Fibrinolysis products

The individual responsiveness to desmopressin is consistent, and a test dose administered at the time of diagnosis or prior to therapy is the best predictor of response. Generally, DDAVP is more effective in vWD than in hemophilia patients, with an average 30% to 50% increase in vWF and factor VIII levels. In patients with an adequate response, desmopressin is first-line therapy because it allows for once-daily administration (elevates plasma levels for 8-10 hours), does not pose a threat in terms of viral transmission, and the cost is substantially less than that of the plasma-derived products. Fibrinolysis inhibitors (50-60 mg/kg of aminocapriotic acid every 4—6 hours or trenex-amic acid 10-15 mg/kg every 8-12 hours) and OCs are used successfully in the management of epistaxis and menorrhagia or as adjuvant treatments. 

Fig. 14.1. The Thl/Th2 balance is central to the regulation of normal wound repair. Tissue injury results in the initiation of an inflammatory response, mediated by a variety of cells and their by-products. Immune cells are recruited and cross-regulate the Thl/ Th2 balance that occurs in response to the cytokine environment. This balance is in turn cross-regulated by the chemokine/chemokine-receptor expression profile, which functions to amplify the inflammatory process. Cells residing in the injured tissue release profibrotic mediators, which promote fibroblast activation, proliferation, and differentiation to the myofibroblast phenotype. Myofibroblasts produce collagen to repair damaged tissue, which is an event that is favored by the inhibition of MMP activity. The Thl/Th2 balance is central to whether a normal or aberrant wound-repair process is established A Thl environment promotes normal tissue resolution (fibrinolysis), whereas a Th2 environment maintains the progression of fibrotic disease (excessive collagen deposition).

The procoagulant factors produced by endothelial cells are the coagulation factors von Willebrand factor (WF), F-V, F-VIII, tissue factor (TF), and plasminogen activator inhibitor (PAI), which blocks the activators u-PA and t-PA and counteracts fibrinolysis (G21, FI6). It has been shown that under the influence of complement activation (C9), in response to endotoxin in vitro (C24), in experimental E. coli sepsis in baboons (D30), and after stimulation with TNF (Al, N6), endothelial cells up-regulate the expression of TF, down-regulate TM and inhibit the production of t-PA and PAF. Thus, the balance may shift in the procoagulant direction with a large excess of PAI-1. 

N2. Nakashima, Y., Sueishi, K., and Tanaka, K Thrombin enhances production and release of tissue plasminogen activator from bovine venous endothelial cells. Fibrinolysis 2, 227-234 (1988). 

By far the most widely measured marker of hemostatic activation is D-dimer, which is a product formed by the action of plasmin on cross-linked fibrin (95). D-dimer levels in plasma are generally elevated in DIC. The consumption of platelets and coagulation proteins as a result of thrombin generation leads to the deposition of fibrin thrombi at multiple organ sites. This triggers fibrinolysis with an increase in the formation of fibrin degradation products, which can cause bleeding at multiple sites. Because DIC can have a variety of causes and may coexist with systemic fibrinolysis, such as in pulmonary embolism or deep vein thrombosis, the d-Dimer test is not specific for DIC (95). 

The observed enhancement of the catalytical efficiency of immobilized trypsin in the presence of immobilized heparin was shown to be due to the association of the products of fibrinolysis (as in the case of fibrinogen) which removed them out of reach of immobilized trypsin 137>. In fact, as is seen from Fig. 9, the lysis rate gradually decreases as the reaction products are accumulated, i.e., accumulation of the lysis products causes the poisoning of the catalyst. Addition of new polymer, but this time of that containing immobilized heparin only, again leads to an increase of the lysis rate (Fig. 10). 

A third underlying mechanism seems to involve a reduction in concentrations of free protein S, again more pronounced with third-generation products. When protein S falls, the antifibrinolytic effect of the so-called thrombin-activated fibrinolysis inhibitor is increased in other words, fibrinolysis is impeded, with an increased risk of clotting problems (104). Again, however, these are recent methods, which were not available when the third-generation products were launched. 

Note In fibrinolysis, plasmin, an endopeptidase that is converted from plasminogen by an activator, hydrolyzes fibrin, fibrinogen, factor V, and factor VIII to their inactive products. Hageman factor (factor XII) converts a proactivator to the active activator. Agents such as thrombin, streptokinase, and urokinase therefore enhance the formation of plasmin and hence have fibrin lytic properties. Epsilon-aminocaproic acid inhibits the activator-mediated formation of plasmin and hence may be used as an antidote to streptokinase-urokinase, or in a defibrination syndrome when bleeding from a mucous membrane occurs. 

Structure analysis of several proteases involved in blood coagulation and fibrinolysis reveals a diverse, sometimes repetitive, assembly of discrete protein modules (Fig. 9.4) [56]. While these modules represent independent structural units with individual folding pathways, their concerted action contributes to function and specificity in the final protein product. On the genetic level, these individual modules are encoded in separate exons. Over the course of modular protein evolution, new genes are created by duplication, deletion, and rearrangement of these exons. Mechanistically, the exon shuffling actually takes place in the intervening intron sequences (intronic recombination - for further details see [10]). 

Gram, J., Duscha, H., Zurborn, K.-H., Bruhn, H.D. Increased levels of fibrinolysis reaction products (D-dimer) in patients with decompensated alcoholic liver cirrhosis. Scand. J. Gastroenterol. 1991 26 1173-1178... 

Many androgens and anabolic steroids reduce the dose of oral anticoagulant that a patient requires, sometimes by as much as 25% (73), and hemorrhage has sometimes resulted from their use. From the results of a study in which stanozolol reduced warfarin requirements, the investigators concluded that stanozolol increased fibrinolysis, reduced the production of vitamin K-dependent clotting factors, and increased the amount of the natural anticoagulant antithrombin III (74). 

Epoetin has been abused by athletes, increasing the risk of hypertension and disseminated intravascular coagulopathy (10). In athletes epoetin causes increased blood viscosity, which will further increase during dehydration, leading to risks of myocardial infarction, cerebrovascular accident, or encephalopathy (10). Epoetin induces accelerated fibrinolysis, and so epoetin doping can be detected by analysis of fibrin degradation products in urine (10). In addition, hypochromic macrocytes are increased (10). 

Bleeding at sites other than the primary site (oozing at a central hne insertion site, hemarthrosis, and epistaxis) has been reported during treatment with recombinant factor Vila in four patients (7). The authors suggested that local fibrinolysis may have contributed to or actually caused bleeding from central hne insertion sites. In three cases they found raised fibrin degradation products and in two cases a 15-35% fall in plasminogen activity. 

---