Clot fragmentation

Plasmin is soluble but it remains active in the location of a clot. As it diffuses into the blood with clot fragments, the plasmin binds to a2-antiplasmin, a serine protease inhibitor (see next section). In addition to inhibiting plasmin in the blood (Fig. 11.10b), a2-antiplas-min inhibits various other serine proteases, especially activated protein C (APC) (next section) and elastase (Sect. 6.2.1). Plasmin action is inhibited where fibrin is cross-linked to fibronectin, but the large fibrin fragments tend to promote healing. The fragments of fibrin are named as shown in Fig. 11.10c and d. Factors that activate or inhibit fibrinolysis are summarized in Table 11.2. 

Blood platelets are key players in the blood-clotting mechanism. These tiny fragments of cytoplasm are shed into the circulation from the surface of megakaryocytes located in the bone marrow. When the lining of a blood vessel is injured, activated platelets release clotting factors, adhere to each other and to damaged surfaces, and send out numerous filopodia. The shape changes that occur in activated platelets are the result of actin polymerization. Before activation, there are no microfilaments because profilin binds to G-actin and prevents its polymerization. After activation, profilin dissociates from G-actin, and bundles and networks of F-actin filaments rapidly appear within the platelet. 

The Penumbra stroke system (Penumbra Inc., San Leandro, CA) includes two different revascularization options (1) thrombus debulking and aspiration may be achieved by a reperfusion catheter that aspirates the clot while a separator device fragments it, and (2) direct thrombus extraction may be performed by a ring retriever while a balloon guide catheter is used to temporarily arrest flow. This system has been tested in a pilot trial in Europe. Twenty patients (mean NIHSS 21) with a total of 21 vessel occlusions (7 ICA, 5 MCA, and 9 Basilar) were treated up to 8 hours after symptom onset. Recanalization prior to lA lysis was achieved in all cases (48% TIMI 2 52% TIMI 3). Seven patients were also treated with lA UK or rt-PA. Good outcome at 30 days (defined as mRS < 2 or NIHSS 4-point improvement) was demonstrated in 42%. The mortality rate was 45%, but there were no device-related deaths. There was one asymptomatic SAH and three symptomatic ICHs. A prospective, single-arm, multicenter trial is being conducted in the United States and Europe currently. 

Pmrl Proteinase K Prothrombin fatty acids (378,379) Yeast Golgi Ca2+/Mn2+-ATPase ion pump (380,381) Peptide fragmentation enzyme (382) Thrombin precursor extracellular trigger involved in blood clotting... 

Figure 7.8 Activation of clot formation by endotoxin. The presence of endotoxin causes stepwise, sequential activation of various clotting factors present naturally within the amoebocytes of the American horseshoe crab. The net result is the generation of the polypeptide fragment coagulin, which polymerizes, thus forming a gel or clot...

Chimeric Antibodies The first generation is the chimeric antibodies (chimeric comes from the word Chimera, a Greek mythology beast made of three animals a lion, a snake, and a goat). This type of antibody consists of both murine and human parts. The murine Fv fragments are retained and linked to the Fc fragment of human IgG. An example of the chimeric antibody is ReoPro, which prevents blood clots by binding to a receptor on platelets. 

The clotting factors are protein molecules. Activation mostly means proteolysis (cleavage of protein fragments) and, with the exception of fibrin, conversion into protein-hydrolyzing enzymes (proteases). Some activated factors require the presence of phospholipids (PL) and Ca + for their proteolytic activity. Conceivably, Ca + ions cause the adhesion of factor to a phospholipid surface, as depicted in C. Phospholipids are contained in platelet factor 3 (PF3), which is released from ag-Lullmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

Platelets, small cell fragments produced from bone marrow cells, work with the cascade of proteins in the formation of blood clots. If platelet counts are low, leaks in blood vessels that would normally be small can lead to the loss of large amoimts of blood. Certain chemotherapy drugs knock out the production of the cells that produce platelets. Oprelvekin (Neumega ), produced in E. coli, stimulates bone marrow to produce that very important type of cell. 

Figure 8.2 A developing blood clot is shown in this picture. A blood clot is made of platelets, membrane fragments of a bone marrow cell, and a network of insoluble proteins, particularly fibrin generated from a precursor protein, fibrinogen, through the work of a cascade of protein clotting factors. Several bleeding disorders result from inherited deficiencies in clotting proteins.

Conversion of the unsubstituted acetylene to vinylidene has been widely investigated both experimentally [66-68] and theoretically [69-71]. These studies showed that when metals were not involved, the formation of vinylidene from free acetylene (Scheme 4.4) was very endothermic (44—47 kcal mol ). Since most transition metal fragments can stabilize a vinylidene ligand, the tautomerization of r -acetylene to vinylidene on transition metal centers becomes feasible. Recently, Clot and Eisen-stein have thoroughly reviewed theoretical studies on various tautomerization pathways [44]. For the completeness of this chapter, we here briefly summarize the relevant theoretical flndings. 

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