A recent study in dogs suggested that erythropoietin (EPO) not only promotes the synthesis of increased numbers of reticulated platelets but that these newly produced platelets are hyperreactive compared with controls. Because of the increasing use of EPO in the perioperative setting, we characterized the effects of EPO on platelet reactivity in healthy human volunteers. In a randomized, controlled trial, we studied the effects of EPO on platelet reactivity, thrombopoiesis, and endothelial activation in circumstances similar to those of autologous blood donation. Thirty healthy male volunteers received placebo or EPO (100 or 500 U/kg of body weight given intravenously) three times a week for 2 weeks and underwent phlebotomy on days 8 and 15. Thrombin receptor–activating peptide induced expression of P-selectin, and CD63 increased 2- to 3-fold during EPO treatment. The enhanced platelet reactivity was also reflected by a 50% increase in soluble P-selectin in plasma. Plasma E-selectin levels increased in a dose-dependent fashion by more than 100% during EPO treatment, indicating substantial activation of endothelial cells. A 10% to 20% increase in platelet counts was observed in both EPO groups on day 5. In the placebo group, platelets increased only several days after the first phlebotomy. The increase in platelet counts was not reflected by changes in the amounts of reticulated platelets or circulating progenitor cells. In summary, we found that EPO markedly enhances endothelial activation and platelet reactivity, which may adversely affect patients at cardiovascular risk. However, the increased platelet reactivity could be exploited in patients with platelet dysfunction.

Summary Background: Platelet transfusions are effective for the prevention and treatment of bleeding in patients with disorders of platelet number and/or function. In recent years plateletpheresis concentrates have outnumbered pooled platelet concentrates, albeit with significant differences between nations. Thus, the platelet quality of individual donors has become increasingly important. The aim of this study was to gain an estimate for the prevalence of impaired platelet function among platelet donors. Study design and methods: We determined the inter-donor variability in platelet plug formation with a PFA-100 analyzer, the prevalence of impaired thromboxane formation, and effects of the density in alpha2 integrin polymorphism and density. Results: (i) Collagen-epinephrine induced closure time (CEPI-CT) showed a great inter-subject variability in platelet donors and was higher than in healthy controls (p = 0.008). One-fifth of donors had abnormal CEPI-CT values and 11% exceeded >300 s (max measurable value). (ii) Decreased serum thromboxane B2 levels were found in 9% of all donors, compatible with surreptitious intake of cyclooxygenase inhibitors or with an aspirin-like defect. CEPI-CT correlated inversely with TxB2-levels in donors and controls. (iii) The density of the alpha2-integrin correlated negatively with CEPI-CT and CADP-CT values in controls, but was not responsible for the observed impaired platelet function in donors. (iv) Finally, the ABO blood group system modulates closure times. Conclusion: In sum, a large number of platelet donors present with prolonged closure times. Decreased thromboxane formation and frequent platelet donation partly account for this observation. Abbreviations: 807 CC/CT/TT polymorphisms of the alpha2-integrin gene, CD36… GPIIIb, an alternative collagen receptor, CD42b… GpIb, the von Willebrand receptor, CD49b… alpha2-integrin, subunit of the main collagen receptor, CADP-CT… collagen adenosine diphosphate induced closure time, CEPI-CT… collagen/epinephrine induced closure time, PFA-100… platelet function analyzer, vWF-Ag… von Willebrand factor antigen, TXB2… thromboxane B2

Abstract-During Gram-negative septic shock, lipopolysaccharide (LPS, endotoxin) induces tissue factor (TF) expression.TF expression is mediated by nuclear factor B and amplified by activated platelets. TF forms a highly procoagulant complex with activated coagulation factor VII (FVIIa). Hence, we hypothesized that aspirin, which inhibits LPS-induced, nuclear factor B-dependent TF expression in vitro and platelet activation in vivo, may suppress LPS-induced coagulation in humans. Therefore, we studied the effects of aspirin on systemic coagulation activation in the established and controlled setting of the human LPS model. Thirty healthy volunteers were challenged with LPS (4 ng/kg IV) after intake of either placebo or aspirin (1000 mg). Acetaminophen (1000 mg) was given to a third group to control for potential effects of antipyresis. Neither aspirin nor acetaminophen inhibited LPS-induced coagulation. However, LPS increased the percentage of circulating TF ϩ monocytes by 2-fold. This increase was associated with a decrease in FVIIa levels, which reached a minimum of 50% 24 hours after LPS infusion. Furthermore, LPS-induced thrombin generation increased plasma levels of circulating polymerized, but not cross-linked, fibrin (ie, thrombus precursor protein), whereas levels of soluble fibrin were unaffected. In summary, a single 1000-mg dose of aspirin did not decrease LPS-induced coagulation. However, our study showed, for the first time, that LPS increases TF ϩ monocytes, substantially decreases FVIIa levels, and enhances plasma levels of thrombus precursor protein, which may be a useful marker of fibrin formation in humans. ). 1,2 DIC is defined by enhanced activity of coagulation factors, exhaustion of endogenous coagulation inhibitors, and activation and depletion of platelets by formation of thrombi in the vasculature. 3 Results of several studies suggest that initiation of coagulation in sepsis is driven primarily by the tissue factor (TF)-dependent pathway of coagulation. 4,5 Inhibition of the TF-dependent activation of coagulation using antibodies against TF or activated factor VII (FVIIa) completely prevents LPS-induced activation of coagulation in animals. 6 -8 Thus, inhibition of TF expression on monocytes during endotoxemia may present a promising therapeutic option for dampening the coagulation cascade. A recent in vitro study showed that acetylsalicylic acid (ASA) reduces LPS-induced TF expression on isolated monocytes. 9 Conversely, whole-blood experiments showed that ASA enhanced TF activity on monocytes. 10,11 Furthermore, TF expression on human monocytes is enhanced by the presence of granulocytes and activated platelets, suggesting an even more complex regulation of TF in vivo. [12][13][14][15][16] In addition, results of animal studies suggest that inhibition of thromboxane A 2 -mediated platelet activation may improve DIC induced by LPS. 3 Besides in vitro studies and experiments in animals, infusion of small doses of LPS into humans has emerged as a valuable tool to explore the pathogenesis ...

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