PATH2201 Thrombosis, Embolism & Infarction 2024 Lecture Notes PDF

Pathology – School of Biomedical Sciences, Medicine & Health PATH2201, T3 2024 Thrombosis, Embolism & Infarction Martin Weber [email protected] Acknowledgement: Prof Gary Velan  LEARNING OBJECTIVES At the completion...

Pathology – School of Biomedical Sciences, Medicine & Health PATH2201, T3 2024 Thrombosis, Embolism & Infarction Martin Weber [email protected] Acknowledgement: Prof Gary Velan  LEARNING OBJECTIVES At the completion of this lecture, you should be able to: Describe the appearance of thrombosis in arterial and venous systems Discuss factors that predispose to the formation of thrombi Outline the consequences of thrombosis, including impaired oxygenation of distal tissues, proximal congestion and possible embolism Explain the causes and consequences of pulmonary thromboembolism Discuss the sources and consequences of systemic thromboemboli LECTURE OUTLINE A Lecture in 3 Parts: A. THROMBOSIS B. EMBOLISM C. INFARCTION PART A: THROMBOSIS Definition Normal Haemostasis Virchow’s Triad Types of Thrombi Clinical Significance Definition www.tctmd.com/news/thrombus-watchman- laa-occluder-tied-higher-stroke-risk Thrombus: A solid or semi-solid mass formed from the constituents of blood within the vascular system during life  Thrombus – Inside intact vascular system – During life Adapted from smart.servier.com Blood Clot – Outside vessels (haematoma) – Outside body (e.g. in a test tube) – Outside life (post-mortem) Video from: www.msdmanuals.com/home/blood- disorders/blood-clotting-process/how-blood-clots Extradural Haematoma (Blood Clot) following Trauma to the Head Image from: radiologykey.com/fracture-and-haemorrhage (Courtesy of John Deck, MD) Thrombi can occur in all of the following locations, EXCEPT: A. Veins B. Arteries C. Lymphatic vessels D. Capillaries E. Cardiac chambers  Normal Haemostasis: Response to Haemorrhage Reflex vasoconstriction Primary haemostasis Formation of primary (platelet) plug Secondary haemostasis anti-thrombotic Activation of factors coagulation cascade Fibrin deposition Fibrin cements platelet plug Clot stabilisation and resorption  Platelet Scanning Electron Micrograph Platelets: Resting and Activated Scanning Electron Micrographs Source: profedu.blood.ca  Haemostasis vs. Thrombosis Haemostasis Thrombosis Response to laceration Similar process to of a vessel haemostasis To prevent blood loss But it occurs in an “intact” Adaptive blood vessel (one which has not been lacerated) / intact cardiac chamber Maladaptive  Factors Inhibiting Thrombosis Intact Endothelial Cells Prevent platelet adhesion Anticoagulant Molecules & Platelet Inhibition Thrombomodulin Heparin-like molecules Tissue factor pathway inhibitor (TFPI) Prostacyclin (PGI2) and nitric oxide (NO) Fibrinolysis Clears fibrin deposits from endothelial surfaces Endothelial cells release tissue plasminogen activator (tPA) → converts plasminogen to plasmin → fibrin degradation Laminar Flow  Virchow’s Triad Factors Predisposing to Thrombosis Changes in: Vessel wall Blood flow Constituents of blood Source: Robbins Basic Pathology, 10th Ed. (2018)  Changes in Vessel Wall Injury to or activation of endothelium ± exposure of subendothelial layers (collagen) Due to: Atherosclerosis Inflammation (vasculitis) Trauma (pressure)  Normal Blood Flow Normal = laminar flow Central column of cells Plasma layer at edges Keeps platelets away from endothelium Facilitates removal of (activated) clotting factors & provision of fresh anti- Red blood cell Platelet clotting (and clotting) factors  Changes in Blood Flow I Stasis & Turbulent Flow Disruption of laminar flow Platelets come into contact with endothelium Endothelial activation ↑ procoagulant activity and ↑ cell adhesion ↓ washout and dilution of activated clotting factors by fresh flowing blood, together with ↓ inflow of clotting factor inhibitors Stasis is a major contributor for venous thrombi  Changes in Blood Flow II Branch point Valve Aneurysm  Changes in Constituents of Blood Hereditary Factor V mutations (Factor V Leiden) Inherited deficiency of anticoagulant molecules Acquired ↑ Coagulation factors – ↑ Liver synthesis  Inflammation, cancer, oral contraceptive pill, pregnancy Hyperviscosity – Polycythaemia, dehydration Types of Thrombi Venous Arterial Images from smart.servier.com  Venous Thrombi Usually primarily due to low flow Most originate in deep veins of calf Source: illustratedshorts.com Deep venous thrombosis (DVT)  Venous Thrombosis: Predisposing Factors Immobilisation – ↓ flow Post-surgical – immobilisation PLUS increased clotting factors and platelets Cancer – hypercoagulable state (Trousseau’s syndrome) Pregnancy – increased clotting factors, ↓ flow Heart failure – ↓ flow Dehydration – hyperviscosity Venous Thrombosis Attachment to valves or damaged endothelium Propagates in direction of flow (i.e. towards the heart) Occlusive Propagating Venous Thrombus Venous Thrombus – Laminations (macroscopic) Venous Thrombus – Laminations (microscopic) Venous Thrombus – Laminations (microscopic)  All of the following are potential outcomes of deep venous thrombosis, EXCEPT: A. Lower limb ischaemia B. Organisation and incorporation into vessel wall C. Organisation and recanalisation D. Resolution E. Pulmonary embolism Venous Thrombosis – Outcomes Source: Robbins & Cotran Pathologic Basis of Disease, 7th Ed. (2005) Venous Thrombosis – Organisation Wall of Vein Attempted Recanalisation Granulation Tissue DVT – Clinical Manifestations Wells’ criteria: – Swollen – Tender – Identify predisposing factors – May have associated warmth and redness (thrombophlebitis) – ~50% asymptomatic Differential diagnoses: – Cellulitis Source: hotnews.sg – Muscle injury  DVT – Investigations Source: sonoworld.co.uk Venous Doppler ultrasound study Plasma D-dimers may help to rule out DVT in low-risk individuals Thrombus www.nibib.nih.gov/news-events/newsroom/ultrasound- therapy-breaks-blood-clots  DVT – Prevention Compression stockings Anticoagulants (low- Compression Stockings Source: nursingtimes.net (April 2017, Vol 113, Issue 4) molecular-weight heparin) Intermittent calf pressure Early mobilisation Intermittent Pneumatic Compression Source: The Lancet (August 2013, Vol 382, Issue 9891)  Arterial Thrombi Form under high flow Usually due to injured endothelium (esp. atherosclerosis) Laminated – composed of alternating layers of fibrin & platelets (white) and increased numbers of red cells (red) Arterial Thrombosis – Mural Thrombus in Abdominal Aortic Aneurysm  Prominent Laminations (Lines of Zahn) (macroscopic)  Prominent Laminations (Lines of Zahn) (microscopic) Source: www.facebook.com/PathologyDiscussionForum/photos/a.713140295462926/1094961110614174/?type=3&theater  Arterial Thrombosis - Outcomes Occlusion Embolism Resolution Organisation Incorporation into artery wall Recanalisation Occlusive Thrombus in Coronary Artery Arterial Thrombosis – Important Sites Effects due to occlusion & distal ischaemia Coronary circulation (myocardial infarct) Cerebral circulation (cerebral infarct) Femoral arteries (limb ischaemia)  Mural Thrombus Non-occlusive thrombus Typically forms in cardiac chambers or aortic aneurysms Mural Thrombus in Aortic Aneurysm  Mural Thrombus in the Heart Most commonly in left ventricle after myocardial infarct, due to – ↓ flow (impaired contractility) – Injured endothelium – Procoagulant effects of necrotic tissue Also – In left atrium due to atrial fibrillation – Vegetations on damaged valves Laminated Left Ventricular Mural Thrombus Mural Thrombus in Left Ventricle Overlying Myocardial Infarct Source: www.webpathology.com/image.asp?case=781&n=20  Thrombus vs. Post-Mortem Clot Thrombus Post-Mortem Clot Adherent to wall Not adherent to vessel wall May propagate centrally Often separates into red from this point (in cells and plasma (“red direction of blood flow for currant jelly” / “chicken fat”) venous thrombi / retrograde for arterial thrombi) Laminated http://people.upei.ca/hanna/ARTIFACTS /PM-artifacts-WEB.pdf  KEY POINTS 1 Virchow’s Triad Changes in: Vessel wall / endothelium Blood flow Constituents of blood  KEY POINTS 2 Venous Thrombosis Arterial Thrombosis Form under low flow Endothelial injury Mainly DVT in legs Laminated Predisposing factors Superimposed on atherosclerosis, aneurysms & myocardial infarcts  PART B: EMBOLISM Definition and Overview Venous Thromboembolism – see Online Modules Arterial Thromboembolism Definition Embolism: The transportation by the blood of abnormal material (solid, liquid or gas) and its impaction in a vessel at a point remote from its entry into the circulation. N.B. >99% of emboli are thromboemboli  Embolism – Overview Venous thromboembolism (VTE) Refers to deep venous thrombosis (DVT) and consequent pulmonary (thrombo)embolism (PE) Arterial thromboembolism Other types of emboli Other Types of Embolism Note that >99% of emboli are thromboemboli Other types of emboli include: Fat droplets / bone marrow Nitrogen bubbles (decompression sickness) Air Atherosclerotic debris (cholesterol emboli) Foreign bodies Amniotic fluid Venous Thromboembolism  Pulmonary Embolism Online Module Moves with flow of blood (towards heart) Lodges in pulmonary vessel of matching size Images from smart.servier.com Arterial Thromboembolism  Sources of Arterial Thromboemboli Heart - 80% From mural thrombus in left ventricle following myocardial infarction From mural thrombus in left atrium related to atrial fibrillation From valvular vegetations (e.g. infective endocarditis) Source: www.webpathology.com/image.asp?case=781&n=24  Atherosclerosis Most of remaining 20% Carotid artery bifurcation Abdominal aortic aneurysms Source: Robbins Basic Pathology, 10th Ed. (2018) Which ONE of the following events is most likely to occur as a consequence of a mural thrombus in an abdominal aortic aneurysm? A. Myocardial ischaemia B. Rupture of the aneurysm C. Lower limb ischaemia D. Splenic infarction E. Renal infarction  Effects of Arterial Thromboemboli Leg – Ischaemia / gangrene Brain – Cerebral infarct Kidney / spleen – Wedge-shaped infarct Gut – Infarct Old Cerebral Infarct following Occlusion of the Middle Cerebral Artery Source: http://neuropathology- web.org/chapter2/chapter2bCerebralinfarcts.html Mural Thrombus in Left Ventricle overlying a Myocardial Infarct  Spleen Mural thrombus in left ventricle with embolism to spleen (arrows), causing pale splenic infarction Thrombus Heart: LV wall  Infarct Spleen Mural thrombus in left ventricle with embolism to spleen (arrows), causing pale splenic infarction Thrombus Heart: LV wall  PART C: INFARCTION Definition Causes of Infarction Venous Infarction Macroscopic Appearances Microscopic Appearances Evolution & Timing of Infarcts  Definition Infarct: Circumscribed area of ischaemic necrosis in an organ or tissue resulting from interference of blood flow, usually arterial  Causes of Infarction (Localised) blockage of arterial supply Thrombotic (e.g. heart, brain, etc.) Embolic (e.g. brain, kidney, etc.) Systemic hypotension Blockage of venous drainage E.g. thrombosis, torsion, volvulus, strangulation Factors Determining Effects of Ischaemia Rate of Occlusion » Rapid onset allows no time for tissue adaptation / development of collateral vessels Extent of Occlusion » Complete vs. partial occlusion Systemic Factors » Hypotension, hypoxia, etc. Anatomy of Local Blood Supply » End artery vs. dual blood supply » State of collateral vessels Vulnerability of Tissue to Ischaemia  Venous Occlusion May cause ischaemia due to back pressure and impairment of arterial flow May result from venous thrombosis In torsion / strangulation, veins are more easily occluded than arteries Affected organ is congested and eventually becomes haemorrhagic Image from smart.servier.com  Venous drainage Low pressure Artery High pressure Venous occlusion Images adapted from smart.servier.com  Increasing congestion with increasing pressure proximal to venous obstruction Blood flow ceases once arterial pressure = Venous occlusion capillary / venous pressure Ischaemia and infarction Images adapted from smart.servier.com  Torsion / Volvulus / Strangulation Twisting / compression of vessels Common in organs with long flexible blood supply, e.g. gut, testis Volvulus of Small Bowel Source: medical-dictionary.thefreedictionary.com  Torsion of Testis www.msdmanuals.com  Macroscopic Appearances of Infarcts I Pale Infarcts Wedge-shaped (with occluded vessel at apex), well-defined May be surrounded by red rim of acute inflammation and granulation tissue Typically seen in myocardium, kidney, spleen, thrombotic infarcts in brain Splenic Infarcts (arrows)  Recent pale renal infarct (white arrow) with hyperaemic border (red arrows) Note the thromboembolus (blue arrowhead) obstructing a branch of the renal artery Gangrene of the foot Gangrene  Macroscopic Appearances of Infarcts II Red (Haemorrhagic) Infarcts Venous occlusion (e. testicular torsion, volvulus) Dual blood supply (e.g. lungs) Reperfusion (when flow is re-established to an area of previous arterial occlusion and necrosis, e.g. thromboembolic infarcts in brain) Haemorrhagic Cerebral Infarct Microscopic Appearances of Infarcts Coagulative necrosis Proteins denatured Nuclei disappear Cellular outlines preserved Most organs including heart, kidney, spleen, lung Exception is cerebral infarct → liquefactive necrosis Renal Infarct  Evolution of an Infarct Necrosis Acute inflammatory response Repair by granulation tissue, leading to scar (exception is cerebral infarct, which heals by proliferation of glial cells, i.e. gliosis)  Time Course of Infarction Necrosis takes some time to evolve (after onset of ischaemia) Characteristic patterns of cellular reaction: » Vascular response (vasodilatation, oedema) » Neutrophil infiltration » Macrophage infiltration » Granulation tissue (early, mature) → scarring  Myocardial Infarct with Hyperaemic Border Recent Renal Infarct Coagulative necrosis Hyperaemic border Inflammatory cells invading from edge  Scarring after Myocardial Infarction Online modules (via Moodle) This topic includes 3 online modules on thrombosis, embolism and infarction, and 3 online modules on atherosclerosis. Each module has a short review quiz at the end which contributes towards your final course mark. Multiple attempts are permitted, and only the highest score achieved before 5:00pm on Friday 1st November will be recorded. Thrombosis, embolism and infarction 1 (Pulmonary embolism) Thrombosis, embolism and infarction 2 (Myocardial infarction) Thrombosis, embolism and infarction 3 (Cerebral infarction) Atherosclerosis 1 Atherosclerosis 2 Atherosclerosis 3 Further Reading: Robbins & Kumar Basic Pathology (2023; 11th edition). Chapter 3: Hemodynamic Disorders, Thromboembolism, and Shock (pp. 57-78) Chapter 8: Blood Vessels (Atherosclerosis pp. 280-290) Chapter 9: Heart (Ischemic Heart Disease / Myocardial Infarction pp. 316-325) Chapter 21: Central Nervous System (Cerebral Ischemia / Infarction pp. 731-733)