Hemodynamic Disorders and Thrombosis

Hemodynamic Disorders, Thrombosis, and Shock

• The health of cells and tissues relies on an intact circulation to deliver oxygen and remove waste products, as well as on normal fluid homeostasis.
• Maintaining blood as a liquid until clot formation is necessary is a crucial aspect of normal fluid homeostasis.
• Normal hemostasis is a result of tightly regulated processes keeping blood in a fluid, clot-free state in normal vessels, while simultaneously inducing rapid clot formation at the site of vascular injury.
• Hemostasis and thrombosis involve three components: the vascular wall, platelets, and the coagulation cascade.

Hemostasis and Thrombosis

• Vasoconstriction is the first stage, where endothelium release causes vasoconstriction, reducing blood flow to the injured area.
• Primary hemostasis involves platelet adhesion, shape change, granule release (ADP, TXA2), recruitment and aggregation to form a hemostatic plug.
• Secondary hemostasis involves tissue factor expression, phospholipid complex expression, thrombin activation, and fibrin polymerization to form an insoluble fibrin gel surrounding the platelets, making the plug stable.
• Thrombus formation and anticlotting mechanisms involves the release of t-PA (fibrinolysis), and thrombomodulin to stop the coagulation cascade.

Endothelium

• Endothelial cells play a complex role in hemostasis by modulating various opposing aspects, establishing a balance affecting thrombus formation, propagation, or dissolution.
• Endothelial cells possess antiplatelet, anticoagulant, and fibrinolytic properties under normal conditions but can also exhibit procoagulant activities after exposure to injury/activation.

Antithrombotic Properties

• Endothelial cells maintain a liquid blood flow environment, by preventing platelet adhesion and aggregation, by inhibiting the coagulation cascade, and by breaking down blood clots.
• Intact endothelium prevents platelets and coagulation factors from interacting with thrombogenically active subendothelial ECM and by secreting prostacyclin (PGI2) and nitric oxide, along with Adenosine diphosphatase.
• Endothelial-derived heparin-like molecules and thrombomodulin inhibit the clotting mechanisms.

Fibrinolytic Properties

• The coagulation cascade activation also activates an opposing fibrinolytic cascade, a process regulating the ultimate clot size.
• Plasmin, an enzyme, is responsible for fibrin breakdown, and interfering with fibrin polymerization.
• Plasmin is produced by degrading the inactive plasminogen precursor, either through a factor XII-dependent pathway or by plasminogen activators like t-PA or u-PA.

Coagulation Cascade

• The coagulation cascade is a series of enzymatic reactions that amplify the conversion of inactive proenzymes to active enzymes, culminating in thrombin.
• Thrombin converts the soluble protein fibrinogen into insoluble fibrin monomers, which polymerize into a gel that ensnares platelets and other circulating cells to form the secondary hemostatic plug.
• Activated coagulation cascade in the body needs to be localized to prevent a runaway effect, achieved with a variety of anticoagulants.

Antithrombins

• Antithrombins like antithrombin III inhibits thrombin and other serine proteases, such as factors IXa, Xa, XIa, and XIIa.
• Proteins C and S are Vitamin K-dependent proteins, responsible for inactivating cofactors Va and VIIIa, regulating the clotting cascade.
• Tissue factor pathway inhibitor (TFPI) plays a vital role in controlling clotting, functioning by restricting factor activation.

Thrombosis

• The pathogenesis of thrombosis has three major influences; endothelial injury, abnormal/turbulent blood flow and hypercoagulability.

Endothelial Injury

• Endothelial injury is crucial in thrombus formation, and disruption in the dynamic balance between prothrombotic and antithrombotic functions contribute to local clotting events.
• Endothelial injury is relevant in thrombus formation, particularly in the heart or arterial circulation.

Alterations in Blood Flow

• Turbulence in blood flow causes endothelial injury or dysfunction, contributes to arterial and cardiac thrombosis.
• Blood stasis is a crucial contributor to venous thrombi development.

Hypercoagulability

• Hypercoagulability is defined as alterations in coagulation pathways that increase the susceptibility to thrombosis.
• This can be further classified into primary (genetic) and secondary (acquired) disorders.

Morphology

• Thrombi can originate anywhere in the cardiovascular system, including heart chambers, valves, arteries, veins or capillaries.
• Thrombi develop focally on the underlying vascular surface and may propagate in the direction of blood flow, with arterial thrombi propagating retrogradely and venous thrombi propagating towards the heart.
• Thrombi can have distinct laminations known as Zahn lines, and heart or aortic thrombi are categorized as mural thrombi.
• Arterial thrombi are often occlusive and are primarily composed of platelet activation and coagulation activation, featuring a meshwork of platelets, fibrin, erythrocytes and degenerating leukocytes.
• Venous thrombi are almost always occlusive, having a cast of the lumen, primarily due to the coagulation cascade and containing enmeshed erythrocytes; called red or stasis thrombi

Fate of Thrombus

• Thrombi can propagate, embolize or dissolve.
• Thrombi organization and recanalization can eventually occur.

Clinical Correlations

• Thrombi can significantly obstruct arteries and veins, causing emboli.
• Venous thrombi are more concerning due to their potential to embolize to the lungs causing death.
• Arterial thrombi can lead to tissue infarctions and are clinically more significant when obstructing critical blood vessels.

Venous Thrombosis

• Most venous thrombi arise from superficial or deep leg veins, often in the saphenous system (particularly in the presence of varicosities).
• Superficial venous thrombi typically cause local congestion, swelling, pain, and tenderness.
• Deep venous thrombi, arising in larger leg veins above the knee joint (e.g., popliteal, femoral, iliac) can embolize and be more serious.

Cardiac and Arterial Thrombosis

• Atherosclerosis is a critical contributor to arterial thrombosis, related to loss of endothelial integrity and altered vascular flow.
• Cardiac mural thrombi can arise from myocardial infarction, leading to dyskinetic myocardial contraction or endocardium damage.
• Rheumatic heart disease can lead to atrial mural thrombi due to mitral valve stenosis, accompanied by left atrial dilation and atrial fibrillation.

Embolism

• An embolus is a detached intravascular solid, liquid, or gaseous mass that is transported by blood to a distant site.
• Almost all emboli (99%) are thromboemboli.
• Other rare forms include fat droplets, air bubbles, atherosclerotic debris, tumor fragments, bone marrow and foreign bodies like bullets.

Pulmonary Thromboembolism

• Pulmonary embolism (PE) has a rate of approximately 20-25/100,000 hospitalized patients with a fatality rate of 6% to 2%, though its prevalence is lower post-mid 20th century.
• Most pulmonary emboli (60-80%) are clinically silent because of their small size. Deep leg vein thrombi above the knee joint are the main origin of venous emboli.

Systemic Thromboembolism

• Most systemic thromboemboli originate from intracardiac mural thrombi.
• Commonly associated with left ventricular wall infarctions and dilated left atria (e.g., secondary to mitral valve disease and potentially leading to embolization to lower extremities (75%) and brain (10%).

Deep Veins Thrombosis - Predisposing Factors

• Immobility, pregnancy and postpartum states, post-operative, severe burns, heart failure, and disseminated cancer increase the risk of deep vein thrombosis (DVT).

Prevention and Treatment of DVT

• High risk patients must identify themselves and be offered prophylaxis.
• Treatment of DVT generally includes intravenous heparin and/or warfarin .

Fat Embolism, Air Embolism, and Amniotic Fluid Embolism:

• Fat embolism syndrome, characterized by pulmonary insufficiency, neurological symptoms, anemia and thrombocytopenia, arises following long bone fractures or soft-tissue trauma.
• Air embolism can occur due to large amounts of air entering the circulation, often from obstetric procedures or chest wall injury and can frequently cause distal ischemic injury.
• Amniotic fluid embolism (AFE) is a serious complication of labor and the immediate postpartum period with an unusually high mortality rate.