No abstract

We have shown a reduction in beta adrenoceptor-linked, cyclic AMP-dependent protein kinase [protein kinase A (PKA)] activity in fibroblasts of patients with major depression with melancholic features relative to normal volunteers. We evaluated a group of 35 patients with major depression subtyped by DSM-IV criteria as melancholic, atypical, and those not meeting either subtype designation ('non-subtyped') and 21 normal volunteers to ascertain whether or not the PKA activity abnormality was specific to melancholia. The melancholics showed marked reduction in cyclic AMP-stimulated PKA activity relative to normal volunteers. Although the atypicals were statistically significantly lower, almost all fell into the range for the normals. The non-subtyped group fell between the atypicals and the melancholics. Basal activity was significantly lower in atypical and melancholic groups. The data suggest that reduced PKA activity is consistently found in melancholic major depression and may not be seen with other depressive subtypes.

The alpha angle alpha (degrees) is a thrombelastographic measure of clot propagation. A parametric measurement of clot propagation [maximum rate of thrombus generation (MRTG), dynes/cm2 per s], however, has recently been utilized. Thus, the relationship of changes in alpha with changes in MRTG were determined. alpha and MRTG values obtained from 859 thrombelastograms was collected from nine studies. Data were analyzed and the relationship between alpha and MRTG defined with commercially available software. Additional comparisons were made retrospectively from whole-blood and plasma data obtained from 33 normal individuals. Data from the nine studies demonstrated that MRTG increased in an exponential fashion compared with increases in alpha (R2 = 0.88, P < 0.001). Whole-blood alpha values were in the range 66.7-74.7 whereas MRTG values were 5.5-10.8, and plasma alpha values were 65.1-77.9 with corresponding MRTG values of 3.5-12.0. Assessment of clot propagation utilizing MRTG provides a more parametric evaluation than the determination of alpha. While normal alpha values may vary by only 12-20%, MRTG values vary by approximately 200-300%. The MRTG should be progressively utilized to a greater extent in both laboratory and clinical settings to parametrically quantify clot growth kinetics with thrombelastography.

Factor XIII (FXIII) plays a critical role in clot strength, and FXIII deficiency or excess is associated with hemorrhage or thrombosis, respectively. Our goal was to design a thrombelastography-based method to characterize the effects of FXIII on plasma clot strength. Normal human plasma was exposed to 0 or 200 mug/ml anti-FXIII antibodies for 20 min prior to celite activation and calcium addition. Other plasma had addition of fibrinogen (625 mg/dl)/FXIII (2 U/ml) or 30% dilution with hydroxyethyl starch before exposure to 0 or 200 mug/ml anti-FXIII antibodies. Thromboelastography was performed and data were collected until stable clot strength was observed. The exposure of normal plasma to anti-FXIII antibodies resulted in a significant (P < 0.05) decrease in clot strength (63%) compared with plasma without antibodies. Further samples exposed to anti-FXIII antibodies had clot strength no different from FXIII-deficient plasma. The FXIII-mediated clot strength varied between 44 and 50% in hypercoagulable and hypocoagulable plasma, respectively. In conclusion, the present investigation successfully demonstrated a novel method to detect the impact of FXIII activity in plasma samples. Further actuarial investigation will be required to determine the utility of this approach in the diagnosis and treatment of patients with either acquired FXIII deficiency or excess and concordant coagulopathy.

This review considers the perhaps unappreciated role of contact pathway proteins in the pathogenesis of thrombotic/thromboembolic morbidity associated with mechanical circulatory support. Placement of ventricular assist devices (VADs) has been associated with consumption of circulating contact proteins and persistent generation of activated contact proteins such as Factor XII and high molecular weight kininogen. Importantly, activated contact proteins are absorbed to the surface of VADs via the Vroman effect. Further, hyperfibrinogenemia and persistent platelet activation exist in patients with VADs, likely contributing to speed of clot growth. Using thrombelastographic-based analyses, it has been determined that contact pathway protein activated coagulation results in a thrombus that develops strength at a significantly faster rate that tissue factor initiated coagulation. Further, thrombelastographic analyses that include the addition of tissue-type plasminogen activator have demonstrated that contact protein pathway activation results in thrombin activatable fibrinolysis inhibitor activation to a far greater extent than that observed with tissue factor initiated coagulation, resulting in a thrombus that takes significantly longer to lyse. These observations serve as the rational basis for clinical investigation to determine if regional suppression of thrombin generation with FXII/high molecular weight kininogen inhibition in concert with thrombin-activatable fibrinolysis inhibitor inhibition may decrease mechanical circulatory support-associated thrombotic morbidity.