Transcript PCV with B Thalassemia Intermedia by Suzanne Santos Medical
THE PARADOXICAL RBC
MEDICINE GRANDROUNDS December 2, 2010 Presented by: Suzanne V. Santos, M.D.
Moderator: Jesus A. Relos, M.D., FPCP
Objectives
1. To discuss the diagnostic approach in a patient presenting with erythrocytosis and thrombocytosis.
2. To present an unusual case of Beta Thalassemia intermedia with possible concurrent polycythemia vera.
3. To discuss the pathophysiology, diagnosis and treatment of polycythemia vera and beta thalassemia and their risk for thrombotic events.
General Data
A.B. 56 year old male Seaman
Chief Complaint
Headache
History of Present Illness
14 years PTC elevated BP 150-160/80 (1995) occasional headache Consultation done: Dx. Hypertension stage II
10 years PTC (2005)
Dx: Dyslipidemia Hyperuricemia
History of Present Illness
3 months PTC
occipital headache, (Oct. 2009) throbbing, grade 5-6/10 consultation: CBC: elevated Hgb (19.3), Hct (60) Blood volume studies Referral to hematologist
Review of Systems
No fever No weight loss No loss of appetite No dizziness No nausea/vomiting No easy bruisability No bleeding tendencies No mouth sores No skin rashes No hair loss
Past Medical History
Hypertensive for 14 years Usual BP 120-130/80, Highest BP 160/90 Maintenance: Losartan 100mg/tab, 1 tab OD Amlodipine 10mg/tab, 1 tab OD Imidapril 10mg/tab, 1 tab OD Chronic Kidney Disease x 1 year, Rx: Sodium Bicarbonate 650mg/tab, 1 tab BID Dyslipidemia for 10 years Simvastatin 80mg/tab, 1 tab ODHS Hyperuricemia for 10 yrs, on Allopurinol 300mg/tab 1 tab OD
Personal/Social History
Non-smoker
Occasional Alcoholic Beverage Drinker
No history of Illicit Drug Use
Family History
Unremarkable
Physical Examination
BP: 130/90, CR: 74 bpm regular, R: 20 cpm, 36.8
C T: Ht: 167.64 cm, Wt: 68 kg, BMI: 24 kg/m 2 General appearance: conscious, coherent, not in cardiorespiratory distress, ambulatory, oriented to 3 spheres Skin: flushed, moist skin, no rashes over face or body HEENT: plethoric, pink palpebral conjunctivae, anicteric sclerae, no nasoaural discharge, no cervical lymphadenopathy, no palpable neck mass, thyroid not enlarged
Physical Examination
CHEST and LUNGS: symmetrical chest expansion, no retractions, clear breath sounds, no crackles or rhonchi, no wheeze HEART: quiet precordium, apex beat at 5 distinct heart sounds th ICS left mid clavicular line, regular rate and rhythm, no murmurs. No S3, No S4 gallop, S1>S2 apex, S2>S1 base, JVP at 9 cm, ABDOMEN: Flabby abdomen, soft, nontender, normoactive bowel sounds, no hepatosplenomegaly EXTREMITIES: no cyanosis, no edema, full and equal pulses, no nail changes, no tender or swollen joints Neurological Examination: essentially normal
Salient Features
56 year old male Headache Elevated blood volume studies 14 yrs history of elevated BP 10 yrs history of hyperuricemia Non smoker Plethoric Hgb 19.3, Hct 60
Initial Clinical Impression
Myeloproliferative Disorder probably Polycythemia Vera Hypertensive Cardiovascular Disease Dyslipidemia Hyperuricemia Chronic Kidney Disease probably secondary to Hypertensive Nephrosclerosis
Definition of Terms
Hemoglobin (Hgb): concentration of the major oxygen-carrying pigment in whole blood; tetramer consisting of a pair of α -like chains and β -like chains Hematocrit (HCT): percentage of a sample of whole blood occupied by intact red blood cells.
RBC count: number of red blood cells contained in a specified volume of whole blood.
Erythrocytosis: increased red cell mass Polycythemia: hemoglobin, red blood cell (RBC) count, and total RBC volume are all above normal.
Definition of Terms
Hemoglobin (Hgb): concentration of the major oxygen-carrying pigment in whole blood; tetramer consisting of a pair of α -like chains and β -like chains Hematocrit (HCT): percent of a sample of whole blood occupied by intact red blood cells.
RBC count: number of red blood cells contained in a specified volume of whole blood.
Erythrocytosis: increased red cell mass Polycythemia: any increase in red cells
Definition of Terms
MCV
: volume of the average circulating RBC
MCH:
hemoglobin content of the average circulating RBC
MCHC
: hemoglobin concentration within circulating RBC
Microcytosis:
MCV < 80
Macrocytosis
MCV >100
Hypochromia:
low values of MCH and MCHC
Problem: Erythrocytosis & Thrombocytosis
DATE 2/3/09 2/10/09 2/19/09 Hgb Hct RBC WBC Segs
lymph 20
eos
1 monos 8
Plt MCV MCH
334K
MCH C RDW
19.3 H 17.60 H 14.5
60 H 55.90 H 46.8
7.92
7.47 H 6.27
9.86
76 10.54
65 9.55
65 25 23.6 L 31.5 L 30 9 1 2 459K H 427K 74.8 L 74.6 L 23.1 L 31 L 17.3 H 15.8 H Phlebotomy: 1 st consult (2/3/09) 3 rd 10 th consult (2/5/09) consult (2/12/09)
Complete Blood Count
2/11/10
Problem: Erythrocytosis & Thrombocytosis
Cranial CT scan without contrast: (Feb. 16, 2010)
Suspicious small infarct, anterior limb of the right internal capsule. Microvascular disease.
Atherosclerotic disease of the vertebro-basilar and internal carotid arteries.
Problem: Erythrocytosis & Thrombocytosis
WHO Classification of Chronic Myeloproliferative Disorders (Neoplasm)
Chronic Myelogenous Leukemia Chronic Idiopathic Myelofibrosis Essential Thrombocytosis Polycythemia Vera
Problem: Erythrocytosis & Thrombocytosis
WHO Classification of Chronic Myeloproliferative Disorders
Chronic Myelogenous Leukemia • • • 9q34 Chronic Idiopathic Myelofibrosis translocation between chromosome Polycythemia Vera BCR gene on chromosome 22q11 with the ABL gene on chromosome • • • Detection of BCR-ABL Gene Fusion by FISH (4/12/10): 1% found positive normal WBC high LAP score at 189 elevated WBC, plt count low LAP score
Problem: Erythrocytosis & Thrombocytosis
WHO Classification of Chronic Myeloproliferative Disorders
Chronic Myelogenous Leukemia Chronic Idiopathic Myelofibrosis Polycythemia Vera • marrow fibrosis, extramedullary hematopoiesis, splenomegaly • Blood smear: teardrop-shaped red cells, nucleated red cells, myelocytes, promyelocytes
Patient
•
Bone Marrow Biopsy
done 3/31/10
A.B. 56/Male
10-2949 BM
Scanner 4x
Low Power Objective, 10x
High Power Objective 40x
High Power Objective 40x
Problem: Erythrocytosis & Thrombocytosis
Bone Marrow, Core Biopsy and Aspirate Smears (3/31/2010)
Normocellular bone marrow (40-50%) with orderly trilineage hematopoiesis.
Problem: Erythrocytosis & Thrombocytosis
WHO Classification of Chronic Myeloproliferative Disorders (Neoplasm)
Chronic Myelogenous Leukemia Chronic Idiopathic Myelofibrosis • • Essential Thrombocytosis Polycythemia Vera
Patient
• Platelet count not consistently elevated • • mild neutrophilic leukocytosis normal or elevated LAP score • Bone marrow biopsy reveals megakaryocyte hyperplasia and hypertrophy with increase in marrow cellularity • • elevated LAP score Normal bone marrow biopsy
Problem: Erythrocytosis & Thrombocytosis
Polycythemia Vera Study Group (PVSG)
increased red blood cell mass (red cell volume > 36ml/kg) or increased hgb or hct Disorders causing secondary erythrocytosis are absent.
PVSG criteria: two basic criteria plus 2 of the ff.: Platelet count >400,000/microL White blood cell count >12,000/microL LAP score greater than 100 Presence of a JAK2 gene mutation Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation
Problem: Erythrocytosis & Thrombocytosis
Polycythemia Vera Study Group (PVSG)
increased red blood cell mass (red cell volume > 36ml/kg) or increased hgb or hct Disorders causing secondary erythrocytosis are absent.
PVSG criteria: two basic criteria plus 2 of the ff.: Platelet count >400,000/microL White blood cell count >12,000/microL LAP score greater than 100 Presence of a JAK2 gene mutation Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation
Complete Blood Count
Problem: Microcytic and Hypochromic RBC
Hgb Electrophoresis
Problem: Microcytic and Hypochromic RBC Genetic Studies (May 6, 2010): No apparent chromosomal abnormality
Thalassemia Screening in the Philippines using High Performance Liquid
Chromatography (HPLC) (July 9, 2010): HPLC tracing is indicative of beta-thalassemia, intermedia
Polycythemia Vera
Most common of the myeloproliferative disorders Incidence: 2 per 100,000 persons Etiology: Unknown nonrandom chromosome abnormalities such as 20q, trisomy 8, and 9p JAK2 V617F mutation causing constitutive activation of the kinase
Janus Kinase2-gene (JAK2)
Janus Kinase 2 (JAK2) has tyrosine kinase activity and is involved in signal transduction from EPOR (erythropoietin receptor) to nucleus for gene expression
Polycythemia Vera: Clinical Features
Splenomegaly
Elevated Hgb and Hct
Neurologic symptoms: vertigo, tinnitus,
headache
, visual disturbances, TIAs
Systolic hypertension
Venous or arterial thrombosis Intraabdominal venous thrombosis Digital ischemia, easy bruising, epistaxis, acid peptic disease or GI hemorrhage
Polycythemia Vera: Diagnosis
Erythrocytosis, leukocytosis, thrombocytosis Increased leukocyte alkaline phosphatase (LAP) score Hyperuricemia Elevated Vit B12 or B12 binding capacity BMA: no specific diagnostic information No specific cytogenetic abnormality
Polycythemia Vera: Complications
Increase in blood viscosity Increased turnover of red cells, leukocytes and platelets with the attendant increases in uric acid and cytokine production Spleenic infarction Increased incidence of acute nonlymphocytic leukemia erythromelalgia
Polycythemia Vera: Treatment
Phlebotomy or bloodletting has been the mainstay of therapy.
Elevated platelet counts may be exacerbated by phlebotomy, thus is an indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications.
Polycythemia Vera: Treatment
Hydroxyurea has been the mainstay therapy after the PVSG results indicated it as an effective agent for myelosuppression. The role of HU in leukemic transformation is not clear, but several nonrandomized studies have supported or refuted a significant rise in leukemic conversion with long term use of HU in persons with polycythemia vera (from 2.1% to 10%). Besa, Emmanuel, M.D., and Woermann, Ulrich, M.D. Polycythemia Vera: Treatment and Medication. January 23, 2009.
Thalassemia Syndromes
Inherited disorders of α or β globin biosynthesis, diminished production of Hgb tetramers Unbalanced chain accumulation Massive bone marrow expansion deranges growth and development (“chipmunk” facies) Chronic transfusion leads to iron overload
Thalassemia Syndromes
α Thalassemia β Thalassemia
β Thalassemia
β Thalassemia Major: either no effective production or severely limited production of beta globin. β Thalassemia Minor: heterozygotes who have inherited a single gene leading to reduced beta globin production.
β
Thalassemia Intermedia: disease of intermediate severity, such as those who are compound heterozygotes of two thalassemic variants.
β Thalassemia Intermedia
Malaise, pallor, easy fatigability, splenomegaly CBC reveal anemia with marked hypochromasia and microcytosis Accepted Hgb: 6-7 g/dL without blood transfusions.
Treatment: close monitoring and observation.
Indications for blood transfusions: intercurrent infections, hypersplenism, or other illnesses.
β Thalassemia Minor and Newly Diagnosed Polycythemia Rubra Vera in a 71- year old Woman
Jason Preston Thomas, M.D.
Hospital Physician April 2001
β Thalassemia Minor and polycythemia rubra vera (PRV) are hematologic disorders that give opposite results and the 2 disease entities occurring simultaneously has only been reported ONCE. Due to the low-grade hemolysis resulting from precipitation of impaired alpha globin chains in association with β Thalassemia Minor, the often substantial elevations in Hgb and Hct seen in PRV were probably blunted.
The low grade anemia of β Thalassemia Minor is not evident because of the overproduction of erythrocytes.
Final Diagnosis
Myeloproliferative Disease probably Polycythemia Vera Beta Thalassemia Intermedia Hypertensive Cardiovascular Disease Dyslipidemia Hyperuricemia Chronic Kidney Disease probably secondary to Hypertensive Nephrosclerosis
Complete Blood Count
10/2/10
Conclusion
Beta Thalassemia and PRV are 2 indirectly opposing processes and its occurrence in a patient is rare.
For the long term, chemotherapy could be considered if the patient develops a blood clot or requires phlebotomies too frequently.
Median survival of PRV in the absence of therapy extended to at least 10-20 years.
Thrombotic complications are the main cause of morbidity and mortality, hence close monitoring and observation with repeat CBC should be done every 2 months.
On Follow up
Patient is doing well, asymptomatic.
Has been having regular follow up every 2 months with repeat CBC, and undergoes phlebotomy depending on CBC results.