Paroxysmal Nocturnal Hemoglobinuria a Specific Test for the Disease Based on the Ability of Thrombin to Activate the Hemolytic Factor

By WILLIAM H. CROSBY, MAJOR, MC, AUS P AROXYSMAL nocturnal hemoglobinuria (Marchiafava-Micheli syndrome) is a rare form of chronic hemolytic anemia characterized by the presence of abnormal erythrocytes which are susceptible to lysis by a factor normally present in plasma or serum. It has recently been suggested that this factor resembles closely or may even be identical with the coagulation accelerator globulin.’ This globulin exists in blood as an inert proenzyme which is activated by thrombin. Numerous tests have been proposed for the laboratory diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). I. Hemosiderinuria was noted by Marchiafava” as being constantly present in the 2. cases of PNH which he studied. The importance and ease of this test has recently been emphasized by Stats, Wasserman and Rosenthal.t3 They point out, however, that hemosiderin is occasionally lacking in the urine of patients with PNH and is occasionally found in other types of hemolytic anemia. We have also found that hemosiderinuria is present in every patient with hemolytic anemia associated with hemoglobinemia.2 Conversely, in a patient with PNH of six years’ duration the usual hemoglobinemia, hemoglobinuria and hemosiderinuria all disappeared completely following a severe transfusion reaction which occurred ten months previously. The test is therefore not specific. 2.. “Heat sensitivity.” Micheli first observed intensification of the PNH hemolytic reaction in vitro as the temperature was increased.’2 Heggelin and Maier suggested that this phenomenon might be adapted to a specific test for PNH.8 However, the test is by no means specific. The blood from cases of hemolytic anemia associated with a hemolysin antibody shows marked hemolysis in vitro at 37 C. at 6 hours, provided that the antibody is sufficiently potent. 3. Acid hemolysis. Hijmans van den Bergh first noted intensification of hemolysis of PNH cells in acidified serum.9 This phenomenon has been intensively studied,3’ 6, 10 and although no explanation has been proposed it is a very characteristic feature of the hemolytic mechanism. T. H. Ham has standardized a diagnostic test involving this reaction.* The acid-hemolysis test when done according to his detailed instructions is pathognomonic of PNH. Ham lists the following specific points for diagnosis7: