Thrombotic thrombocytopenic purpura (TTP) is an uncommon but serious disorder of young adults. The disorder is characterized by thrombocytopenia, hemolytic anemia due to red cell fragmentation, and a combination of clinical findings, including CNS dysfunction, fever, and renal failure.

The laboratory and clinical manifestations are the results of microvascular thrombotic lesions, which characterize this disease. TTP and hemolytic uremic syndrome (HUS), primarily a pediatric disorder, can be grouped as thrombotic microangiopathies.90 Pathologically, there is hyperplasia of endothelial cells in arterioles and capillaries, along with hyaline and platelet-rich thrombi in these vessels, and occasional microaneurysms. These endothelial cells release von Willebrand factor multimers, which may play a role in the pathogenesis of TTP.92,93

The pathologic changes of TTP are most common in the brain, pancreas, kidney, heart, spleen, and adrenal glands,94 but may be found throughout the body. The brain stem vessels and the cortical gray matter are often affected.

Epidemiology and clinical presentation

The peak incidence of TTP occurs in persons in their thirties and occurs twice as often in women as in men. Evidence suggests a genetic susceptibility to the development of thrombotic microangiopathies manifesting as TTP or HUS in siblings.95–98

TTP is characterized by the pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, renal dysfunction, and fever.93 Hemorrhages appear most often as purpura and retinal hemorrhages.

About half of TTP patients present with neurologic symptoms, and 90% develop neurologic manifestations during the course of the disease.90,100 Central nervous system involvement frequently presents as fluctuating focal neurologic deficits (from transient small vessel occlusions with recanalization) and changes in the level of consciousness, from either nonconvulsive status epilepticus (see below), or underlying metabolic disorders. These common neurologic symptoms may develop and progress rapidly. Other neurologic manifestations can include headache, cranial nerve palsies, dysphasia or aphasia, paresis, confusion, stupor, coma, and seizures.

Etiologies and risk factors for seizures

Focal or generalized seizures occurred in approximately 20% of TTP patients observed.99 Seizures can be associated with TTP for several reasons:

  • Vascular damage in cortical regions, creating a seizure focus or foci
  • Metabolic imbalance (e.g., uremia, hyponatremia, fever)90,101–103
  • Cerebral hemorrhage due to thrombocytopenia102
  • Other concurrent factors that may cause seizures independently of TTP (e.g., TTP-like infections, drugs such as cyclosporine A or FK506,100 connective tissue diseases, and cancer)

Nonconvulsive status epilepticus (NCSE) can mimic a common manifestation of TTP marked by fluctuating mental status and level of consciousness. TTP patients are at increased risk for NCSE, which tends to develop after generalized tonic-clonicseizures.100,104,105 Having other underlying medical complications with severe encephalopathy places patients at additional risk for NCSE. Garrett and colleagues reported that among TTP patients examined, at least 10% had NCSE.104 The test of choice for confirming a diagnosis of NCSE, which is a treatable condition, is EEG.

Evaluation

TTP must be included in the differential diagnosis of any patient with intravascular hemolysis caused by red cell fragmentation. A number of findings can help to establish the diagnosis of TTP:

  • The reticulocyte count is increased and correlates with the severity of the anemia.
  • Hemolysis laboratory parameters are typical.
  • Lactate dehydrogenase levels and platelet count are sensitive indicators of the response to therapy.
  • Proteinuria, microscopic hematuria, mild azotemia, and abnormalities on liver function tests are common.
  • Cerebrospinal fluid usually reveals increased protein levels and xanthochromia; less often, it is bloody.
  • Brain CT scans show characteristic multiple hypodense lesions.106,107
  • Biopsy of skin, gingivae, and bone marrow may be examined for hyaline thrombi within arterioles.108,109 (Biopsies are diagnostic in only about half of cases and are not specific, however.)

Differential diagnosis

Eclampsia in pregnant women may present with similar manifestations. It may be associated with low-grade intravascular coagulation but has a favorable prognosis.

Other mimickers of TTP include severe idiopathic thrombocytopenic purpura with autoimmune hemolytic anemia, and systemic lupus erythematosus with immune thrombocytopenic purpura and vasculitis. TTP can occur in lupus patients, however, and often carries a poor prognosis. Some authors100,104 emphasize the importance of EEG in these cases to rule out NCSE. An EEG is particularly indicated for patients with persistent or recurrent confusion and stupor, especially after a clinically overt seizure.

Treatment of TTP

More than 80% of patients who are treated aggressively with exchange plasmapheresis now survive the initial episode of TTP,93,109,110 Presenting conditions cannot predict definitively which patients have favorable outcomes, however. The therapeutic effects of plasmapheresis in the critically ill patient with TTP are often dramatic: Severe neurologic manifestations may disappear, and laboratory abnormalities may diminish in a few hours. In a controlled prospective therapeutic trial of this disease, plasma exchange was significantly more effective than infusion without exchange.111 Platelet transfusions should be avoided because they have been accompanied by marked deterioration in either renal or neurologic status.112

Treatment of seizures

The treatment of seizures in TTP is the same as for seizures with other complicated hematologic disorders:

  • If a reversible cause is identified, no treatment is necessary.
  • Benzodiazepines can be given acutely.
  • The nature of chronic treatment depends on the type of injured systems.

If renal function is severely impaired, medications that are metabolized in the kidney—gabapentin, levetiracetam, oxcarbazepine, topiramate, and vigabatrin—are probably not good choices.

Agents that can potentially cause thrombocytopenia, hemorrhage, or bone marrow suppression, such as valproic acid and carbamazepine, are more risky. Side effects of medications (e.g., topiramate, phenobarbital) that are associated with cognitive side effects and sedation may be difficult to differentiate from the fluctuating confusion of symptoms underlying the basic disease.

The side effect profiles of lamotrigine and phenytoin seem somewhat better for these concerns, but if phenytoin is prescribed, protein binding needs to be considered. In the context of proteinuria or hypoalbuminemia, the bound fraction of phenytoin may decrease (normally, 90% of phenytoin is bound) and the unbound fraction increases, which in turn can cause toxicity. Thus, the free phenytoin levels need to be monitored. The therapeutic range of free phenytoin is 1–2 mg/mL.

Adapted from: Sepkuty JP and Kaplan PW. Hematologic and pulmonary disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;209–228.
With permission from Elsevier (www.elsevier.com). 

Reviewed by: Steven C. Schachter, MD on 4/2004
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