1. Thrombosis Shock 2008

2. Normal hemostasis Thrombosis – factors, morphology Embolism Shock DIC TTP,HUS Doc. MUDr. L. Boudová, Ph. D.

3. Hemostasis  normal vessels maintain blood fluid, clot-free  vessel injury induce rapid localized hemostatic plug Thrombosis inappropriate activation of normal hemostatic processes Vascular wall, platelets, coagulation cascade

4. Endothelium  Normal: antithrombotic 1. Anticoagulant - heparin-like molecules thrombomodulin 2. Antiplatelet – barrier between plt and ECM; PGI2, NO, ADPase 3. Fibrinolytic – t-PA  Injured, activated: prothrombotic 1. Procoagulant – tissue factor 2. Platelets - vWF 3. Antifibrinolytic - PAI

5. Thrombosis Virchow's 3 Alteration of: 1.Vessel wall - endothelial injury - dominant 2.Blood flow- stasis, turbulence 3.Blood – hypercoagulability may combine intravital intravascular clotting

6. 1.Vessel wall – endothelial injury – dominant exposure of subendothelial collagen + adherence of platelets exposure of tissue factor, local depletion of prostacyclin and plasminogen activator Atherosclerosis – ulceration Necrosis – myocardial infarction Trauma Inflammation – vasculitis Hypertension, turbulent flow, bact. endotoxins Homocystein, cholesterol, radiation, smoking

7. 2. Alterations in normal blood flow Normal = laminar Turbulence – arteries, heart; combined turb. + stasis (endot. injury + stasis) Stasis – veins, heart Ulcerated atherosclerotic plaques – endot. +turb. Aneurysms – local stasis Mitral valve stenosis – stasis – left atrial dilation Hyperviscosity syndromes – polycythemia; sickle cell anemia (occlusions stasis; small vessels)

8. 3. Hypercoagulability Primary (genetic) Mutations in factor V = Leiden mutation 2-15% of popul. APC resistance antithrombin III, protein C, S deficiencies fibrinolysis def., hyperhomocysteinemia ↑prothrombin levels - 1%, allelic variations Thrombo(embolism) – recurrent, young, no or insignificant other causes Secondary (acquired) - high risk or low risk Any alteration of coagulation pathway predisposing to thrombosis

9. 3. Hypercoagulability Secondary (acquired) ↑ High risk of thrombosis -immobilization, myoc. infarction, tissue damage (trauma, burns, surgery), cancer, prosthetic cardiac valves, DIC, heparin-induced thrombocytopenia, antiphospholipid antibody syndrome (with/out autoimmune dis. - SLE) ↓Lower risk of thrombosis -atrial fibrillation, cardiomyopathy, nephrotic syndrome, hyperestrogenic states, oral contraceptives (3x), pregnancy (8x), sickle cell anemia, smoking Thrombotic diathesis - often complicated, multifactorial

10. Thrombi - overview of morphology, localisation relationship to the vessel wall, lumen mural OR occlusive; line of attachment localization anywhere - heart (chambers, valves), arteries, veins, capillaries sizes, shapes, components (colours) red, white, mixed (coral), hyaline mechanism arteries, heart: endothelial injury, turbulence veins: stasis

11. Thrombi Localization - detailed Arterial – occlusive; mixed coronary, cerebral, femoral atherosclerosis, vasculitis, trauma Venous – occlusive, long cast; red; 90% legs autopsy dif. dg. postmortem clot Heart – valves – vegetations infective or sterile (rheum., NBTE, SLE) Heart chambers, aneurysms of heart or aorta Mural; infarction; embolisation: brain, kidney, spleen

12. Further fate of thrombi 1. Propagation 2. Dissolution - fibrinolysis 3. Organization and recanalization; fibrosis 4. Enz. digestion Puriform. degen. 5. !Embolization! 6. Calcification 1 235 7. Infection

13. Clinical significance of thrombosis 1.Vascular obstruction (mainly arteries) 2.Source of embolism (mainly veins) Veins: mainly lower extremities Spf.: trophic changes - cong., edem., pain; ulcers Deep: 50% asympt.! thromboembolism! Regardless specific clinical setting:  high age  immobilization ! high risk of venous thrombosis !

14. Embolism a detached intravascular mass - solid, liquid, gaseous carried by the blood to a site distant from its origin Thrombus – 99% Fat Gas Fluid – amniotic; Atherosclerotic debris, tumor fragments, foreign bodies VASCULAR BLOCK (ISCHAEMIA INFARCTION)

15. SOURCE: DEEP LEG VEIN THROMBI ABOVE THE KNEE Clinical manifestation 1. Clin. silent (75%), organization, fibrous bridging web 2. Acute cor pulmonale – sudden death (60% circ.) 3. Pulmonary hemorrhage/infarction 4. Pulmonary hypertension (multiple emb.) Pulmonary thromboembolism Saddle embolus Paradoxical embolism

16. Systemic thromboembolism Emboli travelling in the syst. arterial circulation SOURCE: intracardiac mural thrombi (80%) aort. aneurysms, atherosclerotic plaques, valvular vegetations; paradoxical emboli RECIPIENTS: various legs (75%), brain (10%), intestines, kidneys, spleen, upper extr. CONSEQUENCES: collateral blood supply, tissue vulnerability to ischaemia, size of the occluded vessel MAINLY INFARCTION

17. Fat embolism fractures of long bones, soft tissue trauma, burns 90% of people with severe skeletal injuries only 10% symptomatic sudden onset: tachypnea, dyspnea, tachycardia, neurol. symptoms, petechiae; (thrombo, ery ↓) mechanical and biochemical injury may be lethal HISTOLOGICAL DIAGNOSIS ?

18. Air embolism Gas bubbles Obstetric procedures Dural venous sinuses Neck, chest wall trauma Decompression sickness - nitrogen bubbles focal ischemia: muscles, joints – bends; brain, heart; lungs - RDS (chokes) treatment: compression chamber Chronic decompression sickness – caisson disease persistence of gas emboli – multiple foci of ischemic necrosis(heads of femur, tibia, humerus)

19. Amniotic fluid embolism Rare but ! High mortality Mechanism: amniotic fluid in maternal circulation How: tear in the placental membranes, rupture of uterine veins Mother: lungs: diffuse alveolar damage capillaries: epithelial squamous cells from fetal skin, lanugo hair, fat from vernix caseosa, mucin from fetal respiratory tract and GIT Clinically: sudden; severe dyspnea, cyanosis, hypotension, shock, seizures, coma; pulmonary edema, DIC (thrombogenic substances from amniotic fluid);death

20. SHOCK Systemic hypoperfusion caused by  reduction of cardiac output  effective circulating blood volume hypotension, hypoperfusion, hypoxia Cellular injury: first reversible if persistence of shock - irreversible

21. 1. Cardiogenic – pump failure (intrinsic myoc. cause – IM, ventr. arrhytmias, extrinsic compression – tamponade, outflow obstr.- emb.) 2. Hypovolemic - loss of blood or plasma (hemorrhage, burns, trauma) 3. Septic – systemic microbial infection (G - endotoxic, G +, fungal) 4. Neurogenic – spinal cord injury - VSD 5. Anaphylactic – gener. IgE-med. response, VSD, ↑vascular permeability – ↑vascular bed capacitance SHOCK

22. Pathogenesis of septic shock Most G -, endotoxins – lipopolysaccharides Mononuclear cell activation, cytokines (IL-1, TNF) Isolate microbes, activate immune system, eradicate microbes but also! further aggravation cytokines and secondary mediators: systemic VSD - hypotension,↓myoc. contractility, ↑endothel. injury, RDS, coagulation disorder – DIC multiorgan system failure

23. Stages of shock 1.Nonprogressive – neurohumoral compensatory mechanisms, vital organ perfusion 2.Progressive – tissue hypoperfusion, anaerobic glycolysis, lactate acidosis, VSD, ↓cardiac output, anoxic injury of endothelium, DIC risk; vital organs begin to fail 3.Irreversible – lysosomal enzyme leakage

24. Morphology of shock Hypoxic injury, multiple organ systems Brain - ischemic encephalopathy Heart - coagulation necrosis, hemorrhage Kidneys - acute tubular necrosis Lungs - shock lung (normally resistant to hypoxia) Adrenals - cortical lipid depletion GIT - hemorrhages and necroses Liver - fatty change, central hemorrhagic necrosis

25.  secondary complication of some serious condition  consumption coagulopathy  thrombohemorrhagic diathesis  acute, subacute, chronic Disseminated intravascular coagulation (DIC)

26. activation of coagulation sequence microthrombi - consumption of platelets and clotting factors activation of fibrinolysis secondary

27. DIC Thrombotic and hemorrhagic diathesis Microthrombi infarctions depletion of platelets and clotting factors + secondary activation of fibrinolysis hemorrhages Consequences

28. Mechanisms of DIC trigger 1. Release of tissue factor or thromboplastic substances 2. Widespread endothelial injury

29. DIC 1. obstetrics – 50%; abruptio placentae, retained dead fetus, septic abortion, amniotic fluid embolism, toxemia 2. neoplasms – 30%; adenocarcinomas, AML 3. infections – gram-negative sepsis 4. trauma, burns, extensive surgery 5. other – snakebite, heat stroke, giant hemangioma, aortic aneurysm etc.

30. DIC Morphology microthrombi kidneyshemorrhages lungs brain adrenals placenta CLIN.: microangiopathic hemol. anemia, RDS, neurologic sympt., oliguria, ac. ren. and circul. failure, SHOCK

31. Thrombotic microangiopathies thrombotic thrombocytopenic purpura (TTP) hemolytic-uremic syndrome (HUS) Versus Disseminated intravascular coagulation Common: hyaline thrombi !!Differences: DIC: primary importance: activation of clotting system

32. Thrombotic microangiopathies related clinical syndromes thrombotic thrombocytopenic purpura (TTP) hemolytic-uremic syndrome (HUS) ENDOTHELIAL INJURY WIDESPREAD HYALINE MICROTHROMBI OVERLAP - common features (TTP, HUS): thrombocytopenia microangiopathic hemolytic anemia fever

33. Thrombotic microangiopathies TTP neurological deficits (transient) renal failure adult women ADAMTS 13 defic. HUS mostly no neurol. sympt. acute renal failure DOMINANT! children; E. coli O157:H7, verotoxin Common: thrombocytopenia, microangiopathic hemolytic anemia, fever