Hemostasis is the process of stopping bleeding at the site of vascular injury through a complex interaction between platelets and coagulation factors. It occurs in two phases: primary hemostasis involves platelet adhesion, activation, and aggregation to form a platelet plug; secondary hemostasis activates the coagulation cascade culminating in thrombin generation and fibrin deposition to stabilize the platelet plug. Precise regulation of hemostasis prevents excessive bleeding or pathological clotting.
Original Description:
For MBBS students, an overview of Pathology chapter about blood by Robbins
Original Title
3. Hemostasis, Hemorrhagic Disorders and Thrombosis
Hemostasis is the process of stopping bleeding at the site of vascular injury through a complex interaction between platelets and coagulation factors. It occurs in two phases: primary hemostasis involves platelet adhesion, activation, and aggregation to form a platelet plug; secondary hemostasis activates the coagulation cascade culminating in thrombin generation and fibrin deposition to stabilize the platelet plug. Precise regulation of hemostasis prevents excessive bleeding or pathological clotting.
Hemostasis is the process of stopping bleeding at the site of vascular injury through a complex interaction between platelets and coagulation factors. It occurs in two phases: primary hemostasis involves platelet adhesion, activation, and aggregation to form a platelet plug; secondary hemostasis activates the coagulation cascade culminating in thrombin generation and fibrin deposition to stabilize the platelet plug. Precise regulation of hemostasis prevents excessive bleeding or pathological clotting.
HEMOSTASIS DEFINITION Precisely orchestrated process involving platelets, clotting factors, and endothelium that occurs at the site of vascular injury and culminates in the formation of a blood clot, which serves to prevent or limit the bleeding General sequence of events leading to hemostasis at a site of vascular injury: Arteriolar vasoconstriction: occurs immediately and it reduces blood flow to the injured area. It is mediated by reflex neurogenic mechanisms and augmented by the local secretion of factors such as endothelin, a potent endotheliumderived vasoconstrictor. This effect is transient, and bleeding would resume if activation of platelets and coagulation factors does not occur. Primary hemostasis: the formation of the platelet plug; o Disruption of the endothelium exposes subendothelial von Willebrand factor (vWF) and collagen, which promote platelet adherence and activation. Activation of platelets results in a shape change (from small rounded discs to flat plates with spiky protrusions that markedly increased surface area), and release of secretory granules. Secreted products recruit additional platelets, which undergo aggregation to form a primary hemostatic plug. Secondary hemostasis: deposition of fibrin; Tissue factor is exposed at the site of injury. Tissue factor is a membranebound procoagulant glycoprotein that is normally expressed by smooth muscle cells and fibroblasts of vessel wall. Tissue factor binds and activates factor VII, setting in cascade of reactions that culiminates in thrombin generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork, and also is a potent activator of platelets, leading to additional platelet aggregation at the site of injury. Secondary hemostasis, consolidates the initial platelet plug. Clot stabilization and resorption; Polymerized fibrin and platelet aggregates undergo contraction to form a solid, permanent plug that prevents further hemorrhage. At this stage, counter-regulatory mechanisms (e.g., tissue plasminogen activator, t-PA) are set into motion that limit clotting to the site of injury and eventually lead to clot resorption and tissue repair. PLATELETS Platelets are discshaped anucleate cell fragments that are shed from megakaryocytes in the bone marrow into the bloodstream Role of platelets in hemostasis: 1. Platelets form the primary plug that initially seals vascular defects 2. by providing a surface that binds and concentrates activated coagulation factors Their function depends on: 1. several glycoprotein receptors 2. contractile cytoskeleton 3. two types of cytoplasmic granules. i- α-Granules ii- Dense (or δ) granules α-Granules have 1. Adhesion molecule: Pselectin 2. Coagulation factors: fibrinogen, factor V and vWF 3.Proteins involved in wound healing: fibronectin, platelet factor 4 (a heparin- binding chemokine), PDGF, and TGFβ Dense (or δ) granules: contain ADP, ATP, ionized calcium, serotonin, and epinephrine After a traumatic vascular injury, platelets encounter constituents of the subendothelial connective tissue, such as vWF and collagen. On contact with these proteins, platelets undergo a sequence of reactions that culminate in the formation of a platelet plug. Platelet adhesion is mediated largely via interactions with vWF, which acts as a bridge between the platelet surface receptor glycoprotein Ib (GpIb) and exposed collagen. Notably, genetic deficiencies of vWF (von Willebrand disease) or GpIb result in bleeding disorder called Bernard Soulier syndrome. Platelets rapidly change shape following adhesion, being converted from smooth discs to spiky “sea urchins” with greatly increased surface area. This change is accompanied by alterations in glycoprotein IIb/IIIa that increase its affinity for fibrinogen and by the translocation of negatively charged phospholipids (particularly phosphatidylserine) to the platelet surface These phospholipids bind calcium and serve as nucleation sites for the assembly of coagulation factor complexes Secretion (release reaction) of granule contents occurs along with changes in shape; these two events are often referred to together as platelet activation Platelet activation is triggered by a number of factors, including the coagulation factor thrombin and ADP Thrombin activates platelets through a special type of Gprotein– coupled receptor referred to as a protease- activated receptor (PAR), which is switched on by a proteolytic cleavage carried out by thrombin. ADP is a component of dense body granules; thus, platelet activation and ADP release result in additional rounds of platelet activation, a phenomenon referred to as recruitment Activated platelets also produce the prostaglandin thromboxane A2 (TxA2), a potent inducer of platelet aggregation Aspirin inhibits platelet aggregation and produces a mild bleeding defect by inhibiting cyclooxygenase, a platelet enzyme that is required for TxA2 synthesis Platelet aggregation follows their activation; The conformational change in glycoprotein IIb/IIIa that occurs with platelet activation allows binding of fibrinogen, a large bivalent plasma polypeptide that forms bridges between adjacent platelets, leading to their aggregation. Predictably, inherited deficiency of GpIIb- IIIa results in a bleeding disorder called Glanzmann thrombasthenia. The initial wave of aggregation is reversible, but concurrent activation of thrombin stabilizes the platelet plug by causing further platelet activation and aggregation, and by promoting irreversible platelet contraction. Platelet contraction is dependent on the cytoskeleton and consolidates the aggregated platelets In parallel, thrombin also converts fibrinogen into insoluble fibrin, cementing the platelets in place and creating the definitive secondary hemostatic plug Entrapped red cells and leukocytes are also found in hemostatic plugs, in part due to adherence of leukocytes to Pselectin expressed on activated platelets. COAGULATION CASCADE The coagulation cascade is series of amplifying enzymatic reactions that leads to the deposition of an insoluble fibrin clot. The dependency of clot formation on various factors differs in the laboratory test tube (vitro) and in blood vessels in (vivo). Clotting in vitro and in vivo both follow the same general principles. General Principles Each reaction step involves an enzyme (an activated coagulation factor), a substrate (an inactive proenzyme form of a coagulation factor), and a cofactor (a reaction accelerator). These components are assembled on a negatively charged phospholipid surface, which is provided by activated platelets. The enzymatic reactions that produce γ- carboxylated glutamic acid use vitamin K as a cofactor and are antagonized by drugs such as coumadin, a widely used anticoagulant. Assembly of reaction complexes also depends on calcium, which binds to γ(Gamma)carboxylated glutamic acid residues that are present in factors II,VII, IX, and X. Based on assays carried out in clinical laboratories, the coagulation cascade has traditionally been divided into the extrinsic and intrinsic pathways. The prothrombin time (PT) assay assesses the function of the proteins in the extrinsic pathway (factors VII, X,V, II, and fibrinogen). In vitro In brief, tissue factor, phospholipids, and calcium are added to plasma and the time for a fibrin clot to form is recorded. • The partial thromboplastin time (PTT) assay: screens the function of the proteins in the intrinsic pathway (factors XII, XI, IX,VIII, X,V, II, and fibrinogen). In this assay, clotting of plasma is initiated by addition of negative charged particles (e.g., ground glass) that activate factor XII (Hageman factor) together with phospholipids and calcium, and the time to fibrin clot formation is recorded. PT and PTT assays are of great utility in evaluating coagulation factor function in patients, they fail to sum up the events that lead to coagulation in vivo (blood vessels). Deficiencies of factors V,VII,VIII, IX, and X are associated with moderate to severe bleeding disorders, and prothrombin deficiency is likely incompatible with life. In contrast, factor XI deficiency is associated with mild bleeding, and individuals with factor XII deficiency do not bleed and in fact may be susceptible to thrombosis. Most important activities of thrombin 1. Conversion of soluble fibrinogen into crosslinked insoluble fibrin 2. Amplifies the coagulation process, by activating factor XI, co-factors V and VIII. 3. Stabilizes the secondary hemostatic plug by activating factor XIII, which covalently crosslinks fibrin. 4. Platelet activation; Thrombin is a potent inducer of platelet activation and aggregation through its ability to activate (protease activated receptors) PARs, thereby linking platelet function to coagulation. 5. Pro-inflammatory effects; PARs are also expressed on inflammatory cells, endothelium, and other cell types, and activation of these receptors by thrombin is believed to mediate proinflammatory effects that contribute to tissue repair and angiogenesis. • Anticoagulant effects; Upon encountering normal endothelium thrombin changes from a procoagulant to an anticoagulant. This reversal in function prevents clotting from extending beyond the site of the vascular injury. Factors That Limit Coagulation Once initiated, coagulation must be restricted to the site of vascular injury to prevent deleterious consequences. One limiting factor is dilution; blood flowing past the site of injury washes out activated coagulation factors, which are rapidly removed by the liver. A second is the requirement for negatively charged phospholipids, which, are provided by platelets that have been activated by contact with subendothelial matrix at sites of vascular injury. Counterregulatory mechanisms involve factors that are expressed by intact endothelium adjacent to the site of injury. Activation of the coagulation cascade also sets into motion a fibrinolytic cascade that limits the size of the clot and contributes to its later dissolution. Fibrinolysis is accomplished through the enzymatic activity of plasmin, which breaks down fibrin and interferes with its polymerization. An elevated level of breakdown products of fibrinogen (often called fibrin split products), most notably fibrinderived D- dimers, are a useful clinical markers of several thrombotic states. Plasmin is generated by enzymatic catabolism of the inactive circulating precursor plasminogen, either by a factor XII–dependent pathway or by plasminogen activators. The most important plasminogen activator is tPA; it is synthesized principally by endothelium and is most active when bound to fibrin. This characteristic makes tPA a useful therapeutic agent, since its fibrinolytic activity is largely confined to sites of recent thrombosis. Once activated, plasmin is in turn tightly controlled by counterregulatory factors such as α2plasmin inhibitor, a plasma protein that binds and rapidly inhibits free plasmin. ENDOTHELIUM The balance between the anticoagulant and procoagulant activities of endothelium determines whether clot formation, propagation, or dissolution occurs. Normal endothelial cells express factors that inhibit the procoagulant activities of platelets and coagulation factors and that augment fibrinolysis. These factors act to prevent thrombosis and to limit clotting to sites of vascular damage. However, if injured or exposed to proinflammatory factors, endothelial cells lose many of their antithrombotic properties. Antithrombotic activities of normal endothelium; The antithrombotic properties of endothelium can be divided into activities directed at platelets, coagulation factors, and fibrinolysis. • Platelet inhibitory effects. An obvious effect of intact endothelium is to serve as a barrier that shields platelets from subendothelial vWF and collagen. However, normal endothelium also releases a number of factors that inhibit platelet activation and aggregation. Among the most important are prostacyclin (PGI2), nitric oxide (NO), and adenosine diphosphatase. Endothelial cells bind and alter the activity of thrombin, which is one of the most potent activators of platelets. Anticoagulant effects. Normal endothelium shields coagulation factors from tissue factor in vessel walls and expresses multiple factors that actively oppose coagulation, most notably thrombomodulin, endothelial protein C receptor, heparin-like molecules, and tissue factor pathway inhibitor. Thrombomodulin and endothelial protein C receptor bind thrombin and protein C, respectively, in a complex on the endothelial cell surface. When bound in this complex, thrombin loses its ability to activate coagulation factors and platelets, and instead cleaves and activates protein C, a vitamin K– dependent protease that requires a cofactor, protein S. Activated protein C/protein S complex is a potent inhibitor of coagulation factors Va and VIIIa. Heparin-like molecules on the surface of endothelium bind and activate anti- thrombin III, which then inhibits thrombin and factors IXa, Xa, XIa, and XIIa. The clinical utility of heparin and related drugs is based on their ability to stimulate antithrombin III activity. Tissue factor pathway inhibitor(TFPI), like protein C, requires protein S as a cofactor and, as the name implies, binds and inhibits tissue factor/factor VIIa complexes. • Fibrinolytic effects. Normal endothelial cells synthesize t-PA, is a key component of the fibrinolytic pathway. HEMORRHAGIC DISORDERS Disorders of primary hemostasis Usually due to abnormalities in platelets; divided into qualitative or quantitative disorders Clinical features include mucosal and skin bleeding Mucosal bleeding Skin bleeding Epistaxis Petechiae (1-2mm) Hemoptysis Purpura(>3mm) GI bleeding Ecchymoses(>1cm) Hematuria Easy bruising menorrhagia Laboratory studies 1. Platelet count…….normal or decreased 2. Bleeding time……..usually prolonged 3. blood smear……..to assess number and size of platelets 4. Bone marrow biopsy…..to assess megakaryocytes Diseases involving primary hemostasis 1. ITP 2. TTP 3. HUS 4. Bernard soulier syndrome 5. Glanzmann thrombasthenia Disorders of secondary hemostasis Usually due to clotting factors abnormality or the factors needed for their activation o Exp to an activating substance o Phospholipid surface of platelets o Calcium • Clinical features include deep tissue bleeding into muscles and joints and rebleeding after surgical procedures Laboratory studies include 1. PT….measures extrinsic and common pathways of coagulation cascade 2. PTT…. Measures intrinsic and common pathways of coagulation Diseases include; Hemophilia A Factor VIII Hemophilia B Factor IX Coagulation factor inhibitor Antibodies(mixing studies) vW Disease vWF Vitamin K deficiency Newborns, antibiotic therapy, malabsorption Liver failure Thrombosis: The primary abnormalities that lead to thrombosis are (1) endothelial injury, (2) stasis or turbulent blood flow, and (3) hypercoagulability of the blood (the so- called Virchow triad). 1. Endothelial Injury Endothelial injury leading to platelet activation leads to thrombus formation in the heart and the arterial circulation, where the high rates of blood flow impede clot formation. Obviously, severe endothelial injury may trigger thrombosis by exposing vWF and tissue factor. However, inflammation and other noxious stimuli also promote thrombosis by shifting the pattern of gene expression in endothelium to one that is “prothrombotic.” This change is sometimes referred to as endothelial activation or dysfunction and can be produced by diverse exposures, including infectious agents, abnormal blood flow, inflammatory mediators, metabolic abnormalities, such as hypercholesterolemia or homocystinemia, and toxins absorbed from cigarette smoke. Major prothrombotic alterations: Procoagulant changes. Endothelial cells activated by cytokines down regulate the expression of thrombomodulin This may result in sustained activation of thrombin, which can in turn stimulate platelets and augment inflammation through PARs expressed on platelets and inflammatory cells In addition, inflamed endothelium also down regulates the expression of other anticoagulants, such as protein C and tissue factor protein inhibitor, these changes further promote a procoagulant state • Antifibrinolytic effects.Activated endothelial cells secrete plasminogen activator inhibitors (PAIs), which limit fibrinolysis, alterations that also favor the development of thrombi. 2. Alternations in Normal Blood Flow Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, and by forming local pockets of stasis. Stasis is a major contributor in the development of venous thrombi. Normal blood flow is laminar such that the platelets (and other blood cellular elements) flow centrally in the vessel lumen, separated from endothelium by a slower moving layer of plasma. Stasis and turbulence therefore: Promote endothelial activation, enhancing procoagulant activity and leukocyte adhesion, in part through flowinduced changes in the expression of adhesion molecules and pro- inflammatory factors Disrupt laminar flow and bring platelets into contact with the endothelium Prevent washout and dilution of activated clotting factors by fresh flowing blood and the inflow of clotting factor inhibitors Stasis and turbulence occurs in several clinical settings. i.e. Ulcerated atherosclerotic plaques, aortic, arterial aneurysms, acute MI result in areas of noncontractile myocardium and sometimes in cardiac aneurysms, rheumatic mitral valve stenosis results in left atrial dilation; in conjunction with atrial fibrillation, hyperviscosity (such as is seen with polycythemia vera) increases resistance to flow and causes small vessel stasis, and the deformed red cells in sickle cell anemia impede blood flow through small vessels. 3. Hypercoagulability Hypercoagulability (also called thrombophilia) has a particularly important role in venous thrombosis and can be divided into primary (genetic) and secondary (acquired) disorders . Genetic causes of hypercoagulability; point mutations in the factor V gene and prothrombin gene . Single nucleotide mutation in factor V that is called the factor V Leiden. Among individuals with recurrent DVT, the frequency of this mutation is higher, approaching 60%. The mutation results in a glutamine to arginine substitution at amino acid residue 506 that renders factor V to cleavage and inactivation by protein C. As a result, an important antithrombotic counter- regulatory pathway is lost. A single nucleotide change (G20210A) in the 3′untranslated region of the prothrombin gene is another common mutation (1% to 2% of the population) associated with hypercoagulability. It leads to elevated prothrombin levels and an almost threefold increased risk of venous thrombosis. Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well as the development of atherosclerosis. The prothrombotic effects of homocysteine may be due to linkages formed between homocysteine metabolites and fibrinogen. Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione βsynthetase. • Rare inherited causes of primary hypercoagulability include; deficiencies of anticoagulants such as antithrombin III, protein C, or protein S; affected individuals typically present with venous thrombosis and recurrent thromboembolism beginning in adolescence or early adulthood. The most common thrombophilic genotypes (heterozygosity for factor V Leiden and heterozygosity for the prothrombin G20210A variant) cause moderately increased risk of thrombosis; most individuals with these genotypes, when otherwise healthy, are free of thrombotic complications. Moreover, individuals with such mutations have a significantly increased frequency of venous thrombosis in the setting of other acquired risk factors (e.g., pregnancy or prolonged bed rest/prolong plane travel). Causes of acquired thrombophilia/hypercoagualibility: In some cases (e.g., cardiac failure or trauma), stasis or vascular injury may be most important. Hypercoagulability due to oral contraceptive use or the hyperestrogenic state of pregnancy is probably caused by increased hepatic synthesis of coagulation factors and reduced anticoagulant synthesis. In disseminated cancers, release of various procoagulants from tumors predisposes to thrombosis. The hypercoagulability seen with advancing age may be due to reduced endothelial PGI2 production. Smoking and obesity promote hypercoagulability by unknown mechanisms (Reaserch). Among the acquired thrombophilic states, the heparin induced thrombocytopenia and the antiphospholipid antibody syndromes are particularly important clinical problems. i. Heparin-Induced Thrombocytopenia (HIT) Syndrome HIT occurs following the administration of unfractionated heparin, which induce the antibodies that recognize complexes of heparin and platelet factor 4 on the surface of platelets, and complexes of heparinlike molecules and platelet factor 4like proteins on endothelial cells. Binding of these antibodies to platelets results in their activation, aggregation, and consumption (hence the thrombocytopenia in the syndrome name). Lowmolecularweight heparin preparations induce HIT less frequently, and other classes of anticoagulants such as direct inhibitors of factor X and thrombin may also obviate the risk. ii. Antiphospholipid Antibody Syndrome This syndrome (previously called the lupus anticoagulant syndrome) has changeable clinical manifestations, including recurrent thromboses, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia. Depending on the vascular bed involved, the clinical presentations can include pulmonary embolism (PE) (following lower extremity venous thrombosis), pulmonary hypertension (from recurrent subclinical pulmonary emboli), stroke, bowel infarction, or renovascular hypertension. Fetal loss does not appear to be explained by thrombosis, but rather seems to stem from antibodymediated interference with the growth and differentiation of trophoblasts, leading to a failure of placentation. Antiphospholipid antibody syndrome is also a cause of renal microangiopathy, resulting in renal failure associated with multiple capillary and arterial thromboses. Suspected antibody targets include; β2 glycoprotein I, a plasma protein that associates with the surfaces of endothelial cells and trophoblasts, and thrombin, thereby inducing a hypercoagulable state through uncertain mechanisms (Reaserch). These antibodies give a falsepositive serologic test for syphilis because the antigen in the standard assay is embedded in cardiolipin. Antiphospholipid antibody syndrome has primary and secondary forms. Individuals with a well- defined autoimmune disease, such as SLE, having secondary antiphospholipid syndrome (hence the earlier term lupus anticoagulant syndrome). In primary antiphospholipid syndrome, patients exhibit only the manifestations of a hypercoagulable state and lack evidence of other autoimmune disorders; occasionally, it appears following exposure to certain drugs or infections. Therapy involves anticoagulation and immunosuppression. Although antiphospholipid antibodies are clearly associated with thrombotic diatheses. Morphology of Thrombus Thrombi are focally attached to the underlying vascular surface, particularly at the point of initiation. From here, arterial thrombi tend to grow retrograde, while venous thrombi extend in the direction of blood flow; thus both propagate toward the heart. The propagating portion of a thrombus is often poorly attached and therefore prone to fragmentation and embolization. Thrombi have grossly and microscopically apparent laminations called lines of Zahn, which are pale platelet and fibrin deposits alternating with darker red cell–rich layers. Such laminations signify that a thrombus has formed in flowing blood; their presence can therefore distinguish antemortem clots from the bland nonlaminated clots that occur postmortem. Thrombi occurring in heart chambers or in the aortic lumen are designated mural thrombi. Arterial thrombi are frequently occlusive; the most common sites in decreasing order of frequency are the coronary, cerebral, and femoral arteries. They typically consist of a friable meshwork of platelets, fibrin, red cells, and degenerating leukocytes. Venous thrombosis (phlebothrombosis) is almost invariably occlusive. These thrombi form in the sluggish venous circulation, they tend to contain more enmeshed red cells (and relatively few platelets) and are therefore known as red, or stasis thrombi. Venous thrombi are firm, are focally attached to the vessel wall, and contain lines of Zahn. Postmortem clots form after death, are gelatinous and have a dark red dependent portion where red cells have settled by gravity and a yellow upper portion, and are usually not attached to the underlying vessel wall. Thrombi on heart valves are called vegetations. Fate of the Thrombus If a patient survives the thrombosis, in the ensuing days to weeks undergo following four events: • Propagation.Thrombi accumulate additional platelets and fibrin. • Embolization.Thrombi dislodge and travel to other sites in the vasculature. • Dissolution. Dissolution is the result of fibrinolysis, which can lead to the rapid shrinkage and total disappearance of recent thrombi. • Organization and recanalization. Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts. Capillary channels eventually form that reestablish the continuity of the original lumen, albeit to a variable degree. Continued recanalization may convert a thrombus into a smaller mass of connective tissue that becomes incorporated into the vessel wall. Eventually, with remodeling and contraction of the mesenchymal elements, only a fibrous lump may remain to mark the original thrombus. Organized thrombus Occasionally the centers of thrombi undergo enzymatic digestion, presumably as a result of the release of lysosomal enzymes from trapped leukocytes and platelets. In the setting of bacteremia, such thrombi may become infected, producing an inflammatory mass that erodes and weakens the vessel wall. If unchecked, this may result in a mycotic aneurysm. Clinical Features Thrombi come to clinical attention when they obstruct arteries or veins, or give rise to emboli. The clinical presentation depends on the involved site. Venous Thrombosis (Phlebothrombosis); Most venous thrombi occur in the superficial or deep veins of the leg. Superficial venous thrombi typically occur in the saphenous veins in the setting of varicosities. Such thrombi can cause local congestion, swelling, pain, and tenderness, but rarely embolize. The associated edema and impaired venous drainage predispose the overlying skin to the development of infections and ulcers (varicose ulcers). DVT involving one of the large leg veins—at or above the knee (e.g., the popliteal, femoral, and iliac veins)—is more serious because such thrombi more often embolize to the lungs and give rise to pulmonary infarction. Although DVTs may cause local pain and edema due to venous obstruction, these symptoms are often absent due the opening of venous collateral channels. Consequently, DVTs are asymptomatic in approximately 50% of affected individuals and are recognized only in retrospect after embolization. Common predisposing factors include; bed rest and immobilization (because they reduce the milking action of the leg muscles, resulting in stasis), and CHF (also a cause of impaired venous return). Trauma, surgery, and burns not only immobilize a person but are also associated with vascular insults, procoagulant release from injured tissues, increased hepatic synthesis of coagulation factors, and decreased tPA production. Many elements contribute to the thrombotic diathesis of pregnancy, including decreased venous return from leg veins and systemic hypercoagulability associated with the hormonal changes of late pregnancy and the postpartum period. Tumor associated inflammation and coagulation factors (tissue factor, factor VIII), as well as procoagulants (e.g., mucin) released from tumor cells, all contribute to the increased risk of thromboembolism in disseminated cancers, socalled migratory thrombophlebitis or Trousseau syndrome. Advanced age increases the risk of DVT. Arterial and Cardiac Thrombosis;Atherosclerosis is a major cause of arterial thromboses because it is associated with loss of endothelial integrity and with abnormal blood flow. MI can predispose to cardiac mural thrombi by causing dyskinetic myocardial contraction and endocardial injury, and rheumatic heart disease may engender atrial mural thrombi by causing atrial dilation and fibrillation. Both cardiac and aortic mural thrombi are prone to embolization. Although any tissue can be affected, the brain, kidneys, and spleen are particularly likely targets because of their rich blood supply. Disseminated Intravascular Coagulation; DIC is not a specific disease but rather a complication of a large number of conditions associated with systemic activation of thrombin. Disorders ranging from obstetric complications to advanced malignancy can be complicated by DIC, which leads to widespread formation of thrombi in the microcirculation. These microvascular thrombi can cause diffuse circulatory insufficiency and organ dysfunction, particularly of the brain, lungs, heart, and kidneys. DIC uses platelets and coagulation factors (consumptive coagulopathy) and often activates fibrinolytic mechanisms. Thus, symptoms initially related to thrombosis can evolve into a bleeding catastrophe, such as hemorrhagic stroke or hypovolemic shock.