Chapter 11 ? Blood Vessel Pathology Vascular pathology stems from either vessel blockage or weakening of vessel walls Arteriogenesis is the remodeling of existing vessels due to chronic changes in pressure or flow The three (3) significant congenital vascular anomalies are developmental or berry aneurysms, arteriovenous fistulas, and fibromuscular dysplasia. Fibromuscular dysplasias may put the pt at risk for aneurysms near a fibrotic area Intimal thickening is the stereotypical response to any insult on the vessel wall and is permanent Complications to HTN are greater in African Americans Roughly half of untreated pts with HTN die of ischemic heart dz (IHD) or CHF, and another third die of stroke. Malignant HTN is 200/120 and is relatively rapid onset (1-2 yrs) Renin-angiotensin-aldosterone system increases BP by increasing peripheral resistance and increasing reabsorption of sodium. Endogenous inhibitors of the Renin-angiotensin system are the natriuretic peptides secreted by atrial and ventricular myocardium in response to volume expansion Epithelial sodium channel (ENaC) is responsible for determining sodium balance Gene defects in aldosterone metabolism result in increased salt and water retention and thus HTN Liddle syndrome results in mutated Na channels that overreact to aldosterone stimuli and absorb too much salt Weibel-Palade bodies are granules that contain vWF and IL-8 among other cytokines Renal artery stenosis activates the Renin-angiotensin system which drives up BP and is one of the more common causes of secondary (known cause) HTN In pts with HTN, a dz called Hyaline Arteriosclerosis is caused by plasma protein leakage into the media and can lead to glomerular scarring further exacerbating HTN Hyperplasic arteriosclerosis occurs in malignant HTN and causes onion skinning of vessel lumens accompanied by fibrinoid deposits and vessel wall necrosis, particularly in the kidney Family hx is the most significant independent risk factor for atherosclerosis HTN by itself increases the risk of ischemic heart dz (IHD) by 60% Hyperhomocysteinemia is another risk factor for vascular dz, and can be controlled by adequate B12 and folate intake Oxidized LDL may be the single-most important mediator of atherosclerosis. If LDL is not oxidized by free-radicals, then it won?t incorporate into macrophages and cannot damage endothelium The propensity for atherosclerosis is greatest in the lower abdominal aorta followed by the coronary arteries, popliteal arteries, ICAs, and Circle of Willis The superficial fibrous cap on atheromas is generally made from SMCs and dense collagen The atheroma ?shoulder? is usually formed of macrophages, T-cells, and SMCs Rupture, ulceration, or erosion of the intimal layer of a plaque can cause thrombosis, vessel occlusion, and downstream ischemia Atherosclerotic plaques that contain large areas of foam cells and extracellular lipid, and those in which the fibrous caps are thin or contain few SMCs or have clusters of inflammatory cells , are more likely to rupture, and are known as ?vulnerable plaques? Inflammation may promote collagen degradation in plaques and thus destabilize them. Statins help stabilize plaques by reducing inflammation and reducing cholesterolemia. Pseudo-aneurysms occur when vessel walls are damaged and blood communicates with surrounding ECM (pulsating hematoma) Saccular aneurysms are spherical outpouchings, whereas fusiform aneurysms are concentric dilations. Neither is specific for any particular dz state or clinical situation Connective tissue abnormalities like Marfans (fibrillin misfold, high TGF-?) , Loeys-Dietz syndrome (TGF-? receptor mutation, elastin and collagen 1,3 abnormalities), and Ehlers Danlos dzs lead to increased incidence of aneurysm and rupture. Increased MMP production, esp. by macrophages in atherosclerotic plaques, is the major contributor to aneurysm development by negatively remodeling vessel wall ECM Genetic predisposition to aneurysm may be related to polymorphisms of MMPs or TIMPs (tissue inhibitors of MMPs) Outer medial ischemia (due to atherosclerosis or HTN) can lead to SMC degradation and vessel wall weakening as well as increased ground substance (glycosaminoglycan) production termed cystic medial degeneration Syphilis infection has a predilection for obliterative endocarditis of vaso vasorum and can involve the aortic valve annulus. Most pts die of heart failure due to valve incompetence. Mycotic AAAs (typ. from Salmonella gastroenteritis) are more serious than inflammatory AAAs due to further destruction of the intima by suppuration, potentiating rapid dilation and rupture Pts with AAA are at great risk for IHD or other atherosclerosis because these are systemic diseases Over 90% of Aortic dissection cases involve men age 40-60 with prior HTN. 10% are in younger pts with connective tissue anomalies or iatrogenic...and rarely during or after pregnancy for unknown reasons It is important to differentiate btw infectious (bacterial) or non-infectious (immunological) causes for vasculitis pts because immunosuppressive therapy will work in non-infxs and make infxs worse Immune complex deposition (Type 3 HS), anti-neutrophil Abs, and anti-endothelial Abs are the most common causes of non-infectious vasculitis. Don?t neglect trauma, radiation, or toxins (ALL non-infectious causes) Anti-neutrophil cytoplasm antibodies (ANCAs) cause degranulation and injury by ROS release. In Temporal ateritis (giant cell arteritis), 50% of pts exhibit sudden onset of ocular symptoms (diplopia or vision loss) and have nodular temporal arteries/veins Takayasu arteritis is a granulomatous vasculitis of medium and larger arteries characterized by ocular disturbances and marked weakness of UE pulses. Polyarteritis nodosa (PAN) typ. involves renal and visceral vessels but spares pulmonary PAN is characterized by necrotizing inflammation of small to medium sized arteries (kidneys, heart, liver) leading to vessel wall weakening and potential rupture PAN is a dz of young adults frequently enigmatic with common symptoms including malaise, fever, weight loss, HTN, abdominal pain and bloody stools, diffuse muscular aches and pains, and peripheral neuritis PAN is likely fatal unless treated with corticosteroids and cyclophosphamide which are also effective in microscopic polyangitis Churg-Strauss (granulomatous angiitis) is eosinophilic in nature and involves p-ANCAs with lung and GI involvement. Opposite to PAN (no lung involvement and no eosinophilia) Kawasaki dz is Heart dz due to coronary artery vasculitis due to a Type 4 HS rxn to an unknown antigen resulting in monoclonal Ab production to endothelial cells and SMCs. Kawasaki?s presents with conjunctival and oral erythema and erosion, peripheral edema, desquamative rash, strawberry tongue (like toxic shock syndrome) and cervical node enlargement Wegener granulomatosis is a necrotizing vasculitis with a TRIAD of acute necrotizing granulomas of the UR/LR Tracts and kidneys PR3-ANCAs are present in 95% of Wegener?s cases Thromboangiitis Obliterans (Buerger Disease) is characterized by segmental thrombosing inflammation of tibial and radial arteries. This dz occurs almost exclusively in smokers before 35. Buerger?s can manifest as Raynaud?s and pain in the instep induced by exercise, with ulceration of the toes, feet, or fingers. Secondary Raynaud phenomenon is linked to SLE, scleroderma, Buerger?s, or even atherosclerosis. IVC syndrome can be caused by neoplasms or thrombi. Hepatocellular carcinoma and renal cell carcinoma like to grow in veins and may occlude the IVC. Renal vein involvement will show proteinuria. The most common organism in lymphangitis is Group A ?-hemolytic strep. Pyogenic granulomas are rapidly growing pedunculated red nodules on the skin or gingival or oral mucosa and appear similar to exuberant granulation tissue. Glomangiomas are found under the fingernail Sturge-Weber syndrome typically involves port-wine stain with trigeminal distribution and pts have mental retardation, hemiplegia, and seizures with venous angiomatous masses in the cortical leptomeninges Osler-Weber-Rendu syndrome (Hereditary Hemorrhagic Telangiectasia) is autosomal dominant and presents with frequent epistaxis or GI bleeding Kaposi Sarcomas are all due to infection with HHV8, but not all are associated with AIDS. Neoplasms are from proliferating spindle cells (nodular stage) Angiosarcomas are malignant neoplasms of endothelium Ch.12 ? The Heart Sub-endocardial infarction - Inner 1/3rd, ?Non-ST elevation infarcts? Stable angina - pain on exertion - relieved by nitroglycerin Unstable (preinfarction) angina is caused by thrombus - increasingly prevalent at rest over time Prinzmetal angina - coronary vasospasm - intermittent chest pain at rest ? responds promptly to nitroglycerin Arrythmia is most common cause of death in MI Three days after MI, macrophages replace neutrophils. Greatest risk of myocardial rupture between 4 and 7 days (tamponade). At 7 days, fibroblasts proliferate. At 10 days acute phase is over and fibrosis continues Post MI histo (day 1) ? Wavy fibers, coag necrosis, widened space btw cells (edema), PMNs CK-MB peaks 18-24 hrs after MI and is negative at 3 days ? dense PMNs in spaces btw cells at 3-4 days Troponin peaks at 24 hrs after MI but persists up to 7 days post MI 7-10 days post MI, macrophages finish cleaning necrotic debris ? High risk for rupture at 3-7 days, no scar tissue yet ? prior HTN increases this risk Contraction bands and hemorrhage after MI demonstrate reperfusion. Ca causes intense contractions of sarcomeres Repetitive, short-lived ischemia may protect myocardium ? ?preconditioning? LDH levels peak at 3 days post MI and should be absent before then (LDH is non-specific for MI) RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE Rheumatic fever most often affects children between 5 and 15 and also involves transient migratory polyarthritis. Rheumatic fever often occurs 1-4 wks following tonsillitis, pharyngitis, or other GAS infxn which can be dxd by elevated antibodies to antistrptolysin O (ASO) or DNAase. RF is a T2 Hypersensitivity due to molecular mimicry. Aschoff bodies (focal interstitial myocardial inflammations, giant cells) and Anitschkow cells are the classic lesion of Rh fever Rh endocarditis most often occurs at locations of greatest hemodynamic stress (valve closures and posterior wall of LA) which leads to MacCallum plaques. >50% of cases only involve mitral valve. Neovascularization may occur on leaflets? Fish-mouth buttonhole deficiency ? Rh heart dz (RHD) Mitral stenosis ? LA diastolic pressure higher than LV diastolic Erythema marginatum (rash over trunk and extremities) and Sydenham chorea (involuntary purposeless movements and weird grimaces, late stage) may be signs of Rheumatic Fever Infective Endocarditis ? Strep viridians, or other commensal oral bacteria (Kingella, Eikenella, Haemophilus, etc.) Prosthetic valve? ? Staph epidermidis Endocarditis in IV drug users - Tricuspid valve (>50% cases), usually S. aureus infxn Glomerulonephritis may be caused by septic emboli from endocardial vegetations Libman-Sacks endocarditis ? SLE Janeway lesions, Osler nodes (digital pulp nodules), Roth spots (retinal hmrrhage) ? Infective Endocarditis Carcinoid endocarditis ? Right heart only (lung detoxifies tumor products) Mitral prolapse (7% of population) ? Midsystolic click and characteristic murmur ? ?myxomatous degeneration? (proteoglycan deposition in spongiosa) histologically Mitral insufficiency may be due to prolapse, endocarditis, or damage to papillary muscle due to stretching of mitral ring in ventricular dilation (HTN) ?Degenerative calcific aortic stenosis? can only be used if pt has normal tri-cusp valve Aortic insufficiency may arise from non-dissecting aortic aneurysm, Rh heart dz, or syphilis infxn Lutembacher syndrome ? ASD with mitral stenosis (stenosis generally from Rh fever) Tetralogy of Fallot ? ventricular endocardial cushion defect. Communication btw ventricles and main arteries. Aorta overrides both ventricles and pulm artery is hypoplastic (no dev in utero). Look for cyanosis from birth and pts in squatting position. Boot shaped cardiac silhouette PDA is necessary for survival of pts with Transposition Coarctation is evidenced by notching of ribs on chest x-ray due to enlarged intercostal arteries (Turner syndrome) Rubella infxn ? Congenital heart dz, microcephaly, MR, deafness, blindness Cyanosis with congenital anomalies include Tetralogy, Transposition, Persistent Truncus, anomalous pulmonary venous connection, and Pulmonary HTN. Look for Paradoxical Emboli Cardiomyopathies - NON-INFLAMMATORY and NON-HTN. Think alcohol, thiamine def., protein gene mutation Hypertrohpic cardiomyopthay - louder w/Valsalva ? banana shaped LV lumen ? septal hypertrophy - haphazard orientation of myofibers ? physical exam may show a ?double tap? on PMI and carotid pulses (outflow obstruction from mitral valve on aortic valve) Restrictive Cardiomyopathy ? amyloidosis or hemochromatosis, decrease in LV compliance Dilated Cardiomyopathy (DCM) ? check dystrophin gene and doxorubicin administration Myocarditis ? Coxsackievirus B ? biventricular failure w/myocardial degeneration and necrosis. T. cruzi, Borrelia (Lyme dz), Trichinella, and Nisseria can also cause myocarditis Straw-colored fibrinous exudate from pericardium ? SLE, Rh fever, viral infxn Chronic constrictive pericarditis ? tuberculous staph infxn ? mimics right heart failure, may see focal calcifications and fibrous tissue Constrictive pericarditis ? mimics restrictive Cardiomyopathy ? muffled heart sounds L. atrial myxoma is most common primary cardiac tumor (adults, benign) ? mesenchymal origin, presents with paroxysmal nocturnal dyspnea, platypnoea (difficulty breathing upright), and palpitations. Usually asymptomatic until 13cm (5in.) wide??BALL VALVE? Right-heart failure is most commonly caused by Left-heart failure. Pulm HTN is 2nd cause. Renal hypoxia and fluid retention is first sign of Right-heart failure. ?Nutmeg liver? is next, then JVD Right-heart failure and portal HTN lead to enlargement of the spleen (congestive splenomegaly) Emphysema may cause RV hypertrophy? Hemosiderin-laden macrophages are telltale signs of previous pulmonary edema and are often referred to as Heart Failure cells BUN:Cr ratio above 20 is indicative of prerenal azotemia caused by hypoperfusion due to CHF. Inability to excrete nitrogenous waste is termed Azotemia Eisenmenger syndrome describes right-to-left reversal from left-to-right shunt in late cyanotic congenital heart dz ASD primum anomalies (5%) are near the AV valves 90% of VSDs (most common congenital cardiac anomaly) are in the membranous IV septum PDA - ?machinery? murmur ?Water-bottle? heart ? symmetric enlargement (dilation) Harsh mid-sys murmur in left 2nd space at left sterna border ? pulmonic stenosis Mid-sys murmur in right 2nd space at right sterna border radiating to neck ? aortic stenosis Murmur on left sterna border 3rd-4th spaces, louder on Valsalva ? Hypertrophic Cardiomyopathy Blowing holosystolic murmur at apex to left axilla ? Mitral regurgitation Blowing holosystolic murmur at lower left sterna border radiating to right of sternum ? Tricuspid regurg Soft, late systolic murmur at left sterna border or apex, mid-systolic click ? Mitral prolapse Harsh, holosystolic murmur at lower left sterna border, thrill ? VSD Low pitched diastolic murmur at apex, louder at S1, opening snap after S2 ? Mitral stenosis Blowing, high pitched diastolic murmur at left 2nd-4th spaces radiating to apex ? Aortic regurgitation Systolic flow murmur, fixed splitting of S2 ? ASD T-wave inversion ? Transmural ischemia ST-depression ? Subendocardial injury ST-elevation ? Transmural injury Q waves present ? Transmural infarction MI? ? Q waves and ST elevation on EKG DCM ? ABCDE - Alcohol, Beri Beri (thiamine def), Coxsackie B, Chagas, Cocaine, Doxorubicin, PrEgnancy Chapter 13 ? WBC Diseases Lymphopenia ? Congenital immunodeficiency, HIV, glucocorticoid therapy, cytotoxic drugs, autoimmune disorders, malnutrition, acute viral infxns that sequester T-cells. Mediated by Type I Interferons Neutropenia aka Agranulocytosis ? suppression of hematopoietic stem cells, committed granulocyte (PMN) precursors, Dz?s asscd w/ineffective hematopoiesis (megaloblastic anemia, where precursors die in marrow), or congenital conditions (Kostmann syndrome) ? Or due to fast removal or destruction of PMNs from injury to PMNs, splenomegaly, or increased peripheral utilization Most common cause of agranulocytosis ? drug toxicity ? alkylating agents (cancer treatment), aminopyrine, chloramphenicol, sulfonamides, chlorpromazine, thiouracil, phenylbutazone Dohle bodies ? Sever inflammatory disorders ? patches of dilated ER appear as sky blue ?puddles? Acute cervical lymphadenitis ? most commonly due to infxn in teeth or tonsils Follicular hyperplasia ? Rh arthritis, toxoplasmosis, HIV ? lymph node architecture preserved and zones are recongnizable?all of these characteristics are absent in neoplastic follicles (lymphomas) Follicular lymphoma ? t(14;18)?you go to the Germinal Center if your 18 translocates with a 14? Mantle cell lymphoma ? Put your 11 and 14 chr on the mantle b/c they are na´ve B-cells Acute leukemias - mutations block differentiation early in pathway and enhance growth/survival Increased risk for Acute leukemia ? Bloom, Fanconi, ataxia telangiectasia, Down?s, Neurofibromatosis 1 EBV can cause Burkitt lymphoma, 30-40% Hodgkin lymphomas, and B and NK-cell lymphomas Leukemias ? arise in bone marrow Lymphomas ? arise in discrete tissue masses 2/3 of NHL and ALL Hodgkin lymphomas present w/enlarged tender lymph nodes >2cm Multiple myeloma ? plasma cell neoplasm ? bony destruction ? hypercalcemia and neural disruptions ? Most commonly produce monoclonal IgG or IgA. Treatment - Proteasome inhibitors (can cause myeloma cell apoptosis) Neoplastic plasma cells often make excess Light and Heavy chains, light chains can be excreted or deposited (AL amyloidosis) ? Bence Jones proteinuria? Acute Lymphoblastic Leukemia/lymphoma ? neoplasms of immature T/B-cells ? 85% are B-cell origin T-cell ALL?s typically present in adolescent males as thymic lymphomas ? NOTCH1 mutations (50-70%) B-ALL?s present with CD10 and CD19 on flow cytometry Terminal deoxynucleotidyl-transferase (TdT) is found in >95% of ALL cases CD3,4, and 8 are positive in late T-cell ALL ALLeukemia and AML involve crowding in marrow by neoplastic ?blasts? ALL ? abrupt stormy onset within days/weeks after first symptoms ? fatigue, anemia, fever, bleeding, bone pain, lymphadenopathy, spleno/hepatomegaly, compression of large vessels in mediastinum, CNS sx due to meningeal spread Factors asscd w/worse ALL prognosis ? Under 2 y/o (MLL gene translocation more likely), Adolescent/adult presentation, peripheral blood blasts >100k, t(9;22) ?Philadelphia chromosome? Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) - >4k lymphocytes/mm3 - adults Lymphocytes in ?proliferation centers? in nodes ? Pathognomonic for CLL/SLL ? deletion of 11q, 13q, or 17p?or trisomy 12 Diffuse Large B-cell Lymphoma (DLBCL) ? most common NHL (25k cases/yr in US) ? adult presentation ? dysregulation of BCL6 (silences p53) ? HIV pts also at risk for EBV infxn and DLBCL ? tumors are aggressive and rapidly fatal if not treated All forms of Burkitt lymphoma (B-cell neoplasms) are associated with translocations of c-MYC on chr8 (8;14, 2;8, or 8;22) Memory B neoplasms - Extranodal marginal zone (MALToma), Hairy cell leukemia (old man, pancytopenia, splenomegaly) Waldenstrom macroglobulinemia ? excess IgM ? hyperviscous blood ? older adults w/lymphoplasmacytic lymphoma (monoclonal IgM production by plasma cells ? B-cells express the Ig?) ? This is incurable, median survival 4 yrs w/plasmapheresis to remove excess IgM? Marginal Zone Lymphomas or MALTomas may arise due to a reactive response to chronic inflammation; pathogen (H. pylori, EBV), autoimmune process (Sjogrens, etc) resulting in increased selectivity for monoclonal B-cells which may carry an oncogenic mutation?thus lymphoma progression MALTomas ? constitutive activation of NF-kB due to MALT1 or BCL10 translocations Anaplastic large cell Lymphoma ? CD8 lymphomas with ALK protein expression, typ. decent prognosis Adult T-cell Lymphoma - monoclonal helper T-cells with HTLV-1 infxn ? endemic in Caribbean, Japan, W.Africa (presents with cutaneous lesions and hypercalcemia) ? viral ?tax? gene activates NF-kB ? (different than Mycosis fungiodes/Sezary syndrome ? cutaneous only, still helper T-cells) ? cloverleaf cells Reed-Sternberg cells (neoplastic B-cells >45um w/multiple nuclei or lobes and large inclusion-like nucleus about the size of a lymphocyte) are diagnostic features of Hodgkin Lymphoma Nodular sclerosis type Hodgkin?s Lymphoma is most common (65-70% of cases) ? collagen bands separate nodules. HL typically presents as painless lymphadenopathy (frequently mediastinal), but can progress to fever, NS, and weight loss (stages III-IV) HL spread is typically nodal -- splenic -- hepatic-- marrow and other tissues. Staging of HL is more important in treatment than in NHL Acute Myeloid Leukemia ? accumulation of blasts due to mutations that impede differentiation (disrupted transcription factors) in marrow suppresses hematopoiesis ? pancytopenia. Aberrant tyrosine kinase activity is a universal feature of AML Myelodysplastic and Myeloproliferative disorders often transform to AML. Diagnosis of AML is >20% myeloid blasts in a bone marrow smear Myeloblasts have more cytoplasm than lymphoblasts and have 2-4 nucleoli AML flow cytometry with little or no CD64 ? no maturation Most AML patients present within weeks or a few months with sx related to anemia, neutropenia, and thrombocytopenia ? similar to Acute Lymphoblastic Leukemia (ALL) AML with t(8;21) or inv(16) have relatively good prognosis, particularly in the absence of c-KIT mutations as compared to AML?s that follow Myelodysplastic syndromes or genotoxic therapies (these must be treated by marrow transplantation) t-MDS (therapy mediated MyeloDysplaticSyndrome) median survival rate is 4-8 months. Treatment for younger pts is marrow transplant, older pts treated supportively w/Ab?s and blood transfusions Chronic Myeloid Leukemia (CML) ? BCR-ABL fusion gene (100% sensitive) CML has an insidious (fast) onset marked by anemia and hypermetabolism leading to fatigue, weakness, weight loss, and anorexia and may include splenomegaly or ULQ pain caused by splenic infarct Imatinib (BCR-ABL inhibitor) ? greater than 90% remission Polycythemia Vera ? mutation in JAK2 reduces need for erythropoietin ? Low serum levels whereas secondary forms of absolute polycythemia have high levels of EPO Late stage PCV results in marrow fibrosis and hepatosplenomegaly due to extramedullary hematopoiesis Essential Thrombocytosis ? Characteristic sx is erythromelalgia (throbbing and burning of hands and feet) PCV, ET, and Primary Myelofibrosis ? all share mutation in JAK2?probably all variations of same disease Langerhans Cell Histiocytosis ? monoclonal proliferation of dendritic cells with Birbeck granules (?tennis rackets?) is split into three categories (multisystem multifocal, aka Letterer-Siwe disease, is the worst) Multifocal unisystem LCH is seen in children (calvarial defects, DI, and exopthalmos, aka Hand-Schuller-Christian triad) may regress spontaneously or be treated with chemo Thymomas are tumors of thymic epithelial cells, not the T-cells found in the Thymus and are usually discovered during evaluation of pts with Myasthenia Gravis or sx of mediastinal impingement Thymic carcinomas often have involvement with EBV Chapter 14 ? RBCs and Bleeding Disorders Petechiae and purpura DDX: (normal PT and PTT?TTP and HUS also have normal PT and PTT) Ehlers Danlos Cushing?s Scurvy Meningiococcemia Drug rxns Henoch-Schonlein purpura HHT (Hereditary hemorrhagic Telangiectasia) aka. Weber-Osler-Rendu syndrome Perivascular amyloidosis
Want to see the other 13 page(s) in Path_Block_2_notes.docx?JOIN TODAY FOR FREE!