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Micrograph showing an acute thrombotic microangiopathy, as may be seen in TTP. A thrombus is present in the hilum of the glomerulus (center of
image). Kidney biopsy. H&E stain.
[1]
ICD-10
M31.1
ICD-9
446.6
OMIM
274150
DiseasesDB
13052
MedlinePlus
000552
eMedicine
emerg/579
MeSH
D011697
(ILDS M31.110)
[2]
[3]
[4]
[5]
[6]
neuro/499
[7]
med/2265
[8]
[9]
Idiopathic TTP
The idiopathic form of TTP was recently linked to the inhibition of the enzyme ADAMTS13 by antibodies,
rendering TTP an autoimmune disease. ADAMTS13 is a metalloproteinase responsible for the breakdown of von
Willebrand factor (vWF), a protein that links platelets, blood clots, and the blood vessel wall in the process of blood
coagulation. Very large vWF multimers are more prone to lead to coagulation. Hence, without proper cleavage of
vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the microvasculature, part of the blood vessel
system where vWF is most active due to high shear stress.
In idiopathic TTP, severely decreased (<5% of normal) ADAMTS13 activity can be detected in most (80%) patients,
and inhibitors are often found in this subgroup (44-56%). The relationship of reduced ADAMTS13 to the
pathogenesis of TTP is known as the Furlan-Tsai hypothesis, after the two independent groups of researchers who
published their research in the same issue of the New England Journal of Medicine in 1998.
Secondary TTP
Secondary TTP is diagnosed when the patient's history mentions one of the known features associated with TTP. It
comprises about 40% of all cases of TTP. Predisposing factors are:
Cancer
Bone marrow transplantation
Pregnancy
Medication use:
Upshaw-Schlman syndrome
A hereditary form of TTP is called the Upshaw-Schlman syndrome; this is generally due to inherited deficiency of
ADAMTS13 (frameshift and point mutations). Patients with this inherited ADAMTS13 deficiency have a
surprisingly mild phenotype, but develop TTP in clinical situations with increased von Willebrand factor levels, e.g.
infection. Reportedly, less than 1% of all TTP cases are due to Upshaw-Schlman syndrome.[10] Patients with
Upshaw-Schlman syndrome have 5-10% of normal ADAMTS-13 activity
Differential diagnosis
TTP is characterized by thrombotic microangiopathy (TMA), the formation of blood clots in small blood vessels
throughout the body, which can lead to microangiopathic hemolytic anemia and thrombocytopenia. This
characteristic is shared by two related syndromes, hemolytic-uremic syndrome (HUS) and atypical hemolytic-uremic
syndrome (aHUS). Consequently, differential diagnosis of these TMA-causing diseases is essential. In addition to
TMA, one or more of the following symptoms may be present in each of these diseases: neurological symptoms (e.g.
confusion, cerebral convulsions seizures,); renal impairment (e.g. elevated creatinine, decreased estimated
glomerular filtration rate [eGFR], abnormal urinalysis); and gastrointestinal (GI) symptoms (e.g. diarrhea
nausea/vomiting, abdominal pain, gastroenteritis. Unlike HUS and aHUS, TTP is known to be caused by an acquired
defect in the ADAMTS13 protein, so a lab test showing 5% of normal ADAMTS13 levels is indicative of TTP.
ADAMTS13 levels above 5%, coupled with a positive test for shiga-toxin/enterohemorrhagic E. coli (EHEC), are
more likely indicative of HUS, whereas absence of shiga-toxin/EHEC can confirm a diagnosis of aHUS.
Prognosis
The mortality rate is around 95% for untreated cases, but the prognosis is reasonably favorable (80-90% survival) for
patients with idiopathic TTP diagnosed and treated early with plasmapheresis.
Treatment
Due to the high mortality of untreated TTP, a presumptive diagnosis of TTP is made even when only
microangiopathic hemolytic anemia and thrombocytopenia are seen, and therapy is started. Transfusion is
contraindicated in thrombotic TTP, as it fuels the coagulopathy. Since the early 1990s, plasmapheresis has become
the treatment of choice for TTP. This is an exchange transfusion involving removal of the patient's blood plasma
through apheresis and replacement with donor plasma (fresh frozen plasma or cryosupernatant); the procedure must
be repeated daily to eliminate the inhibitor and abate the symptoms. If apheresis is not available, fresh frozen plasma
can be infused, but the volume that can be given safely is limited due to the danger of fluid overload.
Most patients with refractory or relapsing TTP receive additional immunosuppressive therapy, with glucocorticoid
steroids (e.g. prednisolone or prednisone), vincristine, cyclophosphamide, splenectomy, rituximab or a combination
of the above.
Children with Upshaw-Schlman syndrome receive prophylactic plasma every two to three weeks; this maintains
adequate levels of functioning ADAMTS13. [citation needed]
Measurements of LDH, platelets, and schistocytes are used to monitor disease progression or remission.[citation
needed]
Epidemiology
The incidence of TTP is about 4-5 cases per million people per year. Idiopathic TTP occurs more often in women
and black/African American people, and TTP secondary to autoimmune disorders such as systemic lupus
erythematosus occurs more frequently in blacks/African Americans, although other secondary forms do not show
this distribution. Pregnant women and women in the post partum period accounted for a notable portion (12-31%) of
the cases in some studies; TTP affects about one in 25,000 pregnancies.
History
TTP was initially described by Dr Eli Moschcowitz at the Beth Israel Hospital in New York City in 1925.
Moschcowitz ascribed the disease (incorrectly, as now known) to a toxic cause. Moschcowitz noted his patient, a
16-year-old girl, had anemia, petechiae (purpura), microscopic hematuria, and, at autopsy, disseminated
microvascular thrombi.[11] In 1966, a review of 16 new cases and 255 previously reported cases led to the
formulation of the classical pentad of symptoms and findings (i.e., thrombocytopenia, microangiopathic hemolytic
anemia, neurological symptoms, kidney failure, fever); in this series, mortality rates were found to be very high
(90%). While response to blood transfusion had been noted before, a 1978 report and subsequent studies showed
blood plasma was highly effective in improving the disease process. In 1991, plasma exchange was reported to
provide better response rates compared to plasma infusion. In 1982, the disease had been linked with abnormally
large von Willebrand factor multimers, and the identification of a deficient protease in people with TTP was made in
the late 1990s. ADAMTS13 was identified on a molecular level in 2001.
References
[1] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ M31. 1
[2] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=446. 6
[3] http:/ / omim. org/ entry/ 274150
[4] http:/ / www. diseasesdatabase. com/ ddb13052. htm
[5] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000552. htm
[6] http:/ / www. emedicine. com/ emerg/ topic579. htm
[7] http:/ / www. emedicine. com/ neuro/ topic499. htm#
[8] http:/ / www. emedicine. com/ med/ topic2265. htm#
[9] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2014/ MB_cgi?field=uid& term=D011697
[10] Tsai HM. Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and related disorders. In: Greer JP, Foerster J, Rodgers GM,
et al, eds. Wintrobes Clinical Hematology. 12th ed. Philadelphia, PA: Lippincott, Williams, and Wilkins; 2009;1314-1325.
[11] Reprinted in Mt Sinai J Med 2003;70(5):322-5, PMID 14631522.
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