Disease-a-Month 60 (2014) 500–504

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Thrombotic thrombocytopenic purpura Albara Said, MD, Rami Y. Haddad, MD, Robert Stein, MD, Edgar V. Lerma, MD, FACP, FASN

Moschowitz first described thrombotic thrombocytopenic purpura (TTP) in 1925 in a 16-yearold female who presented with fever, petechiae, and a microangiopathic hemolytic anemia.1,2 Autopsy examination at the time revealed hyaline thrombi in the vascular beds of many organs.1 By 1947, several more cases were described and Singer suggested the term TTP.1 In 1964, Amorosi and Ultmann published a review of all cases and introduced the “classic pentad” used to diagnose TTP.1,2 With recent advances and discoveries, it is now accepted that TTP and hemolytic uremic syndrome (HUS) are distinct diseases (although there is significant overlap) under the larger category of thrombotic microangiopathies, both presenting with a microangiopathic hemolytic anemia (MAHA), with no apparent cause along with renal and/or neurologic manifestations.

Epidemiology Idiopathic TTP has an annual incidence of between 3.7 and 11 cases per million,1 with more recent estimates being on the higher end, possibly due to an increase in awareness and diagnosis. There is a slight female predominance (3:2) with peak incidence in the 4th decade.1,2 In multiple series, it was found that African-Caribbean ancestry and obesity were also risk factors.2

Pathophysiology In all thrombotic microangiopathies (TMA), including TTP, several disease pathways eventually lead to the same process: an inciting event leading to vascular endothelial injury, which leads to thrombosis and hemolysis. There is a wide range of inciting events, and an apparent genetic or acquired predisposition in some patients to developing TMA after these events. The most common of these predispositions is an inherited or acquired deficiency of A Disintegrin And Metalloprotease with a Thrombospondin type 1 motif, member 13 (ADAMTS13).1,2 This protease is involved in the production of normal von Willebrand factor multimers by cleaving the large multimers (unusually large von Willebrand factor, or ULVWf) produced in endothelial cells. When ADAMTS13 is deficient, it leads to an accumulation of ULVWf, which induces platelet aggregation in the microvasculature, leading to thrombosis. This http://dx.doi.org/10.1016/j.disamonth.2014.08.005 0011-5029/& 2014 Mosby, Inc.. All rights reserved.

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process leads to the microangiopathic thrombosis and hemolysis found in TTP.1–3 It is important to note, however, that not all patients with TTP have decreased ADAMTS13, and not all those with decreased ADAMTS13 develop TTP in their lifetime. It is an important risk factor to developing TTP, but is not a prerequisite.1 Although ADAMTS13 deficiency appears to be the main role player, other mechanisms appear to contribute to the development of TTP, especially when considering that there is a patient population with normal circulating levels of ADAMTS13. One hypothesis includes a deficiency of vascular endothelial growth factor (VEGF), which appears to lead to renal TMA.2 Another theory seeks to explain why TTP has predominately renal and neural manifestations, and this theory implicates CD36 (usually found in these two aforementioned organs). ADAMTS13 is bound by CD36 found on endothelial cells, where it cleaves ULVWf into normal VWf; therefore, a deficiency of CD36 (or an antibody against it) may lead to decreased ADAMTS13 activity, despite normal serum levels, leading to a predisposition to developing TTP.2 Several other hypotheses exist along with these, and more research is being done to try and better understand all of the mechanisms involved in the disease process.

Diagnosis The 1964 review article by Amorosi and Ultmann first described the classic pentad of TTP, which sums up the clinical manifestations:

    

microangiopathic hemolytic anemia, thrombocytopenia (with purpura), acute kidney injury, neurologic abnormality and fluctuating mental status, and Fever.1,2

In early studies, most patients (75%) presented with MAHA, neurologic abnormality, and thrombocytopenia; however, due to recent advancements and increased awareness leading to early diagnosis, TTP is presumptively diagnosed with only MAHA and thrombocytopenia in the absence of the others.1 In fact, in a study of 68 patients with TTP, only three (5%) presented with all five components.2 Along with the five clinical features of TTP, many patients present with non-specific symptoms of fatigue, malaise, or fever for days or weeks prior, and 10–40% describe an upper respiratory tract infection during this period.1 Along with thrombocytopenia, MAHA is the most important clinical feature needed to diagnose TTP. It is diagnosed by the appearance of schistocytes on peripheral smear. Elevated LDH and indirect bilirubin, along with decreased haptoglobin levels, are also seen. The level of anemia may be mild to severe depending on timing of presentation. Thrombocytopenia is the second major clinical feature and like the anemia can be mild to severe. However, the majority of patients tend to have profound drops in their platelet count, with counts below 20,000 per mL being common. Although less important presenting features, the presence of AKI, neurologic abnormality, and fever may indicate more severe illness, or late presentation.1 The renal disease associated with TTP is due to TMA in the renal vasculature. Presentation can be mild or severe, with some patients being anuric and requiring dialysis. Urinalysis in these patients can be near normal with mild proteinurea.1 The neurological symptoms can be subtle, presenting as headaches or mild confusion, or more serious, such as coma or seizure.2 Lastly, fever appears to be uncommon and may suggest the presence of sepsis as opposed to TTP. It is important to note that TTP is a clinical diagnosis, and diagnosis is imperative as early intervention improves prognosis dramatically.4 As a result, measurement of serum ADAMTS13 activity is not performed for diagnosis, as turn-around time tends to be long and awaiting results

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may delay life-saving treatment. Nevertheless, measurement of activity of ADAMTS13 can be performed in order to elucidate etiology and the patient's risk of developing TTP again.4 Microangiopathic hemolytic anemia Thrombocytopenia with purpura

Sufficient to start treatment

Acute kidney injury Neurologic abnormality with fluctuating mentation

Presence may indicate more severe illness or late presentation

Fever Fatigue, malaise, or upper respiratory tract infection

Non specific

Differential diagnosis The differential of TTP is extensive and includes TMA that is drug induced, due to pregnancy, following infectious bloody diarrhea, and due to autoimmune disorders.1 Of the drugs, quinine is the most common; others include cyclosporine, tacrolimus, and gemcitabine.1–4 Pregnant patients presenting with HELLP or eclampsia can appear to be presenting with TTP. Escherichia coli O157:H7 or shiga-like toxin-producing E. coli leads to HUS, which can appear to be TTP unless a careful history is taken. Finally, systemic lupus erythematosus (SLE) patients can present with symptoms very similar to TTP.1,2,4

Treatment Treatment for TTP has had a significant impact on the prognosis of the disease. Prior to plasma exchange, patients with TTP progressed to severe manifestations of the “classic pentad,” leading to permanent renal failure and neurologic compromise, with a mortality exceeding 90%.1 Until the mid-1970s splenectomy was the only treatment with any real response.1 After the implementation of plasma exchange the mortality in TTP has dropped to below 10–25%.1,4 Plasma exchange attains two goals that are required for remission of TTP: 1. removal of ADAMTS13 inhibitor (IgG), along with some removal of the ULVWf circulating in the patients serum and 2. replacement of deficient ADAMTS13.4

Plasma exchange, the mainstay of therapy, should be performed daily and can end 2–3 days after symptoms have improved (thrombocytopenia, MAHA, and neurologic problems).4 Serum platelet and LDH levels can be obtained to monitor response, which usually occurs in the first 10 days, but may require up to 3 weeks.2,4

Other treatments Corticosteroids can be useful in patients with autoantibodies to ADAMST13; however, whether or not ADAMTS13 inhibitor is a component is not information that is available at presentation. For this reason, steroids are used often in initial therapy, especially in patients who appear to have idiopathic TTP, or those who do not respond to the first few treatments. It is important to note that steroids are useful in addition to plasma exchange, and not as a monotherapy.2,4

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Rituximab, the anti-CD20 antibody medication, has been studied in cases of refractory or relapsing TTP. It was found to be effective in these cases in decreasing the levels of ADAMTS13 inhibitor and can be used as salvage therapy in these patients.2,4 Other treatments such as splenectomy, antiplatelet agents (aspirin, dipyridamole, etc), cyclosporine, and cyclophosphamide have some anecdotal supportive data, and as such should only be used if no other treatment appears effective.2,4 Treatment

Place in therapy

Plasma exchange

Used in all patients. Should be performed daily and can end 2–3 days after symptoms have improved. Consider in all patients until information on ADAMTS13 inhibitor involvement is available. Not to be used as monotherapy. Salvage therapy in cases of refractory or relapsing TTP. Only anecdotal evidence of use is available and as such should only be used if no other treatment appears effective.

Steroid therapy Rituximab Splenectomy, antiplatelet agents, cyclosporine, and cyclophosphamide

Prognosis The prognosis of TTP has significantly improved after the introduction of plasma exchange; however, there are a number of factors that increase risk of relapse. These include neurologic involvement, cardiac involvement, severe thrombocytopenia (o 15,000 per mL) on day two of treatment, and age over 60 years. The presence of ADAMTS13 deficiency or inhibitor may also have an impact. Mortality after plasma exchange is as low as 10%, some risk factors that increase mortality are age 4 60 years, persistent elevation of LDH after two treatments, and severe neurologic symptoms.2,4 In the long term, many patients have reduced physical activity and reduction in mental function. Patients with TTP also have an increased risk of developing hypertension.

Complications Complications of treatment with plasma exchange are mostly due to the use of central venous catheter such as infection, hemorrhage, and catheter obstruction. Plasma-related complications were less common; however, anaphylaxis, serum sickness, and hypotension can occur.4

Summary Idiopathic TTP is a disease of increasing incidence, likely due to increased awareness and diagnosis. It is imperative to diagnose early as mortality without treatment exceeds 90%, while treatment can reduce it to below 10%. Although there is a well-described “classic pentad” of clinical manifestations, MAHA and thrombocytopenic purpura are the two major criteria, and treatment should be considered when only these two are present. The other components of the pentad can be later manifestations of the illness, and one should not wait for their presence to initiate therapy. ADAMTS13 activity can be ordered to help discover etiology and for prognosis, but it is incorrect to wait for the results before treatment. The mainstay of treatment is plasma exchange, performed daily while monitoring LDH and platelet counts. Treatment with steroids should be considered in most patients. Treatment with rituximab should be considered as salvage therapy.

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References 1. McCrae KR, Sadler JE, Cines DB. Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. In: Hoffman R, editor. Hematology: Basic Principles and Practice. 6th ed. Philadelphia: Saunders; 2012, [chapter 136]. 2. George JN. Causes of thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome in adults. In: Basow DS, editor. UpToDate. Waltham, MA: UpToDate; 2013. 3. George JN. Diagnosis of thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome in adults. In: Basow DS, editor. UpToDate. Waltham, MA: UpToDate; 2013. 4. Kaplan AA, Geroge JA. Treatment and prognosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndromes in adults. In: Basow DS, editor. UpToDate. Waltham, MA: UpToDate; 2013.

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