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Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) and the related disorder, hemolytic uremic syndrome (HUS) are characterized by thrombocytopenia and microangiopathic hemolytic anemia, both resulting from microvascular platelet thrombi in terminal arteries and capillaries. Small vessel occlusion in various organs, notably the brain and kidney, is responsible for the clinical manifestations which include fluctuating neurologic abnormalities and a variable degree of renal insufficiency. On clinical grounds, cases with more of a neurologic presentation have been termed TTP, while those with more pronounced renal involvement often are referred to as HUS. However, clinical overlap is common and some authors use the combined term TTP/HUS.

The classic pentad of findings, consisting of thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic changes, and renal dysfunction, are seen in only a minority of patients. A high clinical index of suspicion is appropriate because delays in recognition may adversely affect outcomes. Acceptable criteria for a provisional diagnosis include thrombocytopenia and microangiopathic hemolytic anemia in the absence of an alternative cause.

Platelet count is typically less than 100,000/uL.Microangiopathic hemolysis is suggested by the presence of schistocytes on the blood smear. Schistocytes are increased to approximately 4 per field using a 100X oil objective. Laboratory tests indicative of intravascular hemolysis include increased plasma free hemoglobin, decreased haptoglobin, elevated lactate dehydrogenase and hemoglobinuria.

Neurological symptoms include episodes of focal weakness, visual disturbances, reduced mentation or decreased consciousness, headache, seizure, and coma.  Abdominal pain resulting from intestinal and/or pancreatic ischemia may also occur along with nausea, vomiting, and ileus. Even in cases without severe azotemia, renal involvement may be evident, including proteinuria and hematuria.

TTP is classified as primary or secondary depending on whether it occurs on an idiopathic basis or secondary to other medical conditions or treatments.


  • Acute
  • Chronic relapsing (familial)

Secondary (Acquired)

  • Autoimmune diseases
  • Drug-induced - Ticlopidine, clopidogrel, cyclosporine, tacrolimus, quinine and cancer chemotherapy including mitomycin, cis-platinum, gemcitabine, pentostatin
  • Cancer
  • Transplant-related: allogeneic stem cell transplantation
  • Pregnancy/post-partum
  • Infection
  • Toxin-associated (E. coli 0157:H7, Shigella strains)
  • HIV
  • Post-operative

Clinical differences have been reported, including faster response to plasma exchange, lower mortality, and higher relapse rates in idiopathic TTP compared with secondary cases.

Considerable evidence now implicates abnormal processing of vonWillebrand Factor (vWF) in the pathogenesis of TTP. The physiological function of vWF is to link platelets with collagen fibers in the subendothelium that is exposed when endothelial cells are injured, thereby promoting clot formation. Under physiologic conditions, von Willebrand Factor (vWF) is released from endothelial cells as circulating ultra-large molecular weight multimers (ULvWF), which have greater adhesive properties and a greater propensity to promote platelet-platelet and platelet-subendothelial interactions. ULvWF are rapidly cleaved by a plasma metalloprotease, called ADAMTS13, (A Disintegrin-like And Metalloprotease with ThromboSpondin type I motif 13) into smaller molecular weight multimers.

The presence of ULvWF in many patients with TTP/HUS has been attributed to a deficiency of ADAMTS13. More than 50 mutations in the ADAMTS-13 gene, which result in decreased levels of ADAMTS13, have been detected in patients with familial TTP. The mutations are inherited in an autosomal recessive fashion and only homozygotes or compound heterozygotes with a total absence of protease appear to be affected. Parents of TTP patients, who have ADAMTS13 activity as low as 6 -20% are generally asymptomatic. This data suggests that ADAMTS13 activity as low as 5 -10% is sufficient for prevention of microvascular platelet thrombi.

Decreased vWF cleaving activity has also been detected in patients with idiopathic TTP due to the presence of IgG autoantibody inhibitors. The antibody inhibitors decrease enzyme activity by promoting ADAMTS13 clearance or by interfering with its binding to endothelium. These results have illustrated a common mechanism for the pathogenesis of both familial and acquired TTP and also provided an explanation for the differences in reponse to plasma infusion between these two forms of the disease. Plasma infusion is sufficient to replace deficient enzyme levels in familial TTP cases, but plasma exchange is required to replace enzyme and remove inhibitor in acquired cases.  

The value of ADAMTS13 measurements for establishing the diagnosis of TTP and determining the indication for plasma exchange remains uncertain. Although a severe deficiency of ADAMTS13 activity (<10%) in a patient with thrombocytopenia is specific for TTP, it is not predictive of clinical severity. Some patients have the clinical symptoms of TTP with >50% ADAMTS13 activity, while other individuals have had severe ADAMTS13 deficiency for many years without evidence of illness. Also, patients with TTP and severe ADAMTS13 deficiency are remarkably heterogeneous in their clinical severity. These observations suggest that acquired TTP is not caused by ADAMTS13 deficiency alone and may be triggered by other factors that cause autoimmune reactivity to ADAMTS13 and induce endothelial injury or platelet activation.

Determination of ADAMTS13 activity and inhibitor level is helpful in determining prognosis. Severe ADAMTS13 deficiency identifies a subgroup of patients with a high likelihood of response to plasma exchange. An ADAMTS13 level of <5% predicts an 83% reponse rate, while a level of >5% has a 33% rate. Patients with high titer ADAMTS13 inhibitors require a more prolonged course of plasma exchange and have more complications and high risk of relapse. Specimens for ADAMTS13 activity should be drawn prior to transfusion, because blood components artifactually increase ADAMTS13 activity. The circulating half life of ADAMTS13 is 2.6 days. 

Treatment with therapeutic plasma exchange (TPE) has reduced mortality in idiopathic TTP from more than 90% to less than 20%. The only randomized controlled clinical trial in TTP was conducted by the Canadian Apheresis Study Group. This study compared plasma infusion (15 ml/kg) with TPE (1.5 plasma volumes per day for 3 days, followed by 1 plasma volume per day).  Patients treated with plasma exchange had a survival rate of 78% compared to only 63% for the plasma infusion group. Based in part on the results of this study, TPE has become the standard of care for the management of TTP. Plasma exchange is more beneficial than plasma infusion because it permits delivery of much higher plasma volumes without risk of circulatory overload. TPE is believed to work by simultaneously replacing deficient ADAMTS-13 enzyme and removing the IgG inhibitor. 

Once a diagnosis of TTP has been made, TPE should be initiated as soon as possible. If plasma exchange will be delayed for more than a few hours, plasma should be continuously infused at a dose of 15-30 mL/kg until the procedure is started. Daily plasma exchanges with one plasma volume should be performed until the platelet count increases above 150,000/uL for at least 2 days. TPE is stopped without tapering.

The American Society for Apheresis (ASFA) has defined a treatment response as a normal platelet count (>150,000/uL) for 2 days, normal or near normal LDH and stable or improving neurologic deficits. A durable treatment response is one that lasts for at least 30 days after stopping therapeutic plasma exchange. Refractory disease is defined as not treatment response by Day 30 or failure to achieve a durable response by Day 60. Recurrent TTP is defined as an exacerbation of symptoms within 30 days, while relapse occurs after 30 days. The overall published relapse rate is between 30-40%.

Approximately 50% of patients with acquired TTP will achieve a clinical response and an additional 20% may respond by the end of the second week. However, 30% of patients may require up to 4 weeks of daily TPE.

The ideal time to discontinue TPE is not currently known. Discontinuing TPE too early may result in relapse. Guidelines from ASFA and British Committee for Standards in Haematology recommend stopping TPE once a treatment response is achieved. Platelet count, hemoglobin and lactate dehydrogenase (LDH) should be monitored daily throughout the treatment period. LDH level should also be followed closely since it reflects tissue ischemia. Approximately one third of patients may still have schistocytes visible on peripheral blood smear analysis and a slightly elevated LDH.

Although plasma exchange is considered a safe procedure, it should be remembered that complications may occur.  Approximately two thirds of patients have an allergic reaction to plasma. The University of Oklahoma has reported a major complication rate of 26%. Most of the complications were catheter related and included pulmonary hemorrhage, systemic infection, catheter obstruction, venous thrombosis and hypotension. Two percent of patients have died of complications.

The specific type of plasma used for TPE does not impact clinical effectiveness. Fresh frozen plasma, plasma frozen within 24 hours, thawed plasma and cryoprecipitate poor plasma all have similar levels of ADAMTS13 activity and can be substituted without loss of efficacy.

A retrospective study conducted by the US TTP Apheresis Study Group found no statistical difference in the rate of relapse when comparing taper to no-taper apheresis schedules. Adjuvant pharmacological therapy may be necessary in refractory cases. Since the discovery of the autoimmune basis of idiopathic TTP, there has been renewed interest in the use of immunosuppressive therapy. The role of glucocorticoids remains unclear with comparable mortality rates reported in the literature. If not used initially, they are frequently added later if response to plasma exchange is delayed. Another immunosuppressive approach involves the anti-CD20 monoclonal antibody, Rituximab.  The time until remission averages 2 to 5 weeks. Rituximab is removed during TPE and should not be given if TPE is scheduled in the next 24 hours. Splenectomy has also proven successful in preventing relapses, reducing the attack rate from 2.3 +/- 2 events per year to 0.1 +/- .1 events per year.

Antiplatelet agents have not proved to be particularly beneficial in the treatment of TTP and may increase the risk of hemorrhage, particularly with severe thrombocytopenia.  Both ticlopidine and clopidogrel have been associated with induction of autoantibodies to ADAMTS-13, resulting in drug-induced TTP and should not be used as therapy.

Raval JS, e tal. How we approach an acquired thrombotic thrombocytopenic purpura patient. Transfusion. October 2014;54:2375-82. 

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