Upshaw-Schulman syndrome

Thrombotic thrombocytopenic purpura
Classification and external resources
10 9 OMIM DiseasesDB MedlinePlus eMedicine MeSH D011697

Thrombotic thrombocytopenic purpura (TTP or Moschcowitz syndrome[1]:822) is a rare disorder of the blood-coagulation system, causing extensive microscopic clots to form in the small blood vessels throughout the body.[2][3] 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, survival at six months is around 80%. Immunosuppressants, such as glucocorticoids, rituximab, cyclophosphamide, vincristine, or cyclosporine, may also be used if a relapse or recurrence follows plasma exchange.[4]

Most cases of TTP arise from inhibition of the enzyme ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand factor (vWF) 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.[5]

Red blood cells passing the microscopic clots are subjected to shear stress which damages their membranes, leading to intravascular hemolysis 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.[5]

Signs and symptoms

Classically, the following five features ("pentad") are indicative of TTP;[6] in most cases, some of these are absent.[3]

The symptoms of TTP may at first be subtle, starting with malaise, fever, headache, and sometimes diarrhea. As the condition progresses, clots (thrombi) form within blood vessels, and platelets (clotting cells) 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 (ecchymoses) 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. [7]

High blood pressure (hypertension) may be found on examination.[8]

Causes and pathogenesis

TTP, as with other microangiopathic hemolytic anemias (MAHAs), is caused by spontaneous aggregation of platelets and activation of coagulation in the small blood vessels. Platelets are consumed in the coagulation process, and bind fibrin, the end product of the coagulation pathway. These platelet-fibrin complexes form microthrombi which circulate in the vasculature and cause shearing of red blood cells, resulting in hemolysis.[3]

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.[3]

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.[5]

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.[9][10][11]

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:[3]

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,[12] although the formation of thrombi resulting in vessel occlusion may not be essential in the pathogenesis of secondary TTP.[13] 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 (frameshift and point mutations).[14][15][16] 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.[17] Patients with Upshaw-Schülman syndrome have 5-10% of normal ADAMTS-13 activity [16][18]

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).[19] 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,[20][21] cerebral convulsions[21] seizures,[22]); renal impairment[23] (e.g. elevated creatinine,[24] decreased estimated glomerular filtration rate [eGFR],[24] abnormal urinalysis[25]); and gastrointestinal (GI) symptoms (e.g. diarrhea[20][26] nausea/vomiting,[22] abdominal pain,[22] gastroenteritis.[20][23] 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.[27] ADAMTS13 levels above 5%, coupled with a positive test for shiga-toxin/enterohemorrhagic E. coli (EHEC), are more likely indicative of HUS,[28] whereas absence of shiga-toxin/EHEC can confirm a diagnosis of aHUS.[27]


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.[29]


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.[30] 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. [7]

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. [7]

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.


The incidence of TTP is about 4-5 cases per million people per year.[31] 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.[32] 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.[33]


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.[34] 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 helolytic anemia, neurological symptoms, kidney failure, fever); in this series, mortality rates were found to be very high (90%).[6] 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.[35] In 1991, plasma exchange was reported to provide better response rates compared to plasma infusion.[36] 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.[35]


External links

  • MedlinePlus
  • National Heart, Lung, and Blood Institute
  • University of Oklahoma Health Sciences Center
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