What are the typical symptoms of Thrombotic Thrombocytopenic Purpura (TTP)?

The presenting symptoms of TTP are markedly variable. Vomiting or diarrhea prevails in the classic forms. Many patients present with nonspecific symptoms such as malaise and weakness. Hypertension is often present. Patients may exhibit neurologic signs and symptoms of Thrombotic Thrombocytopenic Purpura after a few days of preliminary illness, which are classically multifocal and transient, but recurrent in nature and can include headache, cranial nerve palsies, hemi paresis, dsyphasia/aphasia, confusion, stupor, coma, and seizures. Bleeding is frequent at presentation, often involving the gastrointestinal tract.

Regardless of the main symptoms at presentation, laboratory studies invariably indicate anemia and a variable degree of renal involvement in patients with Thrombotic Thrombocytopenic Purpura. Anemia is the result of intravascular hemolysis (red cell destruction), with evidence of increased bilirubin (red bile pigment). Fragmented red blood cells (schistocytes with typical helmet and burr cells) may be visible in the peripheral blood smear, as well. Hemolysis (destruction of red blood cells) is also indicated by the serum LDH concentration, which may be increased to extremely high levels and reflects ischemic (anemia due to obstruction of the blood supply) injury to multiple organs, as well as red cell destruction. The increase in LDH is the most sensitive index of ongoing hemolysis, and is usually associated with hyperbilirubinemia (increased bile in the blood mainly direct) and low haptoglobulin levels. The reticulocyte count is increased to a degree proportionate to the severity of the anemia. Moderate neutrophilia (increased white blood cell count) is present.

Thrombocytopenia (decreased platelets) is more severe in Thrombotic Thrombocytopenic Purpura than Hemolytic Uremic Syndrome, and is caused by peripheral destruction, as indicated by a very short platelet survival time. Most patients have platelet counts below 50,000/muL. [LDH levels and platelet count are sensitive indices of the patient’s response to therapy.] Intravascular platelet aggregation results in the reduced platelet survival and determines the thrombotic occlusion of the small arterioles and capillaries. Coagulation changes are found less consistently, but may include prolongation of the prothrombin time and elevated levels of fibrin-degradation products, especially when TTP is associated with bacterial infections such as E. coli O157:H7.

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Renal Involvement in Patients with Thrombotic Thrombocytopenic Purpura:

A high percentage of patients classified as having Thrombotic Thrombocytopenic Purpura have renal (kidney) failure. In a study involving 15 patients with TTP, published by Eknoyan (1986), 12 cases (80%) had some degree of elevation of BUN (blood urea nitrogen) or creatinine level at some time during the course of their disease, which was of three types: severe and dominant renal insufficiency (acute renal failure - ARF); variable and less severe renal insufficiency; and with mild Thrombotic Thrombocytopenic Purpura, renal involvement consisting of abnormal urine sediment and uremia (azotemia) that improved rapidly following fluid replacement. 

Eknoyan indicated that “it is to be expected that the kidney, as the most vascular organ in the body, should be involved in a disease process in which the major pathologic feature was recognized from the outset as widespread microvascular thrombi.” In his study, the most common finding in all of the 15 patients was an abnormal urinary finding, such as Hematuria, white blood cells, proteinuria, casts (hyaline), and elevated specific gravity, as well as some degree of elevation of BUN and creatinine at some time during the course of the primary disease.

Remuzzi (1987) indicates that since Gasser first described cortical necrosis in the kidneys of children with Hemolytic Uremic Syndrome, there have been three patterns of renal lesions described that occur as a result of thrombotic microangiopathy. In the first, glomerular lesions of the microangiopathic type predominate as commonly seen in young children with HUS; in the second, arterial involvement is prevalent and this is seen in older children and adults; and in the third, both glomerular and arterial involvement are evident in the same patient.

In the study by Conlon et al. (1995), 44% of patients presented with an elevated serum creatinine, and 16% required hemodialysis support. In five of the patients who subsequently expired, microvascular fibrin/platelet thrombi were found in peripheral ancillary loops, glomerular hilar arterioles, and in extraglomerular vessels. These studies clearly indicate that renal involvement in patients with TTP can be substantial.

CNS (Neurologic) Involvement in Thrombotic Thrombocytopenic Purpura:

In the study published by Silverstein (1968), involving over 300 patients with Thrombotic Thrombocytopenic Purpura, 90% of the patients had neurologic involvement and the illness began as a neurologic one in 60% of the patients. Additionally, he pointed out that since 1947, almost all reviewers of this disease reported that the initial neurologic manifestations were transient, fluctuating and diagnostic for TTP. The neurologic features of this disease have been attributed to histologic observations of cerebral thrombi in varying stages, with development of collateral circulation when particular vessels are occluded, persistence of some patent vessels to a given area of the brain, and the rarity of cerebral infarction despite extensive thrombi. In those patients who undergo angiographic studies, the neuropathologic changes (occlusions of small vessels, small infarcts, and petechial hemorrhages) usually occur in the gray matter and are diffuse.

As previously mentioned, the nature of the neurologic signs and symptoms can include varying degrees of mental syndromes, from confusion to stupor and coma, hemi sensory findings and even seizures. Changes in mental function are noted to be the most frequent initial neurologic manifestation of Thrombotic Thrombocytopenic Purpura, but are less clinically apparent in children than in adults. Contrary to the findings of others, Silverstein found that less than 50% of the patients that he studied had significant improvement. Some patients seemed to have typical transient ischemic attacks. There were no correlations at all between the absence or presence of neurologic improvement and the reported neuropathologic findings.

In a more recently published study by Bakashi (1999), on 12 patients with Thrombotic Thrombocytopenic Purpura, clinical neuroimaging revealed a variety of brain lesions, which included reversible cerebral edema lesions which resembled RPLS (reversible posterior leukoencephalopathy syndrome) and were seen in patients with hypertension and renal dysfunction. Patients with edema alone (no strokes or hematomas) had a favorable neurologic outcome. However, TTP has also been associated with strokes (involving the posterior cerebral artery, middle cerebral artery, and cerebellar territories) indicating that large and/or small-vessel involvement can occur, as well as hemorrhagic infarctions. These patients were noted to have a poorer outcome.

Cardiac Involvement in Thrombotic Thrombocytopenic Purpura:

Since TTP is a diffuse disease involving virtually every organ in the body, and because some of the patients studied had cardiac rhythm disturbances, as well as sudden cardiac arrest, it was important to investigate the potential effects of this disease on the heart and the conduction system. 

In 1966 James and Monto undertook a study of the conduction system in three patients dying with Thrombotic Thrombocytopenic Purpura. Each had sudden convulsions at some time in the illness and one had documented episodes of complete “conduction block” (atrioventricular dissociation) and cardiac arrest that occurred with the seizures. In one patient, there was a very rapid heart rate (sinus tachycardia) which was out of proportion to the degree of anemia or fever that was present, and another had evidence of atrial rhythm disturbance (atrial tachycardia). Consideration was given to the fact that lesions in the vasoregulatory centers of the brain could lead to disturbances in cardiac rhythm and conduction abnormalities, just as arrhythmias and conduction disturbances (which result in generalized hypoxia to all organs), may result in hypoxia of the brain, thereby, precipitating neurologic events (seizures) in the central nervous system. When the heart of these patients was studied at necropsy, some of the characteristic manifestations of TTP were evident; in one patient, there were numerous epicardial petechias, particularly over the right atrium, a majority of the local arterioles were occluded to some extent, and multiple focal hemorrhages were present in the conduction system (sinus node, AV node, Bundle of His).

In 1979, Bell et al. studied the relationship between the heart lesions of Thrombotic Thrombocytopenic Purpura and clinical cardiac dysfunction in 17 autopsied patients. Thirteen patients had extensive small-vessel thromboses and in some instances there were hemorrhages and focal necroses within the heart. Serial sectioning of the cardiac conduction system in ten patients revealed microthrombi in seven and associated hemorrhages in five. One patient showed changes consistent with an inferior myocardial infarction of indeterminate age. Epicardial, mural, and sub endothelial petechia were noteworthy gross findings in the majority of the hearts examined. In one patient who had clinical symptoms of myocardial ischemia (chest pain) there was only mild thrombotic myocardial disease found at autopsy, suggesting that the symptom of myocardial ischemia was most likely related to the patient’s anemic state and high-output cardiac status. The findings in this study were similar to that of James and Monto, that thrombi and hemorrhages are common findings in the conduction tissues in patients with TTP and may account for transient rhythm disturbances, myocardial infarction and cardiac arrest. Just as critically placed thrombi in the vital regulatory centers of the central nervous system (brain) may lead to sudden death, so might the lesions within the cardiac conduction system.

Webb et al. published a study in 1990 in which four patients with Thrombotic Thrombocytopenic Purpura developed severe cardiac dysfunction and when end myocardial biopsy was performed in one patient, focal myocarditis was demonstrated and associated with platelet microthrombi formation. A fourth patient died secondary to extensive intramyocardial hemorrhages.

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