Thrombosis
Shock
2008
Normal hemostasis
Thrombosis – factors, morphology
Embolism
Shock
DIC
TTP,HUS
Doc. MUDr. L. Boudová, Ph. D.
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
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
3
Thrombosis
intravital
intravascular
clotting
Alteration of:
1. Vessel wall - endothelial injury - dominant
2. Blood flow- stasis, turbulence
3. Blood – hypercoagulability
may combine
1.
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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
1
Puriform. degen.
5. !Embolization!
6. Calcification
7. Infection
2
5
3
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
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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