In 1924, Moschcowitz described the fatal case of a 16-year-old-girl who coursed with fever, weakness, transient focal neurologic symptoms, severe thrombocytopenia, and microangiopathic hemolytic anemia. This was the first description of thrombotic thrombocytopenic purpura (TTP), a rare and life-threatening condition. The majority of cases are related to the severe deficiency of ADAMTS-13, the specific Von Willebrand Factor (vWF) cleave protease, most frequently acquired via autoantibodies. TTP is considered as a hematologic emergence because, even with treatment, the mortality rounds 10% to 20%. The differential diagnosis is challenging given their significant overlap in clinical presentation with numerous conditions. Long-term follow-up is necessary to evaluate the sequelae, to identify other autoimmune disorders, and because the tendency to relapse is the rule.
The history behind TTP is exciting and shows the transition from a clinical disorder into a specific condition with exclusive biological criteria: the ADAMTS-13 severe deficiency. ADAMTS-13, a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13, is an enzyme synthesized in the liver able to cleave large vWF multimers.
In physiological conditions, endothelial cells release ultra-large vWF multimers to the circulation. In the blood, these multimers exude high shear forces, and at a critical point, the force unfolds the A2 dominium of vWF. The ADAMTS identify this site and cleave vWF progressively, thus leading to smaller multimers that are less adhesive to platelets.
Some conditions correlate with ADAMTS-13 deficiency and may be considered a risk factor for TTP, such as female sex, obesity, Black ethnicity, and LA-DRB1*11.
In most cases, the mechanism of deficiency is the result of acquired autoantibodies against ADAMTS-13 (known as immune TTP), this is in accordance with the finding of positive anti-ADAMTS-13 IgG in a high percentage of cases during the acute phase. The majority of autoantibodies inhibit the proteolytic activity of ADAMTS-13, limiting its capacity to cleave vWF and thus called inhibitor antibodies. No inhibitors antibodies appear in 10% to 25% of cases; they might enhance the clearance of ADAMTS-13.
Nonetheless, in 25% of cases, the autoantibodies are not present, and the mechanism of enzyme deficiency remains unclear. These can be explained by lack of sensitivity of assays in detecting another form of IgG and immune complexes, degradation of ADAMTS-13 by sepsis enzymes or inhibition by free hemoglobin and interleukins.
Another mechanism of severe deficiency is recessively inherited biallelic mutations of ADAMTS-13 gene, also known as Upshaw-Schulman syndrome (USS) or congenital TTP (cTTP). It accounts for less than 5% of all cases of TTP, representing 33% in childhood-onset and only 2.5% of adult onset. About 150 distinct mutations are reported worldwide.
TTP is an infrequent condition, with an annual incidence of 3 to 11 cases per million people and an annual prevalence of 10 cases per million people. It is predominant in women, with a relation 2:1 to 3.5:1. The peak of incidence is in the fifth decade in the United States; meanwhile, in Europe, its peak is in the third decade.
Autoimmune manifestations and other disorders are related to the disease, especially systemic lupus erythematosus (SLE). The first acute episode affects adults in 90% of cases. In this subgroup, the acquired form is the most frequent. Childhood-onset forms account up to 10%, with the majority of these cases being genetic via recessively inherited mutations. Pregnant women are an exception, as they show a high frequency of inherited forms about 33%, reaching 25% to 66% when considering only the first pregnancy.
ADAMTS-13 deficiency is the cornerstone, lead to accumulation of ultra-large vWF with the formation of platelet-rich microthrombi that can embolize and occlude arterioles. The vWF-platelet aggregates are large enough to obstruct microvessels, thus conduce to the clinical and histopathological changes (microangiopathic hemolytic anemia, thrombocytopenia, and ischemic organ failure). Although deficiency of ADAMTS-13 is necessary to cause TTP, it is not sufficient to induce the clinical syndrome. This was observed in some patients during the long-term, and following they showed a low activity of ADAMTS-13 without the clinical syndrome. The hypothesis of “second trigger” explains that some conditions such as infections, pregnancy, and inflammation increase plasmatic vWF level conducing to overt TTP.
The thrombotic microangiopathies (TMA) 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 with the other forms of TMA as a hemolytic uremic syndrome, where the fibrin is a relevant component. Thrombi are present in all tissues, but lung and liver are less affected because the low shear forces experimented in these low blood pressure system.
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 morphologic abnormalities appreciated in erythrocytes (schistocytes) are secondary to the pass of them through a partially occluded vessel, which exhibits high shear forces.
A high index of suspicion is necessary for a timely diagnosis because the initial findings may be very unspecific and include weakness, headache, confusion, nausea, vomiting, and diarrhea. Patients frequently refer infections in the days to weeks preceding an acute episode. Today, the classic pentad of signs, including fever, impairment of mental status, anemia, thrombocytopenia and renal failure, appear in less than 10% of cases. The more prevalent findings are profound thrombocytopenia (usually less than 30,000 x 10/l) and microangiopathic hemolytic anemia (with schistocytes in blood smear); both are associated with their relative signs (cutaneous and mucosal bleeding, weakness and dyspnea).
The brain is affected in up to 60% of cases with a broad range of symptoms, from a headache and impairment of mental status to ischemic stroke, seizures, and coma. Chest paint and elevated troponin I may be present in 25% of patients and arrhythmias and congestive heart failure might occur, but myocardial infarction is rare.
Mesenteric ischemia might be frequent (up to 25% in some series), the digestive tract involvement can include abdominal pain, nausea, vomiting, and diarrhea. Renal failure requiring replacement therapy is not typical, and their presence may suggest another condition such as a hemolytic uremic syndrome. However, the presence of renal failure does not exclude the diagnosis.
Furthermore, patients may have signs related to another concomitant or previous condition. Approximately fifty percent of patients show an associated clinical condition as bacterial infection, systemic lupus erythematosus, antiphospholipid syndrome, HIV infection, pregnancy, drugs such as quinine, mitomycin C, clopidogrel, ticlopidine, cancer, and organ transplantations. The other 50% is called idiopathic TTP.
In the absence of treatment, patients evolve to multiple organ failures and die within days or weeks.
Reference methods for determinate the ADAMTS-13 activity are complex, and the results usually cannot be available in an emergency setting. Thus the initial management should be started on the basis of clinical presentation. Blood samples for evidence thrombocytopenia (usually counts under 30,000 x 10/L), microangiopathic hemolysis (schistocytes more than 1% in blood smear), ischemic organ injury, ADAMTS-13 activity and presence of autoantibodies should be obtained before initiating the treatment. The direct Coombs test should be negative (except in some cases as SLE), and the coagulation test should not be prolonged. Other biomarkers as troponin and lactate dehydrogenase (LDH) can be helpful to prognosis. In all cases, the hematologist should be consulted.
In a patient with thrombocytopenia and hemolytic anemia, the severe deficiency of plasma ADAMTS-13 activity below 10%, with or without detectable inhibitory autoantibodies is specific for TTP and in the absence of another probable cause. 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, disseminated cancer). In pregnancy, it is very important to discharge conditions as HELLP syndrome, named for the three features of the disease (hemolysis, elevated liver enzyme levels, and low platelet levels) syndrome or Upshaw-Schulman syndrome.
A special comment is necessary to address renal failure; in most of the cases the creatinine level is below 2 mg/dL, contrary to the previous descriptions, and the renal component is modest and might be present with isolated proteinuria or hematuria.
A timely diagnosis and treatment are crucial, and in most of the cases, it is necessary to admit the patient to an intensive care unit for continuous assessment. The presence of an LDH level 1 times the upper normal value, a cardiac troponin level greater than 0.25 ng/mL on diagnosis, and older age are associated with death and treatment refractory. 
The first-line therapy for an acute episode is based on daily therapeutic plasma exchange (TPE). It should be started as soon as possible at 1.5 times the patient plasma volume. When the TPE supply is deficient ADAMTS-13, then remove autoantibodies, immune complexes, vWF multimers, and probably pro-inflammatory cytokines. The therapy is performed daily until the platelet count has stably recovered (greater than 150 x 10 to the power of 9/L for 2 consecutive days) with normal or normalizing LDH and no additional organ dysfunction. In refractory disease, a twice-daily TPE might be useful.
In cTTP regular plasma infusions supply ADAMTS-13. This prophylactic approach is used to avoid the acute episodes. The requirements can vary among patients, and there are no official guidelines to drive the management.
Corticosteroids continue as first-line therapy in conjunction with TPE in the absence of obvious contraindication. The role in acute episodes is related to the autoimmune nature of TTP. The benefits of this intervention include the reduction in the number of sessions of TPE to achieve remission and reduction of treatment-associated complications. Higher doses are preferred to standard doses (methylprednisolone 10 mg/kg/day for 3 days following of 2.5 mg/kg/day compared to 1 mg/kg/day) because they lead to higher remission rate.
The transfusion of platelets is controversial, and the results of studies realized in decades previous to the appearance of the standard of care suggest that this practices might be harmful. However, the majority of evidence was anecdotal, the groups studied were different, and many of them did not evaluate this relationship. Data from the Oklahoma TTP-HUS registry demonstrated no difference in the frequency of dead or severe neurologic abnormalities in patients who received platelets from those who did not. It is important to consider that this evidence should not be used to take a liberal polity for transfusion: the use of platelets should be limited to patients with overt bleeding or before invasive procedures.
Up to 50% of patients are refractory or unresponsive to the first-line therapy. In this situation, the use of rituximab might stop the autoantibody production by killing the ADAMTS-13-specific B cells. Usually, it is administered as 4 weekly doses of 375 mg/m2.
Other drugs like vincristine, cyclosporine A, cyclophosphamide, and Bortezomib could be helpful in refractory cases by suppressing the production of autoantibodies.
Historically the splenectomy showed mixed results; now it would be considered to treat patients who relapse or are refractory to TPE and/or rituximab. This in accordance with evidence that suggests that splenic B cells that produce ADAMTS/13 autoantibodies might escape to anti-CD20 therapy.
A major challenge is the unpredictable risk of relapse, usually occurring 1 or 2 years after the first episode. In patients with low activity of ADAMTS-13, the use of rituximab can reduce the risk of relapse; however, some patients experiment a relapse as late as 20 years, and the harms of treatment should be considered (infusion reactions, hepatitis B reactivation, pulmonary fibrosis and progressive multifocal leukoencephalopathy). Limited comparative studies exist about this topic, but some data suggest that the risk of relapse exceeds the harms of rituximab administration.
Patients who survive an acute episode of TTP are at risk of relapse and long-term morbidity. Thus TTP should be seen as a chronic disease with acute episodes. Many patients experiment a reduced quality of life. Also, their concentration, information processing, rapid language generation, and memory show a significant reduction. These can be related to diffuse subcortical microvascular disease, sequel related to an acute episode. 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. The long-term following should include determination of ADAMTS-13 activity and titles of autoantibodies to identify patients at risk of relapse timely for preventive therapy. There is evidence that the presence of immune complexes and the low activity of ADAMTS-13 are highly predictive of recurrence in the next 2 years of disease onset. Nevertheless, some patients do not develop acute events for years even if undetectable activity persists for a long period. The decision to treat a patient to prevent relapses should consider the severity and frequency of previous episodes. Only patients at high risk should be included in an effort to reduce overtreatment (because some patients never will relapse). In the case of USS, the relapses could be frequent, and patients need regular plasma infusions to avoid new acute episodes, the development of recombinant ADAMTS-13 could change this practices in the next years.
TTP is a systemic disorder which if not promptly diagnosed and managed has a very high morbidity and mortality. Experts recommend that TTP is best managed in an integrated manner with a team of healthcare professionals specializing in neurology, nephrology, hematology, infectious disease and critical care. There is little room for error as the disorder can progress rapidly leading to multiorgan failure. Once the patient is treated, observation and monitoring are critical. Nurses should regularly assess the mental status, urine output, coagulation status, bleeding and vital signs. The patient and the family must be educated on proper care of the intravenous catheters used for plasmapheresis. The pharmacist must be aware of the medication used to manage refractory cases of TTP. When drugs like corticosteroids and vincristine are initiated, the side effects need to be monitored. Close communication with other specialists is vital if one wants to lower the morbidity and mortality. (Level V)
For patients who are managed promptly with plasmapheresis, the outcome is good, but it still carries a 15-20% mortality. Long-term survival is dependent on other comorbidities like renal failure, cancer or chemotherapy for an organ transplant. Patients with comorbidities have a less than 50% survival at ten years. Even patients who survive tend to have at least one relapse. Further, there is evidence that TTP predisposes patients to autoimmune disorders like Sjogren disease or lupus.(Level V)
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