Plasma exchange in thrombotic thrombocytopenic purpura.

Three patients were recently treated for thrombotic thrombocytopenic purpura (TTP). One presented with toxic shock syndrome; TTP developed but promptly responded to a regimen of antiplatelet agents, steroids and plasma exchange. In another the manifestations of TTP developed after presentation with hypertension and abdominal pain. This patient responded to a similar regimen but required extended treatment before remission could be maintained with medications alone. In the third patient the full TTP syndrome appeared after several days of plasma exchange treatment for hemolyticuremic syndrome. He did not respond. It is suggested that TTP may present in many forms initially, that microangiopathic hemolysis may be a late manifestation and that the optimal therapy is not known.     

Extramedullary haematopoiesis in thrombotic thrombocytopenic purpura.

Extramedullary hematopoiesis was detected in routine sections of spleen and liver from two patients with thrombotic thrombocytopenic purpura (TTP). In patients with other types of hemolytic anemia and in normal persons, extramedullary hematopoiesis was not found in spleen or liver. The results of this study raise the possibility that TTP may fit within the myeloproliferative category, perhaps representing an acute variant of Di-Guglielmo Syndrome.     

Apoptotic myocardial degeneration in thrombotic thrombocytopenic purpura

The objective of this study was to determine whether the known myocardial degeneration in TTP is due to apoptosis. In TTP the heart is often involved, including the cardiac conduction system. Despite many platelet occlusions of small coronary arteries, there is little myocardial necrosis. Why the intermittent clinical episodes begin or end is unknown. Six hearts of patients dying with TTP were examined with routine and immunohistochemical stains. In addition to ventricular and atrial myocardium we examined the cardiac conduction system and coronary chemoreceptor. Numerous small coronary arteries were occluded with platelet thrombi in all these sites, including especially the sinus node, AV node and His bundle. The myocardial degeneration we found was conspicuously devoid of inflammation and the myocytes were relatively intact. These characteristics combined with TUNEL-positivity in the degenerating cells are typical of apoptosis. The focal degeneration in TTP is primarily apoptotic. Because circulating serotonin is carried by platelets and is released during aggregation, and because serotonin can cause a powerful cardiogenic hypertensive chemoreflex, we suggest that such a response may dislodge early platelet aggregations. Lessons from TTP may have special relevance for better understanding of myocardial reperfusion problems associated with angioplasty, thrombolysis and ischemic preconditioning.     

Prostacyclin and thromboxane A2 in thrombotic thrombocytopenic purpura.

A study was conducted to find whether a deficiency in prostacyclin (prostaglandin I2; PGI2) is implicated in the pathogenesis of thrombotic thrombocytopenic purpura. Plasma samples from two patients with the disease before treatment and from 22 healthy controls were therefore assayed for concentrations of 6-oxo-PGF1 alpha and thromboxane B2, the stable metabolites of PGI2 and thromboxane A2, respectively. Neither of the patients responded to treatment, which in one case included an infusion of PGI2. Both patients had normal concentrations of 6-oxo-PGF1 alpha and thromboxane B2, thus implying that circulating amounts of PGI2 and thromboxane A2 were also normal. These findings suggest that 6-oxo-PGF1 alpha may be detectable in normal amounts in thrombotic thrombocytopenic purpura and that the condition need not be associated with a high concentration of thromboxane A2.     

Use of plasmapheresis in the treatment of thrombotic thrombocytopenic purpura

A course of diagnostic process and treatment of the young female patient with thrombotic thrombocytopenic purpura is discussed. First sign of the imminent disease was significant fragmentation of peripheral blood erythrocytes. Therapy included vincristine and three plasma exchanges with Fenwal CS 3000 separator with substitution of the freshly frozen plasma. It seems that such a management produced significant improvement and recovery. The authors review literature on the role of plasmapheresis in the treatment of this rare but often fatal disease.     

Gastric carcinoma and thrombotic thrombocytopenic purpura: association with plasma immune complex concentrations.

A patient with metastatic adenocarcinoma of the stomach developed microangiopathic haemolytic anaemia, thrombocytopenia, renal insufficiency, and fluctuating neurological abnormalities in association with appreciably raised plasma concentrations of immune complexes. This syndrome, similar to thrombotic thrombocytopenic purpura, occurred while the tumour was in sustained objective remission after successful treatment with fluorouracil, doxorubicin, and mitomycin. Reversal of the syndrome was achieved with plasmapheresis, azathioprine, corticosteroids, and antiplatelet treatment; this response was paralleled by a reduction in immune complex concentration, suggesting an immune aetiology for the syndrome. Antibodies eluted from the immune complexes reacted with 50% of cells from the gastric cancer but less than 10% of cells from normal gastric mucosa. There was no reactivity with either carcinoembryonic antigen or mitomycin. A 17S immune complex reacted with a glycoprotein from the patient''s autologous platelets and produced platelet aggregation. It is postulated that reducing the tumour and the pre-existing state of antigen excess by chemotherapy allowed soluble antigen-antibody complexes to form and the syndrome to develop.     

Platelet-agglutinating protein p37 from a patient with thrombotic thrombocytopenic purpura has characteristics similar to prethrombin 2

Thrombotic thrombocytopenic purpura (TTP) is characterized by widespread platelet thrombi in arterioles and capillaries. Unusually large or multimeric von Willebrand factor, as well as one or more platelet-agglutinating factors, have been implicated in the pathogenesis of TTP. But, the actual mechanisms of platelet agglutination have not been satisfactorily explained. Recent studies suggested the 37-kDa platelet-agglutinating protein (PAP) p37 to be partially responsible for the formation of platelet thrombi in patients with TTP. We studied mobility in SDS-PAGE, the sequence of N-terminal amino acid residues, DNA and antigenic characteristics of PAP p37, which might be related to the pathogenesis of TTP. PAP p37 was purified from the plasma of a 31-year-old male Korean patient with acute TTP. The findings are as follows: (1) We compared PAP p37 with thrombin through the use of SDS-PAGE, either with or without beta-mercaptoethanol. PAP p37 did not appear to be cleaved between the A- and B-chains of prethrombin 2. However, thrombin did cleave between those of prethrombin 2, but linked with disulfide bridge. (2) N-terminal 21 amino acid sequence of PAP p37 was T-F-G-S-G- E-A-D-X-G-L-R-P-L-F-E-K-K-S-L-E. It appeared to be identical to that of 285-305 amino acid residues of human prothrombin (prethrombin 2). (3) No prothrombin gene DNA mutation was revealed. (4) The antigenicity of PAP p37 was similar to thrombin, which was a result of the competitive binding against the anti-thrombin antibody. With these results, we conclude that PAP p37 has similar characteristics to prethrombin2.     

Acquired idiopathic ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in a population from Japan

Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA). Studies report that the majority of TTP patients present with a deficiency of ADAMTS13 activity. In a database of TMA patients in Japan identified between 1998 and 2008, 186 patients with first onset of acquired idiopathic (ai) ADAMTS13-deficient TTP (ADAMTS13 activity <5%) were diagnosed. The median age of onset of TTP in this group of patients was 54 years, 54.8% were female, 75.8% had renal involvement, 79.0% had neurologic symptoms, and 97.8% had detectable inhibitors to ADAMTS13 activity. Younger patients were less likely to present with renal or neurologic dysfunction (p<0.01), while older patients were more likely to die during the TTP hospitalization (p<0.05). Findings from this cohort in Japan differ from those reported previously from the United States, Europe, and Korea with respect to age at onset (two decades younger in the other cohort) and gender composition (60% to 100% female in the other cohort). We conclude that in one of the largest cohorts of ai-TTP with severe deficiency of ADAMTS13 activity reported to date, demographic characteristics differ in Japanese patients relative to those reported from a large Caucasian registry from Western societies. Additional studies exploring these findings are needed.