Thrombotic Microangiopathies

 TTP

 HUS
These disorders have different
pathogenesis but both are characterized
by systemic or intrarenal aggregation of
platelets and/or fibrin, mechanical injury
to red blood cells, and thrombocytopenia.
Thrombotic Thrombocytopenia Purpura
“Classic Signs”
 Fever
 Thrombocytopenia
 Neurological abnormalities
 Microangiopathic hemolytic anemia
 Renal dysfunction
 Hemolytic Uremic Syndrome
“Classic Signs”

 Thrombocytopenia
 Renal dysfunction
 Microangiopathic hemolytic anemia
Thrombotic Thrombocytopenia Purpura

 Following general types exist:

-infantile
-acquired
-drug induced

 Overall incidence is low with approximately 3.7

cases/1,000,000 population.
Familial TTP

 May appear in infancy or early childhood

 Recurs at monthly intervals
 Prognosis very poor
 Caused by a deficiency of ADAMTS13, an
endothelial protease
Acquired TTP

 Usually occurs in adults and children, with

a peak in the second decade of life
 Is rare and characterized as a single acute
episode, although recurrences can occur
 Thought to be caused by an autoantibody to
ADAMST13
Drug-Induced TTP

 Anti-platelet agents ticlopidine and

clopidogrel have been associated with TTP
presenting in adults
 Quinine induce autoantibody against
platelets
Hemolytic Uremic Syndrome

 Diverse group of disorders

-Inherited
-Post-Infectious
-Drug related
-Thrombotic Microangiopathy
Post-Infectious HUS
 Most common cause of renal failure in
children less than 4 years of age, epidemic
cases are associated with a bacterial protein
referred to as a shiga toxin
 Organisms most commonly associated- E.
Coli 0157:H7, shigella dysenteria, and rare
cases of Streptococcus pneumonia
 9 to 30% of patients with E. Coli 0157:H7
infection progress to having HUS
Hemolytic Uremic Syndrome

 Beef and cattle are the main reservoir, with

risk of transmission greatest when ingesting
uncooked or partially cooked meat and/or
unpasteurized dairy products.
Inherited HUS- Factor H deficiency

 Relatively common cause of HUS and accounts

for approx. 5-10% of all cases
 Factor H is an important enzyme in the
complement cascade, which when absent, allows
unregulated complement activation
 Thrombosis occur after minor endothelial cell
injury
Drug Induced HUS/TTP
 Associated with immunosuppressants
cyclosporine
 Occurs after prolonged combination chemotherapy
and total body irradiation, with mitomycin and
cisplatin
 Mechanism of these microangiopathies unknown
Pathophysiology of TTP

 Microvascular thrombi consist only of platelet

aggregates.
 No endothelial cell damage.
 Platelet aggregates contain abundant von
Willebrand factor multimers, that bind platelets at
the glycoprotein 2B/3A receptor with high
affinity.
Pathophysiology of TTP:

 A metalloprotease enzyme (ADAMTS13) is

usually produced by hepatocytes, binds to
endothelial cells and cleaves vWf
multimers to produce monomers with a low
affinity for platelet binding.
 In case of TTP their will be inherited defect
in ADAMTS13
 Or autoantibodies will be formed against
ADAMTS13
Pathogenesis of HUS

 75% of cases follow Infection by E-Coli strain

O157:H7 or shigella dysenteriae
 Shiga toxin is of a singular A subunit, and 5 B
subunits
 The B subunit of shiga toxin binds to receptors,
present in glomerular, colonic, cerebral,
endothelial, renal mesangial and tubular cells, and
platelets.
Proposed Mechanism of HUS

 Shiga toxin is carried by neutrophils in

circulation
 Renal glomerular endothelial are targeted
 Toxin have following effect on cell
1. Inc adhesion of leukocytes
2. Inc endothelin
3. Dec of Nitric oxide
 These all favors vasoconstriction
 This toxin also causes endothelial damage
by releasing cytokines
 Toxin also gains direct entry to the cell
causing CELL death
 Endothelial damage causes thrombosis that
is prominent in glomeruler capillaries,
afferent arterioles & intralobular arteries
 Thrombosis and vasoconstriction causes
microangiopathies
 In 10% cases of HUS is not caused by shiga
toxin but by mutational inactivation of
complement regulatory proteins..
 E.g factor H
 HUS- Why the Kidneys?

 Gb3, the glycolipid receptor responsible for

binding the B subunit of shiga toxin, is
expressed 50X more in kidney than in the
endothelial cells of lung or liver.
 Morphology
 Thrombi will be present in glomeruli
 Cortical necrosis may be present
 Widening of subendothelial space in
glomerular capillaries
 Spliting of GBMs
 Lysis of messengial cell
 Chronically glomerular scarring
 Signs & symptoms
 Sudden onset of GIT or flulike epoisode
 Hematemesis and/or melena
 Oliguria, hematuria, microangiopathic
hemolytic anemia
 TTP dominantly involve CNS
 HUS causes acute renal failure