This document summarizes the case of a 32-year-old woman presenting with excessive menstrual bleeding, fatigue, and shortness of breath. Initial testing revealed pancytopenia and hepatosplenomegaly. Bone marrow biopsies showed erythroid hyperplasia and later signs of early myelofibrosis. The patient was ultimately diagnosed with primary myelofibrosis, a rare chronic myeloproliferative neoplasm characterized by bone marrow fibrosis and abnormal growth of blood cells.

1. A Case of Menorrhagia
Dr Jishanth M
Prof Dr A Gowrishankar’s Unit
M3, Dept of Internal Medicine, SMC

2. PATIENT PROFILE
• Ms Latha, 32 yr, unmarried, admitted on 4.9.10
• Presenting Complaints:
Easy fatigability-2months
Breathlessness-2months
Excessive menstrual bleeding-1week

3. • History of Present illness:
• Insidious onset, gradually progressive exertional
breathlessness and fatigability for 2 months
• Pedal edema and puffiness of face +
• Excessive menstrual bleeding for last 7 days with
passage of clots
• H/o joint pain involving both elbows+
• H/o head ache +

4. • No rash, bleeding gums, swelling of joints, bone
pain, fever, night sweats, cough with expectoration,
hemoptysis, chest pain, orthopnoea, PND
• No h/o jaundice, abdominal distension,
hematemesis, melena
• No h/o easy bruisability or uncontrolled bleeding
after trivial trauma

5. • Past medical history:
Admitted at GRH in Feb ’09
• Similar complaints with bleeding gums and arthralgia (Δ:
Iron def anemia), received blood transfusion
• Discharged after complete evaluation with advice for
follow up.
Admitted at RSRM in May ’10
• Excessive bleeding, severe than previous episode, received
blood transfusion, was reevaluated.
• No diabetes, hypertension, RHD, tuberculosis or recurrent
jaundice

6. • Personal History:
• Menarche at 12 yrs,
• Regular cycles 3-4/30days
• Menorrhagia(10/30) with clots for last 6 months
• Family history:
• Born of non consanguinous marriage,
• No bleeding disorders

7. • On Examination:
• Patient was conscious, oriented
• Afebrile, moderately built, poorly nourished
• Dyspnoeic and Tachypnoeic
• Pallor++, facial puffiness +
• No J/Cy/Cl/LNE
• No rash, no petechiae, ecchymosis, hemarthroses
• Mild bilateral Pedal edema +
• No bone tenderness

8. • Vitals
• PR: 90/min, regular
• BP: 110/70 mm Hg
• RR: 24/min
• CVS: S1S2 heard, systolic murmer +
• RS: NVBS b/l, no added sounds
• Abdomen: soft, normal in shape
• No dilated veins, liver palpable 2 cm, firm, non tender
• Splenomegaly(8cm), firm, smooth, non tender
• CNS: No FND, no meningeal signs, fundus N

9. • Provisional Diagnosis:
• Anaemia with Hepatosplnomegaly
• To R/o hematological Malignancy

10. Investigations
• Hb: 3.3 g%
• TC:2600
• DC: P80l18E2
• ESR: 70/95 mm
• PCV: 11%
• Platelet: 33,000
• Sugar: 84
• Urea: 22
• Creatinine: 0.8
• Na: 132
• K: 3.6
• Bleeding Time: 2 min 30s
• Clotting time: 4 min 30s
• CXR: mild cardiomegaly,
↑BVM
• ECG: Sinus rhythm,
tachycardia+

11. Peripheral Smear
• RBCs:
Microcytic, hypochromic RBCs
No nucleated RBCs seen. No sickle cells.
No target cells. No inclusion bodies
• WBCs:
Leukopenia observed
Distribution and morphology normal
No immature cells seen
• Platelets: Thrombocytopenia
• Parasites: No blood parasites

12. • Pancytopenia + Hepatosplenomegaly
• Chronic Infections
• Thalassemias
• Hemoglobinopathies
• Sideroblastic Anemia
• Iron Deficiency (IDA)
• Myelofibrosis

13. What happened in feb 2009
• BT/CT Normal
• CXR: Cardiomegaly
• Usg Abd: Splenomegaly
• Echo: Normal Study
• Stool occult blood: Negative
• Peripheral Smear: Microcytic
hypochromic, ovalocytes+
ellipsocytes+, WBCs normal,
platelets adequate
• Reticulocyte count: normal
• Bone Marrow: Erythroid
hyperplasisa
Hb 5.6 8.0
TC 5200 5900
DC P53L45E2 P58L40E2
ESR 75/120 9/19
Plt 1.56 1.3
Diagnosis: Nutritional anemia/Iron deficiency
with CCF

14. In may 2010
Date 30/4 4/5 5/5 6/5 8/5 20/5
Hb 3.0 4.8 6.2 5.0 8.4 10.4
PCV 9% 15% 18% 15% 25%
TC 4800 4900 4900 5200 3300
DC P80L18E2 P83L15M2
Platelets 33,000 95,000 2.0L 1.1L 14,000
• PT 12.2s/ INR 0.94
• APTT 28.9s
• TFT: Normal
Sr Bb 3.1mg% /
D Bb 0.5mg%
Sr Protein: 6.6g
Alb: 3.4g
SGOT 35 U/L
SGPT 30 U/L
SAP 285 U/L

15. • Diagnosis:
Pancytopenia/ HSM/ Iron deficiency anemia
• She was discharged once general conditions
improved with advice to have a follow up.

16. Investigations contd
• PT 12.6 s/ INR 1.0
• APTT 26.2s
• HBsAg, Anti HCV negative
• HIV negative
• Mantoux test: Negative

17. • LFT Bb: 2.9mg%
D Bb: 2.2mg%
• Protein: 6.1 g%
• Alb: 3.2 g%
• RFT/SE: normal
• USG & portal doppler: Splenomegaly, normal
doppler study
• Reticulocyte count: 1.8%
• Stool occult blood: negative

18. • Hematologist & Rheumatologist opinions
were obtained…
• BMA(8/9/10)
• Adviced to screen for connective tissue
diseases

19. • ANA: negative
• CRP: 13.3 mg/L (<5 mg/L negative)
• RA Factor: negative
• Coombs Test:
DCT Negative
ICT negative

20. • BMA(8/9/10):
Erythroid hyperplasia
• RBC count: 1.06 million
• MCV: 72.6fl ↓ (76-96)
• MCH: 15.1pg ↓ (27-31)
• MCHC: 20.8 ↓ (32-36 %)
• RDW: 22.9 ↑ (11.5-14.5 %)
• Serum Iron: 10.8μg/dl ↓ (37-145)
• Serum Ferritin: 2.35ng/ml ↓ (13-150)
• TIBC: 334.0 μg/dl N (149-491)
• Hematologist review: Severe iron deficiency anemia
• Advised further serum assays.

21. • Serum Vit B12: 737.4 pg/ml N (211-946)
• Folic Acid: 5.85 ng/ml N (3.1-17.5)
• Serum LDH: 267 IU/L N (150-400)
• Hemoglobin Electrophoresis:
Hb F : not detectable (<1%)
Hb A2: 2.8 (2-3.7%)
Hb A: 94 (>95%)
Impression: normal

22. • Peripheral Smear was repeated
• RBCs:
Normocytic hypochromic
Spherocytes +
Occassional teardrop cells +
• Platelets decreased
Giant platelets + (7-8μ)

23. • On 14th
BMA was repeated:
• Hypercellular, mild erythroid hyperplasia
• Megakaryocytes +, Atypical cells 5%
• Dyserythropoiesis+
• Micromegakaryocytes+

24. • Based on this report a bone marrow biopsy was
done on 17th
:
• Cellular marrow showing preponderance of
granulocyte precursors including eosinophil
precursors, plasma cells, megakaryocytes, large
histiocyte like cells with abundant eosinophilic
cytoplasm and vesicular nucleus and foci of
fibrosis
• Imp: Early cellular phase of myelofibrosis

25. Final Diagnosis
Primary Myelofibrosis
(Prefibrotic stage)

26. Anemia Suspected
Thorough Clin, Bleed Hb%, RCC, Hct Decreased
RPI, Retic count <2 RPI, Retic count >2
Hemolytic Anemia
Coombs DAT, IDAT
Hb electrophoresis
Osmotic fragility
MCV, MCH, MCHC, PSE
Microcytic hypochromic Macrocytic hypo/normo
Megaloblastic NormoblasticIron Def. Anemia
Ferritin, TIBC, BM Fe
Thalassemia, Hb pathy
Sederoblastic Anaem.
Chr. Infection, Lead
Folate defici.
B12 def., PA
Ca, Leukemia, Ulcer
Identify the cause
ALD, CLD, Drug
Chr. Renal dis.
Hypothyroid
BM infiltration
Acid hemolysis
Cold agglutinins
Coagulopathy, DIC
Algorithm for Diagnosis of Anemia

27. WHO Operational Categories

28. Primary Myelofibrosis
(Myelofibrosis with Myeloid Metaplasia)
• First described in 1879
• Later classified in 1951 as a myeloproliferative disorder
• Agnogenic myeloid metaplasia/Idiopathic myelofibrosis
• Myeloproliferative disorders include
1. Chronic myeloid Leukemia(Ph)
2. Polycythemia Vera
3. Essential Thrombocytosis
4. Primary Myelofibrosis
In 1960 -Philadelphia chromosome, Ph(t9:22) (BCR-ABL)
In 2005- JAK2V617F- a novel GOF mutation of JAK2 tyrosine
kinase- in PV(100%), ET & PMF (50%)

29. Primary Myelofibrosis
• It is a rare disease
• 1.3/100,00 people
• Median age 57yrs (90% are >40)
• Ashkenazy Jews
• Clonal stem cell disorder
• Classified as chronic myeloproliferative disorder
• WHO system- CIMF( chronic idiopathic myelofibrosis )
• Myeloid metaplasia refers to earlier proliferative
phase where extramedullary hematopoiesis
predominates
• <5% of ET go to MMM after 10-20 years

30. Pathogenesis
Clonogenic mutations
?JAK2 tyrosine kinase
?Thrombopoietin receptor

31. Pathogenesis

32. Clinical features
• Chronic, idiopathic progressive
anemia/thrombocytopenia
• Extramedullary hematopoiesis - HSM
• Splenomegaly is the hallmark
• Constitutional hypercatabolic syndromes (Fatigue,
fevers, weight loss, night sweats)- ultimately go for
cachexia.
• As spleen enlarges, pts may have left upper quadrant
discomfort, abdominal pain & early satiety

33. • Pruritus, easy bruising, lymphadenopathy
• Peripheral edema, ascites
• Bleeding/thrombosis
• Splenic infarcts
• EMH—LN, pleura, peritoneum, lung, paraspinal &
epidural spaces
• Secondary gout
• All myeloproliferative disorders can result in a
spent phase which can be difficult to distinguish
from primary MF

34. Diagnosis
• Peripheral blood smear
• normocytic anemia
• granulocytes and platelets.
• myelophthisis (most characteristic finding)
• leukoerythroblastosis (nucleated RBCs and granulocyte
precursors)
• teardrop-shaped RBCs (dacryocytes)
• Bone Marrow:
cellular phase(↑granulocytic and MKcytic,
↓erythrocytic )
hypocellular phase
fibrosis/osteosclerosis- usually dry tap
• Confirmed by bone marrow biopsy( reticulin stain)

35. Bone Marrow Features
• Ineffective erythropoiesis
• Dysplastic-megakaryocyte hyperplasia (secrete
PDGF, TGF-β, VEGF, bFGF, TNF)
• Increase in ratio of immature to total granulocytes
• Reactive bone marrow fibrosis (polyclonal
fibroblasts)
• Thickening and distortion of the bony trabeculae
(osteosclerosis)
• Bcr-abl negative

36. Normal Bone Marrow

37. Tefferi A. N Engl J Med 2000;342:1255-1265
Myelofibrosis
Peripheral Blood Bone Marrow

38. Bone marrow in myelofibrosis
H&E Stain Reticulin stain

39. Tear Drop Cells
1. Myelofibosis
2. Infiltration of BM
3. Tumours of BM
4. Thalassemia

40. Proposed Modifications in Diagnostic Criteria
MAJOR
1. Atypical megakaryocytic
hyperplasia with
reticulin/collagen fibrosis
2. Exclusion of WHO criteria
for PV, CML, MDS, Other
MPDs
3. JAK2V617F or other clonal
marker, if not rule out
seconadary fibrosis
MINOR (2 out of 4)
1. Leukoerythroblastosis
2. Elevated serum LDH
3. Anemia
4. Palpable splenomegaly

41. Diagnostic Problems
• Neither myelophthisis nor marrow fibrosis is diagnostic
• Myeloid / Lymphoid / Non hematological disorders
• Close mimickers are
 CML
 MDS
 Atypical MPD
 AML
 Specific tests include
• JAK2V617F screening
• cytogenetics
• FISH for BCR-ABL

42. Disorders causing myelofibrosis
Malignant
• Acute leukemia
• CML
• Hairy cell leukemia
• Hodgkin Disease
• Idiopathic myelofibrosis
• Lymphoma
• Multiple myeloma
• Myelodysplasia
• Metastatic carcinoma
• PV, ET
Nonmalignant
• HIV Infection
• Hyperparathyroidism
• Renal osteodystrophy
• SLE
• Tuberculosis
• Vit D deficiency
• Thorotrast exposure
• Gray platelet syndrome

43. Disease Course
• As disease progresses majority of patients become
transfusion dependent ( 2U in 7-14 d)
• Thrombocytopenia/neutropenia
• Spenomegaly and discomforts
• Symptomatic portal hypertension
• Bone pain
• Non thrombotic pulmonary hypertension
• Blastic transformation ~ 10% (2.6 month)
• Death: infection, bleeding, heart failure, liver failure,
portal htn, respiratory failure

44. Prognosis
• Median survival 3-5 yrs
• Adverse prognostic factors:
Anemia, Age >64
Hypercatabolic sx (wt loss, fatigue, NS, fever)
WBC>30 or <4, Blasts>1%
Cytogenetics +8, 12p-
• Most recent PSS (Mayo clinic)
Plt < 100 x10⁹/L
Hb <10 g%
TLC <4 or >30 x10⁹/L
Ab. Monocyte >1 x10⁹/L
 Median survival in pts <60 yrs 14.4/5/2.2 yrs

45. Treatment
• There is no definitive therapy –
“WATCHFUL WAITING”
• Rx is supportive, with PRBC transfusions
• Drug therapy
• Splenectomy
• Radiation therapy
• Allogenic SCT

46. Drug therapy
• Erythropoietin – 40,000 U weekly (endo Epo <125 U/L),
response rate is 50%
• Corticosteroids, prednisone .5-1mg/kg (52/29%)
• Androgens: Testo. Enanthate 400-600 mg im/wk, (30-
40%)
• Androgens + corticosteroids
• Danazol – synthetically modified testo.- 600 mg/d (30-
40%)
• Thalidomide(50mg/d) & Lenalidomide in del5q
( improves splenomegaly & thrombocytopenia)
• Hydroxyurea - DOC for symptomatic SM
• Cladribine/ Melphalan / Busulphan/ Daunorubicin

47. Splenectomy
Indications for surgery:
1. Symptomatic portal hypertension
2. Drug refractory splenomegaly with machanical
& hypercatabolic symptoms
3. Frequent transfusion requirement

48. Radiation Therapy
• Useful mainly for non hepatosplenic extra
medullary hemopoiesis in PMF
• Thoracic vertebral column- most frequent
site
• Other sites: LN, lung, pleura, small bowel,
peritoneum, urogenital tract and heart
• Idiopathic Pulm htn (due to occult pulmonary
EMH)- single fraction whole lung irradiation

49. Allogenic Stem Cell Transplantation
• Risk benefit ratio is not favorable
• But young patients have survival upto 60% at 5 yrs
( comp. to 14% in >44 yrs)

50. Back to our patient
• 32 yr, unmarried, menorrhagia, chronic anemia….of
late we have diagnosed a disease with poor PSS where
the treatment to date is ineffective
• Pending investigations are bone marrow iron staining
cytogenetic analysis
• Patient is now on
1. Danazol 200mg TDS
2. Prednisolone 10 mg OD
3. Folic Acid 5 mg OD
4. FST/Multivitamins
5. PRBC transfusions

51. Future
• Current treatment is inadequate…
• Each patient is different, response to therapy
also different.
• Eagerly looking for “small-molecule drug
therapy” targeting JAK2 or its downstream
effector molecules (STAT3, STAT5)
• Imatinib did wonders…. Future looks
promising

52. References
• Harrisons Principles of Internal medicine 17th
Ed
• Robbin’s Pathology
• Wintrobe’s Hematology