Download - 4 hemostasis&thrombosis
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.
E N D