Activated protein C and free protein S in patients with mild to moderate bleeding disorders.

BACKGROUND: Underlying mechanisms for bleeding and impaired thrombin generation (TG) and plasma clot formation (PCF) in patients with mild to moderate bleeding disorders (MBDs) are still to be elucidated, especially in bleeding disorder of unknown cause (BDUC). The role of the natural anticoagulants activated protein C (APC) and free protein S (PS) has not yet been investigated in this patient population. AIMS: To analyze antigen levels of APC and PS in patients with MBDs and BDUC and investigate associations to clinical bleeding phenotype and severity as well as and hemostatic capacity. METHODS: Antigen levels of APC and free PS were measured in 262 patients from the Vienna Bleeding Biobank (VIBB), a single-center cohort study, by ELISA and compared to 61 healthy controls (HC). RESULTS: Antigen levels of APC were higher in MBD patients than in HC when adjusted for age, sex and BMI (median (IQR) 33.1 (20.6-52.6) and 28.6 (16.4-47.2) ng/mL). This was most pronounced in patients with BDUC (35.3 (21.7-54.3) ng/mL). No differences in PS antigen levels between patients and HC were seen overall, or according to specific diagnoses. Further, no association between APC or PS and bleeding severity or global tests of hemostasis or TG were identified, while paradoxically APC weakly correlated with shorter lag time and time to peak of PCF in BDUC. CONCLUSION: Our data demonstrate increased antigen levels of APC in BDUC, which might contribute to the bleeding tendency in some patients and could be a future therapeutic target in BDUC.

Platelet activation and aggregation in different centrifugal-flow left ventricular assist devices.

Left-ventricular assist devices (LVADs) improve outcomes in end-stage heart failure patients. Two centrifugal-flow LVAD systems are currently approved, HeartMate 3 (HM3) and Medtronic/Heartware HVAD (HVAD). Clinical findings suggest differences in thrombogenicity between both systems. We compared markers of platelet activation and aggregation between HM3 and HVAD. We prospectively included 59 LVAD patients (40 HM3, 19 HVAD). Platelet P-selectin expression, activated glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregates (MPA) were assessed by flow-cytometry. Platelet aggregation was measured by light-transmission aggregometry (LTA) and multiple-electrode aggregometry (MEA). Von-Willebrand factor (VWF) antigen (VWF:Ag), VWF activity (VWF:Ac), and VWF multimer pattern analysis were determined. Soluble P-selectin (sP-selectin) was measured with an enzyme-linked immunoassay. P-selectin, GPIIb/IIIa and MPA levels in vivo and in response to arachidonic acid, adenosine diphosphate, and thrombin receptor activating peptide were similar between HM3 and HVAD (all p > .05). Likewise, agonist-inducible platelet aggregation by LTA and MEA did not differ between HM3 and HVAD (all p > .05). VWF:Ag levels and FVIII:C were similar between both systems (both p > .05), but patients with HVAD had significantly lower VWF:Ac (p = .011) and reduced large VWF multimers (p = .013). Finally, sP-selectin levels were similar in patients with HVAD and HM3 (p = .845). In conclusion, on-treatment platelet activation and aggregation are similar in HM3 and HVAD patients. Potential clinical implications of observed differences in VWF profiles between both LVAD systems need to be addressed in future clinical trials.