Endothelial injury triggers these two disorders
which sit on the ends of a clinical spectrum. Stellate Ito cells
in the liver produce2 ADAMTS13, the deficit of
which is involved in TTP. Microvascular thromboses cause microangiopathic
RBC changes seen in blood smears. In TTP, the microthrombi occur
throughout the microcirculation; and microvascular thromboses may
be found in the brain, skin, intestines, skeletal muscle, pancreas,
spleen, adrenals, and heart...CNS findings alert to the TTP end
of the spectrum. On the other hand, in HUS, microthrombi are essentially
confined to the kidneys.
In most cases of familial TTP and acquired idiopathic TTP, the
endothelial cells become stimulated to secrete and release the
ultra-large (UL) von Willebrand factor (ULVWF) multimers. There is a congenital variant. Acquired is commonly due to E. coli (O157:H7) (see CN-06-58). The sheering
stress of fluid and platelet thrombi in the microcirculation should
enhance proteolysis of ULVWF. The agitated endothelial cells are
the main source of ULVWF multimers in the bloodstream where they
bind to specific surface platelet receptors. In 1982, Moake, et.
al., showed that the ULVWF multimers were unusually large in patients
with chronic relapsing TTP. ULVWF multimers entangle with platelets
adhering to the subendothelium. Two independent research groups
reported a lack of ULVWF-cleaving protease activity in the blood
of patients with TTP. The lack of ULVWF-cleaving protease activity
was suggested to be (1) due to the presence of antibodies or (2) a severe
deficiency of ULVWF-cleaving protease.
The ULVWF multimers are cleaved by the protease, ADAMTS-13, as
they are secreted from endothelial cells. Failure to degrade the
ULVWF multimers is believed to cause the familial and acquired
idiopathic types of TTP. The ULVWF-cleaving protease, ADAMTS-13,
is (1) presumed inhibited by the production of autoantibodies in
acquired idiopathic TTP and (2) ADAMTS-13 gene mutations in familial
TTP causing inactivity or decreased activity of ADAMTS-13. In
TTP, insufficiency of ADAMTS-13 may be the key component in the
pathogenesis of ULVWF multimer–induced platelet thrombosis.
TTP differs from HUS by having a deficiency in ULVWF-cleaving
protease ADAMTS-13 activity, a deficit not found in HUS, HUS having
sufficient uninhibited protease. The intervention of plasma exchange
is ineffective in HUS because the role of exchange in TTP is to
(1) remove antibodies and (2) replace VWF-cleaving protease. Differentiating
TTP from HUS benefits the patient because plasma exchange is not
a benign intervention. This differentiation also saves costs and
time. Research is ongoing; but, presently, TTP is suggested to
be a different entity than HUS.
ULVWF multimers are abundant and fibrinogen/fibrin turnover is
minimal in TTP, whereas fibrinogen/fibrin turnover is abundant
in disseminated intravascular coagulation (DIC). The ULVWF multimer
is a marker found in the plasma of patients most likely to have
a recurrence of TTP. TTP can occur during pregnancy and is to be
differentiated from the toxemia-related HELLP syndrome.
HUS is treated with supportive measures while TTP
is treated by plasmapheresis.
CAUSES of HUS/TTP3:
- post-diarrhea due to entero. E. coli 0157:H7 (mainly childhood HUS)
- drug induced: quinine, Ticlopidine, Clipidogrel, chemotherapeutic agents, immunosuppressants, oral contraceptives, & valacyclovir.
- pregnancy & post-partum associated.
- AIDS & early symptomatic HIV.
- Autoimmune disease .
- Conditioning regimines for hematopoietic stem-cell transplantation.
check the eMedicine website:
Zhou W, et. al., ADAMTS13 is Expressed in Hepatic
Stellate Cells, Lab. Invest. 85:780-788, June 2005 (noted in
June 2005 Modern Pathology).
- Sebastian A, et. al., "Thrombocytopenia and Elevated Bilirubin...," Labmedicine 38(10):610-612, October 2007