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DISEASES OF BLOOD VESSELS H.A .MWAKYOMA, MD BLOOD VESSELS • • • • • • • • Introduction Atherosclerosis Aneurysms Hypertensive vascular disease Vasculitis Diseases of veins Diseases of lymphatics Tumors (we will not talk much about it except Kaposi’s sarcoma) Types of blood vessels 1. Arteries: - Elastic arteries: Aorta and large arteries. Muscular arteries: Smaller arteries. Atherosclerosis is a disease of large elastic arteries. It rarely affects muscular arteries and does not affects arterioles. 2. Arterioles: - Smallest elements of arterial system. Hypertensive arterial disease is primarily a disease of the arterioles. 3. Capillaries: - Tiniest blood vessels. Capillaries are rarely affected by disease, except in disseminated intravascular coagulation. Types of blood vessels cont-4. Venules 5. Veins Venous thrombosis is more common than arterial, because of the slow blood flow and at a lower pressure. 6. Lymphatics A. Atherosclerosis • A disease of large and medium-sized arteries. So we are talking about the aorta and its main branches: internal and external iliac, carotids, & subclavian arteries. The organ arteries are rarely affected such as renal, splanchnic, upper extremity arteries. The intracerebral arteries & lower extremity arteries are the only exceptions. By far the commonest clinical problem you will face because of atherosclerosis is coronary artery atherosclerosis. • Accumulation within the intima of smooth muscle cells and lipids. • Produces irregular thickening of the wall and narrowing of the lumen. General Comments • Arteriosclerosis – Thickening and loss of elasticity of arterial walls – Hardening of the arteries – Greatest morbidity and mortality of all human diseases via; Narrowing Weakening Three patterns of arteriosclerosis • Atherosclerosis – The dominant pattern of arteriosclerosis – Primarily affects the elastic (aorta, carotid, iliac) and large to medium sized muscular arteries (coronary, popliteal) • Monckeberg medial calcific sclerosis • Arteriolosclerosis –small arteries and arterioles (hypertension and DM) Non-Modifiable Risk Factors • Age – A dominant influence – Atherosclerosis begins in the young, but does not precipitate organ injury until later in life • Gender – Men more prone than women, but by age 60-70 about equal frequency • Family History – Familial cluster of risk factors – Genetic differences Modifiable Risk Factors (potentially controllable) • • • • • • • • Hyperlipidemia Hypertension Cigarette smoking Diabetes Mellitus Elevated Homocysteine Factors that affect hemostasis and thrombosis Infections: Herpes virus; Chlamydia pneumoniae Obesity, sedentary lifestyle, stress • Pathogenesis of atherosclerosis Normal Artery Atherosclerosis • A disease of the intima • A disease of the intima • A disease of the intima • Atheromas, atheromatous/fibrofatty plaques, fibrous plaques • Narrowing/occlusion; weakness of wall ATHEROSCLEROSIS Steps in atherosclerosis development • Fatty streak • Fibrous plaque • Atherosclerotic plaque • Calcification plaque Complication of atherosclerotic plaques. ATHEROSCLEROSIS Fatty streak: Represents the initial lesion Results from abnormal accumulation of lipoproteins in the intima layer Mainly localized at arterial bifurcations Appears since first years of life. ATHEROSCLEROSIS Fibrous plaque: Is the most characteristic lesion of Atherosclerosis, is composed of: Monocytes Macrophages S.M.C. (Smooth Muscle Cells) “Foam cells” *** Lipid-rich “Necrotic core”. Fibrous plaque: Major components of plaque • Cells (SMC, macrophages and other WBC) • ECM –Extracellular Matrix (collagen, elastin, and PGs) • Lipid = Cholesterol (Intra/extracellular) • (Often calcification) Two major processes in plaque formation • Intimal thickening (SMC proliferation and ECM synthesis) • Lipid accumulation ATHEROSCLEROSIS Atherosclerotic plaque: Proliferation at the intima layer of: S.M.C. Macrophages “Foam cells” Conective Tissue elements (CTE) Collagen type I Elastin Fibers Glycosaminoglycans Cholesterol uptake Calcium deposits Complication of the plaque ATHEROSCLEROSIS COMPLICATED PLAQUE: Ulceration • • Thrombosis • Acute ischemia/necrosis Growth • Acute thrombosis with oclussion Disloging and peripheral embolism Chronic ischemia Necrosis • Aneurysm development • PATHOGENESIS OF ATHEROSCLEROSIS Response to injury hypothesis * Injury to the endothelium (dysfunctional endothelium) * Chronic imflammatory response * Migration of SMC from media to intima * Proliferation of SMC in intima • Excess production of ECM • Enhanced lipid accumulation Response to injury hypothesis (I) 1. Chronic EC (Endothelial Cell) injury – EC dysfunction – Increased permeability – Leukocyte adhesion (via VCAM-1) – Thrombotic potential Response to Injury Response to injury hypothesis (I) Response to injury hypothesis (II) 2. Accumulation of LDL (cholesterol) 3. Oxidation of lesional LDL 4. Adhesion & migration of blood monocytes; transformation into macrophages and foam cells 5. Adhesion of platelets 6. Release of factors from platelets, macrophages and ECs Response to injury hypothesis (III) 7. Migration of SMC from media to intima 8. Proliferation of SMC 9. ECM production by SMC 10. Enhanced lipid accumulation Intracellular & Extracellular (SMC and macrophages) Initiation of Fatty Streak Fatty Streak Fatty Streak-Aorta Fatty Streak-Coronary Artery Fibro-fatty Atheroma Summary of Atherosclerotic Process • Multifactorial process (risk factors) • Initiated by endothelial dysfunction • Up regulation of endothelial and leukocyte adhesion molecules • Macrophage diapedesis • LDL transcytosis • LDL oxidation • Foam cells • Recruitment and proliferation of smooth muscle cells (synthesis of connective tissue proteins) • Formation and organization of arterial thrombi Consequences of plaque formation Generalized – Narrowing/Occlusion – Rupture – Emboli – Leading to specific problems: • Myocardial and cerebral infarcts • Aortic aneurysms • Peripheral vascular disease Consequences of plaque formation Altered Vessel Function • Vessel change - Plaque narrows lumen – Wall weakened – Thrombosis – Breaking loose of plaque – Loss of elasticity • Consequence – Ischemia, turbulence – Aneurysms, vessel rupture – Narrowing, ischemia, embolization – Athero-embolization – Increase systolic blood pressure Fibrous cap Cholesterol clefts Elastin membrane destroyed Neovas. Calcification Inflam. cells Foam Cells/Cholesterol Crystals Cholesterol Crystals/Foam Cells Hemorrhage into Plaque Late Changes • Calcification – An example of dystrophic calcification • Cracking, ulceration, rupture – Usually occurs at edge of plaque • Thrombus formation – Caused by endothelial injury,ulceration, turbulence – Organization of thrombus – More thrombus • Encroachment – Weakens vessel wall • Bleeding – Ulceration, cracking and angiogenesis Fibrous Plaques Complicated Lesions Complicated Lesions A. Atherosclerosis • The major complications of atherosclerosis are 1. ischemic heart disease without MI 2. myocardial infarction the most serious complication 3. Stroke which is cerebrovascular ischemia 4. gangrene of the lower extremities 5. • the upper extremities are rarely affected if it was due to atherosclerosis however it is common in other diseases like embolization, vasculitis, compression, trauma. Rarely embolization. Ischemic heart disease is the leading cause of death in developed countries while in the developing countries infectious diseases is the leading cause of death. Complicated Lesion/Ulceration/Thrombosis Ulceration/Hemorrhage/Cholesterol Crystals Thrombosis/Complicated Lesion Complicated Lesion/Calcification B: Aneurysms Localized dilatation of blood vessels caused by a congenital or acquired weakness in the media (by infection or atherosclerosis). Classification may be based on location, configuration, or etiology. Classification of Aneurysms by Etiology 1. 2. Atherosclerotic The commonest large artery aneurysms is caused by atherosclerosis. It affects mostly the thoracic aorta, abdominal aorta, and its large branches. Atherosclerosis affecting the arch of aorta or the ascending aorta is extremely rare. Syphilitic Uncommon, affects the ascending portion of the aorta . Classification of Aneurysms by Etiology 3. Dissecting we don’t use this term anymore, it is called “aortic dissection” necrosis) 4. 5. (cystic medial This will not produce an aneurysm but narrowing of the aorta and occlusion. Mycotic Congenital Congenital Aneurysm “Berry Aneurysm” They are so called Berry aneurysm because they look like small berries توت Cerebral arteries. Congenital defect in arterial wall. Is a cause of subarachnoid or intracerebral hemorrhage. Usually participated by hypertension - Congenital Aneurysm “Berry Aneurysm” saccular or berry aneurysms Unruptured berry aneurysm of middle cerebral artery A ruptured berry aneurysm with subarachnoid hemorrhage leads to sudden onset of an excruciating headache. Hemorrhagic stroke - SAH (Berry Aneurysm) Dissecting Aneurysms A form of hematoma within the vessel wall. History of hypertension or have a weakening in the vessels wall. Cystic medial necrosis. Clinical features. Treatment. Dissecting Aneurysm Dissecting Aneurysm Dissecting Aneurysm Atherosclerotic Aneurysms Abdominal aorta and common iliac arteries. Usually fusiform. May contain a mural thrombosis. Micro: destruction of arterial wall. Clinical features Aortic Aneurysm Aortic Aneurysm Aneurysms Aortic Aneurysm Pulsatile abdominal mass Abdominal pain Bleeding Atheroembolization Narrowing of lumen Usually not a problem Syphilitic Aneurysms Uncommon, but some studies are suggesting that syphilis is coming back specially in the developing countries. Aetiology of syphilis: bacterial spirochetes “Treponema pallidum” Treatment: penicillin Thoracic Aorta Syphilitic Aortitits - “tree bark” appearance Obliterative endarteritis and plasma cell infiltration Syphilitic Aneurysms • In tertiary syphilis, inflammation of the adventitia and the vasa vasorum of the aorta lead to weakening of the media and gradual aneurysm formation. • These aneurysms typically affect the arch of the aorta, and may involve the root of the aorta, leading to incompetence of the aortic valve. • Complications include compression or erosion of adjacent structures as well as rupture Syphlitic Aneurysm of the Aortic Arch Aortic Aneurysm with Thrombus Mycotic Aneurysms • Result of microbial infection (it doesn’t have to be fungal infection, it could be any other infection) and weakening of vessel wall. • Can rupture. • Aorta, cerebral vessels, splanchnic arteries. C: Vasculitis Inflammation and with or without necrosis of blood vessels, including arteries, veins and capillaries. May also be known as angiitis. Many of these disorders involve immune mechanisms such as immune complex deposition, circulating antibodies and various forms of cell-mediated immunity Classification of Vasculitis • Large Vessel Vasculitis: – Giant cell arteritis: Granulomatous arteritis of aorta and large branches. Patients older than 50 – Takayasu arteritis: Granulomatous inflammation of aorta & large branches. Patients younger than 50 • Medium-sized vessel Vasculitis – Polyarteritis nodosa (classic): – Kawasaki disease: Usually children; coronary artery involvement Classification of Vasculitis • Small Vessel Vasculitis very common It involves the dermal blood vessels and the renal blood vessels – Wegener’s granulomatosis: Upper & lower respiratory tracts & kidneys.> ANCA present – Churg Strauss syndrome: Lower respiratory tract; asthma; blood eosinophilia – Leukocytoclastic vasculitis: Hypersensitivity vasculitis involving skin – Henoch Schonlein purpura: IgA dominant immune complex deposition in skin, gut & kidney – Microscopic polyarteritis: Classification according to pathogenesis • Infectious: Bacterial, viral, fungal, rickettsial • Immunologic: commonest - Immune complex mediated:Henoch Schonlein; Lupus vasculitis. Immune complex nephritis is very important, we can see it in purpura or SLE. - Direct antibody attack: Goodpasture’s syndrome it’s a disease that will attack the lungs and the kidney; Kawasaki disease - ANCA associated disorder of the muscles: - Wegener’s granulamatose which is a disease of the lung and the kidney - microscopic PAN, Churg Strauss So they are termed as vasculitis that present pulmonaryrenal syndrome Classification according to pathogenesis – cont-- • Unknown: - Giant cell(temporal) arteritis - Takayasu disease - Classic Polyarteritis nodosum 1. Polyarteritis Nodosa It is called like this because it is segmental and produces small aneurysms that looks like nodes. An acute, necrotizing vasculitis affecting medium and smaller, muscular arteries. Patchy involvement of arteries. Fibrinoid necrosis, acute inflammation, eosinophils. Thrombosis Small aneurysms because of the weakening of the wall. Clinical features: it affects many vessels (polyarteritis) – Kidneys, heart, skeletal muscle, skin, intestine, lung – Association with Hepatitis B – Responds to Steroids and Cyclophosphamide 2. - Angiitis means an inflammation of an artery. Group of vascular disorders thought to be in response to exogenous substances, e.g., bacterial products or drugs. Cutaneous lesions - leukocytoclastic vasculitis. Hypersensitivity Angiitis Due to this many of the vasculitis patients go to dermatology. Systemic lesions - microscopic polyarteritis, inflammation restricted to the smallest arteries and arterioles. May be a feature of other systemic diseases such as Lupus Erythematosus. 3. Allergic granulomatosis and Angiitis (Churg-Strauss Syndrome Systemic vasculitis with prominent eosinophilia Young persons with history of asthma Widespread necrotizing vascular lesions of small and medium-sized arteries, arterioles, and veins 4. Giant Cell Arteritis (Temporal Arteritis, Granulomatous Arteritis) Focal, chronic, granulomatous inflammation of temporal arteries and/or other cranial arteries. The patient will come complaining of headaches and tenderness at the temporal region, so it will produce pain while wearing a hat. you don’t have to wait for testing, it needs to be treated with steroids immediately. Disease of elderly individuals (60 – 70 yrs old). Artery is cord-like and nodular. 4. Giant Cell Arteritis (Temporal Arteritis, Granulomatous Arteritis) cont- Thrombus in lumen. Granulomatous inflammation of arterial wall so the artery becomes really hard. Presenting symptoms of headache and temporal pain. Visual symptoms in 50% of patients. Common symptoms: +/- fever, pain,vessel is very hard, very tender. 5. Wegener’s Granulomatosis Systemic vasculitis involving nasal sinuses, lungs and kidneys( pulmonary-renal syndrome.) Anti-neutrophilic cytoplasmic antibodies – ANCA. Necrosis, granulomatous inflammation, vasculitis of small arteries and veins. Persistent sinusitis, pneumonitis, hematuria and proteinuria. 6. Takayasu Arteritis Aortic arch, large arteries. Unknown cause, may be auto-immune. Worldwide distribution affecting young women. Intimal thickening, obliteration of lumen, thrombosis. Pulseless disease. 7. Kawasaki Disease - It attacks the small vessels or the lymph nodes. Muco-cutaneous lymph node syndrome, because patients have enlarged lymph nodes. Infancy and childhood. Unknown cause. Fever, rash, conjunctival and oral lesions. Lymphadenitis. Necrotizing vasculitis. Coronary artery aneurysms rare. 8. Thrombo-Angiitis Obliterans - You can tell from the name that the patient have thrombosis, obliteration, and vasculitis. Angiitis could affect either arteries or veins. Also referred as Buerger disease. Occlusive, inflammatory disease of blood vessels. Smoking usually in males. Intermittent claudication. Can lead to gangrene of the lower limps. Antineutrophil Cytoplasmic Antibodies (ANCA) - We assess and evaluate the immunological findings like ANCA which is important whenever there is vasculitis. • A heterogeneous group of autoantibodies against enzymes mainly in neutrophil granules. • C-ANCA seen in Wegener’s. • p-ANCA seen in microscopic polyarteritis and Churg-Strauss. D: Varicose Veins • Enlarged tortuous veins • Risk factors for varicose veins of the legs: – Increasing age – Female sex and has fair skin – Hereditary predisposition – Obesity – Posture specially for long hours travelers by car – Increased venous pressure Like pregnancy, intra-abdominal tumor, track drivers, surgeons. Varicose Veins • Pathology: dilatation of veins, valvular deformity so the blood will become static, just dilate and becomes engorged. Aetiology : Weakening of the vein or a deformity • Clinical features: swelling and dull pain • Complications: besides the ugly appearance – stasis dermatitis Stasis of the blood for a long time will produce a form of dermatitis,so the skin above the vessel becomes reddish & inflamed. – stasis ulcers Varicose Veins At Other Sites Hemorrhoids in the anal canal. Esophageal Varices. Associated with upper GI bleeding & shock. They are usually seen as a complication of portal hypertension secondary to a chronic cirrhosis. Varicocele in the scrotum. The engorged veins and the stasis of blood raises the the temperature of the scrotum, this may result in infertility or low sperm count. VASCULAR TUMOURS AND TUMOUR-LIKE LESIONS 1. BENIGN Haemangioma Granuloma pyogenicum Glomus tumour 2. BORDERLINE/ INTERMEDIATE Haemangioendothe lioma 3. MALIGNANT Angiosarcoma Haemangiopericyto ma Kaposi’s sarcoma TUMOURS OF LYMPHATIC SYSTEM •Lymphangiomacapillary, cavernous •Lymphangiosarcoma KAPOSI’S SARCOMA – First described by Moriz Kaposi in 1872 on five patients presenting with ‘sarcoma idiopathicum multiple hemorrhagicum’ – In 1912 Sternberg termed this disease Kaposi’s sarcoma-now referred as classical KS • An indolent tumour seen typically in men of mediterranean or east European Jewish origin Kaposis Sarcoma • In 1914 Hallenberg described the first case of African or endemic KS • In 1960 the first report of KS following organ transplant and immuno-suppressive therapy • In 1981 Hymes described the epidemic form associated with AIDS Kaposis Sarcoma • The conditions were KS and PCP • The defined social group was homosexual male community • By 1998 nearly 57000 people in the USA had developed KS as a result of HIV • Swiss cohort study showed a significant decrease of KS in mid 90s due to HAART Kaposis Sarcoma HHV-8 Associated Diseases First identified in 1995. Kaposi’s Sarcoma: Accounts for 80% of all cancers in AIDS patients. Lesions are flat or raised areas of red to purple to brown discoloration. May be confused with hemangioma or hematoma. – Strong male predominance. – 2/3 of affected patients present oral lesions – Oral lesions are initial presentation in 20% of patients. – Progressive malignancy that may disseminate widely. – Oral lesions are a major source of morbidity and frequently require local therapy. Kaposis Sarcoma • KS associated with gamma-2 herpes virus known as HHV-8(KSHV) • Virus identified using PCR-based techniques in all forms of KS – Classical – Endemic african – Paediatric – Epidemic(HIV related) Kaposi’s Sarcoma • HHV-8 transmitted in saliva • In homosexual men rate of HHV-8 is related to the number of sexual partners • Recent evidence from africa on HHV-8 prevalence in children suggests infection is acquired through normal social contacts within the family Clinical features • Classic lesion of KS is a raised macule purplish in colour • Lesions may coalesce into plaques and may ulcerate and bleed • KS may develop at sites of previous trauma • Oedema is almost always a feature • Visceral Clinical features Clinical features AIDS patient with intraoral Kaposi’s sarcoma of the hard palate AIDS patient with intraoral Kaposi’s sarcoma Scrotal skin- KS Endemic Kaposi’s Sarcoma, nodular form Extensive symmetric tumor lesions of Kaposis’s sarcoma in an AIDS patient. STAGING OF KS • Stage I represents localized nodular KS, with more than 15 cutaneous lesions or involvement restricted to 1 bilateral anatomic site, and few, if any, gut nodules. • Stage II includes both exophytic destructive lesions and locally infiltrative cutaneous lesions as locally aggressive KS. • Stage III (generalized lymphadenopathic KS) has widespread lymph node involvement, with or without skin lesions, but with no visceral involvement. STAGING OF KS • Stage IV (disseminated visceral KS) has widespread KS, usually progressing from Stage II or Stage III, with involvement of multiple visceral organs. • A: Associated opportunistic infection(s) • B: Patient is HIV-I seropositive. • C: Cutaneous anergy or other evidence of severe immunodeficiency is present • EPIDEMIOLOGIC VARIETIES (TYPES) OF KS Classic Kaposi's sarcoma • older men of Eastern European, Mediterranean, or Jewish descent. • The male/female ratio :(15:1 -3:1). – – – – Bluish-red macules papulesplaquesnodules edema on the distal lower extremities are often the first sign of KS. – The process is slow and the course is benign. – Visceral or mucosal involvement is found in 10% of patients. Endemic Kaposi's sarcoma (African) • male to female ratio similar to that of classic KS and a mean age of onset of 48 years exept lymphadenopathic type • 1.nodular variant = classic KS. • 2.florid / infiltrative are aggressive. • 3.lymphadenopathic form is particularly common among the young Bantu children . – Rapid visceral involvement can cause early death. Skin lesions are sparse Iatrogenic Kaposi's sarcoma • especially true for male patients of Eastern European, Mediterranean, or Jewish origin. • The lesions typically appear several years after transplantation in transplant recipients. • the lesions commonly regress when the medications are reduced or discontinued. • HHV-8 been reported in transplant recipients. Epidemic Kaposi's sarcoma (aids associated) • most common AIDS-associated malignancy • early lesions commonly appear on the face, especially on the nose, eyelids, and ears. • trunk lesions may follow the lines of cleavage. • reddish to pink macules and papules. • Only in prolonged courses do the macules and papules sufficiently coalesce to form plaques Epidemic Kaposi's sarcoma (aids associated) • The lymph nodes and the gastrointestinal tract are commonly involved. • The oral mucosa is the initial site of disease in 10% to 15% of patients, (palate) Other HHV 8 associated diseases • 1-Primary effusion lymphoma rare.. DNA copy number is extremely high IN HIV B cell lymphoma • 2.Multicentric Castleman's disease IL6 IN HIV Fever+ anemia+ hypergammaglobulinemia • 3.POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, multiple myeloma, skin changes) Mortality/Morbidity • Usually die with not from KS • The mean survival rate of patients with KS-AIDS has been approximately 15-24 months (without treatment) • Fatality: gut perforation, cardiac tamponade, massive pulmonary obstruction or, rarely, brain metastases • Patients with iatrogenic KS tend to have gut bleeding resulting from KS lab • Serum glucose levels may reflect an increased incidence of diabetes mellitus in patients with classic KS. • Immunohistochemical detection of human herpes virus-8 • Eosinophilia • cytopenia • Anemia • PCR CONT. • CT chest • Endoscopy GI • angiography may demonstrate KS. • Radionucleotide scans may be USEFUL • Markers for endothelial cells: Factor VIII–related antigen, Human leukocyte antigen DR (HLA-DR), von Willebrand factor, and The lectin Ulex europaeus I is highly suggestive. • CD34 antigen, (TISSUE BIOPSY): KS - MICROSCOPIC • KS tends to demonstrate increased spindle cells with • vascular slits and vascular structures with a predominance of endothelial cells. • Extravasated erythrocytes and hemosiderinladen macrophages often are evident. • Some spindle cells may show nuclear pleomorphism. • Early KS may resemble granulation tissue with a diffuse chronic inflammatory infiltrate and capillaries dilated and increased in number. KS - MICROSCOPIC KS - MICROSCOPIC