Hemostasis and Thrombosis Hemostasis and Thrombosis

Dr.CSBR.Prasad, M.D.

Normal hemostasis is the result of a set of well-regulated processes that accomplish two important functions:

(1) They maintain blood in a fluid, clot-free state in normal vessels;

and

(2) They are poised to induce a rapid and localized hemostatic plug at a site of vascular injury.

NORMAL HEMOSTASIS NORMAL HEMOSTASIS The general sequence of events in hemostasis at the site of vascular

injury

•    There is a brief period of arteriolar vasoconstriction, reflex neurogenic mechanisms and local secretion of factors such as endothelin •    Primary hemostasis: Exposure of subendothelial extracellular matrix

(ECM) platelets to adhere > activated > release secretory granules >

aggregation > Hemostatic plug

•    Secondary hemostasis: Tissue factor + secreted platelet factors > activate the coagulation cascade > activation of thrombin

fibrin clot, resulting in local fibrin deposition. further platelet recruitment and granule release

•   Activation of counterregulatory mechanisms, t-PA are set into motion to limit the hemostatic plug to the site of injury

Diagrammatic representation of the normal hemostatic process: A, transient vasoconstriction:

B, Platelets adhere to exposed extracellular matrix (ECM) via von Willebrand factor (vWF) and are activated, undergoing a shape change and granule release; released adenosine diphosphate (ADP) and thromboxane A2 (TxA2) lead to further platelet aggregation to form the primary hemostatic plug.

C, Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, "cementing" the platelets into a definitive secondary hemostatic plug.

D, Counter-regulatory mechanisms, such as release of tissue type plasminogen activator (t-PA) (fibrinolytic) and thrombomodulin (interfering with the coagulation cascade), limit the hemostatic process to the site of injury.

EndotheliumEndothelium

Antithrombotic Properties: Antiplatelet, anticoagulant & fibrinolytic effects

Prothrombotic Properties: vWF, TNF, IL1, Antifibrinolytic effects

PlateletsPlatelets

Coagulation Coagulation cascadecascade

The fibrinolytic system

The fibrinolytic system, illustrating the plasminogen activators and inhibitors

Thrombosis Thrombosis

Components of Blood

• Plasma – proteins, electrolytes and water• Cells – RBCs, WBCs & PLTs

Definition

• Thrombus – a blood clot.• Thrombosis – a pathological process

whereby there is formation of a blood clot in uninjured vasculature or after relatively minor injury.

ProcoagulantFactors

AnticoagulantFactors

The Hemostatic Balance

Definition

• Embolus – A detached intravascular solid, liquid or gaseous mass that is carried by the blood to a site distant from its point of origin.

Dr. Rudolph Virchow1821-1902

AbnormalBlood Flow

AbnormalVessel Wall

AbnormalBlood

The Hypercoagulable State•Primary (genetic)•Secondary (acquired)

Virchow’s triad

ENDOTHELIAL INJURY

ABNORMAL

BLOOD FLOW HYPERCOAGULABILITY

THROMBOSIS

Endothelial InjuryEndothelial Injury

• Dominant factor• Sufficient as the sole factor• Examples include

– Myocardial infarction– Ulcerated atheromatous plaques– Hemodynamic injury such as hypertension,

turbulent flow over heart valves– Endotoxins, inflammation, etc

Atherosclerosis involving aorta

Normal aorta for comparison

Arterial Thrombosis

Polyarteritis nodosa (PAN)

Polyarteritis nodosa (PAN)

Giant cell arteritis

ThrombosisVenous

Deep Vein ThrombosisPulmonary Embolism

Arterial Myocardial InfarctionStroke

HemophiliaSingle Gene Mutation

Thrombosis Multigenic + Environmental

Factors

Genetic Associations and Hemostasis

Genetic diagnosisavailable

Genetic therapyfeasible

Genetic pathogenesisstill under investigation

Single Gene Disorder

XII XIIa

XI XIa

IX IXa

X Xa

II IIa

Fibrinogen Fibrin

VIIIa+Ca+Pl

Va+Ca+Pl

TF / VIIa TFPIIIa/Thrombomodulin interaction

Protein CProtein S

Protein S

Fibrinolysis

Loss of Function MutationsNatural Anticoagulant Proteins

Antithrombin

Protein C

Protein S

0.02 – 0.2% of General Population

1-3% prevalence in Thrombosis Population

Stronger Risk Factors For VTE ~ 10 to 25-fold

Acquired/Environmental Thrombotic Factors

Immobility – Blood stasis

Surgery

Cancer

Pregnancy

Oral Contraception

Hormone Replacement Therapy

Abnormal Blood FlowAbnormal Blood Flow

• Turbulence in arterial flow as a result of changes in the diameter of the vessel leading to non-laminar flow, resulting in:

Platelet coming into contact with endothelium. Prevent dilution by fresh flowing blood of activated

clotting factors. Retard inflow of clotting factor inhibitors. Promote endothelial cell activation predisposing to

local thrombosis.

Hypercoagulability• Alteration of the coagulation pathway

that predisposes to thrombosis• Higher viscosity of blood changing the

flow dynamics of blood

Primary (Genetic)Common

  Mutation in factor V gene (factor V Leiden)

  Mutation in prothrombin gene

  Mutation in methyltetrahydrofolate gene

Rare

  Antithrombin III deficiency

  Protein C deficiency

  Protein S deficiency

Very rare

  Fibrinolysis defects

Secondary (Acquired)High risk for thrombosis

  Prolonged bed rest or immobilization

  Myocardial infarction

  Atrial fibrillation

  Tissue damage (surgery, fracture, burns)

  Cancer

  Prosthetic cardiac valves

  Disseminated intravascular coagulation

  Heparin-induced thrombocytopenia

  Antiphospholipid antibody syndrome (lupus anticoagulant syndrome)

Lower risk for thrombosis

  Cardiomyopathy

  Nephrotic syndrome

  Hyperestrogenic states (pregnancy)

  Oral contraceptive use

  Sickle cell anemia

  Smoking

Morphology of thrombusMorphology of thrombus• Thrombi may develop anywhere in the cardiovascular system: within the

cardiac chambers; on valve cusps; or in arteries, veins, or capillaries.

• They are of variable size and shape

• Arterial or cardiac thrombi usually begin at a site of endothelial injury (e.g., atherosclerotic plaque) or turbulence (vessel bifurcation)

• Venous thrombi characteristically occur in sites of stasis.

• Characteristic of all thromboses – firmly attached at the point of origin

• Growth of thrombi: Arterial thrombi – grow in a retrograde direction Venous thrombi - grow in the direction of blood flow

• Complication: Embolus.

• Lines of Zahn • Mural thrombi • Arterial thrombi • Venous thrombosis, or

phlebothrombosis• Vegetations

Aortic aneurysm with thrombus formation – note the Lines of Zahn

“Lines of Zahn"

Vegetations in Infective endocarditis involving the aortic valve

Infected prosthetic valve with vegetations

Libman-Sacks endocarditis

ArterialArterial VenousVenous Occlusion of vascular lumen

Usually Occlusive Always occlusive

Endothelial injury Present May be absent

Adhesion to vessel wall

Firmly adherent Loosely adherent

Colour Grey white red

Consistency Friable Firm

Site Coronary, cerebral, femoral

Lower limbs, dural sinuses, portal vein

Venous thrombi Venous thrombi VsVs PM clots PM clots• Postmortem clots are gelatinous • A dark red dependent portion where red cells

have settled by gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat;

• They are usually not attached to the underlying wall

• In contrast, red thrombi are firmer, almost always have a point of attachment, and on transection reveal vague strands of pale gray fibrin.

Venous Venous thrombusthrombus PM clotPM clot

Adhesion to vessel wall

Adherent at one point

Not adherent

Colour Red with pale grey fibrin lines on c/s

Red / yellow layers

Consistency Firm Gelatinous

Site Lower limbs, dural sinuses, portal vein

Any where in the body

Venous thrombi Venous thrombi VsVs PM clots PM clots

Fate of a ThrombusFate of a Thrombus

Four events in the ensuing days to weeks: • The thrombus may propagate• The thrombus may become organised and

recanalised• The thrombus may become organised and

incorporated into the wall of the vessel• The thrombus may be dissolved completely• The thrombus may dislodge and become an

embolus or emboli

Fate of a ThrombusFate of a Thrombus

Propagation of Thrombus

Cerebral Embolism Formation

Classification of ThrombiClassification of Thrombi• Anatomical

– Cardiac– Arterial– Venous– Capillary

• Morphological– Pale (platelet thrombus)– Red (RBC thrombus)– Mixed (intermittent layers)

Thrombosis of the descending aorta extending from the origins of the renal arteries down to the iliac vessels

Renal Artery

Iliac Artery

Thrombus

A mixed thrombus

Red thrombus

Pale thrombus

Venous ThrombosisVenous Thrombosis• Two distinct types

– Phlebothrombosis – predisposes to thromboemboli to lungs

– Thrombophlebitis – unusual to have associated pulmonary thromboemboli

Migratory thrombophlebitis or Trousseau syndrome

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

DIC is not a primary disease but rather a potential complication of any condition associated with widespread activation of thrombin

It’s a thrombohemorrhagic disorderThrombin formation is the main mechanismBoth platelets and coagulation factors are depletedLab findings: Low PLT count, >aPTT, >PT,

fragmented RBCs in the smear

Effects of ThrombosisEffects of Thrombosis

• Dependent on location and degree of vascular occlusion.

• Effects also dependent on the availability of collateral blood supply and susceptibility of area of supply to interruption of blood supply.

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