General Pathology

Theme 11: Haemodynamic Disorders II • Thrombosis, Embolism and Infarction

1. Define the terms: Thrombosis, Embolisma nd infarction.
2. Describe the pathogenesis, fates, effects and complications of a thrombus.
3. Characterise the various forms of emboli, their effects and complications.
4. Describe the causes, effects and complicatios of infarction.

Thrombosis

Thrombosis refers to inappropriate activation of blood clotting in uninjured vasculature or thrombotic occlusion of a vessel after relatively minor injury. Three primary influences on thrombus formation, so-called Virchow's triad, are as follows:

1. Endothelial injury is dominant and by itself can cause thrombosis, especially in the heart and arterial circulation (e.g., myocardial infarction, endocarditis, or ulcerated atherosclerotic plaque). Injury may occur from diverse causes, including hemodynamic stress (e.g., hypertension or turbulent flow over scarred valves), bacterial endotoxins, homocystinuria, hypercholesterolemia, radiation, or products absorbed from cigarette smoke. Thrombosis results from exposed subendothelial extracellular matrix and tissue factor, adherence of platelets, and depletion of prostaglandin I₂ and plasminogen activator inhibitors.

2. Alterations occur in normal blood flow. Normal blood flow is laminar (i.e., the cellular elements flow centrally in the vessel lumen, separated from endothelium by a clear zone of plasma).
   Stasis and turbulence (the latter forms eddy currents with local pockets of stasis):
   • Disrupt laminar flow and bring platelets into contact with the endothelium.
   • Prevent dilution of activated clotting factors by fresh flowing blood.
   • Retard the inflow of clotting factor inhibitors and permit the build-up of thrombi.
   • Promote endothelial cell activation.
   Stasis is important in causing thrombosis in the venous circulation, cardiac chambers, and arterial aneurysms; turbulence in the arterial circulation also directly causes endothelial injury and dysfunction. Hyperviscosity syndromes (e.g., polycythemia) or deformed erythrocytes (e.g., sickle cell anemia) result in small vessel stasis and also predispose to thrombosis.

3. Hypercoagulability contributes less frequently to thrombotic states but is an important component in certain conditions; it is loosely defined as any alteration of the coagulation pathways that predisposes to thrombosis.

Of the heritable hypercoagulable states, factor V gene mutations are the most common; 2 to 15% of the white population (60% of patients with recurrent deep vein thrombosis) carry a mutation (called the Leiden mutation) that renders their factor V resistant to cleavage by activated protein C. Others with inherited lack of anticoagulants (e.g., antithrombin III, protein C, or protein S) also typically present with venous thrombosis and recurrent thromboembolism.

Acquired thrombotic diatheses have diverse causes. With oral contraceptive use or the hyperestrogenic state of pregnancy, hypercoagulability may result from increased hepatic synthesis of coagulation factors and reduced synthesis of antithrombin III. In disseminated cancers, release of procoagulant tumor products predisposes to thrombosis. In the heparin-induced thrombocytopenia syndrome, administration of unfractionated heparin induces circulating antibodies that cause platelet activation and endothelial cell injury. In the antiphospholipid antibody syndrome, patients have antibodies against anionic phospholipids, which presumably cause similar platelet activation; such patients may have a well-defined autoimmune disease, such as systemic lupus erythematosus [SLE] (i.e., lupus anticoagulant syndrome), or may exhibit only the manifestations of a hypercoagulable state.

Morphology of the Thrombi

At sites of origin, thrombi are generally firmly attached. Arterial thrombi tend to extend retrograde from the attachment point, whereas venous thrombi extend in the direction of blood flow. The propagating tail may not be well attached and may fragment to create an embolus.

Cardiac and arterial thrombi are gray-red and tend to have gross and microscopic laminations (lines of Zahn) produced by pale layers of platelets and fibrin alternating with darker red cell-rich layers. Major sites include the left ventricle overlying an infarct, ruptured atherosclerotic plaques, and aneurysmal sacs.

Venous thrombosis (phlebothrombosis) often creates a long red-blue cast of the vein lumen because it occurs in a relatively static environment, and the thrombus contains more enmeshed erythrocytes among sparse fibrin strands (red or stasis thrombi). Fibrin and attachment to the vessel wall distinguish stasis thrombi from postmortem clots. Phlebothrombosis most commonly affects the veins of the lower extremities (> 90% of cases).

Thrombi may also form on heart valves. In infective endocarditis, bacteria or fungi form large infected thrombotic masses (vegetations), causing underlying valve damage and systemic infection. Sterile vegetations (non-bacterial thrombotic endocarditis) can also develop on non-infected valves in patients with hypercoagulable states, particularly in those with disseminated cancer. Uncommonly, non-infective, verrucous (Libman-Sacks) endocarditis occurs in patients with SLE (owing to circulating immune complexes).

Fate of the Thrombus

• Propagation, causing complete vessel obstruction.
• Embolization to other sites in the vasculature, particularly to the lungs with venous thrombi.
• Dissolution by fibrinolytic activity.
• Organization and recanalization, re-establishing vascular flow by ingrowth of endothelial cells, smooth muscle cells, and fibroblasts to create through-and-through capillary channels or by incorporating the thrombus as a subendothelial swelling of the vessel wall.
• Rarely, when bacterial seeding of a degrading thrombus occurs, a mycotic aneurysm may result.

Clinical Significance

Thrombi are significant because:
1. They cause obstruction of arteries and veins.
2. They are possible sources of emboli.

Venous Thrombosis (Phlebothrombosis)

• Superficial thrombi usually occur in varicose saphenous veins, where they cause local congestion and pain but rarely embolize. Local edema and impaired venous drainage can predispose to skin infections and to varicose ulcers.
• Deep thrombi in larger leg veins typically above the knee (e.g., popliteal, femoral, and iliac veins) more readily embolize. Although they may also cause pain and edema, the venous obstruction is usually offset by collateral flow. Thus, deep vein thromboses are entirely asymptomatic in approximately 50% of affected patients and are recognized only after embolization to the lungs.
  Deep venous thrombosis occurs in a variety of clinical settings:
  1. Advanced age, bed rest, or immobilization, which diminishes the milking action of muscles in the lower leg and slows venous return.
  2. Congestive heart failure (CHF)
  3. Trauma, surgery, and burns resulting in reduced physical activity, injury to vessels, release of procoagulant substances from tissues, or reduced tissue plasminogen activator (tPA).
  4. The puerperal and postpartum states, which are associated with amniotic fluid embolization and hypercoagulability.
  5. Tumor-associated procoagulant release, which causes the thromboses seen in disseminated cancers (migratory thrombophlebitis or Trousseau syndrome) and which may affect multiple sites simultaneously or sequentially.

Arterial Thrombosis

• Myocardial infarction with dyskinesis and endocardial damage may result in mural thrombus.
• Rheumatic valvular disease can cause mitral valve stenosis, followed by left atrial dilation and thrombus formation within the atrium or auricular appendages; concurrent atrial fibrillation augments atrial blood stasis.
• Atherosclerosis is a major cause of arterial thrombi, related to abnormal vascular flow and loss of endothelial integrity.

Disseminated Intravascular Coagulation (DIC)

Embolism

Embolism refers to any intravascular solid, liquid, or gaseous mass carried by the blood to a site distant from its point of origin. Most (99%) arise from thrombi, hence the term thromboembolism; unless otherwise specified, embolism should be considered to be thrombotic in origin. Other forms include droplets of fat, gas bubbles, atherosclerotic debris (atheroemboli), tumor fragments, bone marrow, or foreign bodies such as bullets. Emboli lodge in vessels too small to permit further passage, resulting in partial or complete vascular occlusion and ischemic necrosis of distal tissue (infarction).

Pulmonary Thromboembolism

• Most PEs (60 to 80%) are small and clinically silent. They eventually organize and get incorporated into the vessel wall or leave a delicate, bridging fibrous web. Embolic obstruction of small end-arteriolar pulmonary branches may cause infarction.
• Embolic obstruction of medium-sized arteries may result in pulmonary hemorrhage but usually does not cause pulmonary infarction because of collateral bronchial artery blood flow. In the setting of left-sided cardiac failure (with sluggish bronchial artery flow), infarcts may result.
• Sudden death, right heart failure (cor pulmonale), or cardiovascular collapse occurs when 60% or more of the pulmonary circulation is obstructed with emboli. Multiple emboli over time may cause pulmonary hypertension with right heart failure.

Systemic Thromboembolism

Fat Embolism

Pathogenesis involves mechanical obstruction by microemboli of neutral fat, followed by local platelet and erythrocyte aggregation. Subsequent free fatty acid release causes toxic injury to endothelium; platelet activation and granulocyte recruitment (free radicals, proteases, and eicosanoids) contribute.

Diagnosis depends on identifying microvascular fat globules. Because lipids are dissolved out of tissue by routinely used solvents, documentation requires frozen sections and special fat stains. Associated edema and hemorrhage (and hyaline membranes in lungs) may also be seen microscopically.

Air Embolism

Decompression sickness is a special form of air embolism caused by sudden changes in atmospheric pressure; scuba and deep-sea divers and individuals in unpressurized aircraft in rapid ascent are at risk. Air breathed at high pressure (e.g., during a deep-sea dive) causes increasing amounts of gas (particularly nitrogen) to be dissolved in blood and tissues. Subsequent rapid ascent (depressurization) allows the dissolved gases to expand and bubble out of solution to form gas emboli.

Formation of gas bubbles in skeletal muscles and joints causes a painful condition called the bends. In lungs, edema, hemorrhage, and focal emphysema lead to respiratory distress, the so-called chokes. Gas emboli may also cause focal ischemia in a number of tissues, including brain and heart. Treatment consists of repressurizing the individual and forcing the gas bubbles back into solution, followed by subsequent slow decompression.

A more chronic form of decompression sickness is called caisson disease; persistent gas emboli in the normally poorly vascu- larized portions of the skeleton (heads of the femurs, tibia, and humeri) lead to multiple foci of ischemic necrosis.

Amniotic Fluid Embolism

Infarction

Infarction refers to an area of ischemic necrosis usually caused by occlusion of the arterial supply (97% of cases). Almost all infarcts result from thrombotic or embolic events, although rarely there are other causes (e.g., vasospasm; extrinsic compression of a vessel by tumor, edema, or entrapment in a hernia sac; and twisting of vessels, such as testicular torsion or bowel volvulus); traumatic vessel rupture is a rare cause.

Occluded venous drainage (e.g., venous thrombosis) can cause infarction but more often induces congestion only; usually, bypass channels rapidly open, providing outflow. Infarcts resulting from venous thrombosis are more likely in organs with a single venous outflow, such as testis or ovary.

Factors that Influence Development of an Infarct

• Anatomic pattern of vascular supply (i.e., availability of an alternative blood supply): Dual circulations (lung, liver) or anastomosing circulations (radial and ulnar arteries, circle of Willis, small intestine) protect against infarction. Obstruction of end-arterial vessels generally causes infarction (spleen, kidneys).
• Rate of development of occlusion: Slowly developing occlusions less often cause infarction by providing time to develop alternate perfusion pathways (e.g., collateral coronary circulation).
• Vulnerability to hypoxia: Neurons undergo irreversible damage after 3 to 4 minutes of ischemia; myocardial cells die only after 20 to 30 minutes. In contrast, fibroblasts within ischemic myocardium are viable even after many hours.
• Oxygen content of blood: Anemia, cyanosis, or CHF (with hypoxia) can cause infarction in an otherwise inconsequential blockage.

Morphology of Infarcts

• Red infarcts occur:
  1. In venous occlusions (e.g., ovarian torsion)
  2. In loose tissues (such as lung)
  3. In tissues with dual circulations (e.g., lung and small intestine)
  4. In tissues previously congested because of sluggish venous outflow
  5. At a site of previous occlusion and necrosis when flow is re-established.
• White infarcts occur in solid organs (such as heart, spleen, and kidney) with end-arterial circulations (i.e., few anastomoses).
• Bland infarct (black) —> no infection.
• Septic infarct (greenish) —> abscess formation: Septic infarctions occur with embolization of infected heart valve vegetations or when microbes seed an area of necrosis; the infarct becomes an abscess, which only slowly organizes to scar.

All infarcts tend to be wedge-shaped; the occluded vessel marks the apex, and the organ periphery forms the base. Lateral margins may be irregular, reflecting the pattern of adjacent vascular supply. The dominant histologic characteristic of infarction is ischemic coagulative necrosis.

An initial inflammatory response (lasting hours to days) is followed by a reparative response (lasting days to weeks) beginning in the preserved margins.

In stable or labile tissues, some parenchymal regeneration may occur where the underlying stromal architecture is spared; most infarcts are ultimately replaced by scar tissue.

The brain is an exception; ischemic injury results in liquefactive necrosis.