Thrombosis Shock 2008. Normal hemostasis Thrombosis – factors, morphology Embolism Shock DIC TTP,HUS Doc. MUDr. L. Boudová, Ph. D.

ThrombosisShock 2008

Normal hemostasisThrombosis – factors, morphologyEmbolismShockDICTTP,HUS

Doc. MUDr. L. Boudová, Ph. D.

Hemostasisnormal vesselsmaintain blood fluid, clot-freevessel injuryinduce rapid localized hemostatic plug

Thrombosisinappropriate activation of normalhemostatic processes

Vascular wall, platelets, coagulation cascade

EndotheliumNormal: antithrombotic1. Anticoagulant - heparin-like moleculesthrombomodulin2. Antiplatelet – barrier between plt and ECM;

PGI2, NO, ADPase3. Fibrinolytic – t-PA

Injured, activated: prothrombotic1. Procoagulant – tissue factor2. Platelets - vWF3. Antifibrinolytic - PAI

ThrombosisVirchow's 3Alteration of:

1. Vessel wall - endothelial injury - dominant

2. Blood flow- stasis, turbulence

3. Blood – hypercoagulability

may combine

intravital intravascularclotting

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

• 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

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, smokingThrombotic diathesis - often complicated, multifactorial

Thrombi - overview of morphology, localisationrelationship to the vessel wall, lumen

mural OR occlusive; line of attachmentlocalization anywhere - heart (chambers, valves), arteries,

veins, capillariessizes, shapes, components (colours)

red, white, mixed (coral), hyalinemechanismarteries, heart: endothelial injury, turbulenceveins: 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 thrombi1. Propagation2. Dissolution - fibrinolysis3. Organization and recanalization; fibrosis4. Enz. digestion Puriform. degen.5. !Embolization!6. Calcification

1

2 35

7. Infection

Clinical significance of thrombosis1. Vascular obstruction (mainly arteries)2. Source of embolism (mainly veins)

Veins: mainly lower extremitiesSpf.: trophic changes - cong., edem., pain; ulcersDeep: 50% asympt.! thromboembolism!

Regardless specific clinical setting: high age immobilization

!high risk of venous thrombosis!

Embolisma 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)

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 embolusParadoxical embolism

Systemic thromboembolismEmboli travelling in the syst. arterial circulation

• SOURCE: intracardiac mural thrombi (80%)aort. aneurysms, atherosclerotic plaques, valvular vegetations; paradoxical emboli

• RECIPIENTS: variouslegs (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, burns90% of people with severe skeletal injuriesonly 10% symptomatic

• sudden onset: tachypnea, dyspnea, tachycardia, neurol. symptoms, petechiae; (thrombo, ery ↓)

• mechanical and biochemical injury• may be lethal

• HISTOLOGICAL DIAGNOSIS ?

Air embolismGas 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 diseasepersistence 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 damagecapillaries: 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

SHOCKSystemic hypoperfusion

caused by reduction of cardiac output effective circulating blood volume

hypotension, hypoperfusion, hypoxia

Cellular injury: first reversible

if persistence of shock - irreversible

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

Pathogenesis of septic shockMost 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

secondary complication

of some serious condition consumption coagulopathy

thrombohemorrhagic diathesis

acute, subacute, chronic

Disseminated intravascular coagulation (DIC)

Disseminated intravascular coagulation (DIC)

activation of coagulation sequence

microthrombi

- consumption of platelets and clotting factors

activation of fibrinolysissecondary

DIC Thrombotic and hemorrhagic diathesis

Microthrombi infarctions

depletion of platelets and clotting factors

+ secondary activation of fibrinolysis

hemorrhages

Consequences

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 microthrombi

• kidneys hemorrhages

• lungs

• brain

• adrenals

• placenta

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

Thrombotic microangiopathiesthrombotic thrombocytopenic purpura (TTP)hemolytic-uremic syndrome (HUS)

VersusDisseminated intravascular coagulation

Common: hyaline thrombi

!!Differences: DIC: primary importance:

activation of clotting system

Thrombotic microangiopathiesrelated clinical syndromesthrombotic 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

neurological deficits (transient)

renal failureadult womenADAMTS 13 defic.

HUS

mostly no neurol. sympt.acute renal failure DOMINANT!children; E. coli O157:H7, verotoxin

Common: thrombocytopenia, microangiopathic hemolytic anemia, fever