Protamine sulfate is considered a weak
anticoagulant, yet little is known concerning the mechanism of this effect or its relation to prior
heparin exposure. This investigation defined the influence of increasing doses of
protamine, with and without prior
heparin anticoagulation, on the activated clotting time (ACT),
thrombin clotting time (TCT), prothrombin time (PT), partial thromboplastin time (PTT),
fibrinogen level, platelet count, and platelet aggregation to
ADP in dogs (n = 8). Four doses of intravenous
protamine sulfate (1.5, 3.0, 6.0, and 15.0 mg/kg) were studied in each animal, with at least 5 days between individual studies. Four dogs received
heparin, 150 IU/kg 10 min prior to
protamine sulfate administration, and four dogs received
protamine sulfate alone.
Protamine sulfate caused anticoagulation, both in the presence and absence of
heparin, with significant changes occurring in the ACT, PTT, platelet count, and platelet aggregation. Relevant changes did not occur in the TCT, PT, or
fibrinogen levels. Platelet effects were capable of causing
bleeding with standard or excess use of
protamine sulfate, especially if platelet numbers were already decreased, as might occur in
surgical procedures where
thrombocytopenia commonly accompanies major blood loss and replacement. The ACT, reflecting both the coagulation cascade and platelet function, was the test most profoundly affected by
protamine overdosage, and therefore may be misleading as a measure of
protamine reversal of
heparin. The TCT, which is sensitive to
heparin anticoagulation but not
protamine-induced anticoagulation, should be more accurate in differentiating inadequate
heparin reversal from the effects of excess
protamine.