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Thrombotic Thrombocytopenic Purpura - 12/7/2012

posted Dec 7, 2012, 8:35 AM by Rohit Das   [ updated Dec 27, 2012, 6:38 AM by Purnema Madahar ]

Thrombotic thrombocytopenic purpura – otherwise known as TTP. Pathogenically, very interesting; prognostically, very serious. Initially defined in 1925 as the pentad of thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal failure, and fever, with the advent of effective therapy, the definition has been simplified to otherwise unexplained thrombocytopenia and microangiopathic hemolytic anemia. This has led to a higher incidence of TTP” but also much better outcomes – a disease that once killed 90% of patients is now, for the most part, very treatable.

Depending on what you read, authors differentiate TTP and HUS, stating that TTP is a disease of adulthood and typically a neurologically dominant syndrome, whereas HUS is a disease of childhood and typically a renal dominant syndrome. However, only rarely do all five parts of the pentad present simultaneously, and as mentioned, TTP can be diagnosed in the absence of renal or neurologic abnormalities. Generally, the syndrome is believed to exist within a clinical spectrum, and thus the term “TTP-HUS” was coined. Bottom line…it doesn’t really matter, and I’m just going to call it TTP because it’s easier to type and rolls off the tongue nicely…So…

·         What is the pathogenesis of TTP? Though the majority of cases of TTP are idiopathic, what are some common underlying causes to be aware of?

·         When should one suspect TTP, and how is it diagnosed?

·         How is TTP managed, and what is the prognosis?

What is the pathogenesis of TTP? Though the majority of cases of TTP are idiopathic, what are some common underlying causes to be aware of?

·         Some quick epidemiology – despite the less stringent clinical diagnostic criteria, TTP is still a very rare disease. Registries estimate an annual U.S. incidence of 4-11 cases per million people, most commonly afflicting black women.

·         On to the pathology – the hallmark of TTP-HUS is systemic presence of thrombi composed primarily of platelets. This leads to endothelial injury and impaired perfusion to affected organs (most commonly the renal and cerebral vascular beds), and thus the clinical syndrome. The large majority of cases are idiopathic (40%), and generally half of such cases are related to ADAMTS13 deficiency…

·         ADAMTS13 deficiency was first described in the late 1990s as a potential etiology for idiopathic TTP. ADAMTS13 is a protease that cleaves von Willebrand factor multimers, which are responsible for platelet aggregation. ADAMTS13 deficiency leads to accumulation of these multimers, and thus platelet thrombi formation. Additionally, a significant proportion of patients with TTP have autoantibodies to ADAMTS13, thus perhaps representative of, to some degree, an autoimmune insult leading to acquired deficiency. In a couple of case series, ADAMTS13 deficiency has been associated with obesity, SLE, Afro-Caribbean ethnicity, and female gender.

·         TTP also occurs in the context of several underlying causes. Examples include Shiga toxin producing E.coli (particularly 0157:H7), drug-related (Quinine, Clopirogrel, various chemotherapies, immunosuppressive agents), autoimmune diseases (particularly SLE), disseminated malignancy (particularly occult adenocarcinomas), post-allogenic stem cell transplant, and pregnancy (HELLP syndrome). Importantly, there is also an association between TTP and HIV.

When should one suspect TTP, and how is it diagnosed?

·         TTP is a clinical diagnosis. One should have a low index of suspicion in any patient with otherwise unexplainable thrombocytopenia and microangiopathic hemolytic anemia. By definition, schistocytes need to be seen, and the presence of ≥2 per field at 100x magnification is highly suggestive of microangiopathic hemolysis (which results from RBCs shearing against platelet-rich thrombi). It is obviously important to be cognizant of signs consistent with hemolysis – anemia, indirect hyperbilirubinemia and elevated LDH levels/reticulocyte indices. Thrombocytopenia is generally severe, with mean counts being below 25,000/umol prior to treatment.

·         The most common presenting symptoms are actually very nonspecific – abdominal pain, nausea/vomiting, and lethargy. In regard to other parts of the pentad – as mentioned previously, they are not required for diagnosis. Neurologic symptoms are not present in 30-60% of patients. The incidence of fever as a part of TTP is declining in recent case series, and its presence should rather alert one to the possibility of coexisting infection, especially if above 102oF.

·         ADAMTS13 deficiency IS NOT required for diagnosis, and actually has very little diagnostic utility. As mentioned, only one-half of idiopathic cases have severe (<10% activity) deficiency.  I’ll speak more of its prognostic utility a little bit later…

How is TTP managed, and what is the prognosis?

·         Plasmapharesis, with replacement of 1.0 to 1.5 of the patient’s predicted plasma volume, is the standard of care, and is generally done until the platelet count is normal. This was first documented in 1991 in a trial of 102 patients randomized to plasma exchange or plasma infusion, and then confirmed in several observational trials. Steroids are also used for patients with an idiopathic etiology, a poor response to initial plasmapharesis, and recurrence of thrombocytopenia after discontinuation of pheresis. There are no controlled trials documenting the efficacy of glucocorticoids. There is also some data to support the use of rituximab in persistent/relapsing disease.

·         Prognostic scores have been created for TTP, the most credible of which is from the French TMA study (attached – see Table 4), which created a score based on a prospective cohort that was subsequently validated. Based on age, LDH level, and cerebral signs, scores of 0, 1, 2 and 3 corresponded to 30-day mortalities of 0, 13, 27 and 33% respectively.

·         ADAMTS13 measurement is not useful for predicting response to treatment or long-term survival. However, it is very useful in predicting risk for relapse. In the attached study from Blood, patients with <10% activity had a relapse rate of 40% at 7.5 years, as compared to only 4% in in patients >10% activity. This study also suggests that the coexisting presence of severe deficiency AND the autoantibody inhibitor is predictive of worse survival.

Hope that provided a nice summary. The attached review article is pretty useful, and recommend sticking that, at least, into your library. Congrats to our senior residents for getting through this whole match business…definitely a nice relief. Have a good weekend!