4 hemostasis&thrombosis
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4 hemostasis&thrombosis
- 1. Hemostasis and ThrombosisHemostasis and Thrombosis Dr.CSBR.Prasad, M.D.
- 2. Normal hemostasis is the result of a set of well- regulated processes that accomplish two important functions: (1) They maintain blood in a fluid, clot-free state in normal vessels; and (2) They are poised to induce a rapid and localized hemostatic plug at a site of vascular injury.
- 3. NORMAL HEMOSTASISNORMAL HEMOSTASIS The general sequence of events in hemostasis at the site of vascular injury • There is a brief period of arteriolar vasoconstriction, reflex neurogenic mechanisms and local secretion of factors such as endothelin • Primary hemostasis: Exposure of subendothelial extracellular matrix (ECM) platelets to adhere > activated > release secretory granules > aggregation > Hemostatic plug • Secondary hemostasis: Tissue factor + secreted platelet factors > activate the coagulation cascade > activation of thrombin fibrin clot, resulting in local fibrin deposition. further platelet recruitment and granule release • Activation of counterregulatory mechanisms, t-PA are set into motion to limit the hemostatic plug to the site of injury
- 4. Diagrammatic representation of the normal hemostatic process: A, transient vasoconstriction: B, Platelets adhere to exposed extracellular matrix (ECM) via von Willebrand factor (vWF) and are activated, undergoing a shape change and granule release; released adenosine diphosphate (ADP) and thromboxane A2 (TxA2) lead to further platelet aggregation to form the primary hemostatic plug. C, Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, "cementing" the platelets into a definitive secondary hemostatic plug. D, Counter-regulatory mechanisms, such as release of tissue type plasminogen activator (t-PA) (fibrinolytic) and thrombomodulin (interfering with the coagulation cascade), limit the hemostatic process to the site of injury.
- 5. EndotheliumEndothelium Antithrombotic Properties: Antiplatelet, anticoagulant & fibrinolytic effects Prothrombotic Properties: vWF, TNF, IL1, Antifibrinolytic effects
- 8. The fibrinolytic system The fibrinolytic system, illustrating the plasminogen activators and inhibitors
- 10. Components of Blood • Plasma – proteins, electrolytes and water • Cells – RBCs, WBCs & PLTs
- 11. Definition • Thrombus – a blood clot. • Thrombosis – a pathological process whereby there is formation of a blood clot in uninjured vasculature or after relatively minor injury.
- 13. Definition • Embolus – A detached intravascular solid, liquid or gaseous mass that is carried by the blood to a site distant from its point of origin.
- 14. Dr. Rudolph Virchow 1821-1902 Abnormal Blood Flow Abnormal Vessel Wall Abnormal Blood The Hypercoagulable State •Primary (genetic) •Secondary (acquired) Virchow’s triad
- 16. Endothelial InjuryEndothelial Injury • Dominant factor • Sufficient as the sole factor • Examples include – Myocardial infarction – Ulcerated atheromatous plaques – Hemodynamic injury such as hypertension, turbulent flow over heart valves – Endotoxins, inflammation, etc
- 17. Atherosclerosis involving aorta Normal aorta for comparison
- 33. Thrombosis Venous Deep Vein Thrombosis Pulmonary Embolism Arterial Myocardial Infarction Stroke
- 34. Hemophilia Single Gene Mutation Thrombosis Multigenic + Environmental Factors Genetic Associations and Hemostasis Genetic diagnosis available Genetic therapy feasible Genetic pathogenesis still under investigation Single Gene Disorder
- 35. XII XIIa XI XIa IX IXa X Xa II IIa Fibrinogen Fibrin VIIIa+Ca+Pl Va+Ca+Pl TF / VIIa TFPI IIa/Thrombomodulin interaction Protein C Protein S Protein S Fibrinolysis
- 36. Loss of Function Mutations Natural Anticoagulant Proteins Antithrombin Protein C Protein S 0.02 – 0.2% of General Population 1-3% prevalence in Thrombosis Population Stronger Risk Factors For VTE ~ 10 to 25-fold
- 37. Acquired/Environmental Thrombotic Factors Immobility – Blood stasis Surgery Cancer Pregnancy Oral Contraception Hormone Replacement Therapy
- 38. Abnormal Blood FlowAbnormal Blood Flow • Turbulence in arterial flow as a result of changes in the diameter of the vessel leading to non-laminar flow, resulting in: Platelet coming into contact with endothelium. Prevent dilution by fresh flowing blood of activated clotting factors. Retard inflow of clotting factor inhibitors. Promote endothelial cell activation predisposing to local thrombosis.
- 40. Hypercoagulability • Alteration of the coagulation pathway that predisposes to thrombosis • Higher viscosity of blood changing the flow dynamics of blood
- 41. Primary (Genetic) Common Mutation in factor V gene (factor V Leiden) Mutation in prothrombin gene Mutation in methyltetrahydrofolate gene Rare Antithrombin III deficiency Protein C deficiency Protein S deficiency Very rare Fibrinolysis defects Secondary (Acquired) High risk for thrombosis Prolonged bed rest or immobilization Myocardial infarction Atrial fibrillation Tissue damage (surgery, fracture, burns) Cancer Prosthetic cardiac valves Disseminated intravascular coagulation Heparin-induced thrombocytopenia Antiphospholipid antibody syndrome (lupus anticoagulant syndrome) Lower risk for thrombosis Cardiomyopathy Nephrotic syndrome Hyperestrogenic states (pregnancy) Oral contraceptive use Sickle cell anemia Smoking
- 42. Morphology of thrombusMorphology of thrombus • Thrombi may develop anywhere in the cardiovascular system: within the cardiac chambers; on valve cusps; or in arteries, veins, or capillaries. • They are of variable size and shape • Arterial or cardiac thrombi usually begin at a site of endothelial injury (e.g., atherosclerotic plaque) or turbulence (vessel bifurcation) • Venous thrombi characteristically occur in sites of stasis. • Characteristic of all thromboses – firmly attached at the point of origin • Growth of thrombi: Arterial thrombi – grow in a retrograde direction Venous thrombi - grow in the direction of blood flow • Complication: Embolus.
- 43. • Lines of Zahn • Mural thrombi • Arterial thrombi • Venous thrombosis, or phlebothrombosis • Vegetations
- 44. Aortic aneurysm with thrombus formation – note the Lines of Zahn
- 45. “Lines of Zahn"
- 47. Vegetations in Infective endocarditis involving the aortic valve
- 48. Infected prosthetic valve with vegetations
- 51. ArterialArterial VenousVenous Occlusion of vascular lumen Usually Occlusive Always occlusive Endothelial injury Present May be absent Adhesion to vessel wall Firmly adherent Loosely adherent Colour Grey white red Consistency Friable Firm Site Coronary, cerebral, femoral Lower limbs, dural sinuses, portal vein
- 53. Venous thrombiVenous thrombi VsVs PM clotsPM clots • Postmortem clots are gelatinous • A dark red dependent portion where red cells have settled by gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat; • They are usually not attached to the underlying wall • In contrast, red thrombi are firmer, almost always have a point of attachment, and on transection reveal vague strands of pale gray fibrin.
- 54. VenousVenous thrombusthrombus PM clotPM clot Adhesion to vessel wall Adherent at one point Not adherent Colour Red with pale grey fibrin lines on c/s Red / yellow layers Consistency Firm Gelatinous Site Lower limbs, dural sinuses, portal vein Any where in the body Venous thrombiVenous thrombi VsVs PM clotsPM clots
- 55. Fate of a ThrombusFate of a Thrombus Four events in the ensuing days to weeks: • The thrombus may propagate • The thrombus may become organised and recanalised • The thrombus may become organised and incorporated into the wall of the vessel • The thrombus may be dissolved completely • The thrombus may dislodge and become an embolus or emboli
- 56. Fate of a ThrombusFate of a Thrombus
- 62. Classification of ThrombiClassification of Thrombi • Anatomical – Cardiac – Arterial – Venous – Capillary • Morphological – Pale (platelet thrombus) – Red (RBC thrombus) – Mixed (intermittent layers)
- 63. Thrombosis of the descending aorta extending from the origins of the renal arteries down to the iliac vessels Renal Artery Iliac Artery Thrombus
- 64. A mixed thrombus Red thrombus Pale thrombus
- 65. Venous ThrombosisVenous Thrombosis • Two distinct types – Phlebothrombosis – predisposes to thromboemboli to lungs – Thrombophlebitis – unusual to have associated pulmonary thromboemboli Migratory thrombophlebitis or Trousseau syndrome
- 66. DISSEMINATED INTRAVASCULARDISSEMINATED INTRAVASCULAR COAGULATION (DIC)COAGULATION (DIC) DIC is not a primary disease but rather a potential complication of any condition associated with widespread activation of thrombin It’s a thrombohemorrhagic disorder Thrombin formation is the main mechanism Both platelets and coagulation factors are depleted Lab findings: Low PLT count, >aPTT, >PT, fragmented RBCs in the smear
- 69. Effects of ThrombosisEffects of Thrombosis • Dependent on location and degree of vascular occlusion. • Effects also dependent on the availability of collateral blood supply and susceptibility of area of supply to interruption of blood supply.
- 70. E N D
Notas del editor
- NORMAL HEMOSTASIS The general sequence of events in hemostasis at the site of vascular injury is shown in Figure 4-6 .[2][3] • After initial injury, there is a brief period of arteriolar vasoconstriction, largely attributable to reflex neurogenic mechanisms and augmented by the local secretion of factors such as endothelin (a potent endothelium-derived vasoconstrictor). The effect is transient, however, and bleeding would resume if not for activation of the platelet and coagulation systems (see Fig. 4-6A ). • Endothelial injury exposes highly thrombogenic subendothelial extracellular matrix (ECM), which allows platelets to adhere and become activated, that is, undergo a shape change and release secretory granules. Within minutes, the secreted products have recruited additional platelets (aggregation) to form a hemostatic plug; this is the process of primary hemostasis (see Fig. 4-6B ). • Tissue factor, a membrane-bound procoagulant factor synthesized by endothelium, is also exposed at the site of injury. It acts in conjunction with the secreted platelet factors to activate the coagulation cascade, culminating in the activation of thrombin. In turn, thrombin converts circulating soluble fibrinogen to insoluble fibrin, resulting in local fibrin deposition. Thrombin also induces further platelet recruitment and granule release. This sequence, secondary hemostasis, takes longer than the initial platelet plug (see Fig. 4-6C ). • Polymerized fibrin and platelet aggregates form a solid, permanent plug to prevent any further hemorrhage. At this stage, counterregulatory mechanisms (e.g., tissue plasminogen activator {t-PA}) are set into motion to limit the hemostatic plug to the site of injury (see Fig. 4-6D ).
- Diagrammatic representation of the normal hemostatic process. A, After vascular injury, local neurohumoral factors induce a transient vasoconstriction. B, Platelets adhere to exposed extracellular matrix (ECM) via von Willebrand factor (vWF) and are activated, undergoing a shape change and granule release; released adenosine diphosphate (ADP) and thromboxane A2 (TxA2) lead to further platelet aggregation to form the primary hemostatic plug. C, Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, "cementing" the platelets into a definitive secondary hemostatic plug. D, Counter-regulatory mechanisms, such as release of tissue type plasminogen activator (t-PA) (fibrinolytic) and thrombomodulin (interfering with the coagulation cascade), limit the hemostatic process to the site of injury.
- Schematic illustration of some of the pro- and anticoagulant activities of endothelial cells. Not shown are the pro- and antifibrinolytic properties. vWF, von Willebrand factor; PGI2, prostacyclin; NO, nitric oxide; t-PA, tissue plasminogen activator. Thrombin receptor is referred to as protease activated receptor (PAR; see text). ----------------------------------------------------------------------------------------------- Antithrombotic Properties Under most circumstances, endothelial cells maintain an environment conducive to liquid blood flow by mechanisms that block platelet adhesion and aggregation, interfere with the coagulation cascade, and actively lyse blood clots. • Antiplatelet effects.[5] An intact endothelium prevents platelets and plasma coagulation factors from meeting the highly thrombogenic subendothelial ECM. Nonactivated platelets do not adhere to the endothelium, a property intrinsic to endothelial plasma membrane. Moreover, even if platelets are activated after focal endothelial injury, they are inhibited from adhering to the surrounding uninjured endothelium by endothelial prostacyclin (PGI2) and nitric oxide ( Chapter 2 ). Both mediators are potent vasodilators and inhibitors of platelet aggregation; their synthesis by endothelial cells is stimulated by a number of factors (e.g., thrombin and various cytokines) produced during coagulation. Endothelial cells also express adenosine diphosphatase, which degrades ADP and thereby contributes to the inhibition of platelet aggregation (see below). • Anticoagulant effects. These effects are mediated by membrane-associated heparin-like molecules and by thrombomodulin, a specific thrombin receptor (see Fig. 4-7 ). The heparin-like molecules act indirectly; they are cofactors that interact with antithrombin III to inactivate thrombin, factor Xa, and several other coagulation factors (see below). Thrombomodulin also acts indirectly; it binds to thrombin, converting it from a procoagulant to an anticoagulant capable of activating protein C. Activated protein C, in turn, inhibits clotting by proteolytic cleavage of factors Va and VIIIa; it requires protein S, synthesized by endothelial cells, as a cofactor.[7] Endothelium is also a major synthetic source for tissue factor pathway inhibitor, a cell-surface protein that complexes and inhibits activated tissue factor-factor VIIa and factor Xa molecules.[8] • Fibrinolytic effects. Endothelial cells synthesize tissue-type plasminogen activator (t-PA), promoting fibrinolytic activity to clear fibrin deposits from endothelial surfaces (see Fig. 4-6D ).[9] Prothrombotic Properties While endothelium normally limits blood clotting, it can also become prothrombotic, with activities that affect platelets, coagulation proteins, and the fibrinolytic system. • Platelet effects. Recall that endothelial injury leads to adhesion of platelets to the underlying extracellular matrix; this is facilitated by endothelial production of von Willebrand factor (vWF), an essential cofactor for platelet binding to collagen and other surfaces.[10] It should be noted that vWF is a product of normal endothelium; it is not specifically synthesized after endothelial injury. • Procoagulant effects. Endothelial cells are also induced by bacterial endotoxin or by cytokines (e.g., tumor necrosis factor [TNF] or interleukin-1 [IL-1]) to synthesize tissue factor, which, as we will see, activates the extrinsic clotting cascade.[11] By binding activated factors IXa and Xa, endothelial cells further augment the catalytic activities of these coagulation factors (see below). • Antifibrinolytic effects. Endothelial cells also secrete inhibitors of plasminogen activator (PAIs), which depress fibrinolysis (not shown in Fig. 4-7 ).[12] In summary, intact endothelial cells serve primarily to inhibit platelet adherence and blood clotting. Injury or activation of endothelial cells, however, results in a procoagulant phenotype that augments local clot formation.
- Figure 4-8 Platelet adhesion and aggregation. von Willebrand factor functions as an adhesion bridge between subendothelial collagen and the GpIb platelet receptor complex (the functional complex is composed of GpIb in association with factors V and IX). Aggregation involves linking platelets via fibrinogen bridges bound to the platelet GpIIb-IIIa receptors. ---------------------------------------------------------------------- After vascular injury, platelets encounter ECM constituents that are normally sequestered beneath an intact endothelium; these include collagen (most important), proteoglycans, fibronectin, and other adhesive glycoproteins. On contact with ECM, platelets undergo three general reactions: (1) adhesion and shape change; (2) secretion (release reaction); and (3) aggregation (see Fig. 4-6B ). • Platelet adhesion to extracellular matrix is mediated largely via interactions with vWF, which acts as a bridge between platelet surface receptors (e.g., glycoprotein Ib, complexed with serum factors V and IX) and exposed collagen ( Fig. 4-8 ). Although platelets can also adhere to other components of the ECM (e.g., fibronectin), vWF-glycoprotein Ib associations are the only interactions sufficiently strong to overcome the high shear forces of flowing blood. Thus, genetic deficiencies of vWF (von Willebrand disease; Chapter 13 ) or of its glycoprotein Ib (GpIb) receptor (Bernard-Soulier syndrome) result in defective platelet adhesion and bleeding disorders. • Secretion (release reaction) of the contents of both granule types occurs soon after adhesion. The process is initiated by the binding of agonists to platelet surface receptors followed by an intracellular protein phosphorylation cascade. The release of the dense body contents is especially important because calcium is required in the coagulation cascade, and ADP is a potent mediator of platelet aggregation (platelets adhering to other platelets; see below). ADP also augments further ADP release from other platelets. Finally, platelet activation leads to the surface expression of phospholipid complexes, which provide critical nucleation and binding sites for calcium and coagulation factors in the intrinsic clotting pathway [14] (see below). • Platelet aggregation follows adhesion and secretion. Besides ADP, the vasoconstrictor thromboxane A2 (TxA2) ( Chapter 2 ), secreted by platelets, is also an important stimulus for platelet aggregation. ADP and TxA2 set up an autocatalytic reaction leading to build-up of an enlarging platelet aggregate, the primary hemostatic plug. This primary aggregation is reversible, but with activation of the coagulation cascade, thrombin is generated. Thrombin binds to a platelet surface receptor (PARs, see later) and, along with ADP and TxA2, causes further aggregation. This is followed by platelet contraction, creating an irreversibly fused mass of platelets (viscous metamorphosis) constituting the definitive secondary hemostatic plug. At the same time, thrombin converts fibrinogen to fibrin within and about the platelet plug, essentially cementing the platelets in place (see below). Thrombin is thus central in the formation of thrombi ( Fig. 4-6C ) and, as such, is a major target for therapeutic modulation of the thrombotic process.[15] Noncleaved fibrinogen is also an important cofactor in platelet aggregation. ADP activation of platelets induces a conformational change of the platelet surface GpIIb-IIIa receptors so that they can bind fibrinogen. Fibrinogen then acts to connect multiple platelets together to form large aggregates (see Fig. 4-8 ). The importance of these interactions is demonstrated by the bleeding disorder seen in patients with congenitally deficient or inactive GpIIb-IIIa (Glanzmann thrombasthenia).[16] Recent therapeutic advances have also taken advantage of this interaction; small molecular weight GpIIb-IIIa inhibitors are being increasingly employed as potent anticoagulants and to prevent thrombosis following vascular procedures (e.g., angioplasty).[17] It is worth reiterating that the endothelium-derived PGI2 is a potent vasodilator and inhibits platelet aggregation, whereas the platelet-derived TxA2 is a potent vasoconstrictor and activates platelet aggregation (see also Chapter 2 ). The interplay of PGI2 and TxA2 constitutes an exquisitely balanced mechanism for modulating human platelet function: In the normal state, it prevents intravascular platelet aggregation, but after endothelial injury, it favors the formation of hemostatic plugs. The clinical utility of aspirin in patients at risk for coronary thrombosis—aspirin irreversibly acetylates and inactivates cyclooxygenase—is largely due to its ability to block TxA2 synthesis. Nitric oxide, similar to PGI2, also acts as a vasodilator and inhibitor of platelet aggregation (see Fig. 4-7 ). Both erythrocytes and leukocytes are also found in hemostatic plugs; leukocytes adhere to platelets via the adhesion molecule P-selectin and to endothelium using a number of adhesion receptors ( Chapter 2 ); they contribute to the inflammatory response that accompanies thrombosis. Thrombin also directly stimulates neutrophil and monocyte adhesion and generates chemotactic fibrin split products from the cleavage of fibrinogen. The series of platelet events can be summarized as follows (see Fig. 4-6 ): • Platelets adhere to ECM at sites of endothelial injury and become activated. • On activation, they secrete granule products (e.g., ADP) and synthesize TxA2. • Platelets also expose phospholipid complexes that are important in the intrinsic coagulation pathway. • Injured or activated endothelial cells expose tissue factor, which triggers the extrinsic coagulation cascade. • Released ADP stimulates the formation of a primary hemostatic plug, which is eventually converted (via ADP, thrombin, and TxA2) into a larger, definitive, secondary plug. • Fibrin deposition stabilizes and anchors the aggregated platelets.
- Figure 4-9 The coagulation cascade. Note the common link between the intrinsic and extrinsic pathways at the level of factor IX activation. Factors in red boxes represent inactive molecules; activated factors are indicated with a lower case "a" and a green box. PL, phospholipid surface; HMWK, high-molecular-weight kininogen. Not shown are the anticoagulant inhibitory pathways (see Fig. 4-7 and Fig. 4-12 ). --------------------------------------------------------------------------------------------------------- Traditionally, the blood coagulation scheme has been divided into extrinsic and intrinsic pathways, converging where factor X is activated (see Fig. 4-9 ). The intrinsic pathway may be initiated in vitro by the activation of Hageman factor (factor XII), while the extrinsic pathway is activated by tissue factor, a cellular lipoprotein exposed at sites of tissue injury.[8][19] However, such a division is mainly an artifact of in vitro testing; there are, in fact, interconnections between the two pathways. For example, a tissue factor-factor VIIa complex also activates factor IX in the intrinsic pathway (see Fig. 4-9 ). --------------------------------------------------------------------------
- Once activated, the coagulation cascade must be restricted to the local site of vascular injury to prevent clotting of the entire vascular tree. Besides restricting factor activation to sites of exposed phospholipids, clotting is also regulated by three types of natural anticoagulants: • Antithrombins (e.g., antithrombin III) inhibit the activity of thrombin and other serine proteases—factors IXa, Xa, XIa, and XIIa. Antithrombin III is activated by binding to heparin-like molecules on endothelial cells; hence the clinical usefulness of administering heparin to minimize thrombosis (see Fig. 4-7 ). • Proteins C and S, two vitamin K-dependent proteins, are characterized by their ability to inactivate factors Va and VIIIa. The activation of protein C by thrombomodulin was described earlier (see Fig. 4-7 ). • Tissue factor pathway inhibitor (TFPI), a protein secreted by endothelium (and other cell types), complexes to factor Xa and to tissue factor-VIIa and inactivates them to rapidly limit coagulation[21](see Fig. 4-7 ). Besides inducing coagulation, activation of the clotting cascade also sets into motion a fibrinolytic cascade that limits the size of the final clot. This is primarily accomplished by the generation of plasmin. Plasmin is derived from enzymatic breakdown of its inactive circulating precursor plasminogen, either by a factor XII-dependent pathway (see Chapter 2 ) or by two distinct types of plasminogen activators (PAs; Fig. 4-12 ). The first is the urokinase-like PA (u-PA), present in plasma and various tissues and capable of activating plasminogen in the fluid phase. Plasmin, in turn, converts the inactive pro-urokinase precursor to the active u-PA molecule, thus creating an amplification loop. The second, and physiologically the most important, kind of PA is the tissue-type PA; t-PA is synthesized principally by endothelial cells and is most active when attached to fibrin. The affinity for fibrin makes t-PA a much more useful therapeutic reagent, because it targets the fibrinolytic enzymatic activity to sites of recent clotting.[9] Plasminogen can also be activated by the bacterial product streptokinase, which may have some significance in certain bacterial infections. Plasmin breaks down fibrin and interferes with its polymerization ( Fig. 4-12 ). The resulting fibrin split products (FSPs or so-called fibrin degradation products) can also act as weak anticoagulants. Elevated levels of FSPs (the fibrin split product characteristically measured by clinical laboratories is the fibrin D-dimer) are helpful in diagnosing abnormal thrombotic states, such as disseminated intravascular coagulation (DIC), deep venous thrombosis, or pulmonary thromboembolism (described in detail later). Any free plasmin rapidly complexes to α2-plasmin inhibitor and is inactivated.
- Endothelial Injury. This is the dominant influence; endothelial injury by itself can lead to thrombosis. It is particularly important for thrombus formation occurring in the heart or in the arterial circulation, where the normally high flow rates might otherwise hamper clotting by preventing platelet adhesion or diluting coagulation factors. Thus, thrombus formation within the cardiac chambers (e.g., following endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely due to endothelial injury. Clearly, physical loss of endothelium will lead to exposure of subendothelial ECM, adhesion of platelets, release of tissue factor, and local depletion of PGI2 and PAs. However, it is important to note that endothelium need not be denuded or physically disrupted to contribute to the development of thrombosis; any perturbation in the dynamic balance of the pro- and antithrombotic effects of endothelium can influence local clotting events (see Fig. 4-7 ). Thus, dysfunctional endothelium may elaborate greater amounts of procoagulant factors (e.g., platelet adhesion molecules, tissue factor, PAI) or may synthesize less anticoagulant effectors (e.g., thrombomodulin, PGI2, t-PA). Significant endothelial dysfunction (in the absence of endothelial cell loss) may occur due to the hemodynamic stresses of hypertension, turbulent flow over scarred valves, or bacterial endotoxins. Even relatively subtle influences, such as homocystinuria, hypercholesterolemia, radiation, or products absorbed from cigarette smoke may initiate endothelial injury.
- This is a case of polyarteritis nodosa (PAN) seen in dermis at low magnification.
- This is a case of polyarteritis nodosa (PAN) seen in dermis at high power. Note that in this case the inflammation is more acute and that there are neutrophils with leukocytoclasis.
- Acute Thrombophlebitis (48000-41000)This slide shows a vessel with thrombosis and acute inflammation of the vessel wall. In this low power view, note the thrombus in the lumen and the infiltrate in the wall.
- Acute Thrombophlebitis (48000-41000)This higher power view demonstrates that the thrombus is attached to the wall and the inflammatory infiltrate is predominantly neutrophilic. The major predisposing factors to the development of thrombosis are hypercoagulable states, stasis, and endothelial damage. Many cases of phlebothrombosis (thrombus in a vein) show only thrombus in the vessel lumen, but thrombosis in a vein may be accompanied by inflammatory changes in the vessel wall (thrombophlebitis). The chief clinical danger associated with venous thrombosis is embolization.
- The main components associated with the formation of a platelet plug at the site of vascular injury – vWF (von Willebrand Factor); ADP adenosine diphosphate, Factor PDGF platelet-derived growth factor; GP glycoprotein; 5 HT serotonin (5-hydroxytryptamine)
- The main components of the coagulation cascade: The terms used in this figure are explained in the text
- Regulatory mechanisms in thrombus formation: Factors are deposited on healthy endothelium adjacent to a damaged area where thrombus has formed; these factors limit the spread of the thrombus. PC protein C; PS protein S; Pl platelet; T thrombin; TM thrombomodulin; 'a' denotes the factor is in an activated form
- Alterations in Normal Blood Flow. Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction as well as by forming countercurrents and local pockets of stasis; stasis is a major factor in the development of venous thrombi.[5][22] Normal blood flow is laminar such that the platelets flow centrally in the vessel lumen, separated from the endothelium by a slower-moving clear zone of plasma. Stasis and turbulence therefore (1) disrupt laminar flow and bring platelets into contact with the endothelium; (2) prevent dilution of activated clotting factors by fresh flowing blood; (3) retard the inflow of clotting factor inhibitors and permit the build-up of thrombi; and (4) promote endothelial cell activation, predisposing to local thrombosis, leukocyte adhesion, and a variety of other endothelial cell effects.[23] Turbulence and stasis clearly contribute to thrombosis in a number of clinical settings. Ulcerated atherosclerotic plaques not only expose subendothelial ECM, but are also sources of turbulence. Abnormal aortic and arterial dilations called aneurysms cause local stasis and are favored sites of thrombosis ( Chapter 12 ). Myocardial infarctions not only have associated endothelial injury, but also have regions of noncontractile myocardium, adding an element of stasis in the formation of mural thrombi. Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation. In conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and a prime location for thrombus development. Hyperviscosity syndromes (such as polycythemia; Chapter 13 ) cause small vessel stasis; the deformed red cells in sickle cell anemia ( Chapter 13 ) cause vascular occlusions, with the resulting stasis predisposing to thrombosis.
- Of the inherited causes of hypercoagulability, mutations in the factor V gene and prothrombin gene are the most common. Approximately 2% to 15% of Caucasians carry a specific factor V mutation (called the Leiden mutation, after the city in the Netherlands where it was discovered), substituting a glutamine for the normal arginine residue at position 506 and rendering the protein resistant to cleavage by protein C. Such resistance to protein C-mediated inactivation of factor Va promotes unchecked coagulation (see Fig. 4-7 ). Among patients with recurrent deep venous thrombosis, the carrier frequency is considerably higher, approaching 60% in some series. A single nucleotide change (G to A transition) in the 3'-untranslated region of the prothrombin gene is a fairly common allele (1% to 2% of the population) that is associated with elevated prothrombin levels and an almost threefold increased risk of venous thromboses.[27][28] Elevated levels of homocysteine contribute to arterial and venous thrombosis and indeed to the development of atherosclerosis, as is discussed in Chapter 11 . This effect is most likely due to inhibition of antithrombin III and endothelial thrombomodulin.[26] Hyperhomocystenemia may be inherited or acquired. Homozygosity for the C677T mutation in the methyltetrahydrofolate reductase gene causes mild homocystenemia in 5% to 15% of white and East Asian populations, thus matching the frequency of factor V Leiden. However, the relationship between the C677T mutation and thrombosis is less well established.[24] In addition to these well characterized point mutations, polymorphisms in coagulant factor genes also appear to impart an increased risk of venous thrombosis.[29] Other, less common, primary hypercoagulable states include inherited deficiencies of anticoagulants such as antithrombin III, protein C, or protein S; affected individuals typically present with venous thrombosis and recurrent thromboembolism in adolescence or early adult life. Although individually these inherited disorders are uncommon, collectively they are significant for two reasons. First, the mutations underlying these inherited thrombophilias may be co-inherited, and the effect of having two mutations on the risk of thrombosis is much more than additive.[24] Second, those with such mutations have a much higher risk than normal individuals of developing venous thrombosis when acquired causes of hypercoagulability, such as pregnancy, are also present. Inherited causes of hypercoagulability must be considered in patients under the age of 50 who present with thrombosis in the absence of any acquired predisposition. Unlike these uncommon hereditary disorders, the pathogenesis of the acquired thrombotic diatheses in a number of common clinical settings (see Table 4-2 ) is more complicated and multifactorial. In some situations (e.g., cardiac failure or trauma), factors such as stasis or vascular injury may be most important. In other cases (e.g., oral contraceptive use and the hyperestrogenic state of pregnancy), hypercoagulability may be partly caused by increased hepatic synthesis of many coagulation factors and reduced synthesis of antithrombin III;[30] heterozygosity for factor V Leiden may also be an underlying contributory component. In disseminated cancers, release of procoagulant tumor products predisposes to thrombosis.[31][32] The hypercoagulability seen with advancing age may be due to increased susceptibility to platelet aggregation and reduced PGI2 release by endothelium. Smoking and obesity promote hypercoagulability by unknown mechanisms. Among the acquired causes of thrombotic diatheses, the so-called heparin-induced thrombocytopenia syndrome and antiphospholipid antibody syndrome (previously called the lupus anticoagulant syndrome) deserve special mention. Heparin-induced thrombocytopenia syndrome. [33][34] Seen in upward of 5% of the population, this syndrome occurs when administration of unfractionated heparin (for purposes of therapeutic anticoagulation) induces formation of antibodies that bind to molecular complexes of heparin and platelet factor 4 membrane protein. This antibody can also bind to similar complexes present on platelet and endothelial surfaces; the result is platelet activation, endothelial injury, and a prothrombotic state. To reduce this problem, specially manufactured low-molecular-weight heparin preparations—which retain anticoagulant activity but do not interact with platelets—are used. These have the additional benefit of a prolonged serum half-life. Antiphospholipid antibody syndrome. [35][36] This syndrome has protean clinical presentations, including multiple thromboses; the clinical manifestations are associated with high titers of circulating antibodies directed against anionic phospholipids (e.g., cardiolipin) or, more accurately, against plasma protein epitopes that are unveiled by binding to such phospholipids (e.g., prothrombin). Patients with anticardiolipin antibodies also have a false-positive serologic test for syphilis because the antigen in the standard tests is embedded in cardiolipin. In vitro these antibodies interfere with the assembly of phospholipid complexes and thus inhibit coagulation. However, in vivo, the antibodies induce a hypercoagulable state. Patients with antiphospholipid antibody syndrome fall into two categories. Many have a well-defined autoimmune disease, such as systemic lupus erythematosus ( Chapter 6 ) and have secondary antiphospholipid syndrome (such patients previously carried the designation of lupus anticoagulant syndrome). The remainder show no evidence of other autoimmune disorder and exhibit only the manifestations of a hypercoagulable state (primary antiphospholipid syndrome). Occasionally the syndrome can occur in association with certain drugs or infections. How antiphospholipid antibodies lead to hypercoagulability is not clear, but possible explanations include direct platelet activation, inhibition of PGI2 production by endothelial cells, or interference with protein C synthesis or activity. Although antiphospholipid antibodies are associated with thrombotic diatheses, they have also been identified in 5% to 15% of apparently normal individuals and may therefore be necessary but not sufficient to cause full-blown antiphospholipid antibody syndrome. Individuals with the antiphospholipid antibody syndrome present with an extreme variety of clinical manifestations; these are typically characterized by recurrent venous or arterial thrombi but also include repeated miscarriages, cardiac valvular vegetations, or thrombocytopenia.[37] Venous thromboses occur most commonly in deep leg veins, but renal, hepatic, and retinal veins are also susceptible. Arterial thromboses typically occur in the cerebral circulation, but coronary, mesenteric, and renal arterial occlusions have also been described. Depending on the vascular bed involved, the clinical presentations can vary from pulmonary embolism (due to a lower extremity venous thrombus), to pulmonary hypertension (from recurrent subclinical pulmonary emboli), to stroke, bowel infarction, or renovascular hypertension. Fetal loss is attributable to antibody-mediated inhibition of t-PA activity necessary for trophoblastic invasion of the uterus. Antiphospholipid antibody syndrome is also a cause of renal microangiopathy, resulting in renal failure owing to multiple capillary and arterial thromboses ( Chapter 20 ). Patients with antiphospholipid antibody syndrome are at increased risk of a fatal event (upward of 7% in one series of patients with lupus erythematosus, particularly with arterial thromboses or thrombocytopenia). Current treatment includes anticoagulation therapy (aspirin, heparin, and warfarin) and immunosuppression in refractory cases.[35][37][38]
- Thrombi may develop anywhere in the cardiovascular system: within the cardiac chambers; on valve cusps; or in arteries, veins, or capillaries. They are of variable size and shape, depending on the site of origin and the circumstances leading to their development. Arterial or cardiac thrombi usually begin at a site of endothelial injury (e.g., atherosclerotic plaque) or turbulence (vessel bifurcation); venous thrombi characteristically occur in sites of stasis. An area of attachment to the underlying vessel or heart wall, frequently firmest at the point of origin, is characteristic of all thromboses. Arterial thrombi tend to grow in a retrograde direction from the point of attachment, whereas venous thrombi extend in the direction of blood flow (i.e., toward the heart). The propagating tail may not be well attached and, particularly in veins, is prone to fragmentation, creating an embolus.
- When formed in the heart or aorta, thrombi may have grossly (and microscopically) apparent laminations, called lines of Zahn; these are produced by alternating pale layers of platelets admixed with some fibrin and darker layers containing more red cells. Lines of Zahn are significant only in that they imply thrombosis at a site of blood flow; in veins or in smaller arteries, the laminations are typically not as apparent, and, in fact, thrombi formed in the sluggish flow of venous blood usually resemble statically coagulated blood (similar to blood clotted in a test tube). Nevertheless, careful evaluation generally reveals irregular, somewhat ill-defined laminations. When arterial thrombi arise in heart chambers or in the aortic lumen, they usually adhere to the wall of the underlying structure and are termed mural thrombi. Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) leads to cardiac mural thrombi ( Fig. 4-14A ), while ulcerated atherosclerotic plaque and aneurysmal dilation are the precursors of aortic thrombus formation ( Fig. 4-14B ). Arterial thrombi are usually occlusive; the most common sites, in descending order, are coronary, cerebral, and femoral arteries. The thrombus is usually superimposed on an atherosclerotic plaque, although other forms of vascular injury (vasculitis, trauma) may be involved. The thrombi are typically firmly adherent to the injured arterial wall and are gray-white and friable, composed of a tangled mesh of platelets, fibrin, erythrocytes, and degenerating leukocytes. Venous thrombosis, or phlebothrombosis, is almost invariably occlusive; the thrombus often creates a long cast of the vein lumen. Because these thrombi form in a relatively static environment, they tend to contain more enmeshed erythrocytes and are therefore known as red, or stasis, thrombi. Phlebothrombosis most commonly affects the veins of the lower extremities (90% of cases). Less commonly, venous thrombi may develop in the upper extremities, periprostatic plexus, or the ovarian and periuterine veins; under special circumstances, they may be found in the dural sinuses, the portal vein, or the hepatic vein. At autopsy, postmortem clots may be confused for venous thrombi. Postmortem clots are gelatinous with a dark red dependent portion where red cells have settled by gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat; they are usually not attached to the underlying wall. In contrast, red thrombi are firmer, almost always have a point of attachment, and on transection reveal vague strands of pale gray fibrin. Under special circumstances, thrombi may form on heart valves. Bacterial or fungal blood-borne infections may establish a foothold, leading to valve damage and the development of large thrombotic masses, or vegetations (infective endocarditis; Chapter 12 ). Sterile vegetations can also develop on noninfected valves in patients with hypercoagulable states, so-called nonbacterial thrombotic endocarditis ( Chapter 12 ). Less commonly, noninfective, verrucous (Libman-Sacks) endocarditis attributable to elevated levels of circulating immune complexes may occur in patients with systemic lupus erythematosus ( Chapter 6 ).
- These are "lines of Zahn" which are the alternating pale pink bands of platelets with fibrin and red bands of RBC's forming a true thrombus
- A large mobile thrombus within the right atrium which sometimes prolapsed through the tricuspid valve into the right ventricle.
- Fate of the Thrombus. If a patient survives the immediate effects of a thrombotic vascular obstruction, thrombi undergo some combination of the following four events in the ensuing days to weeks ( Fig. 4-15 ): • Propagation. The thrombus may accumulate more platelets and fibrin (propagate), eventually leading to vessel obstruction. • Embolization. Thrombi may dislodge and travel to other sites in the vasculature. • Dissolution. Thrombi may be removed by fibrinolytic activity. • Organization and recanalization. Thrombi may induce inflammation and fibrosis (organization) and may eventually become recanalized; that is, may reestablish vascular flow, or may be incorporated into a thickened vascular wall.
- This section of coronary artery demonstrates remote thrombosis with recanalization to leave only two small, narrow channels.
- A small clot may break off from a larger thrombus and be carried to other places in the bloodstream. When the embolus reaches an artery too narrow to pass through and becomes lodged, blood flow distal to the fragment ceases, resulting in infarction of distal brain tissue due to lack of nutrients and oxygen. As a cause of stroke, embolism accounts for approximately 32% of cases.
- Venous Thrombosis (Phlebothrombosis). The great preponderance of venous thrombi occur in either the superficial or the deep veins of the leg.[39] Superficial venous thrombi usually occur in the saphenous system, particularly when there are varicosities. Such thrombi may cause local congestion, and swelling, pain, and tenderness along the course of the involved vein but rarely embolize. Nevertheless, the local edema and impaired venous drainage do predispose the involved overlying skin to infections from slight trauma and to the development of varicose ulcers. Deep thrombi in the larger leg veins at or above the knee (e.g., popliteal, femoral, and iliac veins) are more serious because they may embolize. Although they may cause local pain and distal edema, the venous obstruction may be rapidly offset by collateral bypass channels. Consequently, deep vein thromboses are entirely asymptomatic in approximately 50% of affected patients and are recognized only in retrospect after they have embolized. Deep venous thrombosis may occur with stasis and in a variety of hypercoagulable states as described earlier ( Table 4-2 ). Cardiac failure is an obvious reason for stasis in the venous circulation. Trauma, surgery, and burns usually result in reduced physical activity, injury to vessels, release of procoagulant substances from tissues, and/or reduced t-PA activity. Many factors act in concert to predispose to thrombosis in the puerperal and postpartum states. Besides the potential for amniotic fluid infusion into the circulation at the time of delivery, late pregnancy and the postpartum period are also associated with hypercoagulability. Tumor-associated procoagulant release is largely responsible for the increased risk of thromboembolic phenomena seen in disseminated cancers, so-called migratory thrombophlebitis or Trousseau syndrome. Regardless of the specific clinical setting, advanced age, bed rest, and immobilization increase the risk of deep venous thrombosis, particularly in those who have inherited susceptibility states ( Table 4-2 ); reduced physical activity diminishes the milking action of muscles in the lower leg and so slows venous return.