Page 2133 - Hematology_ Basic Principles and Practice ( PDFDrive )

1894 Part XII Hemostasis and Thrombosis

Protein C Inhibitor direct contact with lymph are known as lymphatic endothelial cells.
Protein C inhibitor is a member of the serine proteinase inhibitor Vascular endothelial cells line the entire circulatory system (from the
family and is also known as plasminogen activator inhibitor-3 (PAI-3). heart to the capillaries).
It circulates in blood at a concentration of 5 µg/mL 180,181 (see Table The endothelium varies in morphology and physiologic function
126.1 and Fig. 126.7) and is cleared from the circulation with a in different parts of the vasculature. This complex cellular network
half-life of 1 day. When in complex with a target (e.g., APC), it is not only provides a structural barrier to contain flowing blood but
cleared from circulation with a t 1/2 of 20 minutes. 182 also regulates blood pressure, vascular tone, permeability, and pro-
Protein C inhibitor is considered a nonspecific inhibitor in that cesses involving other cells such as smooth muscle cells, leukocytes,
its targets range from procoagulant (serine proteinases), anticoagulant, and platelets, and deposits an intricate basement membrane and
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and fibrinolytic enzymes to plasma and tissue kallikreins, the sperm extracellular matrix. In addition, the endothelium is involved in
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protease acrosin, and prostate-specific antigen. 183,184 The major target inflammatory and immune responses and angiogenesis. Defects in
of protein C inhibitor, as its name suggests, appears to be APC. 182,185,186 vascular endothelium function, therefore, have profound physiologic
Protein C inhibitor has been shown to regulate TAFI activation by implications. Excessive bleeding can result from structural abnormali-
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inhibiting the thrombin–thrombomodulin complex. Its importance ties of the endothelial cell layer or supporting matrix. Impaired
as a dual regulator of coagulation and fibrinolysis remains unre- expression or secretion of PAI-1 by the endothelium likewise pro-
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solved. 188,189 Other targets for protein C inhibitor include human motes bleeding through increased fibrinolytic activity. Conversely,
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plasma kallikrein, factor XIa, factor Xa, and thrombin. Because endothelial cells are also involved in mediating processes that promote
there are no documented patients with a deficiency to date, the actual atherosclerotic plaque formation and thrombotic pathologies. 220
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function of protein C inhibitor in vivo has yet to be elucidated. The early work of Ware and Seegers identified the phospholipid
requirements for coagulation. The biologic elements contributing to
α 2 -Macroglobulin the phospholipid include damaged vascular tissue-activated platelets
α 2 -Macroglobulin is a nonspecific proteinase inhibitor that targets a and inflammatory cells. The contributions of the membrane to the
broad spectrum of protease substrates. It is present in human plasma formation and expression of procoagulant complexes are essential.
at concentrations ranging from 2 to 4 µmol/L (2–3 mg/mL). α 2 - However, the nature of the membranes that support procoagulant
Macroglobulin can also be found at higher concentrations in extra- reactions is poorly understood. Mechanically damaged cells can
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vascular fluids. This protease inhibitor can be produced in a variety provide the anionic membrane bilayer inner leaflet phospholipids,
of cells, including hepatocytes, fibroblasts, and macrophages. 192,193 which can support general procoagulant complex formation; however,
Human α 2 -macroglobulin circulates in plasma as a tetramer. 191–198 more subtle cellular activation events also generate selective complex-
α 2 -Macroglobulin has a unique mechanism of action, which accounts forming sites on intact cells. Activated platelet membranes express
for its broad specificity. The initial step involves the “bait region” of individual binding sites for the factor IXa–factor VIIIa and factor
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α 2 -macroglobulin. After proteolysis in this bait region, α 2 - Xa–factor Va complexes. Hemorrhagic pathology is therefore associ-
macroglobulin undergoes conformational changes that trap the ated with thrombocytopenia and is also displayed in a rare disease,
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proteinase inside the molecule. Consequently, α 2 -macroglobulin Scott syndrome, which appears to result from the improper presenta-
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inhibits a broad range of proteinases. It is distinctive in its capacity tion of these platelet binding sites. Binding sites have also been
to inhibit members from each of four mechanistic classes of protein- reported on a number of peripheral blood cells, especially activated
ases (serine, cysteine, and aspartic proteinases, and metalloprotein- monocytes. The vascular endothelium itself can provide binding sites
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ases). α 2 -Macroglobulin functions as a secondary inhibitor of serine after stimulation by cytokine growth factors. The endothelium also
proteinases in plasma by inhibiting thrombin, kallikrein, and provides the anticoagulant thrombomodulin, TFPI and heparan
plasmin. 200,201 It may also be important in preventing thromboem- sulfate. The EPCR provides cell-specific binding sites for both protein
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bolic events when there is a congenital deficiency of antithrombin or C and APC. 44,224 EPCR is downregulated by TNF-α. Monocytes
acquired deficiency in sepsis. 202,203 α 2 -Macroglobulin also inhibits appear to express specific binding sites for APC that are distinct from
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various growth factors and cytokines, including transforming growth the endothelial cell protein C receptor. The cell-expressed binding
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factor-α (TGF-α), interleukin (IL)-1β, IL-6, acidic fibroblast sites may be important in the antiinflammatory properties of APC. 46
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growth factor, basic fibroblast growth factor, tumor necrosis A further consequence of damage to the endothelium is the release
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factor-α (TNF-α), and IL-2. Polymorphisms identified in α 2 - of pathologic quantities of vWF, which promote platelet aggregation
macroglobulin have been thought to play a role in Alzheimer and adhesion to the subendothelium, and thus the formation of
disease. 210–212 Overall, the biologic role of α 2 -macroglobulin in vivo potentially fatal thrombi. Endothelial dysfunction is also linked with
is still being elucidated. hypertension, diabetes, obesity, and hyperlipidemia.
Reduced levels of α 2 -macroglobulin in humans have been observed
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in individuals with chronic obstructive lung disease and metastatic
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cancer. Complete deficiency has not been reported, suggesting that Platelets
absence of α 2 -macroglobulin is incompatible with survival. Inactiva-
tion of the α 2 -macroglobulin gene in mice has no obvious phenotype, Platelets, or thrombocytes, are vital to procoagulant events and
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but the mice are resistant to endotoxin challenge. It has been contribute to the fibrinolytic process as well. They are small, irregu-
suggested that α 2 -macroglobulin serves as a neutralizer of TGF-α and larly shaped clear cell fragments, which are derived from megakaryo-
an inducer of nitric oxide synthesis in mice. 216 cytes. The average lifespan of a platelet is approximately 5–9 days.
Platelets are at the balance of bleeding or clotting events: when
platelet numbers are low (thrombocytopenia), excessive bleeding can
Endothelium occur, and when platelet numbers are high (thrombocytosis), throm-
bosis can occur. Disorders that reduce the number of platelets but
Blood cells and the vasculature are crucial to normal hemostasis. typically cause thrombosis instead of bleeding are heparin-induced
Multiple processes involving components of the vessel wall, circulat- thrombocytopenia and thrombotic thrombocytopenic purpura.
ing platelets, and plasma protein moieties interact to maintain blood Similar to the endothelium, the undisturbed platelet presents a
fluidity. These must be precisely choreographed to allow the vascula- nonthrombogenic surface. Important components of platelet physiol-
ture to perform its myriad complex physiologic activities (Fig. 126.8). ogy are surface adhesion protein complexes and the platelet secretory
The endothelium, the thin layer of cells that lines the interior of granules: α-granules, lysosomes, and dense granules. Contents of the
blood and lymphatic vessels, plays a key role because of its strategic α-granules include procoagulant and adhesive proteins such as
interface among organs, tissues, and circulating blood. The cells that fibrinogen, fibronectin, thrombospondin, vWF, P-selectin, HMWK,
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form the endothelium are called endothelial cells, those in direct platelet factor 4, osteonectin, factor V, and factor XI. Other
contact with blood are called vascular endothelial cells, and those in α-granule contents, α 1 -antitrypsin, protein S, TFPI, and platelet