«JAMA. 2001;285(5):581-587. doi:10.1001/jama.285.5.581 Figure Legend: Chronic endothelial injury, inflammation, and oxidative stress arecentral to the ...»
Embolism and Infarction
Thrombus formation (called Virchow's triad):
(1) endothelial injury,
(2) stasis or turbulent blood flow
(3) hypercoagulability of the blood
Endothelial injury is particularly important for thrombus formation
in the heart or the arterial circulation, where the normally high flow
rates might otherwise impede clotting by preventing platelet adhesion and washing out activated coagulation factors.
Thus, thrombus formation within cardiac chambers (e.g., after endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely a consequence of endothelial cell injury.
From: Prospects for Cardiovascular Research JAMA. 2001;285(5):581-587. doi:10.1001/jama.285.5.581
Chronic endothelial injury, inflammation, and oxidative stress arecentral to the development of atherosclerosis. Endothelial injury resultsfrom a variety of factors including tobacco use, hypercholesterolemia, interventionaltherapies with angioplasty or coronary stents, and from ulceration or fissuringof atherosclerotic plaques. At sites of endothelial injury, production ofendothelial-derived substances (nitric oxide [NO], tissue plasminogen activator[tPA], and prostacyclin [PGI2]) is decreased, creating a prothromboticenvironment characterized by increased platelet and leukocyte adhesion, increasedpermeability to plasma Copyright © 2012 American Medical Date of download: 3/11/2013 lipoproteins, myointimal hyperplasia, and vasoconstriction.Ulceration or fissuring of the atherosclerotic plaque results from Association. All rights reserved.
degradationof collagen matrix in the fibrous cap by metalloproteases released from macrophages.Exposure of the subendothelium after plaque ulceration or fissuring leadsto platelet adhesion and aggregation and local accumulation of largely platelet- derivedmediators (thromboxane A2, serotonin, adenosine diphosphate [ADP],thrombin, platelet activating factor [PAF], oxygen- derived free radicals,tissue factor, and endothelin) that promote thrombus growth, fibroproliferation,and vasoconstriction. LDL indicates low-density lipoprotein.
Endothelial Injury Physical loss of endothelium can lead to exposure of the subendothelial ECM, adhesion of platelets, release of tissue factor, and local depletion of PGI2 and plasminogen activators.
However, it should be emphasized that endothelium need not be denuded or physically disrupted to contribute to the development of thrombosis; any perturbation in the dynamic balance of the prothombotic and antithrombotic activities of endothelium can influence local clotting events.
Thus, dysfunctional endothelial cells can produce more procoagulant factors (e.g., platelet adhesion molecules, tissue factor, PAIs) or may synthesize less anticoagulant effectors (e.g., thrombomodulin, PGI2, t-PA).
Endothelial dysfunction can be induced by a wide variety of insults, including hypertension, turbulent blood flow, bacterial endotoxins, radiation injury, metabolic abnormalities such as hypercholesterolemia.
Alterations in Normal Blood Flow Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis; stasis is a major contributor in the development of venous thrombi.
Normal blood flow is laminar such that the platelets (and other blood cellular elements) flow centrally in the vessel lumen, separated from endothelium by a slower moving layer of plasma.
Stasis and turbulence therefore:
http://www.oocities.org/venkatej/mech/fluid_mechanics/LaminarFlowProfile.gif http://www.phlebolymphology.org/2009/07/recent-findings-in-the-pathogenesis-of-venous-wall-degradation/ http://content.onlinejacc.org/data/Journals/JAC/23086/02059_gr4.jpeg Alterations in Normal Blood Flow Promote endothelial activation, enhancing procoagulant activity and leukocyte adhesion. In part through flow-induced changes in endothelial cell gene expression.
Disrupt laminar flow and bring platelets into contact with the endothelium.
Prevent washout and dilution of activated clotting factors by fresh flowing blood and the inflow of clotting factor inhibitors.
Turbulence and stasis contribute to thrombosis Ulcerated atherosclerotic plaques cause turbulence.
Aortic and arterial dilations called aneurysms result in local stasis and are therefore fertile sites for thrombosis.
Acute myocardial infarctions result in areas of noncontractile myocardium and sometimes cardiac aneurysms; both are associated with stasis and flow abnormalities.
http://www.aafp.org/afp/2012/1115/afp20121115p913-f1.gif Hypercoagulability http://ars.els-cdn.com/content/image/1-s2.0-S0268960X08000362-gr1.jpg PRIMARY (GENETIC) Common
• Factor V mutation (G1691A mutation; factor V Leiden)
• Prothrombin mutation (G20210A variant) 5,10Methylenetetrahydrofolate reductase (homozygous C677T mutation)
• Increased levels of factors VIII, IX, XI, or fibrinogen.
Factor V mutation (G1691A mutation; factor V Leiden) http://www.med.illinois.edu/hematology/Pics,%20etc/Factor%20V%20Leiden%20Main.JPG
http://www.practical-haemostasis.com/images/Images-2/Thrombophilia%20Tests/pc_ps_pathway.jpg http://www.med4you.at/laborbefunde/lbef2/atIII_anim3.gif Thrombomodulin (TM) CD141 or BDCA-3 is an integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme from a procoagulant enzyme.
http://hcp.obgyn.net/image/image_gallery?img_id=2082561&t=1339545353297 Among the acquired thrombophilic states, two that are particularly important.
Heparin-induced thrombocytopenia (HIT) syndrome.
Note: Thrombophilia is a condition where the blood has an increased tendency to form clots http://www.patient.co.uk/health/thrombophilia-leaflet Heparin-induced thrombocytopenia (HIT) syndrome HIT occurs following the administration of unfractionated heparin, which may induce the appearance of antibodies that recognize complexes of heparin and platelet factor 4 on the surface of platelets, as well as complexes of heparinlike molecules and platelet factor 4-like proteins on endothelial cells.
Binding of these antibodies to platelets results in their activation, aggregation, and consumption (hence the thrombocytopenia in the syndrome name).
Effect on platelets and endothelial damage combine to produce a prothrombotic state, even in the face of heparin administration and low platelet counts.
Newer low-molecular weight heparin preparations induce antibody formation less frequently, but still cause thrombosis if antibodies have already formed. Other anticoagulants such as fondaparinux (a pentasaccharide inhibitor of factor X) also cause a HIT-like syndrome on rare occasions.
Antiphospholipid antibody syndrome Antiphospholipid antibodies are a heterogeneous group of auto-antibodies (IgG, IgM, and IgA) This syndrome has protean clinical manifestations, including recurrent thromboses, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia.
Depending on the vascular bed involved, the clinical presentations can include pulmonary embolism (following lower extremity venous thrombosis), pulmonary hypertension (from recurrent subclinical pulmonary emboli), stroke, bowel infarction, or renovascular hypertension.
Fetal loss is attributable to antibody-mediated inhibition of tPA activity necessary for trophoblastic invasion of the uterus.
Antiphospholipid antibody syndrome is also a cause of renal microangiopathy, resulting in renal failure associated with multiple capillary and arterial thromboses.
http://www.acponline.org/graphics/bioterro/canthrax/anti_lipid.jpg Figure 3 Endothelial cell activation by anti-β2GPI autoantibodies Meroni, P. L. et al. (2011) Pathogenesis of antiphospholipid syndrome: understanding the antibodies Nat. Rev. Rheumatol. doi:10/1038/nrrheum.2011.52 beta2 Glycoprotein 1 http://www.nature.com/nrrheum/journal/v7/n6/images/nrrheum.2011.52-f1.jpg Thrombi can develop anywhere in the cardiovascular system (e.g., in cardiac chambers, on valves, or in arteries, veins, or capillaries).
The size and shape of thrombi depend on the site of origin and the cause.
Arterial or cardiac thrombi usually begin at sites of turbulence or endothelial injury.
Venous thrombi characteristically occur at sites of stasis.
Thrombi are focally attached to the underlying vascular surface; arterial thrombi tend to grow retrograde from the point of attachment, while venous thrombi extend in the direction of blood flow (thus both propagate toward the heart).
Such laminations signify that a thrombus has formed in flowing blood; their presence can therefore distinguish antemortem thrombosis from the bland nonlaminated clots that occur postmortem
• Propagation. Thrombi accumulate additional platelets and fibrin.
• Embolization. Thrombi dislodge and travel to other sites in the vasculature.
• Dissolution. Result of fibrinolysis, which can lead to the rapid shrinkage and total disappearance of recent thrombi. (Extensive fibrin deposition and crosslinking in older thrombi renders them more resistant to lysis.) Natural and Therapeutic.
• Organization and recanalization. Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts. Capillary channels eventually form that re-establish the continuity of the original lumen, albeit to a variable degree.
Organized arterial thrombus http://www.geocities.ws/m4pathology/Osce/Slides/histsch03.jpg Recanilizatuion http://farm3.static.flickr.com/2791/4337748744_3a92ba6583.jpg Aortic thrombi from electrical injury Lung hilum thromboembolus with lines of Zahn Right atrial mural thrombus with lines of Zahn Clinical Consequences.
Thrombi are significant because they cause obstruction of arteries and veins, and are sources of emboli.
Which effect predominates depends on the site of the thrombosis.
Venous thrombi can cause congestion and edema in vascular beds distal to an obstruction, but they are far more worrisome for their capacity to embolize to the lungs and cause death (see below).
Conversely, although arterial thrombi can embolize and cause downstream infarctions, a thrombotic occlusion at a critical site (e.g., a coronary artery) can have more serious clinical consequences.
• Detached intravasular solid, liquid, gasous mass carried by the blood
• Pulmonary embolisms Often arise from deep vein thromboses
• Associated with immobilization, hypercoagulability Frequently small, silent, becoming organized Right heart failure, cor pulmonale, when 60% pulmonary circulation obstructed Rupture of obstructed arteries causes bleeding without infarction due to blood supply Multiple emboli lead to hypertension and right ventricular failure An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin.
The term embolus was coined by Rudolf Virchow in 1848 to describe objects that lodge in blood vessels and obstruct the flow of blood. Almost all emboli represent some part of a dislodged thrombus, hence the term thromboembolism. Rare forms of emboli include fat droplets, nitrogen bubbles, atherosclerotic debris (cholesterol emboli), tumor fragments, bone marrow, or even foreign bodies. However, unless otherwise specified, emboli should be considered thrombotic in origin. Inevitably, emboli lodge in vessels too small to permit further passage, causing partial or complete vascular occlusion; a major consequence is ischemic necrosis (infarction) of the downstream tissue. Depending on where they originate, emboli can lodge anywhere in the vascular tree; the clinical outcomes are best understood based on whether emboli lodge in the pulmonary or systemic circulations.
http://www.news.vcu.edu/images/image.aspx?id=2904&w=400 Systemic thromboembolism
• Emboli in arterial circulation
• Arise from intracardiac mural thrombi 60% associated with left ventricular wall infarcts 25% associated with atrial dilation or fibrillation Remainder originate from aneurysms, valvular vegetation
• Deposit in lower extremities or brain
• Consequences depend on caliber of occluded vessel, redundant blood supply http://images.radiopaedia.org/images/540186/4ee4c494df07ac6c3ecd9b2c622c75.jpg An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage.
Tissue infarction is a common and extremely important cause of clinical illness.
Roughly 40% of all deaths in the United States are caused by cardiovascular disease, and most of these are attributable to myocardial or cerebral infarction.
Pulmonary infarction is also a common complication in many clinical settings, bowel infarction is frequently fatal, and ischemic necrosis of the extremities (gangrene) is a serious problem in the diabetic population.
Nearly all infarcts result from thrombotic or embolic arterial occlusions.
Occasionally infarctions are caused by other mechanisms, including local vasospasm, hemorrhage into an atheromatous plaque, or extrinsic vessel compression (e.g., by tumor).
Rarer causes include torsion of a vessel (e.g., in testicular torsion or bowel volvulus), traumatic rupture, or vascular compromise by edema (e.g., anterior compartment syndrome) or by entrapment in a hernia sac.
Although venous thrombosis can cause infarction, the more common outcome is just congestion; in this setting, bypass channels rapidly open and permit vascular outflow, which then improves arterial inflow. Infarcts caused by venous thrombosis are thus more likely in organs with a single efferent vein (e.g., testis and ovary).