DOI: 10.1097/01.CCM.0000266827.47716.6C
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PMID: 17522543
Issn Print: 0090-3493
Publication Date: 2007/06/01
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Excerpt
Recombinant human factor VIIa (eptacog alfa [activated], NovoSeven, NovoNordisk, Princeton, NJ) is frequently used in trauma patients with severe hemorrhage (5–7). Eptacog alfa (activated) boosts thrombin generation, leading to rapid formation of clots with improved mechanical properties and resistance toward proteolysis as a consequence of the high thrombin activity level attained. It is recommended that acidosis be corrected before application of eptacog alfa (activated), because the drug has been found to be less effective at low pH (2). In a retrospective cohort study of 242 trauma patients, of which 38 received eptacog alfa (activated), the initial trauma room pH was the strongest predictor of overall in-hospital death (8).
In an earlier publication, Martini et al. (9) showed that acidosis causes reduced fibrinogen levels and platelet counts and that the effect is more pronounced if acidosis and hypothermia occur in parallel. The central message of the article by Dr. Martini and colleagues (10) in this issue of Critical Care Medicine is that correction of acidosis does not normalize blood coagulation. The authors induced acidosis in 12 pigs by infusing diluted hydrochloric acid. After reaching pH 7.1, six pigs were treated with tris-hydroxymethylaminomethane (THAM) to correct blood pH, whereas the other six pigs were infused with a placebo infusion, which did not correct the pH. Acidosis caused a 30% decrease in plasma fibrinogen level and a 50% decrease in platelet count. Infusion of THAM failed to normalize the fibrinogen concentration and platelet count, and the loss of platelets and fibrinogen was irreversible. Similar results were found with bicarbonate correction of acidosis (11).
Where do platelets and fibrinogen go?
The reduction of plasma fibrinogen levels in acidosis appears to be the result of increased fibrinogen breakdown rather than impaired synthesis (12). This may be caused by increased release of tissue plasminogen activator from the endothelium (13); reduced inhibition of tissue plasminogen activator by plasminogen activator inhibitor-1 (14) at low pH; formation of soluble fibrin, which acts as cofactor in tissue plasminogen activator-induced plasminogen activation (15, 16); or activation of alternative enzyme systems that cause proteolytic degradation of fibrinogen. In this respect it must be kept in mind that the proteolytic system leading to the degradation of the newly synthesized high molecular weight fibrinogen to the lower molecular weight forms in plasma is still unknown (17, 18). Since fibrinogen heterogeneity is normal in patients with aplasminogenemia (18), it definitely is not plasmin.
Whereas increased proteolysis is a good explanation for reduced fibrinogen levels in acidosis, Dr. Martini and colleagues (10) provide no explanation for the reduced platelet count. In addition to fibrin and fibrinogen, plasmin degrades coagulation factors V and VIII, von Willebrand factor, and platelet surface glycoproteins. This may lead to impaired platelet function, but it is unknown if it also results in increased removal of platelets from the circulation. Pooling of platelets in the spleen or microcirculation presumably would not lead to the irreversible reduction in platelet count observed in the experiment.
