Paroxysmal nocturnal hemoglobinuria: a study of 17 cases.
Retrospective analysis of 17 cases of paroxysmal nocturnal hemoglobinuria (PNH) was carried out. The presenting feature of anaemia and hemoglobin of less than 9 gm% were observed in all cases. Fever, jaundice and bleeding tendency were observed in 8, 8 and 7 cases respectively. Bone marrow examination revealed megaloblastic features, erythroid hyperplasia and hypocellularity in 8, 7 and 2 cases respectively. Fourteen cases were refractory to the treatment, while only 3 showed response.
Paroxysmal nocturnal haemoglobinuria (PNH) or Marchiafava Micheli Syndrome is characterised by attacks of intravascular hemolysis and haemoglobinuria which may occur at night. This presentation, though classical, is uncommon and patients present more often with chronic intravascular hemolysis or pancytopenia. A retrospective analysis of 17 cases of PNH is presented here.
Case records of 17 cases diagnosed as PNH at the Dr JC Patel Hematology Department of King Edward Memorial Hospital over a period of 10 years from 1979 to 1989 are analysed. The diagnosis of PNE was based on the clinical picture, hemosiderinuria and a positive sucrose lysis test.
Of the 17 cases detected as PNH, 12 were males and 5 females. The age ranged from 14 to 52 years, the average being 26.3 years.
Anaemia as the presenting symptom was found in all the patients and was of 1 month to 6 years' duration (average: 1 year and 3 months). One case presented with fever and jaundice but developed anaemia over a period of 6 months.
In 9 patients anaemia was of sufficient severity to merit blood transfusion and one of the patients had received 17 units of blood before being referred to us.
Low grade, continuous fever without any noticeable diurnal variation was found in 8 cases. Jaundice was seen in 8 cases. Bleeding tendency was observed in 7 cases. Of these 3 had bleeding gums, 3 had petechiae and one had epistaxis. In all these patients peripheral smear showed low platelet count. A history of passing red urine was elicited in 6 cases (35.5%). Hepatomegaly was observed in 3 cases. Splenomegaly was found in 4 patients; in two of them spleen was not palpable at the time of detection of PNH, but gradual increase in splenic size over several months was observed.
Haemoglobin of less than 9 gm% was observed in all the patients either at the first visit or during the follow-up; the range observed at first visit was 1.5-10.3 gm%. Peripheral smears showed hypochromia, microcytosis, anisocytosis and poikilocytosis. Reticulocytosis was observed in 15 cases; 4 showed a count of greater than 15%. The remaining two cases had only megaloblastic bone marrow. Total WBC count was low (less than 1,500/mm ) in 3 patients. Neutropenia with lymphocytosis was found in 9 cases. Bone marrow examination revealed megaloblastic features, erythroid hyperplasia and hypocellularity in 8, 7 and 2 cases respectively. Sucrose lysis was positive in all cases, however, no correlation was observed between the degree of positivity and severity of symptoms. Hemosiderinuria was present in all the patients.
Response to hematinics was not observed in any of our patients. One patient gave a history of passing 'Coca-cola' coloured urine on two occasions when he received iron injections (inferon). Of the 9 patients who received anabolic steroidal injections (decadurabolin) and followed up regularly with us, a mild response was observed in 3 cases. (Hb rise of 2 to 6 gm%.)
Paroxysmal nocturnal haemoglobinuria is an acquired defect at the stem cell level characterized by an inordinate sensitivity to complement which results in an intravascular hemolysis. Since this defect is at the level of the pluripotent stem cells, besides red blood cell (RBC) precursors, platelets and granulocyte series are also affected.
The defect is generally manifested in the 3rd-5th decades; however one of our patients was a 14-year-old girl. Dacie has reviewed 57 cases of PNH; of them, 23 were males and 34 females. Sharma et al have reported six cases from South India, of which 4 were females. In our study a definite male preponderence was observed, 12 of 17 cases being males.
The average interval between onset of symptoms and diagnosis was 1.25 years. Because of its bizarre symptomatology, it is common to miss the diagnosis for a prolonged time. Hence it has been called a 'successful imposter' by Gaither.
Iron deficiency anaemia is commonly observed as a result of blood loss due to haemoglobinuria and accounts for the grossly abnormal RBC morphology, as observed in our patients. Anaemia is variable in severity depending on the number of defective cells. In all our patients haemoglobin of less than 9 gm% was observed and 9 patients required blood transfusion. Veer describes one patient who had symptoms of anaemia for 15 years with six episodes of rapid fall in haemoglobin from 12 gm% to 3-4 gm% necessitating multiple blood transfusion.
Thrombocytopenia was observed in 7 of our patients. Sharma et al have found thromboeytopenia in 2 of 6 cases studied.
Six of our patients gave a history of passing red coloured urine (35.5%). This incidence is higher as compared to the observations made by Wintrobe (26.2% cases). Singh et al have reported two cases of PNH; both were passing high coloured urine. Vigg et al also have reported a case of 36 year old female patient who was initially diagnosed as a case of aplastic anaemia. The diagnosis of PNH was thought only after it was observed that her urine was 'cola' coloured. A positive sucrose lysis clinched the diagnosis.
Two of our patients did not show reticulocytosis but had megaloblastic bone marrow. This explains the absence of reticulocytosis. Pavlic et al also have described absence of reticulocytosis as a result of "megaloblastic crisis". Megaloblastic features were much commoner in our study compared to that reported by Wintrobe. Sharma et al found hypocellularity with erythroid hyperplasia and megaloblastic change in all six patients studied by them. In 2 of our cases hypocellularity was found. Veer reported a case, in whom bone marrow aspiration resulted in dry tap, while trephine biopsy revealed hypocellularity with increased reticulin.
Venous thrombosis is common in PNH but none of our patients gave a history suggestive of thrombosis. Similarly, evolution from PNH to acute myeloblastic leukemia and erythroleukernia has been reported, but was not observed in any of our patients.
After receiving, intramuscular iron injections, one of our patients passed 'Cocacola' coloured urine. Similar observation has been made by Mengel et al which suggests increased hemolysis.
This disease entity may be diagnosed at an early stage and in more number of patients, only if higher index of suspicion is maintained. One must keep the diagnosis in mind while treating cases of refractory anaemias, Coomb's negative hemolytic anaemia, pancytopenia with a cellular marrow, unexplained iron deficiency anemia and venous thrombosis of obscure aetiology.
The author wishes to express his gratitude to Dr GB Parulkar, Dean, King Edward Memorial Hospital and Dr BC Mehta, Hon. Prof. and Head, Department of Hematology, KEM Hospital, Mumbai for permission to use the case records of the department. Thanks are due to all the residents who maintained the records, which were used for this retrospective analysis.