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HEMOSTASIS

Learning Objectives

• What are the 3 main components of hemostasis?

• What is the basic sequence of events following vessel injury?

• What induces the endothelium to switch from an antithrombotic state to a prothrombotic state?

• Outline the formation of primary hemostatic plugs (3 main steps)

• Compare and contrast thrombocytopenia and thrombocytopathy. What lesions are associated with these conditions?

• Outline the formation of secondary hemostatic plugs

• Describe the resolution of hemostatic plugs

Circulatory Disturbances 3: Hemostasis

Shannon Martinson, Feb 2016

http://people.upei.ca/smartinson/ VPM 152 General Pathology

Edema

Hyperemia and congestion

Shock

Hemorrhage

Thrombosis and embolism

Infarction

Altered hemostasis

Altered Blood flow

HEMOSTASIS

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

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

• Induced by local secretion of endothelin from endothelial cells

HEMOSTASIS

Robbins and Cotran PBD 8th Ed, 2010

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


Endothelial Cells

Endothelium modulates hemostasis

Injury is the major initiating event for

thrombosis and coagulation

Anti-thrombotic properties

Pro-thrombotic properties

HEMOSTASIS

Endothelial cells


Antiplatelet

Anticoagulant

Fibrinolytic

• Acts as a physical barrier

• PGI2

• ADPase

• Heparin-like molecules

• Thrombomodulin

• Tissue factor pathway inhibitor (TFPI)

• Tissue plasminogen activator (tPA)

HEMOSTASIS

ECM

PGI2

ADPase

Inhibit platelet aggregation

Antiplatelet

• Barrier to ECM

• Prostacyclin (PGI2)

• Adenosine diphosphatase

HEMOSTASIS

Endothelial cells


Anticoagulant


• Bind ATIII

• Thrombomodulin

• Tissue Factor pathway inhibitor

Thrombin

Clotting factors

Heparin like molecules Antithrombin III

HEMOSTASIS

Endothelial cells


Thrombin

Activates protein C → cleaves clotting factors

Thrombomodulin

HEMOSTASIS

Endothelial cells


Anticoagulant


• Bind ATIII

• Thrombomodulin


Tissue factor pathway inhibitor

Complexes and inactivates Tissue Factor and Clotting Factors

HEMOSTASIS

Endothelial cells


Anticoagulant


• Bind ATIII

• Thrombomodulin


Fibrinolytic

•Plasminogen activator (tPA)

tPA

Fibrinolytic cascade

Activates plasmin

HEMOSTASIS

Endothelial cells


Activated by infectious agents, bacterial endotoxins, plasma mediators, cytokines & direct injury

Endothelial cells


von Willebrand Factor (vWF)

Tissue Factor (TF)

Plasminogen activator inhibitors (PAIs)

• Synthesize

• Store

• Release

• Secreted by injured endothelium

• ↓Fibrinolysis

• Counteract Plasminogen activators

HEMOSTASIS

HEMOSTASIS



Endothelial cells


• Produced by endothelium

• Binds surface of platelets

• Activates them → helps them aggregate

• Allows platelets to stick to exposed collagen

Von Willebrand factor (vWF)

• Injured endothelium secrete TF

• Activates extrinsic coagulation cascade

Tissue factor (TF)

HEMOSTASIS



Endothelial cells


• Secreted by endothelium

• Counteracts tPA

• Suppresses fibrinolysis

Plasminogen activator inhibitor (PAI)

• 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-coagulant substances

Platelets

HEMOSTASIS

Modified fomr: Zachary PBVD, 2017

Platelet granule content – For your information only

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

HEMOSTASIS

Platelets

Vascular injury

Exposure of ECM

Adhesion and shape change

Secretion of granules

Recruitment and

Aggregation

1 3 2

HEMOSTASIS

Platelets

3 responses of platelets to vascular injury

1. Adhesion and Shape change

vWF

HEMOSTASIS

Platelets

vWF

HEMOSTASIS

Platelets

1. Adhesion and Shape change

2. Secretion of granules

Calcium ADP

vWF

TxA2

HEMOSTASIS

Platelets

Calcium ADP TxA2

vWF

Thromboxane A2 induces vasoconstriction and platelet aggregation

• ADP mediates platelet aggregation

• Calcium is required for coagulation cascade

HEMOSTASIS

Platelets

2. Secretion of granules

3. Recruitment and Aggregation

Calcium ADP

vWF

TxA2

HEMOSTASIS

Platelets

Calcium ADP

vWF

TxA2

TxA2 + ADP → Enlarging platelet aggregate → Primary hemostatic plug

HEMOSTASIS

Platelets

3. Recruitment and Aggregation

Summary

HEMOSTASIS

Edited from Robbins and Cotran PBD 8th Ed, 2010

Platelets

• Decreased # circulating platelets

• <200 x 109 Thrombocytopenia

Diagnosis

History of bleeding

Low platelet counts

Mechanisms

Deficient formation of platelets

Excessive utilization of platelets

Premature destruction of platelets

HEMOSTASIS

Platelets

Estrogen toxicity

Antibodies to platelets

Consumptive coagulopathy

• 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

HEMOSTASIS

Platelets

von Willebrand’s disease

HEMOSTASIS

Platelets • Decreased # circulating platelets Thrombocytopenia

• Defective platelet function Thrombocytopathy

Lesions: Small foci of hemorrhage (petechiae, ecchymoses) – often on the mucosa surfaces

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

Thrombin • Bound to the platelet surface • Converts soluble fibrinogen to fibrin → anchors/ stabilizes the hemostatic plug

HEMOSTASIS


Coagulation Cascade

HEMOSTASIS

Coagulation Cascade


• TF from injured vessel wall for activation

• All factors present in plasma

• Exposure of collagen for activation

Common Pathway

Intrinsic Pathway

Extrinsic Pathway

Thrombin

Fibrinogen Fibrin

HEMOSTASIS

Coagulation Cascade

Common

CLOT

12

10

7

11

9

5

2

1

Intrinsic Extrinsic

=Thrombin

=Fibrinogen

8

13

TF

HEMOSTASIS


Coagulation Cascade

HEMOSTASIS


Coagulation Cascade

Zachary PBVD, 2017

Coagulation Cascade Cell based model:

• Initiation

• Amplification

• Propagation

HEMOSTASIS

Zachary PBVD, 2017

End result of the cascade:

•Stabilization of the clot by fibrin

•Contraction of fibrin-platelet clot

•Reduces size of clot (restores flow)

•Draws damaged vessels edges closer (for healing)

HEMOSTASIS

Coagulation Cascade

Zachary PBVD, 2017

• In general, large hemorrhages or hematomas in the absence of trauma 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

Coagulation Disorders

HEMOSTASIS

(E Box 2-1 Zachary– Pathologic Basis of Veterinary Disease, 2017)

For your information only

HEMOSTASIS

Coagulation Disorders – Inherited

• Vitamin K deficiency

• Affects factors 10, 9, 7 and 2 and proteins C and S

• Anticoagulant toxicity

• Liver failure

• Site of synthesis of coagulation factors

Decreased Production of Coagulation Factors

HEMOSTASIS

Coagulation Disorders - Acquired

HEMOSTASIS

DIC

Activation of plasmin

Fibrinolysis FDPs Inhibition of

clot formation

Microvascular occlusion

Ischemic injury

Mechanical fragmentation

of RBCs Depletion of clotting factors HEMORRHAGE

Tissue Factor

Severe inflammation

Endothelial cell injury

Massive tissue

destruction

Platelet aggregation

• Disseminated intravascular coagulation

• Sepsis, Pancreatitis, Cancer

• Severe trauma or deep burns

• Toxins

Increased Use of Coagulation Factors

• Fibrinolytic cascade limits the size and dissolves the clot • Primarily by the generation of plasmin (from plasminogen)

• Plasminogen is activated by tPA and intrinsic coagulation (factor 12a-kallikrein) • FDPs have anticoagulant activity & used as measure of thrombotic states

Fibrinolytic System – Anticoagulation

Plasminogen

Plasmin

tPA F12-kallikrein

Fibrin FDPs

HEMOSTASIS

HEMOSTASIS


Fibrinolytic System – Anticoagulation

• Fibrinolytic cascade limits the size and dissolves the clot • Primarily by the generation of plasmin (from plasminogen)

• Plasminogen is activated by tPA and intrinsic coagulation (factor 12a-kallikrein) • FDPs have anticoagulant activity & used as measure of thrombotic states

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