Hemostasis and Thrombosis Pathophysiology

• Anti-thrombotic agents include antiplatelets, anticoagulants, and thrombolytics.
• The focus will be on coagulation pathophysiology.

Learning Objectives

• Understand the fundamentals of hemostasis.
• Understand the link between hemostasis and thrombosis.
• Be able to understand the pathogenesis of thrombosis.
• Understand clinical significance.
• Understand the importance of drug therapy.
• Understand mechanisms of regulation.
• Evaluate drug targets.
• Engage in critical thinking.

Hemostasis

• Hemostasis maintains blood fluidity in normal vessels.
• Hemostasis involves primary and secondary processes.
• It limits blood loss by forming a localized plug in injured vessels.
• It balances fluidity and clot formation.
• It is a physiological process that stops bleeding while maintaining normal blood flow.
• It requires complex interactions between vascular endothelium, platelets, and coagulation factors.
• Vascular endothelium is the inner lining of blood vessels that initiates the process by releasing signals in response to injury.
• Platelets are cellular components that adhere to the injury site, activate, and aggregate to form a temporary plug (primary hemostasis).
• Coagulation factors are plasma proteins that activate sequentially to form a stable fibrin clot (secondary hemostasis).

Phases of Hemostasis

• Vasoconstriction
• Primary Hemostasis
• Secondary Hemostasis
• Clot Regulation

Clinical Relevance of Hemostasis

• Hemostasis is essential for preventing excessive blood loss.
• Dysregulation of hemostasis can lead to pathological states.
• Insufficient hemostasis results in bleeding disorders like hemophilia or von Willebrand disease.
• Excessive hemostasis leads to thrombosis, causing conditions such as stroke, myocardial infarction, or deep vein thrombosis.

Pathogenesis of Thrombosis

• Pathogenesis of thrombosis includes a pathologic extension of hemostasis.
• A pathologic clot is termed a thrombus.
• Coagulation reactions are inappropriately regulated so that a clot enlarges uncontrollably and occludes the lumen of a blood vessel.
• Three major factors predispose to thrombus formation: endothelial injury, abnormal blood flow, and hypercoagulability.
• Occlusion of a section of the vascular tree can occur.
• Endothelial injury causes changes in shear stress associated with hypertension or turbulent flow, hyperlipidemia, elevated blood glucose in diabetes mellitus, traumatic vascular injury, and some infections.
• Hypertension and cigarette smoking can lead to coronary artery thrombosis.
• Abnormal blood flow can be caused by atherosclerotic plaques and myocardial infarction, leading to turbulent blood flow and vascular injury.
• Cardiac arrhythmias, such as atrial fibrillation, can also generate areas of local stasis.
• Stasis is the major cause for the formation of venous thrombi, which typically occur in the deep veins of the leg.
• Hypercoagulability refers to an abnormally heightened coagulation response to vascular injury, resulting from primary or secondary disorders.
• Primary disorder examples are overexpression of factor Va, deficiency of protein C, and AT-III.
• Secondary disorder examples include oral contraceptive use, which increases hepatic synthesis of coagulation factors.

Manifestation of Thrombosis

• Occlusive clot-MI
• Stroke
• Deep vein thrombosis
• Pulmonary embolism
• Other vein & arterial thrombosis can occur

Clinical Cases and Implications

• John McCain developed a clot linked to glioblastoma post-surgery, highlighting cancer-related risks.
• Serena Williams experienced pulmonary embolism post-surgery, underscoring risks in post-operative care.
• Dick Cheney had DVT after long-haul travel, illustrating risks from prolonged immobility.

Clinical Significance of Learning Thrombosis

• Understand disease mechanisms to get insights into how pathological clots form and their complications.
• Develop preventive strategies that enable strategies to reduce risks of thromboembolic events.
• Guide effective treatment via the selection and application of anti-thrombotic therapies for diverse conditions.

Embolus vs Thrombus

• Road ahead is to investigate thrombus composition, types, pathophysiology, and regulation
• It is important to understand what an embolus is.
• A thrombus is a blood clot that is stuck in one place.
• An embolus is a detached thrombus that becomes free floating.
• Both are dangerous and may occlude blood vessels, depriving tissues of oxygen and nutrients (ischemia and tissue damage).

Thrombus Composition

• Platelets play a central role in initiating thrombus formation.
• Fibrin stabilizes the thrombus by forming a mesh-like structure.
• Red blood cells (RBCs) get trapped in the fibrin network and contribute to the bulk and appearance of venous thrombi.
• White blood cells (WBCs) are found in smaller amounts and contribute to the inflammatory component of the thrombus.

Thrombus Types

• Arterial thrombi are platelet-rich and associated with high shear stress areas, such as sites of atherosclerosis; examples include pulmonary embolism (PE) and stroke.
• Venous thrombi are fibrin- and RBC-rich, typically forming in low-flow environments (e.g., deep veins); examples include venous thromboembolism (VTE) and deep vein thrombosis (DVT).

Thrombosis: Pathophysiology

• Primary
• Secondary
• Feedback Control
• Vasoconstriction

Thrombosis: Pathophysiology- Primary Hemostasis

• Primary hemostasis involves the transformation of platelets into a hemostatic plug through three major reactions which include:
• Adhesion
• The granule release reaction
• Activation and Aggregation

Primary Hemostasis: Adhesion

• Platelets adhere to subendothelial collagen that is exposed after vascular injury.
• von Willebrand factor (vWF) binds to GlycoProtein Ib [GPIb] on the platelet membrane and to the exposed collagen [like a bridge].
• Platelet GlycoProtein VI (GPVI) interacts directly with collagen as well.

Pathophysiology: Platelet Granule Release

• 3 major chemicals/granules in platelet granule release are ADP, TxA2, and thrombin.
• Platelet granule release helps in vasoconstriction and further granule release.
• Platelet granule release is important in mediating platelet aggregation and causes platelets to become "sticky" and adhere to one another.
• Other Granules are Ca++, ATP, Serotonin, and Platelet factor 4.

Thrombosis: Pathophysiology - Activation and Aggregation

• Activation is carried out by TxA2, ADP and Thrombin
• Activated fibrinogen-binding protein GPIIb/IIIa bind to other platelets via fibrinogen causing aggregation.
• Drugs that target any of these steps are Anti-platelets.

Coagulation Pathways - Secondary Hemostasis

• Secondary Hemostasis is the coagulation cascade.
• Coagulation factors circulate as inactive proenzymes synthesized by the liver.
• They are activated by the activated factors that precede them in the cascade.
• Intrinsic Pathway involves activation by damage inside the blood vessel (endothelial injury).
• Extrinsic Pathway involves are activated by damage to tissue outside the blood vessel.
• Common Pathway involves final convergence of intrinsic and extrinsic pathways.
• Coagulation Pathways: clinical significance revolves around the discovery of the drug targets.
• Known drug types includes coagulation factors (Factors II, V, VII, IX) inhibitor and Factor IIa (thrombin) inhibitor and Factor Xa inhibitor.
• It is very important to consider the Feedback Control = Regulation of hemostasis in the body.

Roles of Thrombin

• Thrombin activates Factor 1: This is achieved by converting the soluble protein fibrinogen into insoluble polymer fibrin.
• Thrombin activates Factor XIII: This is achieved by converting the polymers into highly stable meshwork of clots.
• Thrombin amplifies the clotting cascade
• Thrombin activates Platelets

Regulation of Hemostasis

• Regulation of hemostasis is needed so that clotting must be restricted to the local site of vascular injury.
• The size of the primary and secondary hemostatic plugs must be restricted so that the vascular lumen remains patent.
• This achieved when endogenous anticoagulant factors restrict propagation of the clot beyond the site of injury.
• The activated endothelium maintains a balance of procoagulant and anticoagulant factors to limit hemostasis to the site of vascular injury.
• Endogenous anticoagulant factors are Prostacyclin (PGI2), Anti-thrombin III, Proteins C and S, Tissue Factor Pathway Inhibitor (TFPI), and Tissue-type Plasminogen Activator (t-PA)..
• Endogenous anticoagulant also include Heparin-like molecules.
• Anti-thrombin (ATIII) causes the Inactivation of Thrombin (lla), IXa, Xa, Xla, and Xlla
• It is enhanced by a heparin-like molecules
• It is very important to find other Drug targets for antithrombin related treatments.
• Food for thought: Consider the affect of heparin treatment to treat someone lacking AT-III.
• Protein C: Inactivates factors factors Va and VIIIa and is a Part of a feedback control mechanism
• Tissue factor pathway inhibitor limits action of tissue factor (TF).; and Limits activation of factor VII and subsequent factors
• Tissue Plasminogen Activator converts fibrin fibrin into fibrin degration products and is used as a drug The types of anti-thrombotic drugs are:
• Anti-Platelets help Prevent occurrence or enlargement of a thrombus
• Anti-Coagulants
• Thrombolytics help Dissolve already existing clots