Short Summary

 74-year-old female evaluated for pancytopenia of unknown etiology, which required blood transfusions. Bone marrow aspirate and biopsy showed a hypocellular bone marrow with trilineage maturation. The treatment include immunosuppressive agents and erythropoietin.


Patient's Questions

1. What is the most likely diagnosis?
2. What further clinical tests or examinations would you suggest?
3. What treatment would you suggest?
4. What is the prognosis?




Medical Background

• Bilateral saphenectomy
• Left meniscectomy
• Approximately 3 years ago, polypectomy during colonoscopy
• Osteoporosis and arthrosis

Admitted to the internal medicine department , diagnosed with “pancytopenia and myelodysplasia" (currently in the process of being assigned a histological definition); arterial hypertensionobesity; and unilateral (left) multicystic kidney”.

Following further tests at the day hospital, without reaching any diagnostic certainty as to the pancytopenia (WT-1 gene analysis repeatedly negative;hypo cellular haemopoietic bone marrow with regular trilinear maturation); regular (every 4 days) need for transfusion support for red blood cells and platelets.

In order to obtain a better clinical assessment of the case, initial values are provided, to allow for comparison with a more recent patient hemochrome:
RESULTS (Interval of reference):
Red blood cells 2.46 x106 cells/mcl (4x106–5.6x10cells/mcl)
Haemoglobin 8.8 gr/dl (12-16 gr/dl)
Hematocrit 26.7% (36-48%)
MCV 108.5 fl (81-98 fl)
MCH 35.7 pg/cell (27-33 pg/cell)
MCHC 32.9 gr/dl (31.5-36 gr/dl)
RDW-SD 63.5 fl (37- 54 fl)
RDW-CV 16.3% (11.88-14.32%)
PLATELETS 25,000 platelets/mcl (140,000-440,000 platelets/mcl)
MPV 11.1 fl (9-14 fl)
PDW 12.3 fl (9-17 fl)
P-LCR 32.7% (13-43%)
LEUKOCYTES 3,370 cells/mcl (4,000-10,000 cells/mcl)
NEUTROPHILS 1,310 cells/mcl (1,600-7,400 cells/mcl)
LYMPHOCYTES 1,779 cells/mcl (760-4,800 cells/mcl)
MONOCYTES 279 cells/mcl (80-1,100 cells/mcl)
EOSINOPHILS 0 cells/mcl (8-700 cells/mcl)
BASOPHILES 0 cells/mcl (0-150 cells/mcl)

7 months later:
Red blood cells 2.63x106 cells/mcl (4x106–5.6x10cells/mcl)
Haemoglobin 7.9 gr/dl (12-16 gr/dl)
Hematocrit 23.8% (36-48%)
MCV 90.4 fl (81-98 fl)
MCH 30.0 pg/cell (27-33 pg/cell)
MCHC 33.1 gr/dl (31.5-36 gr/dl)
RDW-SD 49.8 fl (37- 54 fl)
RDW-CV 16.6% (11.88-14.32%)
PLATELETS 36,000 platelets/mcl (140,000-440,000 platelets/mcl)
MPV 11 fl (9-14 fl)
PDW 13.1 fl (9-17 fl)
P-LCR 33.6% (13-43%)
LEUKOCYTES 2,070 cells/mcl (4,000-10,000 cells/mcl)
NEUTROPHILS 728 cells/mcl (1,600-7,400 cells/mcl)
LYMPHOCYTES 1250 cells/mcl (760-4,800 cells/mcl)
MONOCYTES 80 cells/mcl (80-1,100 cells/mcl)
EOSINOPHILS 10 cells/mcl (8-700 cells/mcl)
BASOPHILES 0 cells/mcl (0-150 cells/mcl)

In addition:
Bone marrow needle aspiration report-
“The lymphocytes and monocytes show no phenotypical abnormalities. Blastic levels are within normal limits. The myeloid population would appear to show a slight maturative unbalance with a reduction of the most differentiated component. The erythroblast levels would appear to basically fall within normal limits”.
Erythropoietin 493 mUI/mL.

Last admitted to the department of internal medicine at the hospital, because following a check-up at the day hospital, severe anaemia and thrombocytopenia was reported, with tarry stools in the ampulla of the rectum.
Diagnosis upon discharge was:
-Pancytopenia of uncertain pathogenesis
-Erythematosus gastritis
-Arterial hypertension
-Unilateral (left) multicystic kidney

During the hospital stay:
-Emergency transfusions of concentrated red blood cells and platelets carried out.
-Esophagogastroduodenoscopy performed, reporting erythematosus gastritis without haemorrhaging.
-Improvement of the patient’s condition, and with no further haemorrhaging; repeated blood transfusions.
-Transfusion of platelet concentrates and GRF 2 units.
-Immunosuppressant treatment started with cyclosporine, in view of a hypothesised autoimmune pathogenesis of pancytopenia.

Advised home treatment:
-Sandimmun 100 mg 1 tablet twice a day
-Pantorc 20 mg 1 tablet to be taken in the morning.


Expert's Opinion

It is important that a diagnosis be established between aplastic anemia due to the hypocellular nature of the specimen and a hypoplastic myelodysplastic syndrome. Although both of these entities can be treated with immunosuppressive agents such as ATG and Cyclosporin, it is my opinion that a repeat bone marrow aspirate and biopsy should be performed, including cytogenetic analysis, FISH analysis can be performed on the bone marrow specimen looking for chromosome 5, 7 and 8 abnormalities. In addition, the patient should be evaluated for the possibility of paroxysmal nocturnal hemoglobinuria with flow cytometries looking for the absence of CD55 and the absence of CD59 on granulocytes since this patient is heavily transfused. In addition, the bone marrow should be evaluated for iron stores if there are ring sideroblasts present in the bone marrow that would suggest myelodysplasia. Absence of iron would suggest paroxysmal nocturnal hemoglobinuria. These frequent transfusions may reflect enhanced hemolysis seen in patients with paroxysmal nocturnal hemoglobinuria so I feel that this diagnosis should be evaluated and, again, flow cytometry looking for CD55 and 59 expressions on peripheral blood granulocytes would be in the standard diagnostic approach.

Since the erythropoietin level is elevated it suggests that she is less likely to respond to erythropoietin, nonetheless, I would recommend that erythropoietin be started with weekly treatments. If the patient has a myelodysplastic syndrome then treatment options include the use of Revlimid which can be given especially if there is evidence for (5q) chromosome abnormality. If that is negative, then Vidaza (5 azacytidine) would be an appropriate choice in reducing transfusion requirements. On the other hand, the use of Cyclosporin and ATG is reasonable if this appears to be a hypoplastic myelodysplasia or aplastic anemia, but this would depend on a very good morphological evaluation of a repeat bone marrow, a cytogenetic analysis as well, to identify that diagnosis and, also, to rule-out the possibility of paroxysmal nocturnal hemoglobinuria causing this primary abnormality or resulting in the secondary defect causing the transfusion requirements that you are experiencing.

For now then, I think that additional diagnostic studies are required. The prognosis for this patient, if this is myelodysplastic syndrome, is poor, however, the newer treatments using Revlimid or Vidaza or Dacogen have been very helpful in improving quality of life and reducing transfusion requirements and reducing the time to blast transformation. Aplastic anemia can be treated successfully with Cyclosporin, ATG and prednisone with very good results. So the prognosis is really dependent on the diagnosis that is established. Paroxysmal nocturnal hemoglobinuria can be treated successfully now with a new antibody directed against compliment. This antibody, given weekly, can reduce the transfusion requirements and also reduce the risk of possible thromboembolic complications.