Thrombotic thrombocytopenic purpura is a rare disorder of the blood-coagulation system,
causing extensive microscopic clots to form in the small blood vessels throughout the
body.
These small blood clots, called thrombi, can damage many organs including the kidneys,
heart and brain.
In the era before effective treatment with plasma exchange, the fatality rate was about
90%.
With plasma exchange, this has dropped to 10% at six months.
Immunosuppressants, such as glucocorticoids, rituximab, cyclophosphamide, vincristine,
or cyclosporine, may also be used if a relapse or recurrence follows plasma exchange.
Most cases of TTP arise from inhibition of the enzyme ADAMTS13, a metalloprotease responsible
for cleaving large multimers of von Willebrand factor into smaller units.
The increase in circulating multimers of vWF increase platelet adhesion to areas of endothelial
injury, particularly at arteriole-capillary junctions.
A rarer form of TTP, called Upshaw-Schülman syndrome, is genetically inherited as a dysfunction
of ADAMTS13.
If large vWF multimers persist, a tendency for increased coagulation exists.
Red blood cells passing the microscopic clots are subjected to shear stress which damages
their membranes, leading to intravascular hemolysis, which in turn leads to anaemia
and schistocyte formation.
Reduced blood flow due to thrombosis and cellular injury results in end organ damage.
Current therapy is based on support and plasmapheresis to reduce circulating antibodies against ADAMTS13
and replenish blood levels of the enzyme.
Signs and symptoms Classically, the following five features are
indicative of TTP; in most cases, some of these are absent.
Thrombocytopenia, leading to bruising or purpura Microangiopathic hemolytic anemia
Neurologic symptoms, such as hallucinations, bizarre behavior, altered mental status, stroke,
or headaches Kidney failure
Fever The symptoms of TTP may at first be subtle,
starting with malaise, fever, headache, and sometimes diarrhea.
As the condition progresses, clots form within blood vessels, and platelets are consumed.
Bruising, and rarely bleeding, results and may be spontaneous.
The bruising often takes the form of purpura, while the most common site of bleeding, if
it occurs, is from the nose or gums.
Larger bruises may also develop.
Neurological symptoms are present in up to 65% of patients, and may include headache,
difficulty speaking, transient paralysis, numbness, fits, or coma, the last of which
is a poor prognostic indicator.
This is a result of clots temporarily interrupting local blood supply.
High blood pressure may be found on examination.
Causes and pathogenesis TTP, as with other microangiopathic hemolytic
anemias, is caused by spontaneous aggregation of platelets and activation of coagulation
in the small blood vessels.
Platelets are consumed in the aggregation process, and bind vWF.
These platelet-vWF complexes form microthrombi which circulate in the vasculature and cause
shearing of red blood cells, resulting in hemolysis.
Roughly, the two forms of TTP are idiopathic and secondary TTP.
A special case is the inherited deficiency of ADAMTS13, known as the Upshaw-Schülman
syndrome.
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,
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 ADAMTS13 activity can be detected in most patients,
and inhibitors are often found in this subgroup.
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: Antiviral drugs
Quinine
Menopause Infection by E.Coli
Platelet aggregation inhibitors Immunosuppressants
Hormone altering drugs
HIV-1 infection The mechanism of secondary TTP is poorly understood,
as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inhibitors cannot
be detected.
Probable etiology may involve, at least in some cases, endothelial damage, although the
formation of thrombi resulting in vessel occlusion may not be essential in the pathogenesis of
secondary TTP.
These factors may also be considered a form of secondary aHUS; patients presenting with
these features are, therefore, potential candidates for anticomplement therapy.
Upshaw-Schülman syndrome A hereditary form of TTP is called the Upshaw-Schülman
syndrome; this is generally due to inherited deficiency of ADAMTS13.
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-Schülman syndrome.
Patients with Upshaw-Schülman syndrome have 5–10% of normal ADAMTS-13 activity
Differential diagnosis TTP is characterized by thrombotic microangiopathy,
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 and atypical
hemolytic-uremic syndrome.
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; renal impairment; and gastrointestinal symptoms, 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 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; 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, vincristine, cyclophosphamide, splenectomy, rituximab or
a combination of the above.
Children with Upshaw-Schülman syndrome receive prophylactic plasma every two to three weeks;
this maintains adequate levels of functioning ADAMTS13.
Measurements of LDH, platelets, and schistocytes are used to monitor disease progression or
remission.
Epidemiology The incidence of TTP is about 4-5 cases per
million people per year.
Idiopathic TTP occurs more often in women and people of African descent, and TTP secondary
to autoimmune disorders such as systemic lupus erythematosus occurs more frequently in people
of African descent, although other secondary forms do not show this distribution.
Pregnant women and women in the post partum period accounted for a notable portion 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 to a toxic cause.
Moschcowitz noted his patient, a 16-year-old girl, had anemia, petechiae, microscopic hematuria,
and, at autopsy, disseminated microvascular thrombi.
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; in this series, mortality rates were found
to be very high.
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