1. Nonbacterial Thrombotic Endocarditis NBTE (marantic endocarditis)
Characterized by the deposition of small masses of fibrin, platelets, and other blood components on the leaflets of the cardiac valves (sterile).
Pathogenesis/ association:
Subtle endothelial abnormalities.
Hypercoagulability.
Association with malignancy (50%).

2. Nonbacterial Thrombotic Endocarditis
Gross:groups of small nodules on the lines of valve closure (similar to those of acute rheumatic fever), valve leaflets are normal.
Aortic valve most common site.
Micro: fibrin and platelets aggregates, no inflammation or fibrosis.
Clinically asymptomatic, if large: may embolize, may become infected.

3. Infective Endocarditis
Definition: infection of the cardiac valves or mural surface of the endocardium, resulting in the formation of an adherent mass of thrombotic debris and organisms.
Divided into:
Acute: high virulent organisms (staphylococcus aureus), infect even normal valves, progress rapidly, little local host reaction.
Subacute: infection of previously abnormal valves by organisms of low virulence (- hemolytic streptococci), progress slowly, induce local inflammatory reaction.

4. Infective Endocarditis: Etiology, Pathogenesis
Bacteremia: i.v. drug abusers, elsewhere infection, previous dental, surgical or interventional procedure (catheterization).
In some cases the source of bacteremia is occult.
Infective endocarditis is a particularly difficult infection to eradicate because of the avascular nature of the heart valves.

5. Infective Endocarditis: Risk Factors
Cardiac abnormalities: chronic valvular diseases, high pressure shunts within the heart (small ventricular septal defects).
Prosthetic heart valves.
Intravenous drug abusers.

6. Infective Endocarditis: Causative Organisms
Most common of non prosthetic valves (50- 60%):
-Hemolytic (viridans) streptococci, which attack previously damaged valves.
Staphylococcus attack healthy or deformed valves (10-20%).
Prosthetic valve endocarditis is caused commonly by coagulase-negative staphylococci (e.g., S. epidermidis).

7. Infective Endocarditis: Morphology
Valvular vegetations containing bacteria or other organisms.
Aortic and mitral valves are the most common sites. (right side valves in i.v.users)
Vegetations may be single or multiple, involve one or more valve(s), differ in appearance according to the causative agent.

8. Infective Acute Endocarditis: Morphology
Vegetations: may obstruct valve orifice, lead to rupture of ( the leaflets, cordae tendineae, or papillary muscles), abscess in perivalvular tissue (ring abscess), friable vegetations may become systemic emboli infarcts + abscesses.
Micro: large number of organisms + fibrin and blood cells. Neutrophilic inflammatory reaction occurs the infection extends beyond the avascular valves.

9. Infective Subacute Endocarditis: Morphology
Vegetations are firmer, less destructive, and ring abscess are uncommon.
Micro: Granulation tissue is seen at the base of the vegetations, later: fibrosis, calcifications and chronic inflammatory infiltrates. Systemic emboli may develop but they don’t undergo suppuration.

10. Infective Endocarditis: Clinical
Onset: gradual or explosive (~organisms).
Low-grade fever, malaise, weight loss.
High fever, shaking chills.
Cardiac murmurs.
Enlargement of spleen, clubbing of digits (particularly in subacute cases).
Systemic emboli (neurologic deficits, retinal abnormalities, necrosis of digits, and infarcts of the myocardium.
Pulmonary emboli in right-sided endocarditis.
Mycotic aneurysms.
Petechiae (due to micro emboli or deposition of immune complexes.
Renal lesions: renal infarcts and glomerulonephritis.
Valvular regurgitation and congestive heart failure due to progressive valvular destruction.
Blood culture for aerobic and anaerobic organisms is very important (only minority of cases remain negative).

11. Endocarditis of the mitral valve (subacute, caused by Streptococcus viridens). The irregular, large friable vegetations are denoted by arrows.
Endocarditis of the mitral valve (subacute, caused by Streptococcus viridens). The irregular, large friable vegetations are denoted by arrows.
Slide 13.40

12. B. Acute endocarditis of a congenitally bicuspid aortic valve (caused by Staphylococcus aureus) with severe cuspal destruction and ring abscess (arrow).
B. Acute endocarditis of a congenitally bicuspid aortic valve (caused by Staphylococcus aureus) with severe cuspal destruction and ring abscess (arrow).
Slide 13.41

13. C. Histologic appearance of vegetation of endocarditis with extensive acute inflammatory cells and fibrin. Bacterial organisms were demonstrated by tissue Gram stain.
C. Histologic appearance of vegetation of endocarditis with extensive acute inflammatory cells and fibrin. Bacterial organisms were demonstrated by tissue Gram stain.
Slide 13.42

14. D. Gross photograph illustrating healed endocarditis with perforations on bicuspid aortic valve.
Slide 13.43

15. Diagrammatic comparison of the lesions in the four major forms of vegetative endocarditis. The rheumatic fever phase of RHD (rheumatic heart disease) is marked by a row of warty, small vegetations along the lines of closure of the valve leaflets. IE (infective endocarditis) is characterized by large, irregular masses on the valve cusps that can extend onto the cords (see Fig. 13–18 A). NBTE (nonbacterial thrombotic endocarditis) typically exhibits small, bland vegetations, usually attached at the line of closure. One or many may be present (see Fig. 13–20). LSE (Libman-Sacks endocarditis) has small or medium-sized vegetations on either or both sides of the valve leaflets.
Diagrammatic comparison of the lesions in the four major forms of vegetative endocarditis. The rheumatic fever phase of RHD (rheumatic heart disease) is marked by a row of warty, small vegetations along the lines of closure of the valve leaflets. IE (infective endocarditis) is characterized by large, irregular masses on the valve cusps that can extend onto the cords (see Fig. 13–18 A). NBTE (nonbacterial thrombotic endocarditis) typically exhibits small, bland vegetations, usually attached at the line of closure. One or many may be present (see Fig. 13–20). LSE (Libman-Sacks endocarditis) has small or medium-sized vegetations on either or both sides of the valve leaflets.
Slide 13.44

16. Slide 13.45 Nonbacterial thrombotic endocarditis (NBTE).
A. Nearly complete row of thrombotic vegetations along the line of closure of the mitral valve leaflets.
B. Photomicrograph of NBTE showing bland thrombus, with virtually no inflammation in the valve cusp (c) or the thrombotic deposit. The thrombus is only loosely attached to the cusp (arrow).
Nonbacterial thrombotic endocarditis (NBTE).
A. Nearly complete row of thrombotic vegetations along the line of closure of the mitral valve leaflets.
B. Photomicrograph of NBTE showing bland thrombus, with virtually no inflammation in the valve cusp (c) or the thrombotic deposit. The thrombus is only loosely attached to the cusp (arrow).
Slide 13.45

17. Pericarditis
Primary: mostly viral, sometimes by other microorganisms (pyogenic bacteria, mycobacteria and fungi.
Secondary to: acute myocardial infarction, cardiac surgery, or radiation to the mediastinum.
Associated systemic disorders, mostly with uremia.
Less common 2ndry causes: rheumatic fever, SLE, and metastatic malignancies (bloody effusions).

18. Pericarditis
Cause immediate hemodynamic complications, if significant effusion is present.
Resolve without significant sequelae.
Progress to chronic fibrosing process.

19. Acute Pericarditis: Morphology
In uremia, and acute rheumatic fever: the exudate is fibrinous and impart a shaggy irregular pericardial surface (bread and butter pericarditis).
Viral pericarditis  fibrinous exudate.
Acute bacterial pericarditis  fibrinopurulent pericarditis.
Tuberculosis caseous materials.
Pericardial metastases: irregular nodules.
Exudate usually resolve unless there is excessive suppuration or caseation, where healing leads to chronic pericarditis.

20. Chronic Pericarditis: Morphology
Ranges from delicates adhesions to dense fibrotic scars that obliterate the pericardial space.
In extreme cases the heart can’t expand during diastole : constrictive pericarditis.

21. Pericarditis: Clinical
Atypical chest pain (worse on reclining).
High pitch friction rub.
Significant exudate cardiac tamponade  faint distant heart sounds, distended neck veins, declining cardiac output, and shock.
Chronic constrictive pericarditis  venous distension and low cardiac output.

22. Acute suppurative pericarditis as an extension from pneumonia
Acute suppurative pericarditis as an extension from pneumonia. Extensive purulent exudate is evident in this in situ photograph.
Acute suppurative pericarditis as an extension from pneumonia. Extensive purulent exudate is evident in this in situ photograph.
Slide 13.56

23. Vascular Diseases

24. Venous Thrombosis & Thrombophlebitis
Arises most often in the deep veins of the legs therefore also called deep vein thrombosis.
Is predisposed by venous circulatory stasis or partially obstructed venous return e.g. in cardiac failure, pregnancy and prolonged bed rest, or varicose veins.
May give rise to pulmonary embolism with resultant pulmonary infarct.
Often associated with inflammation and then termed thrombophlebitis

25. VARICOSE VEINS
Are abnormally dilated and tortuous veins, most often superficial veins of lower extremities.
Are predisposedby increased venous pressure such as occurs with pregnancy, obesity, or thrombophlebitis, and in persons whose occupations require prolonged standing.

26. Aneurysms
An aneurysm is a localized abnormal dilation of a blood vessel or the wall of the heart .
It can erode adjacent structures or rupture.
When an aneurysm is bounded by arterial wall components or the attenuated wall of the heart, it is called a true aneurysm. Atherosclerotic, syphilitic, and congenital vascular aneurysms and the left ventricular aneurysm that can follow a myocardial infarction are of this type.

27. Aneurysms
In contrast, a false aneurysm (also called pseudoaneurysm) is a breach in the vascular wall leading to an extravascular hematoma that freely communicates with the intravascular space ("pulsating hematoma"). The most common false aneurysm is a post-myocardial infarction rupture that has been contained by a pericardial adhesion.

28. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 13 February 2006 09:14 PM)
© 2005 Elsevier

29. Aneurysms Classified by macroscopic shape and size.
Saccular aneurysms are essentially spherical (involving only a portion of the vessel wall) and vary in size from 5 to 20 cm in diameter, often partially or completely filled by thrombus.
Fusiform aneurysm (involving a long segment). Fusiform aneurysms vary in diameter and in length.

30. Aneurysms
Aneurysms and dissections are most important when they involve the aorta. Both true and false aneurysms, as well as dissections, can rupture.
The two most important causes of aortic aneurysms are atherosclerosis and cystic medial degeneration of the arterial media.

31. Aneurysms
Other causes also include a wide variety of disorders that weaken the wall, including trauma, congenital defects such as berry aneurysms, syphilis, trauma or dissecting aneurysm.
Infection of a major artery that weakens its wall gives rise to mycotic aneurysm.
Thrombosis and rupture are possible complications.

32. 1. Atherosclerotic Aneurysm
Atherosclerosis, the most frequent etiology of aneurysms.
Atherosclerotic aneurysms occur most frequently in the abdominal aorta: abdominal aortic aneurysm (AAA).
AAAs are saccular or fusiform

33. The clinical consequences of AAAs
Rupture into the peritoneal cavity or retroperitoneal tissues with massive, potentially fatal, hemorrhage
Obstruction of a vessel, particularly of the iliac, renal, mesenteric, or vertebral branches that supply the spinal cord leading to ischemic tissue injury
Embolism from atheroma or mural thrombus
Impingement on an adjacent structure, such as compression of a ureter or erosion of vertebrae
Presentation as an abdominal mass (often palpably pulsating) that simulates a tumor.

34. Gross photographs of an abdominal aortic aneurysm that ruptured.
A. External view of the large aneurysm; the rupture site is indicated by the arrow.
B. Opened view with the location of the rupture tract indicated by a probe. The wall of the aneurysm is exceedingly thin and the lumen is filled by a large quantity of layered but largely unorganized thrombus.
Slide 12.33

35. 2. Aneurysm due to cystic medial necrosis.
Are the most frequent aneurysms of the aortic root.

36. 3. Berry aneurysm
Are small saccular lesions most often seen in the small arteries of the brain, especially in the circle of Willis.
Are not present at birth but develop at sites of congenital medial weakness at bifurcations of cerebral arteries.
Are unrelated to atherosclerosis.
Are often an association of adult polycystic kidney disease.
Are the most frequent cause of subarachnoid hemorrhage.

37. 4. Syphilitic (luetic) Aneurysm
Is a manifestation of tertiary syphilis. Fortunately, better control and treatment of syphilis in its early stages have decreased the frequency of this complication
It is caused by syphilitic aortitis.
It involves the ascending aorta.

38. 5. Aortic dissection/Dissecting hematoma/ Dissecting aneurysm
Is a longitudinal intraluminal tear usually in the wall of the ascending aorta, forming a second arterial lumen within the media.
Aortic dissection is a catastrophic illness characterized by dissection of blood between and along the laminar planes of the media, with the formation of a blood-filled channel within the aortic wall , which often ruptures outward, causing massive hemorrhage.

39. Morphology of Aortic Dissection
The dissection can extend along the aorta proximally toward the heart as well as distally, sometimes all the way into the iliac and femoral arteries. It often ruptures out, causing massive hemorrhage.
In some instances, the blood reruptures into the lumen of the aorta, producing a second or distal intimal tear and a new vascular channel within the media of the aortic wall (to produce a "double-barreled aorta" with a "false channel").

40. 5. Aortic dissection/Dissecting hematoma/ Dissecting aneurysm
Clinically presents with severe chest pain.
Can be confused with a heart attack.
Can result in the aortic rupture with bleeding into the pericardial sac, causing hemopericardium and fatal cardiac tamponade.
It is typically associated with hypertension or with cystic medial necrosis ( esp. in Marfan syndrome)
It has no relation to atherosclerosis.

41. Vasculitis Mostly immune reaction related: Immune complexes.
Antineutrophil cytoplasmic antibodies (ANCAs).
P-ANCAs (perinuclear  myeloperoxidase)
C-ANCAs (cytoplasmicproteinase 3)

42. Antineutrophil Cytoplasmic Antibodies
ANCAs are a heterogeneous group of autoantibodies directed against enzymes mainly found within the azurophil or primary granules in neutrophils, in the lysosomes of monocytes, and in endothelial cerlls.

43. Antineutrophil Cytoplasmic Antibodies
The description of these autoantibodies is based on the immunofluorescent patterns of staining of ethanol-fixed neutrophils. Two main patterns are recognized:
one shows cytoplasmic localization of the staining (c-ANCA).
The second shows perinuclear staining (p- ANCA) and is usually specific for myeloperoxidase (MPO).

44. Antineutrophil Cytoplasmic Antibodies
c-ANCA is typically found in Wegener granulomatosis and
p-ANCA is found in most cases of microscopic polyangiitis and Churg-Strauss syndrome.
The disorders characterized by circulating ANCAs are called the ANCA-associated vasculitide

45. Antineutrophil Cytoplasmic Antibodies
ANCAs serve as useful quantitative diagnostic markers for these conditions, and their levels may reflect the degree of inflammatory activity.
ANCAs rise in episodes of recurrence, and thus are useful in management..

46. Diagrammatic representation of the preferred site of the vasculature involved by the major forms of vasculitis. The widths of the trapezoids indicate the frequencies of involvement of various portions. Note that large-, medium-, and small-vessel vasculitis affects arteries, but only small-vessel vasculitis involves vessels smaller than arteries. LCA, leukocytoclastic angiitis.
Slide 12.23

47. Wegener granulomatosis
is a necrotizing vasculitis characterized by the triad of
(1) acute necrotizing granulomas of the upper respiratory tract (ear, nose, sinuses, throat), the lower respiratory tract (lung), or both;
(2) necrotizing or granulomatous vasculitis affecting small to medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries), most prominent in the lungs and upper airways but affecting other sites as well;
(3) renal disease in the form of focal necrotizing, often crescentic, glomerulitis.

48. Wegener granulomatosis
Limited forms, or more widespread WG.
C-ANCAs in present in serum of more than 95% of patients.
May lead to death within 2 years in more than 90% if not treated.

49. Wegener granulomatosis: Morphology.
The upper respiratory tract lesions range from inflammatory sinusitis resulting from mucosal granulomas to ulcerative lesions of the nose, palate, or pharynx, rimmed by necrotizing granulomas and accompanying vasculitis.

50. Wegener granulomatosis: Morphology
Microscopically:
granulomas with necrosis surrounded by lymphocytes, plasma cells, macrophages, and variable numbers of giant cells.
In association with such lesions there is a necrotizing or granulomatous vasculitis of small and sometimes larger arteries and veins .
Lesions may ultimately undergo progressive fibrosis and organization.

51. Wegener granulomatosis: Morphology
The renal lesions are of two types .
In milder or early forms: focal necrotizing glomerulonephritis.
More advanced glomerular lesions are characterized by diffuse necrosis, proliferation, and crescent formation (crescentic glomerulonephritis).

52. Wegener granulomatosis: Clinical Features
Males are affected more often than females, at an average age of about 40 years.
Persistent pneumonitis , chronic sinusitis , mucosal ulcerations of the nasopharynx , and evidence of renal disease.

53. Wegener granulomatosis: Clinical Features
Untreated, the course of the disease is malignant; 80% of patients die within 1 year.

54. Wegener granulomatosis
Wegener granulomatosis. There is inflammation (vasculitis) of a small artery along with adjacent granulomatous inflammation, in which epithelioid cells and giant cells ( arrows) can be seen.

55. Necrotizing vasculitis. Arterioles, capillaries, venules.
Microscopic polyangiitis/microscopic polyarteritis/ LEUKOCYTOCLASTIC VASCULITIS)
Necrotizing vasculitis.
Arterioles, capillaries, venules.
All lesions tend to be of the same age.
Involves skin, mucous membranes, lungs , brain, heart, GI , kidneys and muscle.
Precipitating cause~~ immunologic reaction to an antigen (drug: penicillin), (microorganisms: strept.), heterlogous proteins and tumor antigens.
P-ANCAs in 70% of patients.

56. Skin biopsy is often diagnostic.
Microscopic polyangiitis/microscopic polyarteritis/ LEUKOCYTOCLASTIC VASCULITIS)
Skin biopsy is often diagnostic.
Histologically there is infiltration of vessel wall with neutrophils, which become fragmented(leukocytoclasia).

57. Leukocytoclastic vasculitis in a skin biopsy showing fragmentation of neutrophil nuclei in and around vessel walls.
Slide 12.29

58. Polyarteritis Nodosa
PAN is a systemic vasculitis of small or medium-sized muscular arteries (but not arterioles, capillaries, or venules), typically involving renal and visceral vessels but sparing the pulmonary circulation.
Clinical manifestations result from ischemia and infarction of affected tissues and organs

59. Polyarteritis Nodosa:Morphology.
Classic PAN occurs as segmental transmural necrotizing inflammation of arteries of medium to small size, in any organ with the possible exception of the lung
Most frequently kidneys, heart, liver, and gastrointestinal tract.
Individual lesions may involve only a portion of the vessel circumference .
Weakening of the arterial wall due to the inflammatory process may cause aneurysmal dilation or localized rupture.

60. Polyarteritis Nodosa:Morphology.
Impairment of perfusion, causes ulcerations, infarcts, ischemic atrophy, or hemorrhages in the area supplied by these vessels.
The histologic picture during the acute phase is characterized by transmural inflammation of the arterial wall with neutrophils, eosinophils, and mononuclear cells, frequently accompanied by fibrinoid necrosis. The lumen may become thrombosed. .

61. Polyarteritis Nodosa:Morphology
Later, the acute inflammatory infiltrate disappears and is replaced by fibrous thickening of the vessel wall that may extend into the adventitia.
Particularly characteristic of PAN is that all stages of activity may coexist in different vessels or even within the same vessel.

62. Polyarteritis Nodosa: Clinical Course
Disease of young adults. The course may be acute, subacute, or chronic and is frequently remittent and episodic, with long symptom-free intervals.
The most common manifestations are malaise, fever and weight loss; hypertension; abdominal pain and melena (bloody stool); diffuse muscular aches and pains; and peripheral neuritis. Renal arterial involvement is often prominent and is a major cause of death.

63. Polyarteritis nodosa. Polyarteritis nodosa with segmental fibrinoid necrosis and thrombotic occlusion of the lumen of this small artery. Note that part of the vessel wall at the upper right ( arrow) is uninvolved.
Slide 12.28

64. Temporal (giant cell, cranial) arteritis
Segmental acute and chronic (most often granulomatous) vasculitis involving predominantly the larger arteries in the head, particularly the branches of the carotid artery (temporal a.branches of the ophthalmic a.
Over age of 50, F:M = 2:1.

65. Morphology
Characteristically, segments of affected arteries develop nodular thickenings with reduction of the lumen and may become thrombosed.
There is granulomatous inflammation of the inner half of the media ,with lymphocytes and, multinucleate giant cells and fragmentation of the internal elastic lamina.
The healed stage reveals collagenous thickening of the vessel wall; sometimes the artery is transformed into a fibrous cord.

66. Clinical Features
Temporal arteritis is most common in older individuals and rare before age 50.
fever, fatigue, weight loss
facial pain or headache, often most intense along the course of the superficial temporal artery, which may be painful to palpation.
More serious are ocular symptoms (associated with involvement of the ophthalmic artery)range from diplopia to transient or complete vision loss.
The diagnosis depends on biopsy and histologic confirmation.

67. Temporal (giant cell) arteritis.
A. H&E stain of giant cells at the degenerated internal elastic membrane in active arteritis.
B. Elastic tissue stain demonstrating focal destruction of internal elastic membrane ( arrow) and intimal thickening (IT) characteristic of long-standing or healed arteritis.
Slide 12.24

68. Thromboangiitis obliterans (Buerger disease)
Is characterized by segmental, thrombosing, acute and chronic inflammation of medium-sized and small arteries, principally the tibial and radial arteries and sometimes secondarily extending to veins and nerves of the extremities.
Previously a condition that occurred almost exclusively among heavy cigarette-smoking men, Buerger disease has been increasingly reported in women, probably reflecting smoking increases.

69. Thromboangiitis obliterans (Buerger disease)
The disease begins before age 35 in most cases.
The relationship to cigarette smoking is one of the most consistent aspects of this disorder.

70. Thromboangiitis obliterans (Buerger disease)
Later complications are chronic ulcerations of the toes, feet, or fingers and frank gangrene in some patients.

71. Morphology
Characterized by segmental acute and chronic vasculitis of medium-sized and small arteries, mostly of the extremities.
Microscopically, acute and chronic inflammation permeates the arterial walls, accompanied by thrombosis of the lumen, which may undergo organization and recanalization.
The inflammatory process extends into contiguous veins and nerves, and in time all three structures become encased in fibrous tissue.

72. Thromboangiitis obliterans (Buerger disease)
Thromboangiitis obliterans (Buerger disease). The lumen is occluded by a thrombus containing two abscesses ( arrows). The vessel wall is infiltrated with leukocytes.
Slide 12.31