Pathophysiology of

Cardiovascular Diseases
 Vascular disorders are responsible for more morbidity and
mortality than any other category of human disease.

Although the most clinically significant lesions typically involve

arteries, venous diseases also occur.

Vascular pathology results in disease via two principal

mechanisms:
(1) Narrowing (stenosis) or complete obstruction of vessel
lumens, either progressively (e.g., by atherosclerosis) or
precipitously (e.g., by thrombosis or embolism).
(2) weakening of vessel walls, leading to dilation or rupture.

2
 Hemostasis and Thrombosis
Normal hemostasis: is a consequence of tightly regulated
processes that maintain blood in a fluid state in normal
vessels, yet also permit the rapid formation of a hemostatic
clot at the site of a vascular injury.

Thrombosis: it is the pathologic counterpart of hemostasis

and involves blood clot (thrombus) formation within intact
vessels.

Both hemostasis and thrombosis involve three components:

1. the vascular wall (particularly the endothelium)
2. platelets
3. the coagulation cascade.
 The general sequence of events in hemostasis at a site of
vascular injury:

A. Arteriolar vasoconstriction:
Mediated by reflex neurogenic mechanism
Augmented by endothelin
Brief and transient

B. Platelet adherence and activation:

Due to exposure of the thrombogenic subendothelial
extracellular matrix (ECM)
Shape change (small rounded discs to flat plates)
Secretory granules (eg. TXA2, ADP)
Aggregationprimary plug.primary homeostasis
C. Tissue factor (TF, thromboplastin or factor III) is also exposed
at the site of injury (membrane-bound glycopr. procoagulant)
Factor VII
Major in vivo initiator of coagulation cascade
Thrombin generation (factor IIa)
Fibrinogen to fibrin
Secondary homeostasispolymerized fibrin and platelet
aggregates form a solid, permanent plug to prevent any further
hemorrhage

At this stage, counter-regulatory mechanisms (e.g., tissue

plasminogen activator, t-PA) are set into motion to limit the
hemostatic plug to the site of injury
1. Endothelium:
- Endothelial cells are key players in the regulation of
homeostasis.

- The balance between the ANTIHROMBOTIC- and

PROTHROMBOTIC activities of endothelium determines
whether thrombus formation, propagation, or dissolution occurs.

- Normally, endothelial cells exhibit antiplatelet,

anticoagulant, and fibrinolytic properties.

- In the case of an injury/activation, endothelial cells

acquire numerous procoagulant activities.
 Anti-thrombotic properties: Under normal circumstances endothelial cells
actively prevent thrombosis by producing factors that variously block platelet
adhesion and aggregation, inhibit coagulation, and lyse clots.
- Antiplatelet effects.
Intact endothelium
PGI2 and NO.vasodilators and inhibit platelet aggregation
Adenosine diphosphatases
- Anticoagulant effects.
Endothelial membrane-associated heparin-like molecules: cofactors for
antithrombin III which invactivates factors Xa, IXa and IIa
Thrombomodulin: modulates thrombin activity by activating protein C.joined
with its cofactor (protein S) protein C inactivates factors Va & VIIIa
Tissue factor pathway inhibitor (TFPI)protein that inhibits TF-VIIa complexes

- Fibrinolytic effects.
Tissue-type plasminogen activator (t-PA) cleaves plasminogen to
plasmincleaves fibrin to degrade thrombi
 Pro-thrombotic properties: trauma and inflammation of
endothelial cells induce a prothrombotic state that alters the
activities of platelets, coagulation proteins, and the fibrinolytic
system.

- Platelet effects.
Endothelial injury
von Willebrand factor (vWF glycoprotein) and collagen
Activation of platelets, their adhesion? and aggregation?

- Procoagulant effects.
Tissue factor (TF).extrinsic coagulatory cascade

- Antifibrinolytic effects.
Endothelial inhibitors of plasminogen activator (PAIs)limit
fibrinolysis and tend to favor thrombosis
2. Platelets:

- disc-shaped, anucleated cell fragments that are shed from

megakaryocytes in the bone marrow into the blood stream to the
spleen

- In the setting of normal platelets count the half-life is 10 days

- form the hemostatic plug that initially seals vascular defects and
provides a surface (rich of -ve phospholipids) that recruits and
concentrates activated coagulation factors.

- Their function depends on several glycoprotein receptors, a

contractile cytoskeleton (fused plates), and two types of cytoplasmic
granules.
2. Platelets:

The glycoprotein receptors:

Platelet adhesion is mediated by the binding of platelet
receptors to a number of arterial wall receptors
glycoprotein Ia to collagen; glycoprotein Ib to vWF; and
glycoprotein IIb/IIIa to fibrinogen
The contractile cytoskeleton:
Turn platelets to a fused mass.

Two types of cytoplasmic granules

 -Granules, have the adhesion molecule P-selectin on their
membranes and contain:
- fibrinogen
- fibronectin
- factors V and XIII
- platelet factor 4 (a heparin-binding chemokine)
- platelet-derived growth factor (PDGF)
- transforming growth factor- (TGF-)
Dense (or ) granules, contain:
- ADP and ATP
- ionized calcium
- histamine
- serotonin
- epinephrine
3. Coagulation cascade: an amplifying series of enzymatic conversions;
each step proteolytically cleaves an inactive proenzyme into an activated
enzyme, culminating in thrombin formation

Each reaction in the pathway results from the assembly of a complex

composed of
an enzyme (activated coagulation factor),
a substrate (proenzyme form of coagulation factor), and
a cofactor (reaction accelerator).

Most coagulation factors made by the liver

Factor XIII derives from platelets / factor VIII made by endothelial cells
Factors II, VII, IX, X and protein S and C are dependent on the liver
enzyme gamma-carboxylase which is dependent on vitamin K
Warfarin? interfere with vitamin K activity
 Blood coagulation is traditionally classified into extrinsic and
intrinsic pathways that converge on the activation of factor X
and II.

- Extrinsic pathway:
factors VII, X, V, II and fibrinogen
Protein function is assessed by prothrombin time (PT) used
clinically to monitor the effects of warfarin
Require an exogenous trigger!.........activated by tissue
phospholipids (Tissue Factor or Thromboplastin)
 - Intrinsic pathway:
factors XII, XI, IX, VIII, X, V, II, and fibrinogen
Protein function is assessed by the activated partial
thromboplastin time (aPTT) used to monitor the
anticoagulant effects of heparin
Only required exposure of factor XII (Hageman factor) to
thrombogenic surfaces.

Restriction of the coagulation cascade to the site of vascular

injury to prevent runaway clotting of the entire vascular tree:
(1) Antithrombins (e.g., antithrombin III)
(2) Proteins C and Sinactivates factors Va and VIIIa
(3) TFPI..tissue factor pathway inhibitorinhibit factor VIIa
 Activation of the coagulation cascade also sets into motion a
fibrinolytic cascade that moderates the size of the ultimate
clot

Fibrinolysis is responsible for the dissolution of formed blood

clots

An inactive proenzyme, plasminogen, is converted to an

active enzyme, plasmin, that degrades the fibrin mesh into
soluble end products.. interferes with its polymerization
 The most important PAs available are:

1) t-PA; it is synthesized principally by endothelium and is

most active when bound to fibrin.

2) Urokinase-like PA (u-PA): enzyme synthesized in the kindey

3) plasminogen can be cleaved to plasmin by the bacterial

enzyme streptokinase protein

Fibrinolysis Inhibitory substance include:

1. Plasminogen activator inhibitor-1 inhibits the
plasminogen activators
2. 2-antiplasmin inhibits plasmin activity
 Role of THROMBIN:

1. In clotting, thrombin transforms soluble fibrinogen into insoluble fibrin

allowing to form a fibrin clot
2. Thrombin activates many upstream clotting factors, leading to more
thrombin generation,
3. and activates factor XIII, a transaminase that cross-links the fibrin polymer
and stabilizes the clot
4. Thrombin is a potent platelet activator (PDGF)
5. Exerts anticoagulant effects by activating the protein C pathway, which
attenuates the clotting response
6. Activates t-PA and PAI
7. Release TXA2 and PGI2

Role of phospholipids and calcium!