Venous Thromboembolism-1 Dr. Abdelaty Shawky Mohamed Assistant professor of pathology

* Topics: 1. Pathophysiology of VTE. 2. Clinical presentation of VTE. 3. Investigations of VTE.

1. Pathophysiology of VTE

Hemostasis and Thrombosis Hemostasis is the physiologic process that maintains the blood in a fluid state in normal vessels and to induce a rapid and localized hemostatic plug at a site of vascular injury to stop bleeding.

Thrombosis is the pathologic process opposite to hemostasis; it can be considered an inappropriate activation of normal hemostatic processes, resulting in the formation of a (thrombus) in uninjured vessel or after minor injury.

Both hemostasis and thrombosis are regulated by three general components. 1. The vascular endothelium. 2. Platelets. 3. The coagulation cascade.

Q. What is the role of endothelial cells in hemostasis and thrombosis?

Endothelial cells have both antithrombotic activities preventing thrombosis in normal blood vessel and also have prothrombotic activities favoring thrombosis in injured blood vessels. The balance between endothelial antithrombotic and prothrombotic activities critically determines whether thrombus formation, propagation, or dissolution occurs

* Antithrombotic Properties Antiplatelet effects: by secretion of prostacyclin (PGI2) and nitric oxide. Both mediators are potent vasodilators and inhibitors of platelet aggregation. Anticoagulant effects: These effects are mediated by; a. Thrombomodulin receptors for (thrombin) to block its action and also to activate protein C which in turn inactivate factors V and VIII. b. Heparin-like molecules: receptors for anti-thrombin III to block factors IX and X. c. Release of tissue factor inhibitor. These inhibit the coagulation pathway.

Fibrinolytic effects: Endothelial cells synthesize tissue-type plasminogen activator (t-PA), promoting fibrinolytic activity to clear fibrin deposits from endothelial surfaces .

* Prothrombotic Properties: Platelet effects: - Endothelial injury leads to adhesion of platelets to the underlying extracellular matrix; this is facilitated by endothelial production of von Willebrand factor (vWF), an essential cofactor for platelet binding to subendothelial collagen.

Procoagulant effects: Endothelial cells synthesize tissue factor, which activates the extrinsic clotting cascade. Antifibrinolytic effects: Endothelial cells also secrete inhibitors of plasminogen activator (PAIs), which inhibits fibrinolysis.

Coagulation cascade

Thrombosis

* Definition of thrombosis: - Formation of a solid mass composed of the circulating blood elements, inside CVS system (blood vessels or heart) during life.

* Causes of thrombosis: - There are 3 major factors which predispose to thrombosis (Virchow’s triad): 1. Endothelial damage. 2. Slowing & turbulence of blood flow. 3. Blood hypercoagulability.

1. Endothelial damage: - Endothelial damage may be: a. Mechanical: trauma, repeated tourniquet… b. Inflammatory: arteritis, phlebitis and endocarditis. c. Degenerative: atherosclerosis, hypertension.. - The injured endothelium becomes swollen with rough surface.

2. Slowing & turbulence of blood flow. - Occurs in; Left atrium in mitral stenosis. Leg veins in varicose veins and bed-ridden heart failure patients. Inside aneurysmal sacs.

3. Blood hypercoagulability: I. Genetic (inherited): Mutation of factor V gene. Mutation of prothrombin gene. - In both conditions; the resulting factor V and prothrombin are not prone to degradation and have a sustained thrombotic actions.

Protein C and protein S deficiency: These are natural anti-coagulant proteins. Their deficiency leads to hypercoagulability state.

II. Acquired: Prolonged bed rest or immobilization. Myocardial infarction. Tissue damage (surgery, fracture, burn). Cancer. Oral contraceptive pills.

* Pathogenesis (Mechanism) of thrombosis: Endothelial injury leads to: 1. Exposure of sub-endothelial collagen: promote platelet aggregation. 2. Release of tissue factor: promote fibrin formation.

I. Exposure of sub- endothelial collagen: a. Platelets adhesion to the exposed collagen (this is mediated by factor VIII released from endothelial cells). b. Platelet activation and release of Thromboxane A2 (potent vasoconstrictor and induce platelet aggregation)

II. Release of the tissue factor (from endothelial cells) that stimulate the coagulation cascade to form thrombin that convert fibrinogen into fibrin. The end result is fibrin network entangling aggregated platelet (Thrombus)

The lumen of blood vessel is occupied by a red mass which is adherent to the vessel wall at an area called the head of the thrombus .

Gross picture of the thrombus

Microscopic picture of thrombus:

These are "lines of Zahn" which are the alternating pale pink bands of platelets with fibrin and red bands of RBC's forming a true thrombus.

Thanks