The document discusses thrombotic microangiopathy, which includes classifications such as classic hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), detailing their pathophysiology, clinical presentations, laboratory findings, and prognostic features. It also covers various causes and associated conditions, transmissions, and outcomes, highlighting the differences between classic and atypical HUS and TTP, as well as treatment options. The analysis emphasizes the importance of recognizing the underlying mechanisms and varying prognoses associated with these microangiopathies.

1. THROMBOTIC
MICROANGIOPATHY
Mr.Jagdish sambad
M.Sc. Nursing in Nephrology
IKDRC College of Nursing
AHMEDABAD

2.  Pathologic term for a condition
characterized by microvascular
changes including thrombosis in
association with laboratory
abnormalities of microangiopathic
hemolytic anemia (MAHA) and
thrombocytopenia.
Definition

3. Classification
 Classic HUS
 Atypical HUS
 Familial
 Sporadic (idiopathic)
 Streptococcus
pneumoniae associated
 Cobalamin C (cblC)
disorder
 Secondary forms
 Infections
 Autoimmune disorders
 Drugs
 Pregnancy/postpartum
 HELLP syndrome
 Other
 TTP
 Congenital
 Idiopathic
 Secondary forms
 Infections
 Autoimmune disorders
 Drugs
 Pregnancy/postpartum
 HELLP syndrome
 Other

4.  Other TMAs
 Glomerulopathies
 Malignant hypertension
 Malignancies
 Solid organ transplantation
 Scleroderma renal crisis
 Radiation nephropathy
 HSCT

5. Classification of HUS and TTP

6. Thrombotic microangiopathies other than classic
and aHUS and TTP
 Infections
 Systemic infections, human
immunodeficiency virus
infection, H1N1 influenza,
Salmonella typhi, others
 Autoimmune diseases
 SLE, APS, others
 Drugs
 Quinine, ticlopidine,
clopidogrel, anti-VEGF agents,
oral contraceptives,
mitomycin C, interferon,
gemcitabine, CNIs, sirolimus,
and others
 Pregnancy/postpartum
 HELPP syndrome
 Glomerulopathies
 Malignant hypertension
 Malignancies
 Solid organ transplantation
 Scleroderma renal crisis
 Radiation nephropathy
 HSCT

7. CLASSIC HUS
(DIARRHEA-POSITIVE (D+) OR
EPIDEMIC HUS)

8. Epidemiology
 Young children
 O157:H7 serotype of Shiga toxin-producing E.
coli (STEC) infection in United States
 Shiga toxin-producing Shigella dysenteriae
serotype 1 in asia and africa
 Annual incidence of classic HUS is estimated to
be 21 per 1 million with a peak incidence in
children under the age of 5 years

9. Transmission
 Cattle are considered to be the most
important source of human infections
 Human infection typically occurs through
acquisition of the bacteria via consumption
of contaminated food, water, or by
person-to-person transmission

10. Clinical presentation
 Begins with watery diarrhea and may progress rapidly to
bloody diarrhea with hemorrhagic colitis.
 Second phase occurs abruptly within 3 to 4 days of the
onset of gastrointestinal symptoms,characterized by
various combinations of acute renal failure, proteinuria,
hematuria, anemia, bleeding abnormalities, central
nervous system disorders and cardiovascular changes
 The prognosis is relatively good with most patients fully
recovering

11. Renal manifestations
 Oliguria or anuria, hematuria, hemoglobinuria,
proteinuria, various types of casts in the urine
 Hyperkalemia
 Elevated blood urea nitrogen (BUN) and serum
creatinine level

12. Laboratory findings
 Helmet cells, burr cells, and fragmented cells
(schistocytes) in the peripheral blood
 Reticulocytes are increased.
 The Coombs test is almost invariably negative.
 Leukocytosis is common in the early stages.
 Platelets are decreased to varying degrees
 Serum lactic dehydrogenase level and concomitant
reduction in the serum haptoglobin
 Normal PT,APTT

13. MAHA
Shistocytes
Elevated LDH & Bilirubin
Mechanical fragmentation
of erythrocytes
during flow through partially
occluded, high shear small
vessels
1

14.  Nonenteropathic or diarrhea-negative
 Affects both children and adults
 5% to 12% of all cases of HUS
 Majority of cases are sporadic, and approximately
20% to 30% are familial
 Genetic or acquired abnormalities of the
complement regulatory proteins have been
identified as the most common etiology in the
aHUS group
Atypical HUS

15.  Develop without prior diarrhea and/or
hemorrhagic colitis.
 The onset is usually sudden with general distress,
fatigue, vomiting, and drowsiness.
 In most patients, the diagnostic triad of MAHA,
thrombocytopenia, and renal impairment are
present.
Atypical HUS

16.  The prognosis of aHUS is poor
 The mortality rate is 10% to 15% during
the acute phase
 50% of patients develop end-stage renal
disease

17. TTP - First described
Dr. Eli Moschcowitz
Arch Intern Med. 1925;36:89.
3

18. “Classic Signs”
 Fever
 Thrombocytopenia
 Neurological abnormalities
 Microangiopathic hemolytic anemia
 Renal dysfunction
TTP

19.  Rare disease with a reported incidence of 6 cases
per million
 Peak incidence in 3rd decade of life
 Higher among females,African Americans and
obese patients
 The clinical features of TTP are similar to those of
aHUS, and in most instances
TTP

20.  The clinical diagnosis of TTP requires exclusion of
other etiologies, such as systemic infection or
another cause of TMA.
 Since renal involvement in TTP is typically mild,
the renal prognosis is good
TTP

21. Relationship Between Hemolytic-Uremic Syndrome
and Thrombotic Thrombocytopenic Purpura
TTP
 occurs among adults
 affects the central nervous system more
commonly
 exhibits less frequent and less severe
involvement of the kidney
 involves multiple organs and has a poorer
prognosis

22. PATHOGENESIS

23. One underlying fact
Endothelial damage
[stx,Complement,neuraminidase,drugs]
Exposure of subendoth.surface with Platelet
activation and aggregation
Thrombi and cellular proliferation in glomeruli
and arterioles. Red blood cell hemolysis is
caused by mechanical disruption in traversing
fibrin meshwork of microcirculation

24. CLASSIC HUS

25. ATYPICAL HUS

27. Streptococcus pneumoniae-
Associated HUS
 Neuraminidase producing organisms
 Expose the usually hidden T-crypt antigen
 Preformed circulating IgM antibodies to this
antigen, the antigen-antibody reaction followed
by complement activation through the classical
pathway damages endothelial, red-cell, and
platelet surfaces and leads to intravascular
thrombosis, hemolysis, and thrombocytopenia

28. Platelets vWF ADAMTS 13
What is ADAMTS 13, and
What is its role?
4

29. Absence of or
Abs to ADAMTS
13 → Persistent vWF
large multimers →
Platelets microthrombi
What is ADAMTS 13, and
What is its role?
Platelets vWF ADAMTS 13
4

30. TTP

31. THROMBOTIC
MICROANGIOPATHY IN
ASSOCIATION WITH OTHER
RENAL OR SYSTEMIC
DISEASES

32. Systemic infections
 Brucellosis, streptococcal infection with
acute glomerulonephritis, angioinvasive
fungal infections, CMV, HIV, ehrlichiosis,
and Rocky Mountain spotted fever, may
cause microvascular injury

33. TMA,Drugs
 aHUS caused by drugs
 Direct endothelial injury or immune
mediated
 Chemotherapeutic drugs
 Anti-VEGF
 CNIs
 Antiplatelet drugs
 quinine

34. Antiphospholipid antibodies
 The most common renal manifestations of APS
are those of microvascular thrombotic lesions,
that is, TMA.
 Acute TMA may present with rapidly progressive
renal failure, proteinuria, sometimes in the
nephrotic range, and severe hypertension, often
in the malignant range, MAHA and
thrombocytopenia can also be seen.
 Chronic TMA, the clinical presentation is more
subtle

35. Hematopoietic stem cell
transplant
 Multifactorial
 Radiation
 Cyclosporine and tacrolimus
 Cmv,fungal and H.pylori
 GVHD
 HLA mismatched transplants
 No ADAMTS13 abnormaility

36. Postpartum HUS
 Symptoms manifest postpartum within 24
hrs to several weeks
 Etiology-
 Genetic abnormailities in complement system
 Increased susceptibility during postpartum

37. Systemic sclerosis
 Endothelial damage of the arteries and
arterioles in the kidney.
 Undue permeability of the endothelial barrier
 Endothelial damage may also initiate a chain of
events leading to coagulation and release of
factors

38. Cancer associated TMA
 Stomach, breast and prostate cancers
 Insidious onset
 Pathophysiology can be due to either:
 –tumor microemboli leading to microvascular occlusion
 –cytokines (ie.TNFα) leading to endothelial injury
 –acquired ADAMTS-13 deficiency (paraneoplastic
syndrome)
 Poor prognosis

39. Intraluminal platelet thrombosis
Thrombocytopenia
Consumption of
platelets
TTP
Shiga toxin HUS
Atypical HUS
ADAMTS 13
Toxin binds
endothelium
Alternative
Complement
What is the mechanism of TMA in TTP-HUS?
1

40. PATHOLOGICAL
FINDINGS

41. Gross Appearance
 Renal cortical necrosis
 Calcification
 Petechial hemorrhages are seen in an enlarged,
swollen kidney
 In chronic phase,kidney are small with granular
cortical surface

42. Light Microscopy

43.  The glomerulus is slightly hypocellular, and most of the
glomerular capillary lumina are closed due to thickening of
the capillary walls. Red blood cells and fragmented red
blood cells are seen in the mesangial areas.

44.  “Bloodless” glomerulus. The glomerular capillary walls are
thickened, and the mesangial areas blend with the
capillaries.

45.  The mesangial areas of the glomerulus have fibrillary appearance.
Focal reduplication of the glomerular capillary basement
membranes is also seen. A few intracapillary polymorphonuclear
leukocytes are present.

46.  Most of the glomerular capillary lumina are
occluded by homogenous eosinophilic thrombi.

47.  Thrombotic microangiopathy, associated with cyclosporine
administration. Some of the glomerular capillary lumina are
occluded by thrombi

48.  Some of the glomerular capillary tufts are permeated by
eosinophilic acellular material. This change is often
described as fibrinoid necrosis. Intraluminal thrombi are
also present.

49. Thrombotic microangiopathy,
secondary to abruptio placentae
Thrombotic microangiopathy in a
patient with primary antiphospholipid
antibody syndrome
Some of the glomerular capillary lumina are
occluded by fibrin thrombi; the rest of the
capillaries are congested
The dilated vascular pole is occluded by a
thrombus

50. Ectatic glomerular capillary lumina are present as
a result of mesangiolysis. Focal reduplication of the
glomerular capillary basement membranes is also
seen
Thrombotic microangiopathy,
associated with mitomycin
administration
Thrombotic microangiopathy,
postpartum
The dilated infundibulum is occluded by homogenous
eosinophilic material (intraluminal thrombus).
Extensive reduplication of the glomerular capillary
basement membranes

51. Chronic or advanced stage of TMA
 extensive reduplication of the glomerular
capillary basement membranes.

52. Arteriolar fibrinoid necrosis
The infundibulum (i.e., vascular pole)
is occluded by a large thrombus. The
glomerular capillary walls are
thickened
Arteriolar and arterial changes are more common in
patients with aHUS and TTP

53.  The small interlobular artery shows the
edematous intima containing few myointimal cells
(“mucoid intimal hyperplasia”)

54. The interlobular artery shows luminal thrombus
with nuclear debris in the arterial wall. The
glomerulus exhibits ischemic features with
thickening and wrinkling of the glomerular
capillary basement membranes.
Prominent circumferential intimal cellular
proliferation in a small interlobular

55. Tubules and interstitium
 Hyaline casts and red blood cells.
 Acute tubular necrosis as is seen with ischemia may be
present. Iron pigment and hyaline droplets
 In later stages, tubular atrophy may be seen
 Interstitium may be edematous or fibrous, and in some
cases, it contains mild mononuclear cell infiltration.
 Large numbers of red blood cells are present in the
interstitium in areas of cortical necrosis.

56. Immunofluorescence Microscopy
The glomerular capillary walls and lumina (A) and the arterial wall
(B) show strong fibrinogen positivity

57. Electron Microscopy
The subendothelial zone is
lucent and contains fluffy
material

58. Fibrin and platelets in the capillary
loop are clearly recognizable. The
foot processes of the visceral
epithelial cells reveal moderate
effacement
Reduplication of the glomerular
capillary basement membrane with
cellular interposition.Severe
thickening of the glomerular capillary
basement membrane

59. The arteriolar lumen is obliterated, and the subintima is widened
by a lucent zone containing electron-dense strands and granules

60. Outcome and Prognostic
Features
 Acute renal failure manifests in up to 70% of patients with
classic HUS, most patients recover
 Pediatric patients with aHUS have a worse prognosis and
renal outcome than those with classic HUS
 A number of clinical-laboratory features such as the
severity of gastrointestinal tract symptoms , the longer
duration of dialysis , the duration of anuria, hypertension,
initial peripheral leukocytosis, and neurologic involvement
during the acute phase have been proposed as predictors
for poor long-term renal outcome in pediatric patients with
HUS

61. Treatment
 Plasma exchange
 Corticosteroids
 Rituximab
 Eculizumab
 Combined liver-kidney transplants

63. THANK YOU