Robbins Pathology - Chapter 4 - Translational PDF

CHAPTER 4: HEMODYNAMIC DISORDERS, Arteriolar Heat Dilation...

CHAPTER 4: HEMODYNAMIC DISORDERS, Arteriolar Heat Dilation Neurohumoral dysregulation THROMBOEMBOLIC DISEASE, AND SHOCK Reduced Plasma Protein-losing glomerulonephritis (nephrotic syndrome) Osmotic Pressure Ascites (liver cirrhosis); Malnutrition EDEMA AND EFFUSIONS Protein-losing gastroenteropathy Lymphatic obstruction Inflammatory; neoplastic  Disorders that perturb cardiovascular, renal, or hepatic function are often marked by Postsurgical; postirradiation the accumulation of fluid in tissues (edema) or body cavities (effusions) Sodium Retention Excessive salt intake w/ renal insufficiency  Vascular hydrostatic pressure (push H2O & salt) is balanced by plasma colloid Increased tubular reabsorption of sodium (renal hypoperfusion, increased RAAS) osmotic pressure (pull H2O and salt) Inflammation Acute or chronic inflammation  Elevated hydrostatic pressure or diminished colloid osmotic pressure disrupts this angiogenesis balance and results in increased movement of fluid out of vessels  If net rate of fluid movement exceeds the rate of lymphatic drainage  fluid Clinical Features accumulates o Within tissues  edema  Subcutaneous edema – signals potential underlying cardiac or renal disease; impair o Involvement of serosal surface and cavity  effusion wound healing or clearance of infection o May be inflammatory or non-inflammatory  Pulmonary edema – seen in left ventricular failure; also in renal failure, ARDS,  Inflammatory-related  protein-rich exudates accumulate due to ↑ vascular pulmonary inflammation or infection permeability  Pulmonary effusion – accompany edema in lungs; compromise gas exchange  Noninflammatory-related  common; heart failure, liver failure, renal dx, severe  Peritoneal effusion (ascites) – results from portal hypertension; prone to seeding nutritional disorders by bacteria  Various causes of edema:  Brain edema – life threatening; may cause herniation of brain substance through foramen magnum or brain stem vascular supply can be compressed ↑ Hydrostatic  Mainly caused by disorders that impair venous return pressure  If localized, edema is confined to the area HYPEREMIA AND CONGESTION  Systemic increase in venous pressure  widespread edema ↓ Plasma  Common cause are conditions leading to inadequate synthesis or  Hyperemia and congestion both stem from increased blood volumes within tissues, osmotic increased loss of albumin but have different lying mechanisms and consequences pressure  Albumin accounts for half of the total plasma protein  Severe liver disease and protein malnutrition  reduced albumin  Hyperemia – active process where arteriolar dilation leads to increased blood flow synthesis o Tissues turn red (erythema) due to ↑ O2 delivery  Nephrotic syndrome  albumin loss; leaks in urine  Congestion – passive process resulting from reduced outflow of blood from a tissue  ↓ plasma osmotic pressure lead to edema, ↓ intravascular o Systemic (cardiac failure) volume, renal hypoperfusion, secondary hyperaldosteronism o Localized (isolated venous obstruction) Sodium & water  Lead to ↑ hydrostatic pressure (due to extravascular fluid volume  ↑ hydrostatic pressure  congestion leads to edema retention expansion) and diminished vascular colloid osmotic pressure  Chronic passive congestion – result in ischemic tissue injury and scarring (due to dilution)  Renal hypoperfusion – cause salt retention o Chronically congested tissues  hemorrhagic foci, hemosiderin-laden o Most important cause is congestive heart failure  macrophages activates RAAS  Congested tissues has dusky reddish-blue color (cyanosis) due to red cell stasis and Lymphatic  Trauma, fibrosis, invasive tumors, and infectious agents can all deoxygenated hemoglobin obstruction disrupt lymphatic vessels and impair the clearance of interstitial o Acute pulmonary congestion  engorged aleveolar capillaries, septal fluid  result in lymphedema in the affected area edema, focal intraalveolar hemoorahe  Parasitic filiariasis – organism induce obstructive fibrosis of o Chronic pulmonary congestion  hemosiderin-laden macropahges lymph channels and nodes  elephantiasis (heart failure cells) o Acute hepatic congestion – central vein and sinusoids are distended; Pathophysiologic Categories of Edema fatty change Increased Hydrostatic Impaired Venous CHF, Constrictive pericarditis, Ascites (liver o Chronic passive hepatic congestion – red-brown slightly depressed; Pressure Return cirrhosis), Venous obstruction or compression tan-liver (nutmeg liver); hemosiderin-laden macrophage (thrombosis, external pressure,mass, lower extremity inactivity w/ prolonged dependency) abmrmtmd HEMOSTASIS, HEMORRHAGIC DISORDERS, AND THROMBOSIS  Mediated via interaction with vWF (acts as a bridge between  Hemostasis – process where blood clots form at sites of vascular injury Platelet platelet surface receptor GpIb and collagen) o Essential for life adhesion  Genetic deficiency of vWF (von Willebrand disease) and  Hemorrhagic disoriders – characterized by excessive bleeding; hemostatic GpIb (Bernard-Soulier syndrome)  results in bleeding  From smooth disc to spiky “sea urchins” with ↑ surface area mechanisms are either blunted or insufficient to prevent abnormal blood loss o Alterations in GpIIb/IIIa that increase its affinity for  Thrombotic disorders blood clots (thrombi) – form within intact blood vessels or Platelets fibrinogen within the chambers of the heart rapidly change o Translocation of negatively charged phospholipids  DIC – bleeding due to consumption of coagulation factors shape (phosphatidylserine) to the platelet surface o This phospholipids bind calcium and serve as Hemostasis nucleation sites for assembly of coagulation factors  Occurs along with changes in shape  Hemostasis – process involving platelets, clotting factors, and endothelium that  Change in shape and secretion  platelet activation occurs at the site of vascular injury and ends in the formation of a blood clot (prevent Secretion  Platelet activation is triggered by thrombin and ADP (release  Thrombin – activate platelet through GPCR called PAR or limit bleeding) reaction) of (protease activated receptor)  General sequence of events leading to hemostasis: granule  Platelet activation and ADP release begets additional rounds of contents platelet activation phenomenon called recruitment  Occurs immediately; markedly reduced blood flow in the  Thromboxane A2 (TxA2) – potent inducer of platelet Arteriolar area aggregation vasoconstriction  Endothelin – potent endothelium-derived  Aspirin – inhibits platelet aggregation; produce mild bleeding vasoconstrictor defect by inhibiting COX (required for TxA2 synthesis)  Transient effect  GpIIb/IIIa allows fibrinogen binding that forms bridges   The formation of the platelet plug aggregation  vWF and collagen – promote platelet adherence and  Inherited deficiency of GpIIb/IIIa – Glanzmann activation thrombasthenia Primary hemostasis  Activation of platelets results in shape change (round to Platelet  Initial wave of aggregation is reversible  further platelet flat with spikes) and release of secretory granules aggregation aggregation and activation by thrombin stabilization   Secreted products recruit other platelets  aggregation promote irreversible platelet contraction  primary hemostatic plug  Platelet contraction – dependent on cytoskeleton and  Deposition of fibrin consolidates aggregated platelets  Tissue factor is exposed at site f injury  Thrombin converts fibrinogen to fibrin  cements platelets in o Binds and activates factor VII  ends in place and creates secondary hemostatic plug Secondary hemostasis thrombin generation  Thrombin cleaves fibrinogen  fibrin (creates meshwork; potent activator of platelets; lead to additional aggregation) Coagulation Cascade Clot stabilization and  Polymerized fibrin and platelet aggregates undergo  Coagulation cascade – series of enzymatic reactions that leads to the deposition of resorption contraction to form solid, permanent plug an insoluble fibrin clot; Intrinsic or extrinsic  Counterregulatory mechanisms (tPA)  limit clotting  Each reaction step involves: and eventually lead to clot resorption and repair o Enzyme (activated coagulation factor) o Substrate (inactive proenzyme form of a coagulation factor) o Cofactor (reaction accelerator) Platelets  Assembly occurs in negatively charge phospholipid surface and depends on calcium  Platelets play a critical role in hemostasis by forming the primary plug that initially (present in factors II, VII, IX, X )  use vitamin K as cofactor and antagonized by seals vascular defects and by providing a surface that binds and concentrates Coumadin activated coagulation factors PT  Assess function of extrinsic pathway proteins  Disc-shaped anucleate cell fragments from megakaryocytes;  Factors VII, X, V, II and fibrinogen  α-granules have adhesion molecule P-selectin on their membranes APTT  Assess function of intrinsic pathway proteins o Fibrinogen, factor V, vWF  coagulation  Factors XII, XI, IX, VIII, X, V, II and fibrinogen o Fibronectin, platelet factor 4, PDGF, TGF-b  wound healing  Clotting of plasma is initiated by addition of negatively charged  δ-granules  contain ADP and ATP, ionized calcium, serotonin, epinephrine particles (glass)  activate factor XII, phospholipids, Ca2+  On contact w/ these proteins, platelets undergo sequence of reactions that culminate  Time to fibrin clot formation is recorded in the formation of platelet plug: abmrmtmd   Deficiencies of factors V, VII, VIII, IX, X  asso. w/ moderate to severe  EPCR – bind protein C bleeding disorders  Protein C – vitamin K dependent protease that requires a  Prothrombin deficiency – incompatible with life cofactor, protein S  Factor XI deficiency – mild bleeding  Activated protein C/protein S complex  potent  Factor XII deficiency – no bleeding but prone to thrombosis inhibitor of coagulation factors Va and VIIIa  Factor VIIa/tissue factor complex – most important activator of factor IX  Heparin-like molecules  bind and activate antithrombin  Factor IXa/factor VIIIa complex – most important activator of factor X III  inhibits thrombin and factors IXa, Xa, Xia and XIIa  Among coagulation factors, thrombin is the most important  its enzymatic activities  TFPI  also requires protein S as cofactor; binds and control diverse aspects of hemostasis and link clotting to inflammation and repair inhibits tissue factor/factor VIIa complexes  Thrombin’s most important activity: Fibrinolytic  Synthesize t-PAS – key component of fibrinolytic pathway Conversion of  Thrombin converts fibrinogen to insoluble fibrin and effects fibrinogen to amplifies factor XI, V and VIII fibrin  Also stabilize secondary hemostatic plug by activating factor XIII, which covalently cross-links fibrin Platelet activation  Thrombin – important inducer of platelet activation and Hemorrhagic Disorders aggregation through activation of PARs  link function to coagulation  Disorders asso. w/ abnormal bleeding inevitably stem from sirmary or secondary Pro-inflammatory  PARs - also expressed on inflammatory cells, endothelium defects in vessel walls, platelets, or coagulation factors, all of which must function effects and activation by thrombin mediate proinflammatory effects  tissue repair and angiogenesis properly to ensure hemostasis Anticoagulant  This reversal in function prevents clotting from extending  Most common cause of mild bleeding tendencies: defects in vWF, aspirin effects beyond the site of the vascular injury consumption, uremia (renal failure; alters platelet fxn)  General principles related to abnormal bleeding and its consequences: Factors That Limit Coagulation  Simple dilution – blood flowing at the site of injury washes out activated factors ,  Defects of primary hemostasis (platelet defects or von Willebrand disease) w/c are rapidly removed by the liver o Small bleeds in skin or mucosa;  Requirement for negatively charged phospholipids – provided by activated platelets  Petechiae (1-2 mm hemorrhages)  Most important counterregulatory mechanisms involve factors that are expressed by  Purpura (≥3 mm) intact endothelium adjacent to the site of injury o Epistaxis (nosebleeds)  Fibrinolytic cascade – limits the size of clot and dissolution o GIT bleeding  Plasmin – aids fibrinolysis; breaks down fibrin and interferes w/ its polymerization o Menorrhagia (excessive menstruation)  D-dimers – fibrin split product; useful clinical markers of several thrombotic states o Intracerebral hemorrhage  feared complication of thrombocytopenia  Conversion of plasminogen to plasmin – either by factor XII-dependent pathway or by  Defects of secondary hemostasis (coagulation factor defects) plasminogen activators  T-Pa – most important plasminogen activator; synthesized principally by endothelium; o Bleeds into soft tissues (muscles) or joints most active when bound to fibrin; useful therapeutic agent (fibrinolytic activity against o Bleeding into joints (hemarthrosis)  cxc of hemophilia thrombosis) o Peculiar bleeding pattern  α2-plasmin inhibitor – counterregulates plasmin by rapidly inhibiting it o Intracranial hemorrhage  severe platelet defects  Generalized defects involving small vessels o “Palpable purpura” and ecchymoses  volume of extravasated blood Endothelium creates a hematoma (palpable mass of blood)  The balance between the anticoagulant and procoagulant activities of endothelium  Characteristic of systemic disorders that disrupt small blood often determines whether clot formation, propagation, or dissolution occurs vessels  lead to vessel fragility  The antithrombotic properties of endothelium can be divided into activities directed at platelets, coagulation factors, and fibrinolysis, o Ecchymoses – bruises; 1-2 cm in size Platelet  Intact endothelium – barrier that shields plateles from inhibitory subendothelial vWF and collagen  Hemorrhagic (hypovolemic) shock – greater blood loss effects  Also release factors that inhibit platelet activation and aggregation  prostacyclin (PGI2), NO, ADPase  Endothelial cells bind and alter the activity of thrombin Anticoagulant  Thrombomodulin, endothelial protein C receptor, heparin-like effects molecules, and tissue factor pathway inhibitor  Thrombomodulin  bind thrombin abmrmtmd Thromobosis  Single nucleotide change (G20210A) in prothrombin gene  leads to elevated prothrombin levels (3-fold ↑ risk of venous thrombosis)  The primary abnormalities that lead to thrombosis are:  Elevated levels of homocyteine  contribute to arterial and venous thrombosis and o Endothelial injury development of atherosclerosis o Prothrombotic effects may be linked to Thioester linkages o Stasis or turbulent blood flow o Marked elevations may be due to inherited deficiency of cystathione b- o Hypercoagulability of the blood (Virchow triad) synthase  Rare inherited cause of primary hypercoagulability include deficiencies of Endothelial Injury anticoagulants such as: antithrombin 3, protein C or S  Endothelial injury to platelet activation almost inevitably underlies thrombus formation o Affected individuals present with venous thrombosis and recurrent in the heart and rge arterial circulation, where the high rates of blood flow impede clot thromboembolism beginning in adolescence or early adulthood formation  Severe endothelial injury may trigger thrombosis by exposing vWF and tissue factor;  Factor V Leiden heterozygosity may trigger DVT when combined with enforced also prothrombotic genes  endothelial activation or dysfunction inactivity o Can be produced by: physical injury, infectious agents, abnormal blood  Inherited causes of hypercoagulabiltiy must be considered in patients younger than flow, inflammatory mediators, metabolic abnormalities age 50 years who present with thrombosis (hypercholesterolemia or homocystinemia) and toxins  Acquired thrombophilia – multifactorial; pregnancy; oral contraceptice; cancer; o Triggers arterial thrombotic events aging, smoking; heparin-induced thrombocytopenia (HIT) and antiphospholipid  Major prothrombotic alterations: antibody syndrome  Endothelial cells downregulate the expression of  HIT occurs after administration of unfractionated heparin thrombomodulin (key modulator of thrombin activity)   induce appearance of antibodies that recognize complex Procoagulant result in sustained activation of thrombin  stimulate of heparin and platelet factor 4  bind to platelets and changes platelet and inflammation thru PARs cause activation, aggregation, consumption  Inflamed endothelium also downregulates protein C and HIT Syndrome  Effect on platelets and endothelial damage by antibody tissue factor protein inhibitor  promote procoagulant binding combine to produce prothrombotic state, even in the state face of heparin administration and low platelet counts Antifibrinolytic  Activated endothelial cells secrete plasminogen  LMW heparin induce HIT less frequently (also direct effects activator inhibitors (PAIs)  limit fibrinolysis and inhibitors of factor X and thrombin) downregulate expression of t-PA  Aka lupus anticoagulant syndrome  Has protean clinical manifestations: recurrent thromboses, repeated miscarriages, cardiac valve vegetations and thrombocytopenia Alterations in Normal Blood Flow  Clinical presentations can include:  Turbulence contribute to thrombosis by causing endothelial injury or dysfunction and o Pulmonary embolism (lower extremity venous by forming countercurrents that contribute to local pockets of stasis thromboses)  Stasis is a major contributor in the development of venous thrombi o Pulmonary hypertension (recurrent subclinical  Normal blood flow – “laminar”  cellular elements flow at the center Antiphospholipid pulmonary emboli)  Stasis and turbulence therefore: Antibody o Stroke; bowel infarction; renovascular o Promote endothelial activation Syndrome hypertension o Disrupt laminar flow  Fetal loss is due to antibody-mediated interference with o Prevent washout and dilution of activated clotting factors trophoblast  failure of placentation  Renal microangiopathy  result in renal failure asso. w/ multiple capillary and arterial thromboses  Antibodies give false positive test for syphilis (Ag is Hypercoagulability embedded in cardiolipin)  Hypercoagulability (aka thrombophilia) – any disorder of the blood that predisposes  Syndrome has primary and secondary forms to thrombosis o Autoimmune disease (SLE) – secondary  Venous thrombosis  primary (genetic) or secondary (acquired) antiphospholipid syndrome  Point mutations in the factor V gene and prothrombin gene  most common  Primary antiphospholipid syndrome – patients exhibit cause of inherited hypercoagulability only the manifestations of a hypercoagulable state and lack evidence of autoimmune disorders;  2-15% of Caucasians carry mutation in factor V (factor V Leiden) o Also appears following exposure to certain drugs o Mutations result to arginine substitution to amino acid residue 506  makes or infections factor V resistant to cleavage abd inactivation by protein C  Therapy: anticoagulation & immunosuppression o Result: antithrombotic counterregulatory pathway is lost o Hetero (5 fold ↑ risk of venous thrombosis); Homo (50-fold) abmrmtmd  HYPERCOAGULABLE STATES Fate of Thrombus Common Factor V mutation; Prothrombin mutation  If patients survive initial thrombosis, in the ensuing days to weeks thrombi undergo ↑ levels of factors VIII, IX, XI, fibrinogen some combination of the following four events: Primary (Genetic) Rare Antithrombin III deficiency Propagation  Thrombi can accumuluate additional platelets and fibrin Protein C or S deficiency Embolization  Thrombi dislodge and travel to other sites in the vasculature Very Rare Fibrinolysis defect; Homozygous homocystinuria Dissolution  Result of fibrinolysis Prolonged bed rest or immobilization  Lead to rapid shrinkage and total disappearance of thrombi High risk for Myocardial infarction or fibrillation  Extensive fibrin depositon and cross-linking in older thrombi thrombosis Tissue injury (surgery, fracture, burn) renders them more resistant to lysis Secondary (Acquired) Cancer; Antiphospholipid syndrome  E.g., t-PA – effective only when given during the first few Low risk for Cardiomyopathy; nephritic syndrome hours of a thrombotic event thrombosis Hyperestrogenic states (pregnancy, postpartum) Organization  Older thrombi become organized by the ingrowth of endothelial Oral contraceptive; sickle cell anemia; smoking and cells, smooth muscle cells and fibroblasts recanalization  Capillary channels for,m and reestablish continuity of lumen  Occasionally, centers of thrombi undergo enzymatic digestion as a result of lysosomal enzymes from WBC and platelets  Arterial or cardiac thrombi – begin at sites of turbulence or endothelial injury  Bacteremia  mycotic aneurysm o Tend to grow retrograde  Venous thrombi – occur at sites of stasis o Extend in the direction of blood flow; thus propagate toward the heart Clinical Features o Often poorly attached  prone to fragmentation and embolization  Lines of Zahn – laminations of thrombi; pale platelet and fibrin deposits with  Thrombi come to clinical attention when they obstruct arteries or veins, or give rise to alternating darker red cell-rich layers emboli o Signify that thrombus has formed in flowing blood  Venous thrombi can cause painful congestion and edema distal to obstruction  o Antemortem clots (nonlaminated clots  postmortem) mainly of concern due to their tendency to embolize the lungs  Mural thrombi – thrombi occurring in the heart chambers or aortic lumen  Arterial thrombi can also embolize the lungs and cause downstream infarctions  o Abnormal myocardial contractions (arrhythmias, dilated cardiomyopathy, chief clinical problem is related to occlusion of a critical vessel myocardial infarction) or endomyocardial injury (myocarditis or catheter trauma promote cardiac mural thrombi  Most occur in superficial or deep veins of the leg. o Ulcerated atherosclerotic plaque and aneurysmal dilation  precursors of  Superficial venous thrombi – occur in saphenous veins in aortic thrombi the settings of varicosities  can cause local congestion,  Arterial thrombi – frequently occlusive swelling, pain, tenderness but rarely embolize  varicose Venous thrombosis ulcers o Most common sites in decreasing order or frequency: coronary, cerebral, (Phlebothrombosis)  DVT (deep venous thrombosis) – involve one of the femoral arteries large leg veins at or above the knee (popliteal, femoral, iliac) o Consist of friable meshwork or platelets, fibrin, red cells, and degenerating o More serious  often embolize to the lungs  leukocytes pulmonary infarction; asymptomatic  Venous thrombosis (phlebothrombosis) – almost invariably occlusive; thrombus  Migratory thrombophlebitis or Trousseau syndrome – form a long luminal cast increased risk of thromboembolism in disseminated cancers o Form in the venous circulation  contain more enmeshed RBC (few plt) and  Atherosclerosis – major cause of arterial thromboses; asso. w/ loss of endothelial integrity and w/ abnormal blood therefore known as red, or stasis thrombi flow o Firm; focally attached to vessel wall; contain lines of Zahn Arterial and Cardiac  Myocardial infarction can predispose to cardiac mural o 90% of cases 0 veins of lower extremeties Thrombosis thrombi by causing dyskinetic myocardial contraction and  Postmortem clots – gelatinous; have a dark dependent portion where rbc have endocardial injury settled by gravity and a yellow “chicken fat” upper portion o RHD – may engender atrial mural thrombi by  Vegetations – thrombi on heart valves causing atrial dilation and fibrillation o Blood borne bacteria or fungi o Both are prone to embolization o Brain, kidney, spleen – likely targets because of o Infective endocarditis their rich blood supply (also other organs) o Nonbacterial thrombotic endocarditis (hypercoagulable states) o Libman-Sacks endocarditis (sterile verrucous endocarditis; SLE) abmrmtmd KEY CONCEPTS: Thrombosis  Most PE (60-80%) are clinically silent because they are small. With time they become  Thrombus development usually is related to one or more components of the Virchow organized and may leave behind a delicate, bridging fibrous web Triad:  Sudden death, right heart failure (cor pulmonale) or cardiovascular collapse occurs o Endothelial injury (e.g., by toxins, hypertension, inflammation, metabolic when emboli obstruct >60% of the pulmonary circulation products) asso. w/ endothelial activation and changes in endothelial gene  Emboli obstruction of medium arteries w/ vascular rupture can result in pulmonary expression that favor coagulation hemorrhage (usually does not cause pulmonary infarction). o Abnormal blood flow – stasis or turbulence (due to aneurysms,  Embolic obstruction of small end-arteriolar pulmonary branches often does produce atherosclerotic plaque) o Hypercoagulability, either primary (factor V leiden, ↑ prothrombin synthesis, hemorrhage or infarction antithrombin III deficiency) or secondary (bed rest, tissue damage,  Multiple emboli over time may cause pulmonary hypertension and right ventricular malignancy, or development of antiphospholipid antibodies (AAS) or HIT) failure  Thrombi may propagate, resolve, become organized, or embolize  Thrombosis cause tissue injury by local vascular occlusion or by distal embolization Systemic Thromboembolism  Most systemic emboli (80%) arise from intracardiac mural thrombi Disseminated Intravascular Coagulation (DIC)  Asso. w/ left ventricular infarcts (2/3) and left atrial dilation and fibrillation (1/4) o Others from aortic aneurysm, atherosclerotic plaques, valvular vegetations,  DIC is not a specific disease but rather a complication of a large number of conditions or venous thrombi (paradoxical emboli) asso. w/ systemic activation of thrombin o 10-15%  unknown origin  Obstetric complications to advanced malignancy – can be complicated by DIC, which  Most come to rest in lower extremities (75%) or the brain (10%) leads to widespread formation of thrombi in the microcirculation o Intestine, kidney, spleen, upper extremities  Microvascular thrombi can cause diffuse circulatory insufficiency and organ  Consequence of systemic emboli depend on vulnerability of affected tissues to dysfunction (brain, heart, lungs, kidneys) ischemia, the caliber of occluded vessel and whether collateral blood supply exist  The runaway thrombosis uses up platelets and coagulation factors  “consumptive  Outcome is tissue infarction coagulopathy”  activates fibrinolytic system o Bleeding catastrophe, hemorrhagic stroke or hypovolemic shock Fat and Marrow Embolism EMBOLISM  Microscopic fat globules (sometimes asso. w/ hematopoietic bone marrow) can be found in pulmonary vasculature after fractures of long bones or setting of soft tissue  An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried trauma and burns by the blood from its point of origin to a distant site, where it often causes tissue o Rupture vascular sinusoids in marrow or small venules  herniation of dysfunction or infarction marrow or adipose tissue to vascular space and travel to lung  Dislodged thrombi – “thromboembolism”  Very common findings after vigorous cardiopulmonary resuscitation and of no clinical  Rare emboli are composed of: fat droplets, nitrogen bubbles, atherosclerotic debris consequence (cholesterol emboli), tumor fragments, bone marrow or foreign bodies  Occurs in 90% of px w/ severe skeletal injuries  Fat embolism syndrome (FES) – symptomatic minority; cxd by pulmonary Pulmonary Embolism insufficiency, neurologic symptoms, anemia, and thrombocytopenia; fatal (5-15% of cases)  Pulmonary emboli (PE) originate from deep venous thrombosis and are the most o 1-3 days after injury  onset of tachypnea, dyspnea, tachycardia common form of thromboembolic disease o Irritability and restlessness can progress to delirium or coma  Fragmented thrombi from DVTs are carried through larger veins and the right side of  Thrombocytopenia  due to platelet adhesion to fat globules and aggregation or the heart before ending into the pulmonary arterial vasculature splenic sequestration o May occlude the main pulmonary artery or straddle the pulmonary artery  Anemia is due to RBC aggregation and/or hemolysis bifurcation (saddle embolus) or pass out into the smaller branching  Petechial rash (20-50%) due to rapid onset of thrombocytopenia and can be useful arteries diagnostic feature  The patient who has had one PE is at high risk for more  Pathogenesis of FES involves mechanical and biochemical obstruction  Rarely, a venous embolus passes through an interatrial or interventricular defect and  Fat microemboli ass. w/ RBC and platelet aggregates  occlude pulmonary and gains access to the systemic arterial circulation (paradoxical embolism) cerebral microvasculature  Overview of the major functional consequences of pulmonary emboli: abmrmtmd Air Embolism INFARCTION  Gas bubbles w/in the circulation can coalesce to form frothy masses that obstruct  Infarct – area of ischemic necrosis caused by occlusion of either the arterial supply vascular flow and cause distal ischemic injury or the venous drainage  Decompression sickness – form of gas embolism; sudden decreases in atmospheric o Tissue infarction – common and important cause of clinical illness pressure  Arterial thrombosis or arterial embolism underlies the vast majority of infarctions o Air breathed at high pressure  increased amounts of gas (Nitrogen) are  Venous thrombosis can cause infarction but the most common outcome is just dissolved in blood and tissues congestion o Depressurizes too rapidly  nitrogen comes out of solution in the tissues  Infarcts caused by venous thrombosis are more likely in organs with a single and blood efferent vein (e.g., testis and ovary) o The bends – painful condition where rapid formation of gas bubbles w/in skeletal muscles and supporting tissues in and about joints MORPHOLOGY o Chokes – a form of respiratory distress in the lungs where gas bubbles in Infarcts are classified according to color and presence or absence or infection; either red the vasculature cause edema, hemorrhage, and focal atelectasis or (hemorrhagic) or white (anemic) and may be septic or bland 1. w/ venous occlusions emphysema 2. in loose, spongy tissues where blood can collect in infracted zone o Caisson disease – more chronic form of decompression sickness; Red 3. in tissues with dual circulations that allow blood to flow from an persistence of gas emboli in the skeletal system leads to multiple foci of infarcts unobstructive parallel supply into a necrotic zone ischemic necrosis 4. tissues in previously congested by sluggish venous outflow  More common sites: femoral heads, tibia, humeri 5. when flow is reestablish to a site of previous arterial occlusion and  Acute decompression sickness is treated by being placed in a chamber under necrosis sufficiently high pressure to force the gas bubbles back into solution  occur with arterial occlusions in solid organs w/ end-arterial White circulation (heart, spleen, and kidney), and where tissue density o Slow decompression permits gradual resorption and exhalation of gases  infarcts limits the seepage of blood from adjoining capillary beds into prevent reformation of obstructive bubbles necrotic area  Infarcts – wedge-shaped w/ occluded vessel at the apex and the periphery of the Amniotic Fluid Embolism organ forming the base o serosal surface base – presence of overlying fibrinous exudates resulting  Amniotic fluid embolism is the fifth most common cause of maternal mortality from acute inflammation worldwide  Fresh infarcts are poorly defined and slightly hemorrhagic  Ominous complication of labor and the immediate postpartum period  Infarcts resulting from arterial occlusions in organs w/out dual blood supply become  Onset is cxd by: sudden severe dyspnea, cyanosis, shock, followed by neurologic paler and more sharply defined  Extravasated RBC in hemorrhagic infarcts are phagocytosed by macrophages impairment (headache to seizues and coma)  Ischemic coagulative necrosis – dominant histologic characteristic of infarction;  If patients survives  initial crisis (pulmonary edema) develops; w/ DIC esp if occlusion occurred shortly (mins to hrs) before death of person; histologic  Morbidity and mortality stem from the biochemical activation of coagulation changes may be absent factors and components of the innate immune system o Takes 4-12 hrs for dead tissue to show microscopic evidence  Underlying cause is the infusion of amniotic fluid or fetal tissue into the maternal  Acute inflammation is present along the margins of infarcts w/in a few hours and is circulation via a tear in the placental membranes or rupture or uterine veins usually well defined w/in 1-2 days  In stable or labile tissues, parenchymal regeneration can occur at the periphery  Classic findings at autopsy include: presence of squamous cells shed from fetal skin, where underlying stromal can occur at the periphery where underlying stromal lanugo hair, fat from vernix caseosa, and mucin from fetal respiratory or GIT tract architecture is preserved o Other findings: marked pulmonary edema, diffuse alveolar damage,  Most infarcts are ultimately replaced by scar presence of fibrin thrombi in vascular beds due to DIC  The brain is an exception to these generalizations, in that the CNS infarction results in liquefactive necrosis KEY CONCEPTS: Embolism  Septic infarctions – occur when infracted cardiac valve vegetations embolize or  Embolous – solid, liquid, or gaseous mass carried by the blood to sites distant from its when microbe seed necrotic tissue origin; most are dislodged thrombi o Infarct is converted into an abscess w/ greater inflammatory response  Pulmonary emboli – derive from lower extremity DVT; effects depend on size and location; consequence include right-side heart failure, pulmonary hemorrhage, or sudden death  Systemic emboli – derive from cardiac mural or valvular thrombi, aortic aneurysm, or atherosclerotic plaques; infarction depends on site of embolization and presence or absence of collateral circulation abmrmtmd Factors That Influence Development of an Infarct Results from low cardiac output Fluid loss Inadequate blood Hypovolemic due tolow blood volume (hemorrhage, or plasma volume  Anatomy of the vascular supply Shock Massive hemorrhage or fluid vomiting, diarrhea, o Availability of an alternative blood supply is the most important loss (severe burns) burns or trauma determinant of whether vessel occlusion will cause tissue damage Triggered by microbial infxns, Overwhelming Activation of burns, trauma, and or microbial infections cytokine cascades; o E.g., lungs and liver – resistant to infarction pancreatitis. The common (bacterial and peripheral o E.g., renal and splenic circulation are end-arterial, and vascular obstruction pathogenic feature is a massive fungal) vasodilation and generally causes tissue death Shock asso. outpouring of inflammatory Superantigens pooling of blood;  Rate of occlusion w/ systemic mediators from innate and (toxic shock endothelial o Slowly developing occlusions are less likely to cause infarction, because they inflammation adaptive immune cells that syndrome) activation/injury; provide time for development of collateral pathways of perfusion produce vasodilation, vascular Trauma, burns, leukocyte-induced leakage, and venous blood pancreatitis damage, DIC o E.g., small interarteriolar anastosomes pooling. These abnormalities  Tissue vulnerability to hypoxia results in tissue hypoperfusion, o Neurons undergo irreversible damage when deprived of their blood supply cellular hypoxia and metabolic for only 3-4 mins derangements that lead to organ o Myocardial cells die after 20-30 mins of ischemia (appearance of dead cells dysfunction (failure and death) take 4-12 hrs to develop) o Fibroblast w/in myocardium remain viable even after many hours of ischemia Pathogenesis of Septic Shock  Hypoxemia o Abnormally low blood ) content increases both the likelihood and extend of  Most frequently triggered by: gram positive bacteria, gram negative bacteria and fungi infarction  Factors that play major roles in pathophysiology of septic shock: KEY CONCEPTS: Infarction Inflammatory  TLRs – recognize a host of microbe-derived substance  Infarcts – areas of ischemic necrosis most commonly caused by arterial occlusion (due and counter- containing PAMPs, GPCR, NOD1 and NOD2 inflammatory  Upon activation, innate immune cells produce TNF, IL-1, IFN- to thrombosis or embolization); venous outflow obstruction is a less frequent cause responses y, IL-12 and IL-18 and HMGB1  Infarcts caused by venous occlusion or occurring in spongy tissues w/ dual blood supply and where blood can collect typically are hemorrhagic (red); those caused by  Effector molecules upregulate adhesion molecule expression and arterial occlusion in compact tissues are pale (white) stimulate cytokine and chemokine production  Whether or not vascular occlusion causes tissue infarction is influenced by collateral  Complement cascade is also activated  production of blood supplies, the rate at which an obstruction develops, intrinsic tissue susceptibility anaphylotoxins (C3a, C5a), chemotactic fragments (C5a) and to ischemic injury and blood oxygenation opsonins (C3b)  pro-inflammatory state  Factor XII is also activated  widespread activation of thrombin  augment inflammation through PARs  Sepsis  activate counter-regulatory immunosuppressive SHOCK mechanisms  hyperinflammatory and immunosuppressed states  Shock is a state in which diminished cardiac output or reduced effective circulating Endothelial  Leads to widespread vascular leakage and tissue edema blood volume impairs tissue perfusion and leads to cellular hypoxia activation and  Cytokines loosen endothelial cell tight junctions  leaky vessel o May complicate severe hemorrhage, extensive trauma or burns, myocardial injury  accumulation of protein-rich edema infarction, pulmonary embolism, and microbial sepsis  Impedes tissue perfusion o Three general categories:  Upregulates production of NO and vasoactive inflammatory mediators (C3a, C5a, PAF)  contribute to vascular smooth muscle relaxation and systemic hypotension TYPE DEFINITION EXAMPLE MECHANISM Induction of a  May lead to DIC Results from low cardiac output Myocardial Failure of procoagulant  Proinflammatory cytokines - ↑ tissue factors production by due to myocardial pump failure infarction, myocardial pump monocytes and ↓ production of endothelial anti-coagulant factors Cardiogenic ventricular rupture, resulting from (TFPI, thrombomodulin, protein C) Shock arrhythmia, cardiac intrinsic myocardial  Also dampen fibrinolysis by increasing plasminogen activator tamponade, damage, extrinsic inhibitor-1 expression pulmonary compression, or  Vascular leak and tissue edema - ↓ blood flow w/ stasis and embolism obstruction to diminish wash-out of activated coagulation factors outflow abmrmtmd   In full-blown DIC, the consumption of coagulation factors and Stages of Shock platelets is so great that deficiencies of these factors appear  lead to bleeding and hemorrhage  Three general phases: Metabolic  Septic patients exhibit insulin resistance and hyperglycemia abnormalities  Gluconeogenesis – driven by TNF & IL-1 and stress-induced Nonprogressive  Initial stage; reflex compensatory mechanisms are activated and hormones (glucagon, GH, glucocorticoid) phase perfusion of vital organs is maintained  Pro-inflammatory cytokines suppress insulin release and promote  Variety of neurohormonal mechanisms  maintain cardiac insulin resistance; impair expression of GLUT4 output and blood pressure (baroreceptor reflex, catecholamine  Hyperglycemia decrease neutrophil function  suppress release, RAAS, ADH, generalized sympathetic stimulation) bactericidal activity  cause increase adhesion molecule  Net effect: tachycardia, peripheral vasoconstriction, renal expression on endothelial cells conservation of fluid  Sepsis – initially asso.w/ acute surge in glucocorticoid Progressive  Cxd by tissue hypoperfusion and onset of worsening circulatory production and followed by adrenal insufficiency and functional stage and metabolic imbalances, including lactic acidosis deficit of glucocorticoids  stem from depression of synthetic  Widespread tissue hypoxia  aerobic respi is replaced by capacity of intact adrenal glands or frank adrenal necrosis due to anaerobic glycolysis  excess prdxn of lactic acid DIC (Waterhouse-Friderichsen syndrome)  Lactic acidosis  lowers pH; blunts vasomotor response;  Finally, cellular hypoxua and diminished oxidative arterioles dilate, blood begins to pool in microcirculation  phosphorylation leads to increased lactate production and lactic anoxic injury with subsequent DIC acidosis  Organs begin to fail Organ  Systemic hypotension, interstitial edema, small vessel Irreversible  Sets in after the body has incurred cellular and tissue injury so dysfunction thrombosis  decrease delivery ofO2 and nutrients stage severe that even if hemodynamic defects are corrected, survival  Failure to utilize nutrients due to cellular hypoxia is not possible  ↑ level of cytokines and secondary mediators  ↓ cardiac  Widespread cell injury  lysosomal enzyme leakage contractility and output; and ↑ vascular permeability and  Bacteremic septic shock endothelial injury  lead to acute respiratory distress  Patient may develop anuria as a result of acute tubular necrosis syndrome (ARDS) and renal failure  Cause the failure of multiple organs like kidneys, liver, lings, heart and culminate in death Clinical Consequences  Severity and outcome of septic shock are likely dependent on: o Extent and virulence of infection  Hypovolemic and cardiogenic shock o Immune status of host o Hypotension; weak, rapid pulse; tachypnea; cool, clammy, cyanotic skin o Presence of other morbid conditions  Septic shock o Pattern and level of mediator production o Skin may be initially warm and flushed due to vasodilation  Superantigen – bacterial proteins that cause syndromes similar to septic shock (toxic KEY CONCEPTS: Shock shock syndrome;TSS); polyclonal T-lymphocyte activators  Shock – state of systemic tissue hypoperfusion due to reduced cardiac output and/or o Induce release of high levels of cytokines that result in: diffuse rash to reduced effective circulating blood volume vasodilation, hypotension, shock and death  The major types of shock are: o Cardiogenic (myocardial infarction) o Hypovolemic (blood loss) o Asso. w/ systemic inflammatory response (severe infections) o Acute spinal or brain injuries and severe hypersensitivity reactions can also cause neurogenic shock and anaphylactic shock, respectively  Shock of any form can lead to hypoxic tissue injury if not corrected  Septic shock is caused by the host response to bacterial, viral or fungal infections; it is a systemic inflammatory condition characterized by endothelial cell activation, tissue edema, DIC and metabolic derangements that often lead to organ failure and death abmrmtmd