Thrombotic Thrombocytopenic Purpura

In Her Blood
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Diagnosis and reasoning

The patient who presents following a first seizure is not an uncommon encounter in the emergency department; similar to other emergencies, the initial priority should always be assessment, resuscitation, and stabilization. In parallel, the most common causes of seizure should be rapidly ruled out; these include electrolyte and metabolic disturbances, central nervous system (CNS) infections, cerebrovascular accidents, and drug overdose/poisoning. Given the history of hypertension, hypertensive encephalopathy (HE) should also be considered. However, there are no clinical findings which particularly favor the above entities, while the initial battery of tests is also negative. That said, her examination does reveal several worrisome findings: jaundice, pallor, and widespread petechiae; a follow up complete blood count (CBC) and blood film are mandatory. The CBC confirms the presence of moderate anemia and severe thrombocytopenia; the blood film is even more alarming, demonstrating the presence of numerous schistocytes. Note that this suggests at a microangiopathic hemolytic anemia (MAHA); this is further supported by the indirect hyperbilirubinemia, elevated lactate dehydrogenase (LDH) and reduced Haptoglobin levels, and the reticulocytosis seen in the blood smear. Relatively few conditions can give rise to MAHA in association with thrombocytopenia; the most prominent of these are Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS), Disseminated Intravascular Coagulation (DIC), and malignant hypertension. Differentiation between the above conditions requires the judicious use of investigations, including a renal assay and coagulation profile. TTP immediately presents itself as a likely candidate, given the presence of the classic pentad of MAHA, thrombocytopenia, elevated renal functions, neurologic disturbances, and fever. While there is a significant overlap in clinical findings between HUS and TTP, patients with the former typically experience far more severe renal impairment, while prominent neurologic manifestations are rare. Furthermore, in HUS, there is often an antecedent history of diarrhea, while the most patients tend to be of a younger age. DIC is also unlikely given the normal coagulation profile; nor is malignant hypertension probable, given the minimally elevated blood pressure, and absence of other features suggestive of a hypertensive emergency. It should be appreciated that certain drugs have also been implicated as a cause of MAHA; however, Amlodipine has not been identified as one of these. Thus, TTP does indeed appear to be the diagnosis; while it is advisable to confirm this via estimation of ADAMTS13 activity levels, it should be noted that results are usually not available acutely. TTP is a hematological emergency which is ideally treated in a specialist center; plasma exchange is the mainstay of therapy and should be commenced as early as possible; this should be combined with corticosteroids. As the pathophysiology of TTP is related to platelet aggregation leading to microthrombi, certain guidelines recommend the use of antiplatelet agents (e.g. Aspirin); however, they are best commenced during platelet recovery (e.g. when platelet counts are >50,000/mm3). Note that therapy with Sodium Nitroprusside is an option in malignant hypertension; it is potentially deleterious in this anemic patient, as it may lower tissue perfusion.


Discussion

Thrombotic thrombocytopenic purpura (TTP) is one of the thrombotic microangiopathies (TMAs), a group of diseases characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and the occlusion of small vessels by thrombi. The condition is rare, with a reported incidence of approximately 6 cases per million persons per year in the United States. TTP can be broadly divided into an inherited form and an acquired form; the vast majority of cases fall into the latter category. Individuals with acquired TTP develop inhibitory autoantibodies (usually IgG) against ADAMTS13, a metalloprotease which cleaves large multimers of circulating von Willebrand factor (vWF) into smaller units. The resultant increase in "ultralarge" vWF multimers predisposes to increased platelet aggregation at sites of high shear stress - particularly the microcirculation; as might be obvious, this also results in a thrombocytopenia. Subsequently, the widespread microthrombi cause microangiopathic hemolytic anemia (MAHA) due to shearing of erythrocytes. Most cases of acquired TTP are idiopathic in origin; a minority of cases appear to be associated with pregnancy, infections (such as HIV), and the use of drugs such as quinine, simvastatin, trimethoprim, or PEGylated interferon. Inherited TTP is less common; this is due to mutations in the ADAMTS13 gene. Both alleles must be usually affected for clinical manifestations to occur; persons with mutations affecting a single allele are generally asymptomatic. This form of the disease has a variable phenotype and can present at any age, although as a rule of thumb, the more severe the disease, the earlier the presentation. Note that certain individuals may only present in conjunction with an additional trigger (e.g. pregnancy). TTP was originally classified by the pentad of fever, fluctuating neurological signs, renal impairment, thrombocytopenia and MAHA; however, many patients present without the full pentad. In particular, fever and renal impairment may not be prominent, while over one-third of patients do not demonstrate signs of neurological dysfunction (such as confusion, headache, paresis, aphasia, dysarthria, visual problems, or encephalopathy). However, marked thrombocytopenia is often present, with counts frequently as low as 10,000/mm3 to 30,000/mm3; hemoglobin levels are often between 8 to 10 g/dL, while lactate dehydrogenase (LDH) levels are usually elevated, and Haptoglobin levels reduced. The diagnosis of TTP is based on the combination of clinical findings, and investigation results (particularly a blood film demonstrating schistocytosis, indicating the presence of MAHA). ADAMTS13 activity assays help confirm the diagnosis, with most patients demonstrating levels less than 5% of normal. Tests for anti-ADAMTS13 autoantibodies may help in distinguishing between the inherited and acquired forms of the disease. TTP is a hematological emergency; once diagnosed, the patient should be referred to a specialist center for treatment as soon as possible. Plasma exchange (PEX) is the cornerstone of management, as this both replenishes levels of ADAMTS13, while additionally clearing the circulation of anti-ADAMTS13 IgG antibodies. While the exact regimens used vary by unit, there is general agreement that they should be guided by the patient's clinical status, platelet count, and LDH levels. As the patient recovers, PEX should be tapered slowly (as sudden withdrawal may result in clinical deterioration). Note that a definitive diagnosis of TTP is not mandatory to commence PEX; the presence of MAHA and thrombocytopenia in absence of other identifiable causes is adequate. High dose steroids should be administered in conjunction, as this appears improve patient outcomes, with minimal side effects. As the pathophysiology of TTP involves increased platelet aggregation, the use of antiplatelet agents (e.g. Aspirin, Dipyridamole) should theoretically improve outcomes; while their clinical efficacy is still unproven, certain guidelines suggest that they may be used during platelet recovery (i.e. when counts are >50,000/mm3). In patients who show a poor response to the above measures, or if cardiovascular or neurological complications occur, intensification of PEX, or further immunosuppressive therapy with Rituximab should be considered. Important supportive measures include folate supplementation during active hemolysis, and red cell transfusion where there is clinical need. Note that due to the risk of potentially precipitating further thromboses, platelet transfusion is best avoided unless life-threatening bleeding occurs. In the era before PEX, the mortality of TTP was as high as 90%; it has now decreased to between 10% to 30%; the earlier the initiation of therapy, the better the outcome. Unfortunately, between 20% to 50% of cases experience a relapse; this is defined as the recurrence of of acute TTP symptoms 30 days after achieving remission. This is more likely in patients who, even after entering remission, have low plasma ADAMTS13 activity (<10%) or persistent anti-ADAMTS13 antibodies.


Take home messages

  1. While TTP has traditionally been characterized by the pentad of MAHA, thrombocytopenia, fever, neurological disturbances, and renal impairment, many patients present without the full complement.
  2. Plasma exchange is the mainstay of management and should be commenced as soon as possible; the presence of MAHA and thrombocytopenia in the absence of other identifiable causes is sufficient justification for this.
  3. Platelet transfusion may potentially provoke further episodes of thrombosis and should be avoided unless life-threatening bleeding is present.

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