Abstract
Abstract 4239
Paroxysmal Nocturnal Hemoglobinuria (PNH) is associated with clonal expansion of stem cells with an acquired somatic PIG-A mutation. The PIG-A gene is essential for the biosynthesis of glycosylphosphatidylinositol (GPI), and mature blood cells derived from the PNH stem cell clone exhibit a loss of all proteins that require this structure for attachment to the cell surface, notably the complement inhibitors CD55 and CD59. The loss of these proteins on the surface of red cells is responsible for hemolysis, and thrombosis may be the consequence of the loss of these proteins from the surface of platelets: both hemolysis and thrombosis can be attenuated by anti-complement therapy. Thrombosis can occur, however, despite anticomplement therapy and despite anticoagulation and has been historically the most important determinant of death in patients with PNH. Some patients will present with thrombosis and some patients will not be candidates for anticoagulation or anticomplement therapy: therefore treatment of thrombosis remains an important part of the management of PNH patients. Thrombolysis with tissue plasminogen activator (tPA) in PNH has been reported in small series or case reports, generally with encouraging outcomes. Here we report what we believe to be the largest series on the outcome of the use of tPA. Of 38 patients with PNH who had at least one thrombotic event, 13 were thought to have had a thrombus sufficiently recent to be amenable to fibrinolysis; of these, 4 patients were regarded as ineligible on account of active hemorrhage or high risk of hemorrhage. Of the 9 eligible patients who received tPA, all of whom had potentially life-threatening thromboses, 3 also required tPA on subsequent hospitalizations, and the results of a total of 15 hospitalizations during which tPA infusions were given are reported here. tPA was given in the ICU by systemic infusion through a peripheral vein at a dose of 1 mg/kg delivered over 24 hours, with anticoagulants withheld temporarily during this time. Response was monitored by follow-up imaging, and most patients required several 24 hour infusions. Platelets were given for thrombocytopenia and FFP was given to reverse oral anticoagulation or when low circulating plasminogen was documented. On all 15 occasions a radiologically documented response was obtained, including reversal of thrombosis in hepatic veins, portal veins, the IVC, cerebral dural venous sinuses, and an intrahepatic portocaval shunt. Among the 15 courses of tPA, serious hemorrhagic complications developed in 3 cases. At last follow-up visit, of the 9 patients treated, 3 have expired, one patient (who has been non-compliant with post treatment anticoagulation and anticomplement therapy) was in good clinical condition despite extensive residual occlusions, and 5 others were in good to excellent condition in terms of clinical and radiological outcome. The only patient in whom tPA may have contributed to a fatal outcome also had complications of ‘heparin induced thrombocytopenia with thrombosis’ (HITT), which we diagnosed in a milder form in 3 additional patients. The other two fatalities were associated with bowel edema (probably due to progressive small vessel thrombosis) in one case, and a progressive concurrent myeloproliferative disorder associated with a JAK2 mutation in the other case. On the other hand, we feel tPA must be credited as having been immediately life-saving in 2 patients who had been moribund with Budd-Chiari syndrome, and in one who had impending renal failure associated with an IVC thrombosis. Given the high incidence of HITT, we favor the use of direct thrombin inhibitors or fondaparinux rather than heparin products in patients with PNH. Given the high mortality and morbidity associated with thrombosis in PNH patients, and given the excellent radiographic responses, we conclude that, in spite of the risk of hemorrhage, thrombolysis is strongly indicated to reverse intra-abdominal and intracranial thromboses.
Disclosures:
No relevant conflicts of interest to declare.
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