Thrombosis, Embolism, and Infarction PDF

THROMBOSIS, EMBOLISM AND INFARCTION Block: Foundations Block Director: James Proffitt, PhD Session Date: Wednesday, August 07, 2024 Time: 10:00 am – 11:30 am Instructor: Deborah Fuchs, MD Department: Pathology Email: dfuchs@pathology...

THROMBOSIS, EMBOLISM AND INFARCTION Block: Foundations Block Director: James Proffitt, PhD Session Date: Wednesday, August 07, 2024 Time: 10:00 am – 11:30 am Instructor: Deborah Fuchs, MD Department: Pathology Email: [email protected] Instructional Methods Primary Method: IM13: Lecture ☐ Flipped Session ☐ Clinical Correlations Resource Types: RE18: Written or Visual Media (or Digital Equivalent) INSTRUCTIONS Please read lecture objectives and notes prior to attending session. READINGS REQUIRED Reading: Robbins and Cotran Pathologic Basis of Disease. 10E (2021) BOOK / E- BOOK: 10E (2021): Chap. 4: 'Thrombosis' (Skip sections on 'Heparin Induced Thrombocytopenia' and “Antiphospholipid Antibody Syndrome (APS)’, and 'Disseminated Intravascular Coagulation'), ‘Embolism’, and ‘Infarction’; stop at ‘Shock’. LEARNING OBJECTIVES 1. Define thrombosis, differentiate hemostatic versus pathologic thrombosis, and summarize the 3 major predisposing factors. 2. Describe the features that differentiate a true thrombus from a postmortem clot. 3. Describe the mechanism whereby factor V Leiden and the prothrombin gene mutation lead to hypercoagulability. 4. Describe the potential fates of a thrombus and their clinical significance. 5. Define embolism and describe different types (thromboemboli, fat, air, amniotic fluid) and their causes/risk factors 6. Describe the pathophysiologic consequences and potential outcomes of pulmonary embolism. 7. Define infarction and describe the clinical significance. 8. Compare and contrast the gross and microscopic features of red and white infarcts; explain why they occur in different organs. 9. Summarize the factors that influence the development of an infarct. Block: Foundations | FUCHS [1 of 8] THROMBOSIS, EMBOLISM AND INFARCTION CURRICULAR CONNECTIONS Below are the competencies, educational program objectives (EPOs), block goals, disciplines and threads that most accurately describe the connection of this session to the curriculum. Related Related Competency\EPO Disciplines Threads COs LOs CO-01 LO #1 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #2 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #3 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #4 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #5 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #6 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CO-02 LO #7 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #8 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #9 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CONTEXT: In the lectures on introduction to blood earlier in the block we considered normal mechanisms of hemostasis. In this lecture we examine mechanisms that lead to hypercoagulability and abnormal thrombus formation, as well as embolism and ischemic infarction (necrosis of tissue due to lack of blood flow). Infarction is a major cause of morbidity and mortality. Causes of impaired blood supply that lead infarction include vascular insufficiency (atherosclerosis, thromboembolism, and torsion) and hypotension (shock and hemorrhage). This lecture will consider these important disease mechanisms, which affect all organ systems. Block: Foundations | FUCHS [2 of 8] THROMBOSIS, EMBOLISM AND INFARCTION THROMBOSIS: Definition: Thrombosis is formation of a blood clot (thrombus) within a blood vessel in response to vessel wall damage. Recall from the “Introduction to Blood” lecture that the hemostatic system consists of multiple independent, but closely related, components that function to maintain blood fluidity and to promote localized, temporary thrombus formation at sites of vascular injury (hemostatic thrombus). Pathologic thrombosis occurs when this balance is lost and a clot forms at a site with only minimal endothelial injury or the thrombus is not localized. Thrombi can be, in many cases, differentiated from post-mortem blood clots. A post-mortem clot usually lacks the tissue-like consistency of a thrombus and has a more gelatinous appearance. In addition, true thrombi fill or distend the vessel, may be attached to the vessel wall, and have lines of Zahn (laminations produced by alternating pale layers of platelets admixed with fibrin and darker layers of RBCs). These lines signify that the thrombus has formed in flowing blood and are most apparent in the heart or aorta, and not so apparent in veins or smaller arteries where blood flow is more sluggish. Post-mortem clots are not attached to the vessel wall and lack lines of Zahn. Pathogenesis of Thrombosis In the 1850s, Dr. Rudolf Virchow described 3 predisposing factors of thrombus formation (Virchow’s triad). Today, we still consider these as the primary influences, but have a better understanding of how they cause thrombosis. See figure 4.12 from Robbins, 10th ed). 1) Endothelial injury is particularly important for thrombi formed in the heart and arterial circulation. Example: thrombus formation over ulcerated atherosclerotic plaques. Damage to the endothelium during plaque rupture leads to exposure of the subendothelial collagen (to which vWF binds) and release of tissue factor. Endothelial injury can also occur due to physical Block: Foundations | FUCHS [3 of 8] THROMBOSIS, EMBOLISM AND INFARCTION injury, infectious agents, abnormal blood flow, inflammation, and metabolic disorders, such as hypercholesterolemia. Endothelial injury is the main cause of thrombosis in the arterial circulation. 2) Altered blood flow – Turbulence contributes to arterial thrombosis by causing endothelial injury and forming local pockets of stasis. Stasis is a main risk factor for venous thrombosis. Stasis prevents dilution of activated clotting factors by fresh blood and prevents inflow of clotting inhibitors. Stasis also promotes endothelial activation and disrupts normal laminar flow of blood and brings platelets into contact with the endothelium. 3) Increased coagulability of blood (Hypercoagulable States) Any alteration of the coagulation pathways that predisposes to thrombosis. The numerous acquired (secondary) and inherited (primary) causes are listed below (from Robbins, 10th ed, Table 4-2) Hypercoagulable States Primary (Genetic) Secondary (Acquired) Common Strong Risk Factor V Leiden mutation Prolonged bed rest or immobilization Prothrombin gene mutation Myocardial infarction MTHFR gene mutation Atrial fibrillation Rare Tissue damage (surgery, trauma, burns) Antithrombin deficiency Cancer Protein C deficiency Prosthetic cardiac valves Protein S deficiency Disseminated intravascular coagulation Very Rare Heparin-induced thrombocytopenia Fibrinolysis defects Antiphospholipid antibody syndrome Lower risk Cardiomyopathy Nephrotic syndrome Hyperestrogenic states (pregnancy) Oral contraceptive use Sickle cell anemia Smoking A closer look at two inherited hypercoagulable states: Factor V Leiden Mutation - A point mutation in factor V results in replacement of arginine by glutamine at amino acid residue 506, resulting in a mutated factor V, known as factor V Leiden (FVL). FVL is the most commonly identified cause of inherited thrombosis, with approximately 5% of Caucasians are carriers. This mutated Factor V is resistant to inactivation by activated protein C (activated protein C resistance), resulting in loss of one of the major coagulation system inhibitors. Heterozygotes have a 3-5 fold increased risk of thrombosis. Prothrombin Gene Mutation - A point mutation in the prothrombin gene results in increased levels of prothrombin that results in increased fibrin formation. This mutation is present in approximately 1-2% of the population. Block: Foundations | FUCHS [4 of 8] THROMBOSIS, EMBOLISM AND INFARCTION Fate of the thrombus: If a patient survives the initial vascular obstruction caused by the thrombus, thrombi will undergo some combination of the following events: 1) Dissolution – Cleared by the fibrinolysis. 2) Embolization – Portions of the thrombus dislodge and travel through the vasculature to other sites of the body. Emboli lodge in small vessels and cause partial or complete occlusion; this may cause ischemic necrosis (infarction) of distal tissue. 3) Propagation – Accumulation of more platelets and fibrin leads to growth of the thrombus. 4) Organization and recanalization – Thrombus undergoes fibrosis (organization) and may eventually be recanalized (reestablish blood flow). Clinical significance of thrombosis: 1) Vascular obstruction → ischemia or necrosis of tissue 2) Embolization to another site The significance varies based on where the thrombus occurs. While venous thrombosis may cause congestion and edema, a far graver consequence is embolization to the lungs, causing death. Conversely, although arterial thrombi can embolize, their role in local obstruction of critical vessels (e.g., coronary artery) is much more important. Arterial thrombosis: Myocardial infarction, caused by thrombosis of a coronary artery, is the #1 cause of death in Western industrialized countries. The main cause of arterial thrombosis is endothelial injury. Atherosclerosis is a major initiator of thromboses, related to the abnormal vascular flow and endothelial injury caused by atherosclerotic plaques. Most venous thrombi (VT) occur in either the superficial or deep veins of the leg (SVT or DVT). Superficial thrombi may cause swelling and pain, but rarely embolize. DVT are more serious because they may embolize. DVT may cause pain, redness and swelling, but approximately 50% of patients are asymptomatic because collateral circulation bypasses the obstruction. DVT risk factors include stasis and hypercoagulable states. EMBOLISM Definition: Intravascular material (solid, liquid, or gas) is carried through the vascular system from its site of origin to a distant site, where it lodges and occludes a vessel. The majority of emboli are thromboemboli, a detached fragment of a thrombus. Other rare forms of embolism include globules of fat, gas (air, nitrogen) and amniotic fluid. This discussion will emphasize thromboembolism. Pulmonary embolism (PE): Incidence data for PE vary from study to study. Studies have estimated that one million people in the U.S. are affected by PE each year, with 100,000-200,000 of these being fatal. PE is the cause of death in 10-15% of hospitalized patients. In most (95%) cases, the emboli originate from a DVT. Depending on the size of the Block: Foundations | FUCHS [5 of 8] THROMBOSIS, EMBOLISM AND INFARCTION embolus, it may occlude the main pulmonary artery, the pulmonary artery bifurcation (saddle embolus) or pass out into the smaller vessels. Pathophysiologic consequences: 1) Ventilation of a non-perfused segment of lung leads to respiratory compromise 2) Increased resistance to pulmonary blood flow as a result of vascular obstruction leads to hemodynamic compromise Outcomes: 1) Most are small and clinically silent (60-80%). 2) Sudden death, right heart failure (cor pulmonale) or cardiovascular collapse occurs when >60% of the pulmonary circulation is obstructed with emboli. 3) Embolic obstruction of medium-sized pulmonary arteries may result in pulmonary hemorrhage but usually does not cause infarction because of the dual blood supply to the lungs (bronchial and pulmonary arterial); the intact bronchial circulation perfuses the affected area. Infarction may occur in patients with impaired bronchial circulation due to poor cardiovascular function 4) Pulmonary hypertension (2-3%) - usually multiple episodes of small thromboemboli Clinical symptoms: acute onset of chest pain, cough, shortness of breath, rapid heart rate (tachycardia) and rapid respirations (tachypnea) Systemic Thromboembolism: These are thromboemboli within the arterial circulation. Most arise from thrombi in the cardiac chambers in the setting of myocardial infarcts and atrial fibrillation. Other sources include aortic aneurysms and thrombi on ulcerated atherosclerotic plaques. The major sites for arterial embolization are the lower extremities (75%) and the brain (10%). Fat Embolism: These emboli are due to release of fatty marrow into damaged blood vessels. They are most frequently seen after blunt trauma with bone fractures; other less common causes include acute pancreatitis, pathologic fractures, and joint reconstruction. In most cases, these are asymptomatic. Rarely, patients will experience respiratory distress, neurologic symptoms, anemia and thrombocytopenia (fat embolism syndrome). Air Embolism: Air may gain entry into the vascular system during medical procedures (central venous catheter placement – most common), trauma, diving (decompression sickness, “the bends”), and child birth. Small air bubbles may coalesce and obstruct flow of blood in the right heart, pulmonary circulation and cerebral vessels. The severity of symptoms depends on the location and amount of air entering the circulation. Block: Foundations | FUCHS [6 of 8] THROMBOSIS, EMBOLISM AND INFARCTION Amniotic Fluid Embolism: Rare, catastrophic complication of pregnancy in which amniotic fluid, fetal squamous cells, and/or hair enter the maternal circulation causing cardiovascular collapse. In addition, the contents of amniotic fluid activate coagulation resulting in a consumptive coagulopathy called disseminated intravascular coagulation (widespread clotting → organ ischemia; consumption of clotting factors and platelets→ bleeding). Characterized by sudden onset of severe difficulty breathing (dyspnea), cyanosis, and shock; followed by neurological symptoms (headache, seizures, coma). 5 th most common cause of maternal mortality worldwide; mortality is up to 80%. Estimated to occur in 1/8,000-1/80,000 pregnancies. INFARCTION: Definition: An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage. More than half of all deaths In the U.S. are caused by infarction, particularly myocardial and cerebral infarction. Most (~99%) result from thrombotic or embolic events involving arteries. Other, less common causes include vasospasm, twisting of vessels (torsion), compression of blood supply, or traumatic rupture of a vessel. Types of infarcts – Infarcts are classified according to color, which reflects the amount of blood in the affected tissue. 1) White (pale) infarcts occur with arterial occlusion in organs with end- arterial circulation (no/minimal collaterals, no dual blood supply) and in dense tissue which limits seepage of blood from adjoining capillary beds into the necrotic area: heart, kidney, spleen. 2) Red infarcts occur in the following settings: a) venous occlusion (e.g., ovarian or testicular torsion) b) tissues with dual circulation (lung, small intestine) that allow blood flow from an unobstructed parallel supply into a necrotic zone. Blood flow from this parallel circulation is not sufficient to keep the tissue alive. c) loose tissues (such as lung), which allow blood to seep in the infracted zone d) flow is re-established to a site of previous necrosis due to arterial occlusion (re-perfusion) Pathologic features of infarcts: Gross: Usually wedge-shaped with the occluded vessel at apex and periphery of organ forming the base Infarcts resulting from arterial occlusion in organs without a dual blood supply become progressively paler (white infarcts). Limited hemorrhage may be noted early. RBCs that leak from the vessels in hemorrhagic infarcts are taken up by macrophages and converted to hemosiderin. Small amounts of Block: Foundations | FUCHS [7 of 8] THROMBOSIS, EMBOLISM AND INFARCTION hemorrhage may not change the color of the tissue significantly, but in extensive hemorrhage, the tissue may be firm and brown. Microscopic: Ischemic coagulative necrosis: Initial preservation of the basic outline of the cells and architecture of tissue, loss of nuclei (karyolysis) An inflammatory response develops along the margin of the infarct within a few hours and is well developed in 1-2 days. Gradual clearing of the cellular debris by neutrophils and macrophages. Most infarcts are replaced by scar tissue. Note: If the patient dies shortly after vascular obstruction, no demonstrable pathologic changes will be evident Clinical correlations: Not every tissue that suffers a cessation of blood flow will undergo necrosis. What factors influence development of an infarct? 1) Nature of vascular supply. The availability of an alternative blood supply is the most important factor in determining whether occlusion of a vessel will result in infarction. Lungs and liver, for example, have dual circulation. These organs are therefore relatively insensitive to small occlusions if the alternative blood supply is intact. 2) Rate of development of occlusion. Slowly developed occlusions allow time for collateral circulation to develop and are less likely to cause infarction as a result. For example, small connections exist between the 3 major coronary arteries; they normally have minimal flow, but in the setting of a slowly developing narrowing of the coronary artery, flow within this collateral circulation may increase enough to prevent infarction. 3) Vulnerability to hypoxia. Tissues that are particularly sensitive to hypoxia are more likely to infarct. a. Neurons undergo irreversible change within 3-4 min b. Cardiac myocytes die after 20-30 min. of ischemia c. Fibroblasts in myocardium can last several hours 4) Oxygen content of blood. Patients with anemia or pulmonary disease (low oxygen delivery to blood) are more susceptible to even partial flow obstructions of a small vessel that under normal circumstances would be without effect. Block: Foundations | FUCHS [8 of 8]