A Case of Menorrhagia

Dr Jishanth M

Prof Dr A Gowrishankar’s UnitM3, Dept of Internal Medicine, SMC

PATIENT PROFILE

• Ms Latha, 32 yr, unmarried, admitted on 4.9.10

• Presenting Complaints:Easy fatigability-2monthsBreathlessness-2monthsExcessive menstrual bleeding-1week

• 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 +

• 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

• 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

• 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

• 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

• 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

• Provisional Diagnosis:

• Anaemia with Hepatosplnomegaly• To R/o hematological Malignancy

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+

Peripheral Smear• RBCs:

Microcytic, hypochromic RBCsNo nucleated RBCs seen. No sickle cells. No target cells. No inclusion bodies

• WBCs: Leukopenia observedDistribution and morphology normalNo immature cells seen

• Platelets: Thrombocytopenia • Parasites: No blood parasites

• Pancytopenia + Hepatosplenomegaly

• Chronic Infections• Thalassemias• Hemoglobinopathies• Sideroblastic Anemia• Iron Deficiency (IDA)• Myelofibrosis

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

In may 2010Date 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: 6.6gAlb: 3.4gSGOT 35 U/LSGPT 30 U/LSAP 285 U/L

• Diagnosis:

Pancytopenia/ HSM/ Iron deficiency anemia

• She was discharged once general conditions improved with advice to have a follow up.

Investigations contd

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

• 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

• Hematologist & Rheumatologist opinions were obtained…

• BMA(8/9/10)• Adviced to screen for connective tissue

diseases

• ANA: negative• CRP: 13.3 mg/L (<5 mg/L negative)• RA Factor: negative

• Coombs Test:DCT NegativeICT negative

• 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.

• 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

• Peripheral Smear was repeated

• RBCs: Normocytic hypochromicSpherocytes +Occassional teardrop cells +

• Platelets decreasedGiant platelets + (7-8μ)

• On 14th BMA was repeated:

• Hypercellular, mild erythroid hyperplasia• Megakaryocytes +, Atypical cells 5%• Dyserythropoiesis+• Micromegakaryocytes+

• 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

Final Diagnosis

Primary Myelofibrosis (Prefibrotic stage)

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

WHO Operational Categories

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 Vera3. Essential Thrombocytosis4. 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%)

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

Pathogenesis Clonogenic mutations ?JAK2 tyrosine kinase ?Thrombopoietin receptor

Pathogenesis

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

• 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

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 phasefibrosis/osteosclerosis- usually dry tap

• Confirmed by bone marrow biopsy( reticulin stain)

Bone Marrow Features

• Ineffective erythropoiesis• Dysplastic-megakaryocyte hyperplasia (secrete

PDGF, TGF-, 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

Normal Bone Marrow

Tefferi A. N Engl J Med 2000;342:1255-1265

Myelofibrosis Peripheral Blood Bone Marrow

Bone marrow in myelofibrosis

H&E Stain Reticulin stain

Tear Drop Cells

1. Myelofibosis

2. Infiltration of BM

3. Tumours of BM

4. Thalassemia

Proposed Modifications in Diagnostic Criteria

MAJOR1. 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. Leukoerythroblastosis2. Elevated serum LDH3. Anemia4. Palpable splenomegaly

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

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

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

Prognosis

• Median survival 3-5 yrs• Adverse prognostic factors:

Anemia, Age >64Hypercatabolic sx (wt loss, fatigue, NS, fever)WBC>30 or <4, Blasts>1%Cytogenetics +8, 12p-

• Most recent PSS (Mayo clinic)Plt < 100 x10⁹/LHb <10 g%TLC <4 or >30 x10⁹/LAb. Monocyte >1 x10⁹/L

Median survival in pts <60 yrs 14.4/5/2.2 yrs

Treatment

• There is no definitive therapy – “WATCHFUL WAITING”

• Rx is supportive, with PRBC transfusions

• Drug therapy• Splenectomy• Radiation therapy• Allogenic SCT

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

Splenectomy

Indications for surgery:

1. Symptomatic portal hypertension2. Drug refractory splenomegaly with machanical

& hypercatabolic symptoms3. Frequent transfusion requirement

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

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)

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 OD3. Folic Acid 5 mg OD4. FST/Multivitamins5. PRBC transfusions

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

References

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