circulatory disturbances 4: hemostasispeople.upei.ca/smartinson/circ4-hemost-16_sam.pdf ·...
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Circulatory Disturbances 4: Hemostasis
Shannon Martinson, Feb 2016 http://people.upei.ca/smartinson/ VPM 152 General Pathology
HEMOSTASIS
Learning Objectives
• Understand normal hemostasis
• What are the 3 main components of hemostasis?
• Outline the formation (sequence) of primary and secondary hemostatic plugs
• What are the antithrombotic factors produced by endothelial cells?
• Describe the resolution of hemostatic plugs
HEMOSTASIS
• Refers to the arrest of bleeding Hemostasis
Hemostasis
• Well regulated process
• Keeps blood fluid (clot free) within the blood vessels
• Rapid clot formation (hemostatic plug) occurs with vessel injury
Clotting
• Hemostatic clot is normal in cases of vessel injury
• Thrombosis refers to an inappropriate activation of the hemostatic process
HEMOSTASIS
Three components of hemostasis
Vascular wall / Endothelium
Platelets
Coagulation Cascade
HEMOSTASIS
1
• Arteriolar vasoconstriction
• Endothelium
2
• Primary hemostasis
• Platelets
3
• Secondary hemostasis
• Coagulation cascade
4 • Antithrombotic counter-regulation
Sequence of events in normal hemostasis following vascular injury
HEMOSTASIS
1
• Arteriolar vasoconstriction
• Endothelium • Reflex neurogenic mechanism
• Transient
• Local secretion of endothelin from endothelial cells
HEMOSTASIS
2
• Primary hemostasis
• Platelets • Platelets respond to exposure of subendothelial ECM
• Result = Formation of a primary hemostatic plug
HEMOSTASIS
3
• Secondary hemostasis
• Coagulation cascade
• Coagulation results in formation of a secondary hemostatic plug
HEMOSTASIS
4 • Antithrombotic counter-regulation
• Factors are released to limit the size of the hemostatic plug
HEMOSTASIS
4 • Antithrombotic counter-regulation
• Factors are released to limit the size of the hemostatic plug
Endothelial Cells
HEMOSTASIS
Endothelium modulates hemostasis
Injury is the major initiating event for
thrombosis and coagulation
Anti-thrombotic properties
Pro-thrombotic properties
HEMOSTASIS
Endothelial cells
Anti-thrombotic properties
Antiplatelet
Anticoagulant
Fibrinolytic
• Acts as a barrier
• PGI2
• ADPase
• Heparin-like molecules
• Thrombomodulin
• Tissue factor pathway inhibitor (TFPI)
• Tissue plasminogen activator (tPA)
HEMOSTASIS
ECM
PGI2
ADPase
Antiplatelet
• Barrier to ECM
• Prostacyclin I2
• Adenosine diphosphatase
Inhibit platelet aggregation
Endothelial cells
Anti-thrombotic properties
HEMOSTASIS
Anticoagulant
• Heparin-like molecules
• Bind ATIII
• Thrombomodulin
• Tissue Factor pathway inhibitor
Thrombin
Clotting factors
Heparin like molecules Antithrombin III
Endothelial cells
Anti-thrombotic properties
HEMOSTASIS
Anticoagulant
• Heparin-like molecules
• Bind ATIII
• Thrombomodulin
• Tissue Factor pathway inhibitor
Thrombin
Activates protein C and causes proteolysis of clotting factors
Thrombomodulin
Endothelial cells
Anti-thrombotic properties
HEMOSTASIS
Anticoagulant
• Heparin-like molecules
• Bind ATIII
• Thrombomodulin
• Tissue Factor pathway inhibitor
Tissue factor pathway inhibitor
Complexes and inactivates Tissue Factor 7a and 10a
Endothelial cells
Anti-thrombotic properties
HEMOSTASIS
Fibrinolytic
•Plasminogen activator (tPA)
tPA
Fibrinolytic cascade
Endothelial cells
Anti-thrombotic properties
Activates plasmin
Activated by infectious agents, bacterial endotoxins, plasma mediators, cytokines & direct injury
HEMOSTASIS
Endothelial cells
Pro-thrombotic properties
von Willebrand Factor (vWF)
Tissue Factor (TF)
Plasminogen activator inhibitors (PAIs)
• Synthesize
• Store
• Release
• Secreted by injured endothelium
• ↓Fibrinolysis
• Counteract Plasminogen activators
Activated by infectious agents, bacterial endotoxins, plasma mediators, cytokines & direct injury
• Von Willebrand factor (vWF)
• Produced by endothelium
• Bind surface of platelets
• Activates them → helps them aggregate
• Allows platelets to stick to exposed collagen
• Tissue factor (TF)
• Injured endothelium secrete TF
• Activates extrinsic coagulation cascade
HEMOSTASIS
Endothelial cells
Pro-thrombotic properties
Activated by infectious agents, bacterial endotoxins, plasma mediators, cytokines & direct injury
• Plasminogen activator inhibitors (PAI)
• ↓ fibrinolysis (counteract plasminogen activators → tPA)
HEMOSTASIS
Endothelial cells
Pro-thrombotic properties
HEMOSTASIS
Endothelial Cells
• Stimulates smooth muscles and fibroblasts
Platelet Derived Growth Factor (PDGF)
• Stimulates fibroblasts and angiogenesis
Fibroblast Growth Factor (FGF)
• Modulates vascular (& fibrous) repair
Transforming Growth Factor β (TGF- β)
Also play a role in vascular repair – numerous growth factors are secreted by endothelial cells
• Derived from megakaryocytes; circulate as round, smooth discs
• Play central role in hemostasis
• Form the 1o hemostatic plug covers and seals a small damaged area
• Granules contain mostly pro-coagulants
HEMOSTASIS
Platelets
Platelet granule content – For your information only
HEMOSTASIS
Platelets
Procoagulant Anticoagulant
Thromboxane Adenosine Triphosphate
Phospholipids Protease Nexin II
Adenosine diphosphate Tissue Factor Pathway Inhibitor
Calcium Protein S
Platelet Factor 4
Thrombospondin Vascular repair
Fibrinogen Platelet Derived Growth Factor
Factors V, XI, and XIII β Thromboglobulin
Von Willebrand’s Factor Vascular Endothelial Growth Factor
α2-Antiplasmin and α2-Macroglobulin Transforming Growth Factor β
Plasminogen Activator Inhibitor Epidermal Growth Factor
Serotonin
Vascular injury
Exposure of ECM
Adhesion and shape change
Secretion of granules
Aggregation
HEMOSTASIS
Platelets
1 3 2
3 responses of platelets to vascular injury
HEMOSTASIS
Platelets
1. Adhesion and Shape change
vWF
HEMOSTASIS
Platelets
1. Adhesion and Shape change
vWF
HEMOSTASIS
Platelets
2. Secretion of granules
Calcium ADP
vWF
TxA2
HEMOSTASIS
Platelets
Calcium ADP TxA2
2. Secretion of granules
vWF
Thromboxane A2 induces vasoconstriction and platelet aggregation
• ADP mediates platelet aggregation
• Calcium is required for coagulation cascade
HEMOSTASIS
Platelets
3. Aggregation
Calcium ADP
vWF
TxA2
HEMOSTASIS
Platelets
3. Aggregation
Calcium ADP
vWF
TxA2
TxA2 + ADP → Enlarging platelet aggregate → Primary hemostatic plug
HEMOSTASIS
Platelets Summary
1 3
2
HEMOSTASIS
Platelet Disorders
• Decreased circulating platelets
• Normal <200 x 109 Thrombocytopenia
Diagnosis
History of bleeding
Low platelet counts
Mechanisms
Deficient formation of platelets
Excessive utilization of platelets
Premature destruction of platelets
Estrogen toxicity
Consumptive coagulopathy
Antibodies to platelets
HEMOSTASIS
Platelet Disorders
•Defective platelet function Thrombocytopathy
Diagnosis
History of bleeding
Normal platelet counts
Abnormal platelet function tests
Mechanisms
Defect in Adhesion
Defect in Aggregation
Defect in release of granules
von Willebrand’s disease
HEMOSTASIS
Platelet Disorders
http://vet.uga.edu/ivcvm/courses/VPAT5200/01_circulation/hemorrhage/images/Quiz4.jpg
HEMOSTASIS
Coagulation Cascade
Enzyme
Substrate
Activated coagulation
factor
• An enzymatic cascade • A reaction pathway that occurs on a platelet phospholipid complex and is held
together by calcium ions
Thrombin
Coverts fibrinogen to fibrin
HEMOSTASIS
Coagulation Cascade
Thrombin • Bound to the platelet surface • Converts soluble fibrinogen to fibrin → anchors/ stabilizes the hemostatic plug
HEMOSTASIS
Coagulation Cascade
• TF from injured vessel wall interacts with factor 7
• All factors present in plasma
• Exposure of collagen for activation
Common Pathway
Intrinsic Pathway
Extrinsic Pathway
HEMOSTASIS
Coagulation Cascade
Thrombin
Fibrinogen Fibrin
HEMOSTASIS
Coagulation Cascade
HEMOSTASIS
Coagulation Cascade
Common
CLOT
12
10
7
11
9
5
2
1
Intrinsic Extrinsic
=Thrombin
=Fibrinogen
8
13
TF
HEMOSTASIS
Coagulation Cascade
End result of the cascade:
•Contraction of fibrin-platelet clot
•Reduces size of clot (restores flow)
•Draws damaged vessels edges closer (for healing)
CLOT
12
10
7
11
9
5
2
1
Intrinsic Extrinsic
=Thrombin
=Fibrinogen
8
13
TF
Common
• In general, large hemorrhages or hematomas suggest a coagulation disorder
• Coagulation disorders can by inherited or acquired
• Chronic bleeding from a mucosal surface is more indicative of a platelet deficiency or abnormality
HEMOSTASIS
Coagulation Disorders
Peri-renal hematoma
(See Box 2-5 Zachary and McGavin – Pathologic Basis of Veterinary Disease)
HEMOSTASIS
For your information only Coagulation Disorders - Inherited
HEMOSTASIS
Coagulation Disorders - Acquired
• Vitamin K deficiency
• Affects factors 10, 9, 7 and 2 and proteins C and S
• Liver failure
• Site of synthesis of coagulation factors
Decreased Production of Coagulation Factors
• Disseminated intravascular coagulation
• Sepsis
• Severe trauma or deep burns
• Snake venoms and plant toxins
Increased Use of Coagulation Factors
• Fibrinolytic cascade limits the size and dissolves the thrombus • Primarily by the generation of plasmin (from plasminogen)
• Plasminogen activated by tPA and intrinsic coagulation (factor 12a-kallikrein) • FDPs have anticoagulant activity & used as measure of thrombotic states
HEMOSTASIS
Fibrinolytic System – Anticoagulation
Plasminogen
Plasmin
tPA F12-kallikrein
Fibrin FDPs
• Fibrinolytic cascade limits the size and dissolves the thrombus • Primarily by the generation of plasmin (from plasminogen)
• Plasminogen activated by tPA and intrinsic coagulation (factor 12a-kallikrein) • FDPs have anticoagulant activity & used as measure of thrombotic states
HEMOSTASIS
Fibrinolytic System – Anticoagulation
Questions?
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