Hemorrhagic Complications of Anticoagulant Treatment. part 21

3.1 Determinants of bleeding

3.1.1 Relationship between risk of bleeding and heparin dose/response

Since the anticoagulant response to heparin (measured by a test of blood coagulation, eg, the activated partial thromboplastin time [APTT]) is influenced by the heparin dose, it was not possible from reported studies to separate the effects of these two variables (dose and laboratory response) on hemorrhagic rates. To our knowledge, there have been no randomized trials in patients with established VTE directly comparing different doses of heparin. In a study evaluating prophylaxis in patients with recent-onset traumatic spinal cord injuries, the incidence of bleeding was significantly greater in patients randomized to receive heparin adjusted to maintain the APTT at 1.5 times control than compared with heparin, 5,000 U bid. The mean dose of heparin for the adjusted-dose regimen was 13,200 U bid. Bleeding occurred in seven adjusted-dose patients compared with none in the fixed-dose group.

Subgroup analysis of randomized trials and prospective cohort studies provide suggestive evidence for an association between the incidence of bleeding and the anticoagulant response. In the Urokinase Pulmonary Embolism Study, bleeding occurred in 20% of patients assigned to heparin in whom whole-blood clotting time was > 60 min, compared to 5% of those whose whole-blood clotting time was < 60 min (relative risk, 4.0). Norman and Provan reported five major bleeds in 10 patients whose APTT was prolonged to more than twice the upper limit of their therapeutic range for at least 50% of their assays, but in only 1 of 40 patients whose APTT remained therapeutic (relative risk, 20.0). Wilson et al described 80 nonsurgical patients receiving heparin monitored by the whole-blood clotting time. Fifty-six percent who received “excessive heparin” bled, whereas only 16% who did not receive excessive heparin bled (relative risk, 3.5). Anand et al examined the relationship between the APTT and bleeding in 5,058 patients with acute coronary syndrome who received IV heparin in the Organization to Assess Strategies for Ischemic Syndromes-2 trial. For every 10-s increase in the APTT, the major bleeding was increased by 7% (p = 0.0004).

Although none of the studies were designed to compare the effects on bleeding of either different doses of heparin or different levels of heparin response, there is a suggestion that bleeding is more likely to occur when an in vitro test of coagulation is prolonged excessively, but this evidence is by no means definitive. In addition, there is good evidence that serious bleeding during heparin treatment can occur when the anticoagulant response is in the therapeutic range.

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