Due to ? The above figure in the lung is mostly due to a. Increased capillary hydrostatic pressure b. Tuberculosis of lung c. Lymphatic fibrosis d. Decreased plasma osmotic pressure e. Acute lobar pneumonia Due to ?

Thrombosis Dr. Riham Abu-Zeid Prof. of Pathology

ILOS By the end of the Lecture you will be able to: Define thrombus Differentiate between thrombus and clot Explain the pathogenesis of thrombosis Describe a thrombus List sites of thrombosis Explain the fate of a thrombus Explain clinical effect/outcome of a thrombus

Which one is a thrombus? Test tube with a blood sample -Intact endothelium > blood flow by inhibiting activation of platelets and coagulation factors -Endoth cells (stim by injury or inflamm cytokines)upregulate exp of procoagulant factors and inhibit anticocoagulant factors -Loss of endoth>expose vWF BM collagen >plt adhesion,activation and clot formation Test tube with a blood sample Artery seen during a surgery

Thrombus What? When? Where ? Why? solid mass during life within CVS Mechanism

Thrombus A solid mass formed of blood elements that develops within CVS during life Normal hemostasis is a consequence of tightly regulated processes that maintain blood in a fluid, clot-free state in normal vessels while inducing the rapid formation of a localized hemostatic plug at the site of vascular injury. thrombosis; The pathologic form of hemostasis in uninjured vessels( disturbed flow ) or minor injury. the vascular wall, platelets, and the coagulation cascade NB:Clotting: transformation of soluble fibrinogen into a fibrin network outside body-or after death

Mechanism of thrombus formation 1 Endothelial injury 2 Platelet Adhesion >Platelet Activation> Activation of intrinsic coagulation pathway Concomitantly injured endothelial cells (due to injury/ dysfunction) Tissue factor > Activation of extrinsic coagulation pathway 3 LINES of Zahn Platelets >ridges =Pale areas Between it Fibrin & RBCs & WBCs = red areas

Predisposing Factors for pathogenesis of thrombosis Why does a thrombus happen ? Virchow’s Triad

How does endothelial injury initiate thrombosis?

A. Endothelial injury Tissue factor > Platelet adherence Endothelial damage Exposure of subendoth COLLAGEN & ECM factors Tissue factor > activate extrinsic coagulation pathway Depletion (Local)of Prostacyclin?(prevents adhesion) Plasminogen?(fibrinolytic) Platelet adherence The balance between endothelial anti- and prothrombotic activities determines whether thrombus formation, propagation, or dissolution occurs. At baseline, endothelial cells exhibit antiplatelet, anticoagulant, and fibrinolytic properties; Activated endoth after injury (mech –dysfunction –turbulance) shift occurs and they acquire numerous procoagulant activities Prostacyclin prevents platelet adhesion Plasminogen has fibrinolytic effect PGI2 (prostaglandin I2)>> prevents plt adhesion(anticoagulant) tissue factor>activate extrinsic coag factor Activation of intrinsic coagulation pathway Fibrinogen>fibrin

A. Endothelial injury Endothelial inj. -Exposure of subendothelial collagen -Platelet adherence Tissue factor release Local depletion of Prostacyclin (prevent plt adhesion ) Plasminogen (fibrinolytic) heart :Myocardial infarction arterial :atherosclerosis inflammation trauma Endothelial inj.

How does alteration of blood flow (turbulence /stasis) initiate thrombosis?   turbulance :chaotic property اضطراب

B. Altered blood flow Turbulence Stasis Dilated chambers (M.S) eg . Atherosclerotic plaques sites of bifurcation Stasis Dilated chambers (M.S) Myocardial infarction Varicose Veins Small vessels in polycythemia Stasis also in small vessels in polycythemia disturbed flow Promote Endothelial activation (through flow induced changes in endothelial gene expression Laminar flow : plts and white blood cells are in the center separated from endothelium by slow moving plasma pd to local thrombosis & leuc adhesion

B. Stasis & turbulence Retard inflow of clotting factors inhibitors Mechanism of thrombosis due to stasis/turbulance Retard inflow of clotting factors inhibitors No dilution of clotting factors Disturbed laminar flow> Platelet adhesion inhibitor CF CF CF Endothelial activation No dilution of activated clotting factors by fresh –flowing blood Retard inflow of clotting factors inhibitors…….Permit build up of thrombi

B. Altered blood flow Stasis & turbulence 1-Disturb Laminar flow Platelets come in contact with endothelium 2-Endothelial activation >local thrombosis 3-Prevent dilution of activated clotting factors 4-Retard inflow of clotting factors inhibitors Altered flow Stasis/turbulance

How does hypercoagulability cause thrombosis?

C.Hypercoagulability Any alteration of the coagulation pathway that predispose to thrombosis Genetic Acquired (secondary) Prolonged bed rest Cancer Advanced age Fractures Surgery Burns I. Overactivation of clotting factors (mutation in factor V or prothrombin gene) II. Deficiency of anticoagulants Hypercoagulability is associated with oral contraceptive use and the hyperestrogenic state of pregnancy, probably related to increased hepatic synthesis of coagulation factors and reduced synthesis of antithrombin III. In disseminated cancers, release of procoagulant tumor products predisposes to thrombosis. The hypercoagulability seen with advancing age has been attributed to increasing platelet aggregation and reduced endothelial PGI2 release. (normally inhibits plt adhesion) Smoking and obesity promote hypercoagulability by unknown mechanisms. Surgery and trauma > vascular inj >procagulant release > release of clotting factors from liver

Conditions associated with thrombosis and their pathogenesis Hyperestrogenic states e.g pregnancy &OCP Increased hepatic synthesis of coagulation factors & decrease prothrombin III (anticoagulant) Thrombosis Cardiac Stasis Trauma

Release of pro-coagulant tumor products Cancer Increased platelets aggregation and decrease PGI2 (normally inhibits adhesion) Old age Release of anti-phospholipid antibodies….> induce platelets aggregation inhibit PGI2 dec. protein C (normal anticoagulant) SLE PGI2 release. (normally inhibits plt adhesion) Protein C is normally an anticoagulant

A thrombus is formed of Fibrin and red blood cells Red blood cells and white blood cells Platelets, fibrin threads ,red blood cells and white blood cells Fibrin ,red blood cells and white blood cells

Describe a thrombus (Mixed ) Gross : Intravascular solid mass showing pale strands (laminations) alternating with red areas Usually vein in slow blood Pale and red thrombi

Describe a thrombus Lines of Zhan Microscopic Platelets (pale) Occlusion of the lumen by a mass adherent to the vessel wall. shows pale areas :fused platelets and fibrin perpendicular to wall of blood vessel (lines of Zahn) alternating with dark red areas : entangled red blood cells and WBCs. Q1.In flowing blood Q2 No Platelets (pale) Fibrin ,RBCs, Leucocytes Dark red

Fate of Thrombus Dissolution if small and early Enaymaic degradation by lysosomal enz Dissolution is the result of fibrinolytic activation, which leads to rapid shrinkage and even total lysis of recent thrombi. With older thrombi, extensive fibrin polymerization renders the thrombus substantially more resistant to proteolysis, and lysis is ineffectual. This is clinically significant because therapeutic administration of fibrinolytic agents (e.g., t-PA in the setting of acute coronary thrombosis) is generally effective only within a few hours of thrombus formation. Organization with persistance of on or more capillaries in the fibrosed tissue …..recanaliztion It is result of fibrinolytic activation, which leads to rapid shrinkage and even total lysis of recent thrombi. With older thrombi, extensive fibrin polymerization makes thrombus more resistant to proteolysis Thus therapeutic administration of fibrinolytic agents is effective only within a few hours of thrombus formation -arterial thrombi :retrograde -venous thrombi: extend in the direction of blood flow toward the heart Organization>Ingrowth of endothelial cells –smooth muscles –fibroblasts> contracts restore flow OR organization persistance of one or more capillaries in the fibrosed thrombus Formation of capillary channels>recanalize ; arterial thrombi tend to grow in a retrograde direction from the point of attachment, while venous thrombi extend in the direction of blood flow (thus both tend to propagate toward the heart). The propagating portion of a thrombus tends to be poorly attached and therefore prone to fragmentation, generating an embolus. Dissolution by fibrinolysis ;recent thrombi Calcification (phlebolith) Dislodgement Enzymatic fragmentation

Dissolution by fibrinolysis 2. Embolization 3. Organization 4. Propagation 5. Calcification Organization and recanalization Organization & incorporation into wall

Site Morphology Pale thrombus Red thrombus Rapidly flowing blood (arteries ) Nearly stagnant) blood (adj. to vascular occlusion) Morphology Firm pale Red gelatinous Mainly platelets Few platelets +mainly RBCS,WBCS +Fibrin Red thrombus sometimes indistinguishable from clot Pale in artery : main process is endothelial inj.> more platelet adherence Red thrombi in vein occur dt activity of clotting factors (stasis) plt have secondary role sluggish circ.:allow more RBCs to be trapped result of activation of the coagulation cascade, and platelets play a secondary role. Because these thrombi form in the sluggish venous circulation, they also tend to contain more enmeshed erythrocytes and are therefore called red, or stasis, thrombi. The veins of the lower extremities are most commonly affected (90% of venous thromboses); however, ve Mixed: in slowly flowing blood: veins a red thrombus interrupted by a pale thrombus at site of anastomosis

Where does a thrombus occur? Vein Artery Heart Capillaries All of the above jbArtery or cardiac occurs at site of endoth inj while venous at stasis Veins are most frequent due to: 1. Weak, thin wall (superficial or deep veins) 2. Low pressure & velocity

Sites of thrombi A.Cardiac B.Arterial C.Venous D.Capillary Mural :on mural endocardium Vegetation :on valve _ B.Arterial C.Venous D.Capillary Phlebothrombosis Thrombophlebitis thrombosis in veins without inflammation thrombosis in veins with inflammation Mural Cardiac and arterial more common dt endoth inj –turbulance Venous more dt stasis In the dilated left atrium in mitral stenosis or myocardial infarct , where they may be attached to the wall (mural thrombus ) or are free in the atrial lumen and may plug the mitral valve (ball-valve thrombus). Thrombosis in arteries: at sites of endothelial injury, most commonly due to atheroma (Fig.7.13), turbulence (arterial bifurcation) or stasis (aneurysms). Migratory thrombophlebitis Vegetation

A. Cardiac May be free and plug the valve (ball-valve) Dilated Left atrial mural thrombus in MS Large mural thrombus on top of myocardial infarction May be free and plug the valve (ball-valve) Valvular :These may occur in various forms of endocarditis, and hypercoagulability. Aortic Valve Thrombi=vegetation

B.Arterial Pale at the periphery (old organized part) Lumen is obliterated with a laminated thrombus Pale at the periphery (old organized part) Dark in the center (recent thrombus)

B. Arterial On endoth. injury dt. atheroma Turbulence at bifurcation Stasis as aneurysm Occluding thrombus in small arteries coronary–cerebral

Propagates towards heart c. Venous thrombosis Stasis occurs proximal to occlusion . propagating thrombus end by embolus (to the lung). Extend in direction of blood flow, i.e: toward the heart. 1-Phlebothrombosis Saphenous Varicosities Superficial Popliteal-femoral Bed rest-CHF-trauma –surgery Deep Propagates towards heart

Deep Venous Thrombosis In large leg veins or a above knee veins (popliteal-femoral) Local pain and edema Circumvented ( compensated) by collaterals >50% are silent ie. pass unnoticed Embolize to lung more commonly than superficial vein thrombosis (may be 1st symptom) Swollen, painful, dusky red left lower limb Assoc. with stasis & hypercoagulability states (remember) Can occur in healthy ambulatory people without abnormality Deep venous thrombosis (DVT)

After ionizing radiation c. Venous thrombosis 2-Thrombophlebitis Damage of vein after inflammation ….> thrombosis. Aseptic After ionizing radiation Inflammation …...> thrombosis Septic Septic emboli Pyaemic abscess

3-Migratory Thrombophlebitis (Trousseau’s Syndrome) C.Venous thrombosis 3-Migratory Thrombophlebitis (Trousseau’s Syndrome) = Recurrent attacks of multiple venous thrombosis at different and changing sites: in association with various forms of cancer especially cancer pancreas. Due to release of procoagulant substances by the cancer cells. Multiple thrombosis in superficial and deep veins

D. Capillary Inflammation DIC

Effects of thrombosis Venous Arterial Congestion & Edema distal to obst. Embolize Infarction Pyemic abscess Massive pulm. embolism ischemia eg.coronary/cerebral Infarction/gangrene Embolize as venous Embolize> infarction –pyemic abscess -massive embolism

DIC Obstetric complications Advanced Malignancy Wide spread of fibrin thrombi Circ. insufficiency Consumption of platelets & coagulation proteins Fibrinolytic mechanisms are activated Serious bleeding are not usually visible on gross inspection, they are readily apparent microscopically

Difference between thrombus and clot During life inside CVS Postmortem or outside body In flowing blood Stagnant blood Adherent to vessel wall Not adherent Firm & friable Soft and gelatinous Pale or red(stasis) with pale strands (laminations =platelets) Red (no pale strands) Platelets +fibrin+RBCS+WBCS fibrin+RBCS+WBCS Clotting: transformation of soluble fibrinogen into a fibrin network

Which one is a thrombus a b b (intravascular)

A 55 year old male had a major surgery and has been recombinant in bed for 2 weeks. He has been complaining of pain in his thigh above popliteal fossa with slight hotness Angiogram revealed a thrombus Do you expect to find a it in the veins or the arteries?

State true or false and correct the false statement Vegetation is a thrombus in a vein Stasis retards inflow of clotting factor inhibitors and this contributes in thrombus formation 3. White strands in thrombus are formed of leucocytes 4. Migratory thrombophlebitis is multiple emboli in different sites F T F F

Thrombosis Fate of Thrombosis Effects of thrombosis Pathogenesis Fate of Thrombosis Sites: cardiac , arterial venous, capillary Effects of thrombosis Types of thrombi :Pale /Red