General Pathology

Hemostasis

(Web)

Paul Hanna Feb 2015

• well-regulated process to:

keeps blood fluid (clot free) within a normal vessel

rapid clot formation (hemostatic plug) occurs when vessel injured

• a hemostatic clot is normal in cases of vessel injury

• thrombosis refers to an inappropriate activation of the hemostatic process

• HEMOSTASIS = refers to the arrest of bleeding

Hemostasis

Three General Components

• Vascular wall - endothelium

• Platelets

• Coagulation Cascade

Hemostasis

1. Arteriolar Vasoconstriction

• reflex neurogenic mechanism

• local secretion of endothelin

Sequence of Events

Normal Hemostasis

1. Arteriolar Vasoconstriction

2. Primary Hemostasis -

PLATELET

• platelets respond to exposure

of subendothelial ECM by:

Adhesion

Shape Change

Granule Release

Recruitment

• Platelet aggregation

(1o hemostatic plug)

Sequence of Events

Normal Hemostasis

1. Arteriolar Vasoconstriction

2. Primary Hemostasis -

PLATELET

3. Secondary Hemostasis -

COAGULATION

• Tissue factor release

• Phospholipid complex

expression

• Thrombin activation

• Fibrin polymerization

(2o hemostatic plug)

Sequence of Events

Normal Hemostasis

1. Arteriolar Vasoconstriction

2. Primary Hemostasis - PLATELET

3. Secondary Hemostasis - Coagulation

4. Antithrombotic Counter-Regulation

• Factors released to limit the size of the hemostatic plug

Sequence of Events

Normal Hemostasis

1. Arteriolar vasoconstriction

- VASCULAR WALL

2. Primary hemostasis – PLATELET

3. Secondary Hemostasis

– COAGULATION

4. Antithrombotic Counter-

Regulation

Sequence of Events

Normal Hemostasis

• injury to endothelium is the major initiating event for thrombosis & coagulation

• endothelium modulates many aspects of normal hemostasis

– Antithrombotic

– Prothrombotic

Endothelial Cells

Antithrombotic Properties

• Antiplatelet

– barrier to ECM

– PGI2 and NO

– ADPase

• Fibrinolytic

– Plasminogen activators (tPA)

• Anticoagulant

– Heparin-like molecules (- ATIII)

– Thrombomodulin

– Tissue factor pathway inhibitor

Endothelial Cells

Prothrombotic Properties - activated by infectious agents, bacterial endotoxins, plasma mediators, cytokines & direct injury

Endothelial Cells

• Von Willibrand factor (vWF)

- synthesize / stores / releases

• Tissue factor (TF)

- injured endothelium secrete TF

• Plasminogen activator inhibitors

- ↓ fibrinolysis (counteract PA’s)

• Numerous growth factors are secreted by endothelial cells

– Platelet Derived Growth Factor (PDGF)

• stimulates smooth muscles and fibroblasts

– Fibroblast Growth Factor (FGF)

• stimulates fibroblasts and angiogenesis

– Transforming Growth Factor β (TGF- β)

• modulates vascular (& fibrous) repair

Vascular Repair

Endothelial Cells

Figure 12–13.(Mescher) Platelets. Platelets are cell fragments 2–4 µm in diameter

derived from megakaryocytes of bone marrow. Their primary function is to rapidly

release the content of their granules upon contact with collagen (or other materials

outside of the endothelium) to begin the process of clot formation and reduce blood

loss from the vasculature. (a): In a blood smear, platelets (arrows) are often found as

aggregates. Individually they show a lightly stained hyalomere region surrounding a

more darkly stained central granulomere containing membrane—enclosed granules.

X1500. Wright. (b): Ultrastructurally a platelet typically shows a system of

microtubules and actin filaments near the periphery to help maintain its shape and an

open canalicular system of vesicles continuous with the plasmalemma. The central

granulomere region contains glycogen and secretory granules of different types.

• derived from megakaryocytes; circulate as round, smooth discs

• play central role in hemostasis contain mostly procoagulants

• form the 1o hemostatic plug covers and seals a small damaged area

Platelets

For information only

Platelets

Vascular injury

Exposure of ECM

VWF–bridge for

platelets to ECM

Adhesion and Shape Change

Platelet Response

Secretion

Dense granules

(Ca2+ + ADP)

Surface expression of phospholipid complexes

(binding site for Ca2+ and coagulation factors)

Platelet Response

Aggregation

• TXA2 + ADP enlarging platelet aggregate 1o haemostatic plug

Platelet Response

THROMBOCYTOPENIA

Definition: platelet numbers are low

(<100 x 109/L is a thrombocytopenia in many species)

Diagnosis: history of bleeding

low platelet counts

Mechanisms: Deficient formation of platelets (eg, estrogen toxicoses)

Excessive utilization (eg, consumptive coagulopathies)

Premature destruction (eg, antibodies to platelets)

THROMBOCYTOPATHY

Definition: Defective platelet function

Mechanisms: Defect in adhesion (eg, von WIllebrand’s disease)

aggregation

release of granules

Platelet Disorders

• a reaction pathway:

enzyme (previously activated coagulation factor)

+

substrate (next non-activated coagulation factor)

activated coagulation factor

• 3rd arm of hemostasis an enzymatic cascade

• reaction typically occurs on platelet phospholipid complex held together by Ca2+

Coagulation Cascade

• coagulation cascade forms thrombin bound to platelet surface

• thrombin converts soluble fibrinogen to fibrin anchor / stabilize the hemostatic plug

Coagulation Cascade

Intrinsic Pathway

• all factors in plasma

• exposure of collagen for activation

Extrinsic Pathway

• TF from injured vessel wall

• TF + VII TF/VIIa X to Xa

Common Pathway

• fibrin formation

Result

• contraction of fibrin-platelet clot

• reduces size of clot (restores flow)

• draws damaged vessels edges

closer (for healing)

Coagulation Cascade

Coagulation Cascade

• fibrinolytic cascade limits the size &/or dissolves thrombus (temporary patch)

• primarily by the generation of plasmin (from plasminogen)

• plasminogen activated by tPA’s &/or intrinsic coagulation (XIIa-kallirein)

• FDP’s have anticoagulant activity & used as measure of thrombotic states

Fibrinolytic System

COAGULATION DISORDERS For information only

In general, large hematomas suggest a coagulation disorder whereas chronic bleeding from a mucosal surface is more indicative of a platelet deficiency or abnormality

COAGULATION DISORDERS For information only

In general, large hematomas suggest a coagulation disorder whereas chronic bleeding from a mucosal surface is more indicative of a platelet deficiency or abnormality

INHERITED DEFICIENCIES OF COAGULATION – numerous (See Box 2-5 McGavin)

COAGULATION DISORDERS For information only

In general, large hematomas suggest a coagulation disorder whereas chronic bleeding from a mucosal surface is more indicative of a platelet deficiency or abnormality

INHERITED DEFICIENCIES OF COAGULATION – numerous (See Box 2-5 McGavin)

ACQUIRED DEFICIENCIES OF COAGULATION (can be production or use)

Accompany many severe diseases

- transitory depression of factor synthesis

- excessive utilization or consumption of factors

Acquired disorders may be general or specific

- severe trauma or deep burns

- snake venoms and plant toxins

- vitamin K deficiency (required for factors II, VII, IX, X and proteins C and S)

Liver failure

- site of synthesis of many coagulation factors

- acute destruction of hepatocytes or chronic liver disease may result in coagulopathy