PubMed · 13640925
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J A O'GRADY. 1959-04-11. Bleeding tendency in uremia.. https://doi.org/10.1001/jama.1959.03000320029007
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Generation of a hemostatic clot requires thrombin-mediated conversion of fibrinogen to fibrin. Previous in vitro studies have demonstrated that the thrombin concentration present at the time of gelation profoundly influences fibrin clot structure. Clots formed in the presence of low thrombin concentrations are composed of thick fibrin fibers and are highly susceptible to fibrinolysis; while, clots formed in the presence of high thrombin concentrations are composed of thin fibers and are relatively resistant to fibrinolysis. While most studies of clot formation have been performed by adding a fixed amount of purified thrombin to fibrinogen, clot formation in vivo occurs in a context of continuous, dynamic changes in thrombin concentration. These changes depend on the local concentrations of pro- and anti-coagulants and cellular activities. Recent studies suggest that patterns of abnormal thrombin generation produce clots with altered fibrin structure and that these changes are associated with an increased risk of bleeding or thrombosis. Furthermore, it is likely that clot structure also contributes to cellular events during wound healing. These findings suggest that studies explicitly evaluating fibrin formation during in situ thrombin generation are warranted to explain and fully appreciate mechanisms of normal and abnormal fibrin clot formation in vivo.
Examples abound of membrane-bound enzymes for which the local membrane environment plays an important role, including the ectoenzyme that triggers blood clotting, the plasma serine protease, factor VIIa, bound to the integral membrane protein, tissue factor. The activity of this enzyme complex is markedly influenced by lipid bilayer composition and further by tissue factor partitioning into membrane microdomains on some cell surfaces. Unfortunately, little is known about how membrane microdomain composition controls factor VIIa-tissue factor activity, as reactions catalyzed by membrane-tethered enzymes are typically studied under conditions in which the experimenter cannot control the composition of the membrane in the immediate vicinity of the enzyme. To overcome this problem, we used a nanoscale approach that afforded complete control over the membrane environment surrounding tissue factor by assembling the factor VIIa.tissue factor complex on stable bilayers containing 67 +/- 1 phospholipid molecules/leaflet (Nanodiscs). We investigated how local changes in phospholipid bilayer composition modulate the activity of the factor VIIa.tissue factor complex. We also addressed whether this enzyme requires a pool of membrane-bound protein substrate (factor X) for efficient catalysis, or alternatively if it could efficiently activate factor X, which binds directly to the membrane nanodomain adjacent to tissue factor. We have shown that full proteolytic activity of the factor VIIa.tissue factor complex requires extremely high local concentrations of anionic phospholipids and further that a large pool of membrane-bound factor X is not required to support sustained catalysis.
Hypothermia has long been known to be a potent putative neuroprotectant. Experimental evidence and clinical experience show that hypothermia protects the brain from cerebral injury. Recent insights into the mechanisms of cerebral ischemia and reperfusion suggest reasons why hypothermia may be an ideal modality for stroke therapy. Hypothermia protects brain tissue in multiple ways. It retards energy depletion, reduces intracellular acidosis, lessens the ischemia related accumulation of excitotoxic neurotransmitters, and attenuates the influx of intracellular calcium. Additionally, hypothermia suppresses the generation of oxygen free radicals involved in secondary damage associated with reperfusion. It also suppresses the mechanisms related to blood-brain barrier degeneration and postischemic remodeling. The clinical application of therapeutic hypothermia and its limitations will be summarized in this paper. Therapeutic hypothermia is likely to undergo phase III clinical trials in various clinical settings. Novel technologies are being developed to optimize the safety and efficacy of this promising approach.