VTE Pathophysiology

Lecture Objectives

Define thrombus and embolus.

Describe how arterial clots differ from venous clots

Discuss the pathogenesis of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Outline the steps leading to platelet aggregation.

Describe the extrinsic, intrinsic, and common pathways of coagulation that result in the formation of fibrin clots.

Describe the cellular model of coagulation and the processes in the steps of initiation, amplification, propagation, and termination of coagulation.

Discuss how hemostasis is controlled by thrombin, antithrombin, TFPI, thrombomodulin, Proteins C and S, heparan sulfate, and fibrinolysis.

Describe the process of fibrinolysis and its control.

Discuss the role of endothelial cells in control of blood flow and coagulation.

Discuss application of D-dimer in the DVT diagnosis process.

Describe the pathophysiology and causes of disseminated intravascular coagulation (DIC).

Key Definitions

Thrombus: blood clot that is the final product of the blood coagulation process in hemostasis

·       Two Components

o   Aggregated platelets  Platelet plug

o   Fibrin protein

Embolus: detached, traveling mass carried by circulation that is capable of clogging at a distant site from its origin

Venous Thromboembolism (VTE)

Clot formation in venous circulation

Manifestations

·       Deep vein thrombosis (DVT)

·       Pulmonary embolism (PE)

VTE Complications

·       Post-thrombotic syndrome

·       Chronic thromboembolic pulmonary hypertension (CTPH)

Increased Risk of VTE

·       Immobilized patients

·       Orthopedic surgery

Virchow’s Triad

Venous Stasis

·       Immobilization

·       Surgery  General Anesthesia

·       Damage to Venous Valves

·       Obesity

Hypercoagubility

·       Obesity/Diabetes

·       Cancer

·       Clotting Factor Changes (inheritable mutations, overexpression)

·       Pregnancy

·       Drugs (estrogen containing contraceptives)

Vascular Injury

·       Prior DVT/PE

·       Fracture

·       Major Orthopedic Surgery (knee, hip)

·       Trauma (fractures of pelvis, hip, leg)

·       Indwelling Catheters

Hemostasis

·       “Blood slows down”

·       Maintains circulatory system integrity following blood vessel damage

·       Prevents excessive bleeding

·       Hemostatic clots of VTE impairs blood flow wand causes vessel occlusion

·       2 STEPS

o   Platelet plug formation – See below for more

o   Fibrin clot formation via coagulation cascade

·      

Arterial vs. Venous Clots

Platelet Plug Formation

·       Vascular injury  Platelets adhere to site of injury via mediation by vWF (Von Willebrand factor)

·       Platelet ADHESION  ACTIVATION  AGGREGATION

·       Promoted by

o   Epinephrine

o   Thrombin

o   Adenosine Diphosphate (ADP) – chemical signal that triggers platelet aggregation

o   Serotonin – chemical signal that triggers platelet aggregation

o   Thromboxane A2 – chemical signal that triggers platelet aggregation

·       Formation of occlusive platelet thrombus

·       Platelet plug anchored and stabilized by developing fibrin mesh

·       In Blood Clot – Platelets held together by fibrinogen strands bound to GPIIb/IIIa receptor on platelets

Fibrin Clot Formation

·       Vascular injury  Fibrin clot formed due to coagulation cascade

·       Clotting factors normally circulate in inactive form  Coagulation cascade converts into active form

·       Conversion leads to fibrin clot

·       Clotting factors catalyze breakdown of subsequent factor – made in liver

·       Two models – See below for more

Clotting Cascade

Intrinsic Pathway

·       Contact activation system requires blood to contact a negatively charged surface (i.e. Collagen)

·       Phospholipids from aggregated platelets and Ca2+ necessary for activation of factor X  Xa

·       Thrombin (IIa) generated amplifies pathway by promoting conversion – See below for more

o   V  Va

o   VIII  VIIIa

o   XI  XIa

·      

Extrinsic Pathway

·       Vascular/Tissue damage exposes blood to tissue factor (TF, Factor III, “Thromboplastin”)

o   Surface of subendothelial (i.e. smooth muscle, fibroblasts, microparticles released form activated platelets and monocytes)

o   Complexes with VIIa to cause factor X  Xa

o   TF/VIIa also stimulates factor IX  IXa

·      

Common Pathway

·       Starting Point - Intrinsic and extrinsic converge at factor X  Xa

·      

Cellular Model of Coagulation

Initiation

·       Extrinsic tenase complex (TF/VIIa) activates V, IX, X  Initial thrombin generation

·       Site: TF-expressing cells (monocytes, endothelial cells, platelets)

Amplification

·       Thrombin from initiation phase activates platelets, V, VIII, XI

·       Site: Surface of activated platelets

Propagation

·       Platelet surface intrinsic tenase complex (VIIIa-IXa) and prothrombinase complex (Xa-Va) generate thrombin burst and form stable fibrin clot

·       Site: Surface of activated platelets

Termination

·       Endogenous anticoagulants (TFPI, protein C/S, ATIII) limit clot expansion

·       Site: Injured endothelium or vasculature

Summary of Important Terms

·       Factor II = Prothrombin

·       Factor IIa = Thrombin

·       Tissue Factor (TF) = Thromboplastin

·       Extrinsic Tenase Complex = TF/VIIa

·       Intrinsic Tenase Complex = VIIIa-IXa-Ca2+-PL (VIIIa-IXa)

·       Prothrombinase Complex = Xa-Va-Ca2+-PL (Xa-Va)

·       “Tenase” = Enzyme complexes that breakdown factor X

o   TF-VIIa  Extrinsic tenase

o   VIIIa-IXa  Intrinsic tenase

Extrinsic vs. Intrinsic Pathways

Extrinsic

·       Physiological initiation of clotting

·       Extrinsic tenase complex formed in initiation phase

Intrinsic

·       Amplification of clotting after activation by extrinsic pathway

·       Thrombin generated during initiation activates clotting factors of intrinsic pathway

o   Platelets

o   Factor V, VIII, XI

Control of Hemostasis

·       Antithrombin III (ATIII or AT)

o   Inhibits factor Xa and thrombin (IIa)

o   Also inhibits XIIa and IXa

·       Protein C/S

o   Inactivates factors Va and VIIIa  Inhibit function of prothrombinase and intrinsic tenase complexes

o   Prevents coagulation from spreading

·       Heparan Sulfate

o   Heparin-like compound that accelerates antithrombin III (ATIII) activity

·       Tissue Factor Pathway Inhibitor (TFPI)

o   Inhibits Xa

o   TFPI-Xa complex inhibits TF/VIIa (extrinsic tenase)

·       Thrombomodulin

o   Converts protein C to active protein C (cPC)

o   Thrombin bound to thrombomodulin activates PC  Initiating anticoagulant pathway

·       Fibrinolysis

o   “Clot dissolution”

o   Plasmin catalyzes breakdown of fibrin clots into soluble degradation products

Control of Fibrinolysis

·       Plasmin dissolves clots by breaking down fibrin

o   Made of plasminogen

·       Plasminogen  Plasmin conversion enhanced by tissue-Plasminogen Activator (t-PA)

·       T-PA inhibited by plasminogen activator inhibitor-1 (PAI-1)

·       PAI-1 inhibits fibrinolysis

Functions of Thrombin (IIa)

·       Converts fibrinogen  fibrin (forms clot)

·       Activates factor XIII  XIIIa (cross links fibrin and stabilizes clot)

·       Activates platelets  Promotes platelet aggregation

·       Amplifies coagulation by activating upstream clotting factors

o   Factor V  Va

o   Factor VIII  VIIIa

o   Factor XI  Xia

·       Activates protein C (when bound to thrombomodulin)  Anticoagulation

Coagulation – Role of Endothelium

Normal Endothelium:

·       Anticoagulant and fibrinolytic properties

·       Anticoagulant properties

o   Prostacyclin (PGI) production – inhibits platelets

o   Nitric Oxide (NO) production – inhibits platelets

o   Thrombomodulin production – binds thrombin  resulting in protein C activation  inactivation of factor Va and VIIa

o   Heparan Sulfate Proteoglycans – enhance antithrombin activity  inhibits thrombin and factor Xa

o   Plasminogen Activators (tPA, uPA) – fibrin breakdown

Damaged Endothelium:

·       Procoagulant and anti-fibrinolytic properties

·       Procoagulant properties

o   Augmented release of inhibitors of fibrinolysis (PAI-1)

o   Reduced NO availability

o   TF expression

Anticoagulant vs. Procoagulant State

Anticoagulant:

·       Increased anticoagulants and fibrinolysis

·       INCREASED

o   Plasminogen activators (tPA, uPA)

o   Thrombomodulin

o   Prostacyclin

·       DECREASED

o   TF

o   PAI-1

o   Fibrinogen

o   Platelet-activating factor

Procoagulant:

·       Increased coagulants and decreased fibrinolysis

·       INCREASED

o   TF

o   PAI-1

o   Fibrinogen

o   Platelet-activating factor

·       DECREASED

o   Plasminogen activators (tPA, uPA)

o   Thrombomodulin

o   Prostacyclin

PAI-1 – Procoagulant State in Diabetes/Obesity

Diabetes:

·       Increased PAI-1 activity in patients with diabetes

Obesity:

·       Increased PAI-1 activity in obese patients

·       Increased risk of clots and impaired fibrinolysis

Big Picture

D-dimer Measurement

·       Diagnostic method

·       D-dimer: fibrin clot degradation product that is elevated in patients with VTE

·       Very sensitive marker but not sufficiently specific

o   Positive results not conclusive

o   Negative results rules out

·       Other conditions that cause D-dimer elevation

o   Surgery/Trauma

o   Pregnancy

o   Advanced Age

o   Cancer

Disseminated Intravascular Coagulation (DIC)

·       Widespread activation of coagulation cascade  Thrombosis and bleeding

·       Secondary to underlying condition

o   Excessive Activation of Coagulation  

§  Triggered by TF and endotoxins

§  Uncontrolled thrombin generation  Widespread fibrin  Microvascular thrombosis

o   Consumption of Coagulation Factors and Platelets

§  Continuous formation of clots depletes clotting factors/platelets  Increased bleeding risk

o   Secondary Fibrinolysis

§  Body activates plasmin to break down excess fibrin  Elevated D-dimer and bleeding

·       Causes

o   Sepsis – most common

o   Obstetric complications – 2^nd most common

o   Trauma

o   Malignancy