrombolysis in particular.

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