Thrombosis 13 10-2016

HemostasisHemostasis& &

ThrombosisThrombosis

Dr.Vaishali,AP Dr.Vaishali,AP

ObjectsObjects Normal hemostasisNormal hemostasis Virchow’s Triad-pathogenesis of Virchow’s Triad-pathogenesis of

thrombosisthrombosis Arterial vs Venous thrombi Arterial vs Venous thrombi Complications of thrombosisComplications of thrombosis Fate Fate Difference between antemortum and Difference between antemortum and

postmortem clotpostmortem clot DICDIC

Hemostasis Hemostasis Normal hemostasis- 2 important functionsNormal hemostasis- 2 important functions

- Maintain blood in a fluid, clot-free state - Maintain blood in a fluid, clot-free state in normal vesselsin normal vessels

- - Rapid and localized hemostatic plugRapid and localized hemostatic plug at at site of vascular injurysite of vascular injury

Sequence of events in primary Sequence of events in primary hemostasis hemostasis

Vascular injuryVascular injury ↓ ↓ Vasoconstriction (endothelin)Vasoconstriction (endothelin) ↓ ↓

Platelets activation following adhesion to ECM via von Willebrand Platelets activation following adhesion to ECM via von Willebrand factor (vWF)factor (vWF)

↓ ↓

ADP and TxA2 releaseADP and TxA2 release

↓ ↓

Further platelet aggregationFurther platelet aggregation ↓ ↓

Primary hemostatic plug. Primary hemostatic plug.

Local activation of the coagulation cascade Local activation of the coagulation cascade (involving Tissue factor and platelet PL)(involving Tissue factor and platelet PL)

↓ ↓ Fibrinogen → FibrinFibrinogen → Fibrin ThrombinThrombin

Fibrin polymerization + Platelet Fibrin polymerization + Platelet recruitmentrecruitment

↓ ↓

Secondary hemostatic plug Secondary hemostatic plug

EndotheliumEndotheliumAnti- thromboticAnti- thrombotic Pro- thromboticPro- thrombotic1.1. Antiplatelet- Antiplatelet-

PGI2,NO,PGI2,NO,Ad. diphosphataseAd. diphosphatase

ECMECM

2. Anticoagulant-2. Anticoagulant-Heparin- like Heparin- like molecule& molecule& thrombomodulinthrombomodulin

Tissue factorTissue factor

3. Fibrinolytic- t- PA3. Fibrinolytic- t- PA Antifibrinolytic- PAIAntifibrinolytic- PAI

tt

PlateletsPlatelets

2 types of granules- alpha granules2 types of granules- alpha granules - dense (delta) granules- dense (delta) granules

On contact with ECM- 3 general reactions On contact with ECM- 3 general reactions – Platelet adhesion: vWF-GpIb– Platelet adhesion: vWF-GpIb

- Platelet secretion- Platelet secretion - Platelet aggregation: ADP, TxA2- Platelet aggregation: ADP, TxA2

Coagulation cascadeCoagulation cascadeSeries of enzymatic conversions by which Series of enzymatic conversions by which

inactive proenzymes are activated and inactive proenzymes are activated and the end result is formation of thrombin the end result is formation of thrombin

ExtrinsicExtrinsic and and intrinsicintrinsic pathways converge pathways converge where factor X is activated where factor X is activated

Central roles of thrombin in Central roles of thrombin in hemostasishemostasis

- - Generating cross-linked fibrin Generating cross-linked fibrin - Directly induces platelet aggregation and - Directly induces platelet aggregation and

secretionsecretion

- Activates endothelium - Activates endothelium

- Mononuclear inflammatory cells may be - Mononuclear inflammatory cells may be activated by the direct actions of thrombin activated by the direct actions of thrombin

Fibrinolytic cascadeFibrinolytic cascade -- limits the size of the final clot limits the size of the final clot

- primarily accomplished by the primarily accomplished by the generation of generation of plasminplasmin

- fibrin fibrin D-dimerD-dimer are helpful in diagnosing are helpful in diagnosing abnormal thrombotic state- DIC, DVT / abnormal thrombotic state- DIC, DVT / pulmonary thromboembolism pulmonary thromboembolism

THROMBOSISTHROMBOSIS

ThrombosisThrombosis Pathologic opposite to hemostasisPathologic opposite to hemostasis

Inappropriate activation of normal hemostatic Inappropriate activation of normal hemostatic processesprocesses

Both hemostasis and thrombosis are regulated Both hemostasis and thrombosis are regulated by 3 componentsby 3 components

- The - The vascular wallvascular wall- Platelets- Platelets- Coagulation cascade- Coagulation cascade

PathogenesisPathogenesisPredisposing factors for thrombus formationPredisposing factors for thrombus formation Virchow triadVirchow triad: : (1) Endothelial injury(1) Endothelial injury

(2) Stasis or turbulence of blood flow (2) Stasis or turbulence of blood flow

(3) Blood hypercoagulability (3) Blood hypercoagulability

Endothelial InjuryEndothelial Injury

- Significant in heart or in the arterial - Significant in heart or in the arterial circulation (high flow rates)circulation (high flow rates)

- Cardiac chambers ( following endocardial - Cardiac chambers ( following endocardial

injury due to MI )injury due to MI ) - Over ulcerated plaques in atherosclerotic - Over ulcerated plaques in atherosclerotic

arteriesarteries - At sites of traumatic or inflammatory - At sites of traumatic or inflammatory

vascular injury vascular injury (vasculitis)(vasculitis)

Alterations in Normal Blood FlowAlterations in Normal Blood Flow.. TurbulenceTurbulence - Arterial and cardiac - Arterial and cardiac

thrombosis thrombosis StasisStasis - Venous thrombi - Venous thrombi Stasis and turbulence Stasis and turbulence - Disrupt laminar flow - Disrupt laminar flow - Retard the inflow of clotting factor - Retard the inflow of clotting factor

inhibitors and permit the build-up of inhibitors and permit the build-up of thrombithrombi

- Promote endothelial cell activation- - Promote endothelial cell activation- local thrombosislocal thrombosis

Hypercoagulable stateHypercoagulable statePrimary (Genetic)Primary (Genetic) SecondarySecondary

MutationsMutations-factor V-factor V ImmobilizationImmobilization

PTPT MIMI

AT IIIAT III DICDIC

Protein CProtein C CarcinomaCarcinoma

Protein SProtein S Tissue damageTissue damage

Thrombi may form on heart Thrombi may form on heart valvesvalves

Vegetations (infective endocarditisVegetations (infective endocarditis)- )- lead to valve damage and large lead to valve damage and large thrombotic massesthrombotic masses

Nonbacterial thrombotic endocarditis- Nonbacterial thrombotic endocarditis-

Sterile vegetations- hypercoagulable Sterile vegetations- hypercoagulable statesstates

Verrucous ( Libman-Sacks) endocarditis-Verrucous ( Libman-Sacks) endocarditis- SLESLE

Arterial vs Venous Arterial vs Venous thrombithrombi

Begins- site of endothelial Begins- site of endothelial injuryinjury

Site of stasisSite of stasis

Grows - retrograde Grows - retrograde Grows in direction of blood Grows in direction of blood flowflow

Prominent lines of ZahnProminent lines of Zahn Less prominentLess prominent

Mural thrombi seenMural thrombi seen --

Micro- Less RBCsMicro- Less RBCs More RBCs-red thrombiMore RBCs-red thrombi

Less prone to Less prone to fragmentationfragmentation

Prone to fragmentation-Prone to fragmentation-

Coronary> Coronary> cerebral>femoralcerebral>femoral

Leg veinsLeg veins

Clinical effectsClinical effectsArterial thrombosis- eventually gangreneArterial thrombosis- eventually gangrene

Venous thrombosis- In leg veins (95%)Venous thrombosis- In leg veins (95%)

Myocardial infarction- Thrombus in coronary Myocardial infarction- Thrombus in coronary arteriesarteries

Strokes- Thrombus in cerebral vesselsStrokes- Thrombus in cerebral vessels

Thrombophlebitis migrans- In previously healthy Thrombophlebitis migrans- In previously healthy veins in any area of the bodyveins in any area of the body

Fate of thrombiFate of thrombi1. 1. Dissolution- Dissolution- May resolve due to fibrinolysisMay resolve due to fibrinolysis

2. 2. Organization and recanalizationOrganization and recanalization (Intimal proliferation+ capillary sprouting – (Intimal proliferation+ capillary sprouting –

larger vessels)larger vessels)

3. Propagation- 3. Propagation- eventually leading to vessel obstruction eventually leading to vessel obstruction

4. Vital centres- death4. Vital centres- death

5. 5. EmbolizationEmbolization Thrombi may dislodge and travel to other Thrombi may dislodge and travel to other sites in the vasculaturesites in the vasculature

SUMMARYSUMMARY ThrombosisThrombosis Thrombus development depends on Thrombus development depends on

the relative contribution of the components of the relative contribution of the components of Virchow's triad: Virchow's triad:

Endothelial injury (e.g., by toxins, hypertension, Endothelial injury (e.g., by toxins, hypertension, inflammation, or metabolic products)inflammation, or metabolic products)

Abnormal blood flow - stasis or turbulence (e.g., due Abnormal blood flow - stasis or turbulence (e.g., due to aneurysms, atherosclerotic plaque)to aneurysms, atherosclerotic plaque)

Hypercoagulability, which can be either primary Hypercoagulability, which can be either primary (e.g., factor V Leiden, increased prothrombin (e.g., factor V Leiden, increased prothrombin synthesis, antithrombin III deficiency) or secondary synthesis, antithrombin III deficiency) or secondary (e.g., bedrest, tissue damage, malignancy) (e.g., bedrest, tissue damage, malignancy)

Thrombi may propagate, resolve, become organized, Thrombi may propagate, resolve, become organized, or embolize.Thrombosis causes tissue injury by local or embolize.Thrombosis causes tissue injury by local vascular occlusion or by distal embolization. vascular occlusion or by distal embolization.

DISSEMINATED INTRAVASCULAR DISSEMINATED INTRAVASCULAR COAGULATION (DIC)COAGULATION (DIC)

( (Consumption coagulopathy )Consumption coagulopathy ) Sudden or insidious onset of fibrin thrombi in the Sudden or insidious onset of fibrin thrombi in the

microcirculation due to widespread activation of thrombin microcirculation due to widespread activation of thrombin

Causes- Obstetric complications / advanced malignancyCauses- Obstetric complications / advanced malignancy

Microscopically – Multiple thrombi particularly in the Microscopically – Multiple thrombi particularly in the

brain, lungs, heart, and kidneys brain, lungs, heart, and kidneys

Fibrinolytic mechanisms are activated → Initially thrombotic Fibrinolytic mechanisms are activated → Initially thrombotic disorder can evolve into a serious bleeding disorder disorder can evolve into a serious bleeding disorder

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