Thrombosis Shock 2008

Normal hemostasis Thrombosis factors, morphology Embolism Shock DIC TTP,HUS

Doc. MUDr. L. Boudov, Ph. D.

normal vessels maintain blood fluid, clot-free vessel injury induce rapid localized hemostatic plug

Hemostasis

Thrombosis
inappropriate activation of normal hemostatic processes

Vascular wall, platelets, coagulation cascade

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

Virchow's

Thrombosis

Alteration of: 1. Vessel wall - endothelial injury - dominant 2. Blood flow- stasis, turbulence 3. Blood hypercoagulability may combine

intravital intravascular clotting

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

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)

3. Hypercoagulability
Any alteration of coagulation pathway predisposing to thrombosis 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

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

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

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

Further fate of thrombi

1. Propagation 2. Dissolution - fibrinolysis 3. Organization and recanalization; fibrosis 4. Enz. digestion
Puriform. degen.

5. !Embolization! 6. Calcification 7. Infection

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!

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)

Pulmonary thromboembolism
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.) Saddle embolus Paradoxical embolism

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

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

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)

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

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

SHOCK
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

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

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

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

Disseminated intravascular coagulation (DIC)

secondary complication of some serious condition consumption coagulopathy
thrombohemorrhagic diathesis acute, subacute, chronic

Disseminated intravascular coagulation (DIC)

activation of coagulation sequence microthrombi - consumption of platelets and clotting factors

secondary activation of fibrinolysis

DIC
Thrombotic and hemorrhagic diathesis
Consequences Microthrombi infarctions

depletion of platelets and clotting factors + secondary activation of fibrinolysis

hemorrhages

Mechanisms of DIC trigger

1. Release of tissue factor or thromboplastic substances 2. Widespread endothelial injury

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.

DIC
Morphology kidneys lungs brain adrenals placenta microthrombi hemorrhages

CLIN.: microangiopathic hemol. anemia, RDS, neurologic sympt., oliguria, ac. ren. and circul. failure, SHOCK

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

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

Thrombotic microangiopathies
TTP HUS

Common: thrombocytopenia, microangiopathic hemolytic anemia, fever

neurological deficits (transient) renal failure adult women ADAMTS 13 defic. mostly no neurol. sympt. acute renal failure DOMINANT! children; E. coli O157:H7, verotoxin