Thrombotic Thrombocytopenic Purpura Evaluation and Management

Etiology

The history behind TTP is interesting and shows the transition from a clinical disorder into a specific biological etiology: severe deficiency of "a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13"—more commonly known as ADAMTS-13. ADAMTS-13 is an enzyme synthesized in the liver whose sole purpose is to cleave large vWF multimers into smaller components.[2] In physiological conditions, endothelial cells release ultra-large vWF multimers into the circulation. ADAMTS-13 identifies the A2 binding site in the bloodstream and cleaves vWF to smaller multimers that are less adhesive to platelets.[5][7][8]

In most cases, the deficiency is caused by acquired autoantibodies against ADAMTS-13, also known as immune TTP or iTTP. This is in accordance with the frequent finding of positive anti-ADAMTS-13 IgG during the acute phase of TTP. Most autoantibodies inhibit the proteolytic activity of ADAMTS-13, limiting its capacity to cleave vWF, and are thus called inhibitor antibodies. No inhibitor antibodies appear in 10% to 25% of cases, possibly related to enhanced clearance of ADAMTS-13 instead. Undetectable autoantibodies can also be caused by decreased sensitivity of assays in detecting different forms of IgG or immune complexes, degradation of ADAMTS-13 by sepsis enzymes, or inhibition by free hemoglobin and interleukins.[2]

Drug-induced TTP is sometimes considered a separate entity because it is less likely to be associated with ADAMTS-13 deficiency than other causes. An exception is ticlopidine, associated with reduced ADAMTS-13 levels in 80% of cases.[2]

The less common causes of ADAMTS-13 deficiency are recessively inherited mutations of the ADAMTS-13 gene, also known as Upshaw-Schulman syndrome (USS) or congenital TTP (cTTP). This accounts for 3% to 5% of all cases of TTP, more common in childhood-onset (33%) than in adult-onset (2.5%). About 150 distinct mutations are reported worldwide. The hereditary form is often asymptomatic unless a triggering event such as infection occurs, launching an acute attack.[9][10]

Epidemiology

TTP is an infrequent condition, with an annual incidence of 1.5 to 6 cases per million adults annually. About 90% of cases are in adults and 10% in children. It is more common in women, with an incidence of 2 to 3 times that of men. It is also 8-fold more likely in African Americans compared to White Americans.[2] The peak incidence is in the fifth decade in the United States; meanwhile, in Europe, the peak incidence is in the third decade. Pregnant women and children are much more likely to show a genetic (congenital) cause for TTP than other patients.[11][12]

Pathophysiology

Whether caused by genetics or autoantibodies, TTP is due to the overall decrease in ADAMTS13 (to <10%), thereby allowing its substrate von Willebrand factor to induce clotting.[13] ADAMTS-13 deficiency is the inciting factor, leading to the accumulation of ultra-large vWF complexes with the formation of platelet-rich microthrombi that can embolize and occlude arterioles. The vWF-platelet aggregates are large enough to obstruct microvessels, thus causing clinical and histopathological changes (microangiopathic hemolytic anemia, thrombocytopenia, and ischemic organ failure).

Although a deficiency of ADAMTS-13 is necessary to cause TTP, it is insufficient to induce this clinical syndrome. This was observed in some patients with low ADAMTS-13 activity without the associated clinical symptoms. The hypothesis of a “second trigger” suggests that some conditions (such as infection, pregnancy, or inflammation) increase plasma vWF levels, causing overt TTP.[14] There is also evidence that defective vWF multimers may cause activation of the alternative complement pathway at C3b, as ADAMTS-13 knockout mice can still develop TMA presentations, and increased staining of C3a and C5a has been found in biopsies of patients with iTTP.[2]

Histopathology

Thrombotic microangiopathies (TMAs) are a heterogeneous group of disorders characterized by disseminated thrombus formation in arterioles and capillaries. In the case of TTP, microthrombi are composed of vWF, platelets, and very little fibrin. These findings differ from the other forms of TMA, such as a hemolytic uremic syndrome, where fibrin is a significant component. Thrombi are present in all tissues, but the lungs and liver are less affected because of the low shear forces in these low blood pressure systems. Large vessel thrombosis is not found.[15]

Despite widespread thrombi, tissues exhibit little necrosis, which may suggest that the occlusion is not persistent enough to cause necrosis. This is consistent with the intermittent course of some clinical signs, especially neurological findings. The dominant morphologic abnormality seen on peripheral blood smear is the presence of schistocytes, which are secondary to passing through a partially occluded vessel, causing shear injury.[16][17] Schistocytes are more commonly seen with TTP than with other TMAs.

History and Physical

A high index of suspicion is necessary for a timely diagnosis because the initial findings may be nonspecific and include weakness, headache, confusion, nausea, vomiting, and diarrhea. Patients frequently have a history of recent infection in the days or weeks preceding an acute episode. Today, the classic pentad of fever, impaired mental status, anemia, thrombocytopenia, and renal failure appears in fewer than 10% of cases. The more prevalent findings are profound thrombocytopenia (usually less than 30x10⁹/L) and microangiopathic hemolytic anemia (with schistocytes seen on the blood smear). Both are associated with their relative symptoms of cutaneous and mucosal bleeding, weakness, and dyspnea. Fewer than 10% of patients manifest hemorrhage secondary to thrombocytopenia.[18]

The brain is affected in up to 60% of cases with a broad range of symptoms, from headache and impaired mental status to ischemic stroke, seizures, and coma. Chest pain and elevated troponin I are common, and arrhythmias and congestive heart failure may occur. Myocardial infarction is also a rare but serious complication of TTP. Mesenteric ischemia can be frequent—up to 35% in some series. Other digestive tract involvement includes abdominal pain, nausea, vomiting, and diarrhea. Renal failure requiring replacement therapy is not typical, and its presence may suggest hemolytic uremic syndrome. However, the presence of renal failure does not exclude TTP.[2]

Furthermore, patients may have signs related to another concomitant or previous condition (secondary TTP). Many patients show an associated clinical condition such as bacterial infection, systemic lupus erythematosus (SLE), antiphospholipid syndrome, HIV, pregnancy, drugs (eg, quinine, mitomycin C, clopidogrel, ticlopidine), cancer, and organ transplantation.[2]

Evaluation

Reference methods for determining the ADAMTS-13 activity are complex, and the results are not always readily available in an emergency setting. Thus, initial management should be started based on clinical presentation. Blood testing will likely show profound thrombocytopenia (counts <30x10⁹/L), microangiopathic hemolysis (schistocytes >1% in a blood smear), decreased ADAMTS-13 activity, and the presence of autoantibodies to ADAMTS-13. The direct Coombs test should be negative (except in some cases of SLE), and the coagulation test should not be prolonged. Other lab abnormalities include decreased haptoglobin, increased reticulocytes, elevated LDH, and elevated indirect bilirubin.[19][20][21][22] 

In a patient presenting with both thrombocytopenia and hemolytic anemia, the critical diagnostic indicator for acquired thrombotic TTP is an ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity level below 10%, whether or not inhibitory autoantibodies are detectable. This finding is specific for TTP and signifies the absence of another probable underlying cause for these clinical manifestations.

Clinical response is defined as platelets >150x10⁹/L and LDH <1.5 times the upper limit of normal. Clinical remission is a sustained clinical response longer than 30 days after the final plasma exchange. Refractory TTP is persistent severe thrombocytopenia with levels <50×10⁹/L and LDH >1.5X upper limit of normal after 5 plasma exchange treatments and appropriate steroid use.

Treatment / Management

The first-line therapy for an acute episode is based on daily TPE started as soon as possible at 1.5 times the patient's plasma volume. If TPE does not improve ADAMTS-13 levels, removing autoantibodies, immune complexes, vWF multimers, and proinflammatory cytokines may be necessary. TPE is performed daily until the platelet count has stably recovered (150x 10⁹/L for 2 consecutive days) with normalizing LDH and no additional organ dysfunction. In refractory disease, twice-daily TPE may improve parameters.

In cTTP, regular plasma infusions supply ADAMTS-13. Plasma infusions alone are not considered adequate for treating TTP but can be used as a stopgap measure until plasma exchange is available.[1] Some studies have found that transfusion of platelets can worsen symptoms of TTP, so the use of platelets should be limited to patients with overt bleeding or before invasive procedures.[23](B3)

Corticosteroids continue as first-line therapy in conjunction with TPE in the absence of contraindications. The role in acute episodes is related to the autoimmune nature of TTP. The benefits of this intervention include a reduction in the number of sessions of TPE to achieve remission and a reduction of treatment-associated complications. Higher doses are preferred to standard doses because they lead to a higher remission rate.

Up to 50% of patients are refractory or unresponsive to the first-line therapy. In this situation, rituximab may inhibit autoantibody formation from B-cells specific to ADAMTS-13. Rituximab is a monoclonal antibody target against the antigen CD20, which is present on B-cells. Usually, it is administered in 4 weekly doses. Rituximab has a low incidence of adverse effects but can take up to 2 weeks to show clinical improvement.[3] Other drugs like vincristine, cyclosporine A, cyclophosphamide, and bortezomib could also be helpful in refractory cases by suppressing the production of autoantibodies.

Splenectomy is considered effective in treating patients who relapse or are refractory to TPE and rituximab. This is in accordance with evidence that suggests that splenic B-cells that produce ADAMTS-13 autoantibodies might escape anti-CD20 therapy.

Caplacizumab, a humanized immunoglobulin derived from llamas, is the first medication approved specifically to treat TTP. Its main limitations are the high cost and minor bleeding events. It prevents platelet binding to vWF multimers but does not address the underlying ADAMTS-13 deficiency. Therefore, it is usually used in conjunction with TPE and steroids.[3] Another potential therapeutic agent on the horizon is the production of recombinant ADMATS-13.[3]

In cases of secondary immune-mediated TTP, the underlying condition must be treated in addition to the TTP. In patients who are pregnant, TPE and steroids are the mainstays of treatment, as other immunosuppressants have not been studied in this population.

A significant challenge is the unpredictable risk of relapse, usually occurring 1 or 2 years after the first episode. In patients with low ADAMTS-13 activity, the use of rituximab can reduce the risk of relapse. However, some patients experience a relapse as late as 20 years, and the harms of treatment should be considered (infusion reactions including death, hepatitis B reactivation, pulmonary fibrosis, and progressive multifocal leukoencephalopathy). Limited comparative studies exist on this topic, but some data suggest that the risk of relapse exceeds the harms of rituximab administration. 

Differential Diagnosis

The differential diagnosis is challenging and extensive, and the following should be considered: Evans syndrome, antiphospholipid syndrome, disseminated intravascular coagulation (DIC), HUS (especially in patients with pronounced renal failure), and other causes of TMA (drugs, hypertension, malignancy). In pregnancy, it is essential to consider HELLP syndrome (hemolysis, elevated liver enzyme levels, and low platelet levels) or Upshaw-Schulman syndrome (cTTP), which can manifest for the first time during pregnancy.

Complications

Even with treatment, complications can be significant, and morbidity ranges from 10% to 20%. Neurological deficits, acute kidney injury, and bleeding complications are frequent. Microthrombi can also affect other organ systems, such as cardiovascular, pulmonary, and gastrointestinal. Treatment-related reactions (primarily to TPE) include hypotension, anaphylaxis, fluid overload, and hypocalcemia from citrate administration.

Long-term complications are thought to be common, possibly related to the chronic nature of the disease. Long-term neurologic manifestations are especially common, including decreases in concentration, information processing, rapid language generation, and memory. These can be related to diffuse subcortical microvascular disease from multiple acute episodes. Furthermore, in long-term follow-up, patients show a higher prevalence of arterial hypertension, depression, and mortality; however, the origin of these conditions remains unclear, and other comorbidities could be related.[3][2]