The Endothelium In Hemostasis

The role of the endothelium in regulating blood fluidity and trafficking of circulating hematopoietic cells has been the subject of several reviews (Cines et al., 1998; Aird, 2003). ECs express a variety of factors that inhibit coagulation, including soluble substances, such as nitric oxide and prostacyclin (acting to inhibit platelet activation), and tissue-type plasminogen activator (t-PA, acting to promote fibrinolysis), among many others. EC surface-bound molecules with anticoagulant activity include heparan sulfate-containing proteoglycans (see below), thrombomo-dulin (TM), complement regulatory proteins, as well as receptors for activated protein C (APC), urokinase, and plasminogen.

Unperturbed ECs also do not express several moieties that promote platelet and leukocyte adhesion, such as endothelial leukocyte adhesion molecule (ELAM), P-selectin, and platelet-activating factor (PAF). These can be induced, however, when the cells are stimulated by agonists, such as cytokines, thrombin (Drake et al., 1993; Kaplanski et al., 1998), or when the cells are injured by immune factors, atherosclerosis, or shear stress (Yu et al., 2005). Additionally, ECs exposed to such factors express a reduced content of heparan sulfate, internalize and degrade APC, elaborate tissue factor, and secrete abundant plasminogen activator inhibitor-1 (PAI-1), each of which may promote thrombus formation (Cines et al., 1998). Histochemical studies of the endothelium in murine models of inflammation have confirmed many of these observations, predicated in cell culture (Fries et al., 1993), affirming the notion that the endothelium undergoes multifaceted changes from an antithrombotic to a procoagulant phenotype in response to injury.

Also relevant to the pathogenesis of HIT is the remarkable heterogeneity of ECs, within and among different vascular beds, owing to genetic differences and acquired changes in phenotype (for reviews: see Cines et al., 1998; Aird, 2003). For example, only a small fraction of ECs constitutively expresses t-PA or urokinase-type plasminogen activator (u-PA) in vivo (Levin et al., 1994), whereas a different subset expresses tissue factor when exposed to endotoxin (Drake et al., 1993). ECs from different organs express tissue-specific promoters that regulate the expression of von Willebrand factor (vWF) in vivo (Aird et al., 1997). ECs also show regional variation in the synthesis of prostacyclin and expression of leukocyte adhesion molecules and Fcg receptors, among many other phenotypic differences.

There is also evidence to indicate that protein C activation on macrovascular ECs is mediated predominantly through the protein C receptor, whereas TM may dominate in the microvasculature (Laszik et al., 1997; Van de Wouwer et al., 2004). TM changes thrombin from a procoagulant to an anticoagulant enzyme (i.e., TM-bound thrombin activates the natural anticoagulant zymogen, protein C) (Esmon, 2001). Targeted disruption of the endothelial TM gene leads to juvenile onset of thrombosis (Isermann et al., 2001). The anticoagulant function of TM in the microvasculature may contribute to the pathogenesis of warfarin-associated venous limb gangrene that can complicate HIT. This syndrome has been attributed to the coincidence of persistent thrombin generation and acquired protein C deficiency that may occur during the first few days of anticoagulation with warfarin (Warkentin et al., 1997; Srinivasan et al., 2004) (see Chapters 2 and 12).

The behavior of ECs can also be modified during the evolution of vascular disease. For example, atherosclerotic vessels produce less nitric oxide in response to a variety of stimuli than do healthy vessels (Shaul, 2003). Atherosclerotic vessels may also undergo alterations in their expression of glycosaminoglycans (GAGs)

(Talusan et al., 2005) and an increase in expression of various cell adhesion molecules (for review: see Fuster et al., 1998). The binding of advanced glycation end products to specific EC receptors during normal aging and diabetes mellitus increases vascular permeability, exposing the subendothelial matrix to lipoproteins and other injurious substances (Basta et al., 2004). It is also likely that genetic variation in EC behavior contributes to the host response to antibody- and platelet-mediated EC injury, although the methods to identify or monitor such risk factors remain to be developed. Thus, any inquiry into the reason why only a subset of patients who develop anti-PF4-heparin antibodies develop thrombosis, or why thrombi occur at restricted vascular sites, must take into consideration the specific attributes of the affected endothelial vascular bed.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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