Thrombosis described

Two types of Protein S deficiency have been described. In type I deficiency there is tittle to no free Protein S but normal amounts of bound Protein S are present. In type II Protein S deficiency both free and bound Protein S are very low to absent. Deficiency of free Protein S is associated with venous and arterial thrombosis. 

We shall first describe the coagulation pathway leading to the formation of fibrin. Then we shall briefly describe some aspects of the involvement of platelets and blood vessel walls in the overall process. This separation of clotting factors and platelets is artificial, since both play intimate and often mutually interdependent roles in hemostasis and thrombosis, but it facifitates description of the overall processes involved. 

Describe the processes of hemostasis and thrombosis, including the role of the vascular endothelium, platelets, coagulation cascade, and thrombolytic proteins. 

A G (guanine) to A (adenine) transition in position 20210 of the prothrombin gene (prothrombin 20210 A allele) has been described that leads to increased prothrombin concentrations and, in turn, increased risk for venous thrombosis (88). This G-to-A transition that occurs in the 3 untranslated region of the gene may not be the only reason for increased prothrombin concentrations because apparently only 25% of individuals with prothrombin concentrations greater than 115% carry the prothrombin 20210 A allele (88). 

Patients should be monitored for resolution of symptoms, the development of recurrent thrombosis, and symptoms of the postthrombotic syndrome, as well as for adverse effects from the treatments described in this chapter. 

As a high incidence of arteriovenous thrombosis is described in patients with systemic lupus erythematosus (SLE), Matsuda et al. (Ml8) tried to demonstrate a relationship between the presence of anti-phospholipid antibodies and Lp(a) concentrations. They found that serum Lp(a) concentrations were increased in patients with SLE independent of the presence of anti-phospholipid antibodies. Borba et al. (B18) confirmed these findings and also could not correlate Lp(a) concentrations with anti-cardiolipid antibodies. 

Pathophysiologically, thrombosis is the same sequence of events but now occurring in abnormal anatomical sites with intravascular obstruction that results in distal tissue ischaemia. These are often systemic disorders affecting the whole circulation and are described as hypercoagulable syndromes. Defects may lie at the level of the endothelium, inappropriate activation of the coagulation cascade or impaired activity of the fibrinolytic system. Segments of thrombus can become detached and travel peripherally in arterial tree, giving rise to acute insufficiency. Conversely, on the venous side, these are... 

The increasing demand for synthetic biomaterials, especially polymers, is mainly due to their availability in a wide variety of chemical compositions and physical properties, their ease of fabrication into complex shapes and structures, and their easily tailored surface chemistries. Although the physical and mechanical performance of most synthetic biomaterials can meet or even exceed that of natural tissue (see Table 5.15), they are often rejected by a number of adverse effects, including the promotion of thrombosis, inflammation, and infection. As described in Section 5.5, biocompatibility is believed to be strongly influenced, if not dictated, by a layer of host proteins and cells spontaneously adsorbed to the surfaces upon their implantation. Thus, surface properties of biomaterials, such as chemistry, wettability, domain structure, and morphology, play an important role in the success of their applications. 

Morbidity and mortality in HIT are related to thrombotic events. Venous thrombosis occurs most commonly, but occlusion of peripheral or central arteries is not infrequent. If an indwelling catheter is present, the risk of thrombosis is increased in that extremity. Skin necrosis has been described, particularly in individuals treated with warfarin in the absence of a direct thrombin inhibitor, presumably due to acute depletion of the vitamin -dependent anticoagulant protein C occurring in the presence of high levels of procoagulant proteins and an active hypercoagulable state. 

Organic anticoagulants are used in vivo in the treatment of numerons conditions where blood coagulation can be dangerous, as in cerebral thrombosis and coronary heart disease, among others which will be described later. The main anticoagulants used are heparin and coumarin compounds, such as warfarin. 

Both deep vein thrombosis and pulmonary embolism have been described with tamoxifen. 

Thrombosis and pulmonary embolism have been described with tamoxifen (49,50) the number of cases is small, but the association would not be unexpected in view of what is known about the effects of other sex hormones. The primary condition might be responsible, at least in part, for the occurrence of such complications. Tamoxifen does reduce antithrombin III but not to a degree at which a major risk would be expected, and other measurable effects on the coagulation process seem to be slight. 

The complex interaction of the factors described above, and a number of endogenous anticoagulant proteins such as protein C, protein S, and antithrombin III normally control the balance between clot formation and clot breakdown.36,61 Disease or inactivity, however, can alter this balance, leading to exaggerated clotting and venous or arterial thrombosis. Drugs used to treat overactive clotting are addressed in the next section. 

The indications for the use of heparin are described in the section on clinical pharmacology. A plasma concentration of heparin of 0.2-0.4 unit/mL (by protamine titration) or 0.3-0.7 unit/mL (anti-Xa units) usually prevents pulmonary emboli in patients with established venous thrombosis. This concentration of heparin will prolong the activated partial thromboplastin time (aPTT) to 2-2.5 times that of the control value. This degree of anticoagulant effect should be maintained throughout the course of continuous intravenous heparin therapy. When intermittent heparin administration is used, the aPTT should be measured 6 hours after the administered dose to maintain prolongation of the aPTT to 2-2.5 times that of the control value. 

The normal plasma level of heparin cofactor II is approximately 1.2 0.2 jlM (90). Two patients to date have been described as having thrombosis related to heparin cofactor II deficiency (95). 

The compounds potently inhibit factor Xa in vitro with reversible binding kinetics and are able to inhibit not only free but also prothrombinase-bound factor Xa (Ki 41 nM, 0.1 I nM, and 0,5 nM, respectively) (58-60), In contrast, no direct effect on platelet aggregation has been described (60-62), Antithrombotic activity in arterial and venous thrombosis models has been demonstrated and it has a reduced effect on hemorrhage in comparison to standard therapy (58,60,63). Factor Xa inhibitors are able to reduce the endogenous thrombin potential in platelet-poor as well as in platelet-rich plasma (64,65). Thus, thrombin generation seems to be a suitable biomarker for clinical evaluation and has been evaluated in phase I studies (66,67). 

The one-month farm swine studies evaluated safety following implantation of two doses of batimastat loaded on the 18 mm BiodivYsio stent in comparison to control stent without batimastat. Two batimastat doses were evaluated as described in Table 2. No deaths occurred during the implantation procedure and no sub-acute death or stent thrombosis was observed during the follow-up period. Histological examination confirmed that all the vessels were patent, without the presence of thrombus in the vessel lumen, All sections showed stent struts to be completely covered, leading to a smooth endoluminal surface. There was no excessive inflammatory response at stent struts in BiodivYsio-Batimastat-treated sections compared with the control sections. Medial and adventitial layers appeared similar in all three groups. The perivascular nerve fibers, the adipose tissue, and adjacent myocardium appeared normal in control and Biod/VV s/o-Batimastat-treated sections. Therefore, these studies demonstrated that the Biod/VY s/o Batimastat stent at CTD and >CTD was well tolerated up to 28 days. 

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