Venous Thromboembolism: Pathophysiology

What is a thrombus

A blood clot which is the final product of the blood coagulation process in hemostasis

What are the 2 components of a thrombus?

- Platelet plug (aggregated platelets)

- Cross-linked fibrin protein

What is an embolus?

A detached intravascular mass that travels and can clog the arterial capillary beds at a distant site

What is VTE?

Clot formation in the venous circulation

What are the 2 main manifestations of VTE?

-DVT (Deep Vein Thrombosis)

- PE (Pulmonary Embolism)

Which VTE manifestation is potentially fatal?

Pulmonary Embolism

What are the complications of VTE?

- Post-thrombotic Syndrome

- Chronic Thromboembolic Pulmonary Hypertension (CTPH)

What increases VTE risk?

Immobilization and major orthopedic surgery

What are the 3 components of Virchow's triad?

Alteration in blood, vessel wall, and blood flow

What are the 3 major causes of VTE?

- Hypercoagulability

- Venous Stasis

- Vascular Injury

What are examples of venous stasis risk factors?

- Immobilization

- Surgery

- Damage to venous valves

- Obesity

What are examples of vascular injury risk factors?

- Prior DVT/PE

- Fracture

- Major orthopedic surgery

- Trauma

- Catheters

What are examples of hypercoagulability risk factors?

- Obesity/diabetes

- Cancer

- Clotting factor changes

- Pregnancy

- Drugs (estrogen containing contraceptives)

What is hemostasis

Process responsible for maintaining circulator integrity after blood vessel damage

What are the 2 steps of hemostasis?

- Platelet plug formation

- Fibrin clot formation via activation of coagulation cascade

What are arterial clots composed of?

Platelet-rich (white thrombi)

Where do arterial clots form?

High shear environments

What is the main treatment for arterial clots?

Antiplatelets

What are venous clots composed of?

Fibrin and RBC-rich (red thrombi)

Where do venous clots form?

Low flow environments

What is the main treatment for venous clots?

Anticoagulants

What mediates platelet adhesion (acts like molecular glue)?

von Willebrand factor (vWF)

What are the steps for platelet plug formation?

1. Platelet adhesion

2. Platelet activation

3. Platelet aggregation

What receptor binds fibrinogen on platelets?

GPIIb/IIIa

Which substances promote platelet aggregation

- Epinephrine

- Thrombin

- ADP

- Serotonin

- Thromboxane A2

What activates fibrin clot formation?

Coagulation cascade

How are clotting factors activated?

Clotting factors are converted from their inactive form into their active forms (X to Xa)

Where are most clotting factors produced?

Liver

What is the classical model of coagulation?

- Intrinsic: contact activation pathway

- Extrinsic: tissue factor pathway

- Common pathway

What is the cellular model of coagulation?

4 phases of coagulation based on these events:

- Initiation

- Amplification

- Propagation

- Termination

What activates the intrinsic pathway (contact pathway)?

Contact with negatively charged surfaces

What is Factor XII also called?

Hageman factor

What substances are necessary for full activation of factor X?

Phospholipids and calcium

What enhances intrinsic pathway activation?

Thrombin (amplifies V, VIII, XI)

What activates the extrinsic pathway?

Tissue factor (Factor III)

Where is tissue factor expressed?

On the surface of subendothelial components (smooth muscle cells and fibroblasts)

What complex activates Factor X in extrinsic pathway?

TF + VIIa

Where do intrinsic and extrinsic pathways converge?

Conversion of Factor X → Xa

What are the 4 phases of coagulation?

- Initiation

- Amplification

- Propagation

- Termination

What happens during initiation?

TF activates clotting factors and generates thrombin

What happens during amplification?

Thrombin activates platelets and factors V, VIII, and XI

What happens during propagation?

Thrombin bursts and fibrin clot is formed

What happens during termination?

Anticoagulants limit clot expansion

What is Factor II?

Prothrombin

What is Factor IIa?

Thrombin

What is Tissue Factor?

Thromboplastin

What is the Extrinsic Tenase Complex?

TF/VIIa

What is the Intrinsic Tenase Complex?

- VIIIa-IXa-Ca2+-PL

- or VIIIa-IXa

What is Prothrombinase Complex?

- Xa-Va-Ca2+-PL

- or Xa-Va

Which pathway initiates clotting?

Extrinsic

Which pathway amplifies the clotting process after it has been activated?

Intrinsic

What are the clotting factors of the intrinsic pathway?

- Factors V

- Factor VIII

- Factor XI

What does antithrombin III inhibit?

Thrombin and Factor Xa

What do Protein C and S do?

Inactivate Va and VIIIa and inhibits the function of prothrombinase and intrinsic tenase complexes

Which compound is secreted by endothelial cells and accelerates ATIII activity?

Heparan Sulfate

What does TFPI inhibit?

TF/VIIa and Xa

Which compound converts protein C to its active form (aPC)?

Thrombomodulin

What is the process that utilizes plasmin to catalyze the breakdown of fibrin clots into soluble degredation products?

Fibrinoloysis

What activates plasmin?

tissue-Plasminogen Activator (t-PA)

What inhibits fibrinolysis?

Plasminogen Activator Inhibitor-1 (PAI-1)

What does thrombin convert?

Fibrinogen to fibrin

What factor stabilizes fibrin?

Factor XIIIa

What does thrombin activate?

Platelets, factors V, VIII, XI, and Protein C

Which factors promote anticoagulant properties of a normal endothelium?

- Prostacyclin production

- Nitric Oxide production

- Thrombomodulin production

- Heparan sulfate proteoglycans

- Plasminogen activators (tPA, uPA)

Which factors cause anti-fibrinolytic properties of a damaged endothelium?

- Augmented release of inhibitors of fibrinolysis

- Reduced NO availability

- Tissue Factor expression

What characterizes an anticoagulant state?

- Increased anticoagulants and increased fibrinolysis

- Decreased tissue factors, PAI, fibrinogen, platelet-activating factor

- Increased tPA/uPA, thrombomodulin, prostacyclin

What characterizes a procoagulant state?

- Increased clotting factors and decreased fibrinolysis

- Decreased tPA/uPA, thrombomodulin, prostacyclin

- Increased tissue factors, PAI, fibrinogen, platelet-activating factor

How do PAI-1 levels differ in diabetes vs non-diabetes?

Higher in patients with diabetes

How does obesity affect PAI-1 levels?

Obesity increases PAI-1 levels

What is D-dimer?

Fibrin degradation product

When is D-dimer elevated?

Acute thrombosis

What is D-dimer used for?

Ruling out VTE (if negative)

Which conditions can elevate D-dimer?

Recent surgery/trauma, pregnancy, advanced age, cancer

What is Disseminated Intravascular Coagulation (DIC)?

Widespread coagulation causing both clotting and bleeding and is always secondary to underlying condition

What causes Disseminated Intravascular Coagulation (DIC)?

Sepsis, trauma, cancer, obstetric complications