Transcript Hemostasis and clotting - LSU School of Medicine

From Blood to Host Defense
Hemostasis and Clotting
Gregory J. Bagby, Ph.D.
[email protected]
Office: 310 (CSRB)
From Blood to Host Defense
• Blood
– Components and function
– Hemostasis and clotting
• The host defense system
– General overview
– Innate immune system
• pathogen recognition
• inflammatory response
– Adaptive immune system
• Humoral immune system and antibodies
• Cell-mediated immune system
Definition
Hemostasis is the prevention
of blood loss by arresting of bleeding
from injured vessels
Hemostasis and Its Control
• Most effective with small vessels.
• The greater intravascular pressure the harder it is to
prevent blood loss.
• Hematoma - accumulation of blood in tissue.
• Three processes to decrease blood loss.
– Vasoconstriction
– Platelet aggregation
– Blood coagulation or clotting
• Steps to inhibit clot formation and dissolve clots
once formed
– Anticlotting system
– Fibrinolytic system
Steps in Hemostasis following
vessel injury: Vasoconstriction
•
•
Only effective in the smallest of vessels.
Injury leads to local contraction of vascular smooth
muscle.
– Mechanism unclear – endothelial cell disruption, mechanical
stimulation, local mediators (EC, perivascular neurons)
•
Constriction presses opposed endothelial surfaces
together
– Contact induces stickiness between surfaces – adhesion
molecules bind/adhere
•
Decreases blood flow to prolong contact time of
damaged vessel with platelets
Steps in Hemostasis following Vessel
Injury: Platelet Aggregation
•
•
Plasma von Willebrand factor binds
to collagen which binds to platelets
Platelets degranulate to release
mediators
– ADP and thromboxane A2 amplifies platelet adherence and
degranulation.
– Serotonin – stimulates constriction
– Thromboplastin – stimulates
coagulation
•
Plasma fibrinogen – bridges
between platelets (aggregation)
Inhibition of Platelet Aggregation
Adjacent endothelial cells produce agents that inhibit platelet
activation/aggregation and cause vasodilatation:
1. Prostacycyclin (PGI2) – Inhibits platelet function
2. Nitric oxide - Vasodilator
Steps in Hemostasis following
vessel injury: Coagulation
•
Blood coagulation – transformation of blood into a gel
(clot or thrombus)
– Main ingredient – a polymer of fibrin that forms a mesh
– Local response around a platelet plug
– Complex process involving sequential re-enforced activation of
plasma factors (proteins)
•
Key step in clotting pathway is production of the
enzyme thrombin
– Thrombin cleaves fibrinogen to fibrin (soluble) which bind
together to form loose mesh
– Thrombin activates Factor XIII which covalently cross-links
fibrins to stabilize the fibrin network
– Thrombin activates clotting pathway leading to own production
The clotting pathway or cascade involves about 15 proteins.
Thrombin plays directly initiates clot formation by catalyzing
the conversion of fibrinogen to fibrin, and serving as a positive
feedback modulator of the cascade.
Platelets & Calcium Important in Clot Formation
• Blood cells trapped in
the fibrin meshwork, but
not essential
• Clot possible in absence
of cellular elements
except platelets.
• Thrombin activates platelets in addition to vessel injury
• Activated platelets express receptors that bind several of the
clotting factors
• Allows reactions to occur on the surface platelets
• Platelet factor (phospholipid) serves as a cofactor for clotting
pathway reactions
• Calcium also required for several steps (always sufficient)
The Clotting Cascade from Injury to
Thrombin Formation
•
Two pathways leading to pro-thrombin to thrombin
reaction
– Intrinsic pathway – constituents all in the blood
– Extrinsic pathway – cellular elements outside blood are
needed
•
Two pathways activated in sequence with thrombin
serving as the link between them.
Clotting Cascade
• Intrinsic pathway
– Collagen activated
– Inactive to active
proteases
– Cofactors (VIIIa & Va)
• Extrinsic pathway
– Cell-assoc Tissue Factor
– Thrombin produced by this
pathway activates factors in
the intrinsic pathway.
– Results in more thrombin to
accelerate fibrin formation
Procoagulant Actions of Thrombin
• Cleaves fibrinogen to fibrin
• Activates clotting factors
– Factor XIII to cross-link fibrin
– Intrinsic pathway via factor XI
– Important co-factors VIII and V
• Stimulates platelet activation
Hemophilia
• Mostly genetic X-linked disorders
seen primarily in men.
• Hemophilias
– Hemophilia A or classical hemophilia Lack of factor VIII (~77% of cases).
– Hemophilia B - Lack of factor IX.
– Hemophilia C (both sexes) –
Lack of factor XI.
Mild because IX (which is activated by XI)
can also be activated by VII.
• Symptoms in life and disabling.
– Bleeds impair joint function.
– Treated by transfusions of plasma and injections of purified
clotting factors (expensive to treat and inconvenient to the
patient).
– Surgery, simple dental procedures - life-threatening.
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Liver Plays Important Indirect Role in Clotting
• Site of clotting factor synthesis
• Vitamin K
– Bile salts produced by liver
important vitamin K, a lipid
soluble vitamin, absorption
– Vitamin K important for clotting
factor synthesis
• Prothrombin
• Other clotting factors
• Liver failure – results in sever
bleeding problems
An Endogenous Anticlotting and Clot Lysing
System Prevent, Limit or Remove Clots
• Endogenous anticlotting system - Factors that
oppose and limit clot formation.
• The fibrinolytic system – dissolves clots after
they are formed.
• Anticlotting drugs – Used to treat patients to
decrease clotting or dissolve clots that
inappropriately stop blood flow to important
tissue (heart, brain).
Three Factors that Oppose Clot Formation
• Plasma tissue factor pathway inhibitor (TFPI) binds to
and inhibits tissue factor-factor VIIa complexes to
inhibit continuous production of factor Xa
– Extrinsic pathway only generates small amount of thrombin
• Thrombin binding to thrombomodulin on endothelial
cells
– Inactivates thrombins clot-producing effects
– Bound thrombin binds to plasma protein C which inactivates
Factors VIIIa and V
– Thrombin indirectly inactivates clotting
• Plasma antithrombin III
– Inactivates thrombin and other clotting factors
– Works via binding to heparin on endothelial cells
• Prevents spread of the clot to uninjured areas
Fibrinolytic System Removes Clots as Part of the
Repair Process
• It’s as complex as clotting with activators and inhibitors
• Plasminogen activators, important e.g. is t-Pa
Plasminogen activators like Tissue Plasminogen Activator (t-PA)
Plasminogen
Plasmin
Fibrin
Soluble Fibrin
Fragments
Synthetic plasminogen activators can be used
immediately after a stroke or heart attack
to help dissolve clots and restore blood flow.
Anticlotting Roles of Endothelial Cells
• Barrier between blood and subendothelial extracellular
matrix and cells – inhibits platelet aggregation &
formation of TF-VIIa complexes
• Synthesis of PGI2 and nitric oxide – inhibits platelet
activation and aggregation
• Secretes tissue factor pathway inhibitor – inhibits TFfactor VIIa complexes to generate Xa
• Binds thrombin via thrombomodulin to activate protein C
– inactivates factors VIIIa and Va
• Display heparin on surface – binds antithrombin III to
inactive thrombin and other clotting factors
• Secretes tissue plasminogen factor – catalyzes
formation of plasmin to dissolve clots
Anticlotting and Thrombolytic Drugs
•
•
Agents that depress the action of procoagulants
– Aspirin – platelet cyclooxygenase inhibitor.
– Oral anticoagulants (Dicumarol) – inhibits action of vitamin K
required for synthesis of clotting factors by the liver.
– Heparin – activates antithrombin III.
– Fibrinogen blockers - interfere with fibrinogen binding to
platelets.
Agents that dissolve clots (thrombolytic drugs)
– Recombinant t-PA
– Desmodus rotundus salivary plasmninogen activator (DSPA)
– Streptokinase