Hemodynamic Disorders and Thrombosis Quiz

Hemodynamic Disorders, Thrombosis, and Shock

• The health of cells and tissues depends on an intact circulation to deliver oxygen and remove wastes, and on normal fluid homeostasis. Normal fluid homeostasis means maintaining blood as a liquid until clot formation is essential.
• Normal hemostasis results from tightly regulated processes that maintain blood in a fluid, clot-free state in normal vessels, while inducing rapid formation of a localized hemostatic plug at the site of vascular injury.
• Hemostasis and thrombosis both involve three components: the vascular wall, platelets, and the coagulation cascade.

Hemostasis and Thrombosis: Vasoconstriction

• Vasoconstriction: Endothelin release causes vasoconstriction.
• This reduces blood flow to the injured area, limiting blood loss

Hemostasis and Thrombosis: Primary Hemostasis

• Platelet adhesion: Platelets adhere to the exposed collagen in the vascular wall. Von Willebrand factor facilitates this.
• Shape change: Platelets change shape, becoming stickier.
• Granule release: Platelets release ADP and TXA₂, promoting further platelet aggregation.
• Recruitment: Platelets aggregate (clump together) forming a hemostatic plug.
• This plug stops or slows blood loss.

Hemostasis and Thrombosis: Secondary Hemostasis

• Tissue factor expression: Tissue factor is exposed when the endothelium is damaged.
• Phospholipid complex expression: This enhances interactions between clotting factors.
• Thrombin activation: Thrombin activation leads to fibrin polymerization.
• Fibrin polymerization: Fibrin forms a meshwork, further strengthening the hemostatic plug.

Thrombus and Antithrombotic Events

• Release of t-PA (tissue plasminogen activator): Fibrinolysis(breaking down fibrin) is initiated.
• Thrombomodulin: Blocks coagulation cascade
• Trapped neutrophils & red blood cells: The thrombus becomes visible.
• Polymerized fibrin: The blood clot's final stage

Endothelium

• Endothelial cells modulate (influence and regulate) the opposing aspects of normal hemostasis.
• Anti- and prothrombotic activities of endothelial cells regulate thrombus formation, propagation, or dissolution.
• Endothelial cells have antiplatelet, anticoagulant, and fibrinolytic properties at baseline that can become procoagulant after injury or activation.

Antithrombotic Properties

• Endothelial cells maintain a liquid blood flow environment under most circumstances by blocking platelet adhesion and aggregation, inhibiting the coagulation cascade, and lysing blood clots.
• Antiplatelet effects, anticoagulant effects, and fibrinolytic effects are critical.

Antiplatelets

• In the presence of an intact endothelium, platelets and coagulation factors don't interact with the highly thrombogenic subendothelial ECM.
• Prostacyclin (PGI₂) and nitric oxide.
• Adenosine diphosphatase.
• Heparin-like molecules and thrombomodulin.

Fibrinolytic Properties

• Plasminogen Activator (tPA).
• The Extrinsic coagulation sequence and the tissue factor sequence lead to favoring thrombosis.
• There is also an inhibitory pathway to limit thrombosis.

Prothrombotic Properties

• Endothelial injury leads to platelet adhesion. This is facilitated by von Willebrand factor (vWF).
• Endothelial cells can produce procoagulant effects in response to injury or activation by bacterial endotoxin or cytokines (e.g., TNF, IL-1). Tissue factor is synthesized in these cases.
• Endothelial cells can have antifibrinolytic effects by secreting inhibitors of plasminogen activator (PAIs).

Platelets

• Platelets play a central role in normal hemostasis
• Platelet adhesion to the ECM is primarily mediated by interactions with vWF, acting as a bridge between platelet surface receptors (e.g., Gplb) and exposed collagen.
• Platelet activation increases the expression of phospholipid complexes.
• Dense body contents such as ADP and ATP, calcium, histamine, serotonin, and epinephrine are released.

Platelet Aggregation

• Platelet aggregation follows adhesion and granule release.
• ADP and thromboxane A2 promotes platelet aggregation which forms the primary hemostatic plug.
• This primary aggregation, is reversible.
• Thrombin binding to platelet surface receptors (PARs) leads to irreversible aggregation and platelet contraction, leading to the secondary hemostatic plug. Fibrinogen is converted to fibrin.

Coagulation Cascade

• The coagulation cascade is a series of enzymatic reactions that amplify the activation process.
• Inactive proenzymes are proteolytically cleaved, leading to activated enzymes, eventually resulting in thrombin.
• Thrombin converts soluble fibrinogen into insoluble fibrin, which forms a meshwork entrapping platelets and other cells, creating the secondary hemostatic plug.
• To prevent runaway clotting, the coagulation cascade must be restricted to the injury site with natural anticoagulants.

Antithrombins

• Antithrombins, such as antithrombin III, inhibit thrombin and other serine proteases (factors IXa, Xa, Xla, and XIla).
• Proteins C and S are vitamin K-dependent proteins and inactivate cofactors Va and VIIIa.
• Tissue factor pathway inhibitor (TFPI) limits clotting.

Fibrinolysis

• Activation of the clotting cascade initiates a fibrinolytic cascade that limits the size of the clot.
• Plasmin breaks down fibrin and interferes with polymerization
• Plasmin is generated by enzymatic degradation of plasminogen, activated by factor XII-dependent pathways or by plasminogen activators (t-PA being most important).

Thrombosis

• Three primary influences (Virchow's triad) affect thrombus formation: endothelial injury, abnormal blood flow (stasis or turbulence), and hypercoagulability.

Thrombosis: Endothelial Injury

• Endothelial injury is important in thrombus formation in the heart or arterial circulation.
• Any disturbance of prothrombotic and antithrombotic activity of endothelium can influence local clotting.

Thrombosis: Abnormal Blood Flow

• Turbulence causes endothelial injury and dysfunction leading to arterial or cardiac thrombosis.
• Stasis is a major factor in venous thrombosis.

Thrombosis: Hypercoagulability

• Hypercoagulability is any alteration of the coagulation pathways that predisposes to thrombosis.
• Can be primary (genetic) or secondary (acquired).
• Examples include factor V Leiden, prothrombin gene mutation, and antithrombin III deficiency
• Secondary examples include prolonged bed rest, myocardial infarction, atrial fibrillation, cancer, disseminated intravascular coagulation etc.

Thrombosis: Morphology

• Thrombi can develop anywhere in the cardiovascular system, influence location & form of thrombus.
• Arterial thrombi typically propagate retrograde, while venous thrombi extend in the direction of blood flow.
• Thrombi can have grossly or microscopically visible laminations called lines of Zahn.
• Mural thrombi refer to thrombi in the heart chambers or the aorta lumen.

Thrombosis: Arterial Thrombi

• Arterial thrombi are frequently occlusive and consist of a friable meshwork of platelets, fibrin, erythrocytes and altered leukocytes.
• Thrombosis in the major arteries is clinically significant.

Thrombosis: Venous Thrombi

• Venous thrombi, largely the result of coagulation cascade activation, are usually occlusive.
• Platelets play a secondary role.
• Venous thrombi contain more enmeshed erythrocytes, often called "red" or "stasis" thrombi.
• Venous thrombi are frequently associated with slow or sluggish blood flow.

Fate of the Thrombus

• Propagation
• Embolisation
• Dissolution
• Organization and recanalization

Emboli

• An embolus is a detached intravascular solid, liquid, or gaseous mass carried by the blood to a distant site of origin.
• A majority (99%) of emboli originate as dislodged thrombi (thromboembolism).

Pulmonary Thromboembolism

• Has incidence rate of 20 to 25 cases per 100,000 hospitalized patients.
• Deep leg vein thrombi above the knee are the source.
• Most pulmonary emboli (60%–80%) are clinically silent.
• Consequences include ischemic necrosis of downstream tissue and sudden death/right ventricular failure.

Systemic Thromboembolism

• Systemic thromboembolism refers to emboli in the arterial circulation.
• Most (80%) originate from intracardiac mural thrombi.
• Common sites for arterial embolization include lower extremities and brain.

Predisposing Factors for Deep Vein Thrombosis

• Immobility
• Pregnancy
• Post-operative
• Severe burns
• Heart failure
• Cancer

Prophylaxis & Treatment for Deep Vein Thrombosis (DVT)

• High-risk patients should undergo prophylaxis (Heparin, leg compression).
• Treatment involves intravenous heparin and warfarin.

Other Types of Emboli

• Fat embolism (fat globules in the circulation, after fractures or trauma)
• Air embolism (air bubbles obstructing vascular flow, during obstetric procedures or chest wall injuries).
• Amniotic fluid embolism (a rare, serious complication of labor and postpartum).

Clinical Correlations (Venous vs. Arterial Thrombosis)

• Venous thrombi obstruct distal blood vessels and can embolize to the lungs.
• Arterial thrombi are more clinically relevant due to their ability to produce tissue infarction at critical sites like coronary and cerebral vessels.

Test your knowledge on hemodynamic disorders, thrombosis, and shock. This quiz covers the critical processes of hemostasis, including vasoconstriction and primary hemostasis involving platelets and coagulation. Dive into the mechanisms that keep blood flowing and the conditions leading to clot formation.