View
3.771
Download
8
Category
Preview:
DESCRIPTION
HEMOLYTIC ANEMIA Hemo: Referring to blood cells Poiesis: “The development or production of” The word Hemopoiesis refers to the production & development of all the blood cells: Erythrocytes: Erythropoiesis Leucocytes: Leucopoiesis Thrombocytes: Thrombopoiesis. Begins in the 20th week of life in the fetal liver & spleen, continues in the bone marrow till young adulthood & beyond!
Citation preview
drpankajyadav05@gmail.com
HEMOLYTIC ANEMIA
Presented by
Dr. PANKAJ YADAV
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
Normal Red Cells
No nucleusBiconcave discsCenter 1/3 pallorPink cytoplasm (Hb filled)Cell size 7- 8 µ - capill. Negative charge 100-120 days life span
drpankajyadav05@gmail.com
The Factory – Bone Marrow
Sternum, pelvis, vertebrae, long bones, skull bones, Tibia (paed)
From stem cells (pleuripotent)
75% of marrow for WBC
25% of BM for Red cells
Erythrod / Granulocyte Ratio 1:3
Large white areas are marrow fat
drpankajyadav05@gmail.com
Hemoglobin (Hb)
drpankajyadav05@gmail.com
ERYTHROPOIESIS
drpankajyadav05@gmail.com
HEMOPOIESIS• Hemo: Referring to blood cells• Poiesis: “The development or production of”• The word Hemopoiesis refers to the production &
development of all the blood cells: – Erythrocytes: Erythropoiesis – Leucocytes: Leucopoiesis– Thrombocytes: Thrombopoiesis.
• Begins in the 20th week of life in the fetal liver & spleen, continues in the bone marrow till young adulthood & beyond!
drpankajyadav05@gmail.com
Sites of erythropoiesis
• Mesoblastic stage-in the yolk sacStarts at 2 weeks of intrauterine life• Hepatic stage-2-7 monthsBoth liver and spleen• Myeloid stage
drpankajyadav05@gmail.com
Myeloid stage
• Occurs in bone marrow• Starts at 5 months of fetal life and takes over
completely at birth• Red bone marrow of all bone.• Late adult life, red marrow of flat bones
drpankajyadav05@gmail.com
SITES OF HEMOPOIESIS
• Active Hemopoietic marrow is found, in children throughout the:– Axial skeleton:
• Cranium• Ribs.• Sternum• Vertebrae• Pelvis
– Appendicular skeleton:• Bones of the Upper &
Lower limbs
• In Adults active hemopoietic marrow is found only in:– The axial skeleton– The proximal ends of the
appendicular skeleton.
drpankajyadav05@gmail.com
In adults extramedullary hematopoiesis may occur in diseases in which the bone marrow becomes destroyed or fibrosedIn children, blood cells are actively produced in the marrow cavities of all the bones.
By age 20, the marrow in the cavities of the long bones, except for the upper humerus and femur, has become inactive .
Active cellular marrow is called red marrow; inactive marrow that is infiltrated with fat is called yellow marrow.
drpankajyadav05@gmail.com
The bone marrow is actually one of the largest organs in the body, approaching the size and weight of the liver. It is also one of the most active. Normally, 75% of the cells in the marrow belong to the white blood cell-producing myeloid series and only 25% are maturing red cells, even though there are over 500 times as many red cells in the circulation as there are white cells. This difference in the marrow reflects the fact that the average life span of white cells is short, whereas that of red cells is long.
drpankajyadav05@gmail.com
STEM CELLS
• These cells have extensive proliferative capacity and also the:– Ability to give rise to new stem cells (Self Renewal)– Ability to differentiate into any blood cells lines
(Pluripotency)• They grow and develop in the bone marrow.• The bone marrow & spleen form a supporting system,
called the • “hemopoietic microenvironment”
drpankajyadav05@gmail.com
Stem cells
• Totipotential stem cells- convert into any tissue type• Pluripotent stem cell- Pluripotent hematopoeitic
stem cell• Committed stem cells- CFU E, CFU G, CFU M, etc
drpankajyadav05@gmail.com
CLONAL HEMOPOIESISPLURIPOTENT STEM CELL
STEM CELL
MULTIPLICATION COMMITTMENT
COMMITTEDSTEM CELL
COMMITTEDSTEM CELL
MULTIPLICATION
PROGENITOR CELL
CFU: COLONYFORMING UNIT
drpankajyadav05@gmail.com
Hematopoietic stem cells (HSCs) are bone marrow cells that are capable of producing all types of blood cells.
They differentiate into one or another type of committed stem cells (progenitor cells). These in turn form the various differentiated types of blood cells.
There are separate pools of progenitor cells for megakaryocytes, lymphocytes, erythrocytes, eosinophils, and basophils; neutrophils and monocytes arise from a common precursor.
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
PROGENITOR CELLS
• Committed stem cells lose their capacity for self-renewal.
• They become irreversibly committed.• These cells are termed as “Progenitor cells”• They are regulated by certain hormones or substances
so that they can:– Proliferate– Undergo Maturation.
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
ERYTHROPOIESIS
15-20µm- basophilic cytoplasm, nucleus with nucleoli.
14-17µm-mitosis, basophilic cytoplasm, nucleoli disappears.
10-15µm-’POLYCHROMASIA’Hb appears, nucleus condenses.
7-10µm- PYKNOTIC Nucleus.Extrusion, Hb is maximum.
7.3µm- Reticulum of basophilic material in the cytoplasm.
7.2µm- Mature red cell with Hb.
drpankajyadav05@gmail.com
Pronormoblast
• 15-20 microns• Mitosis present• Nucleus with multiple
nucleoli• Basophilic cytoplasm
with polyribosomes
• No hemoglobin
drpankajyadav05@gmail.com
Basophilic erythroblast
• Large nucleus• Basophilic
cytoplasm• Active mitosis• Slight reduction in
size
drpankajyadav05@gmail.com
Polychromatophilic erythroblast
• Chromatin lumps• Hb starts appearing• Reduced mitoses
drpankajyadav05@gmail.com
Orthochromatic erythroblast
• Small and pyknotic nucleus
• Eosinophilic cytoplasm
• Mitoses absent
drpankajyadav05@gmail.com
Reticulocyte • Reticular nuclear
fragments• Nucleus extruded• Slightly larger than
RBCs
drpankajyadav05@gmail.com
ReticulocytesYoung erythrocytesContain a short network of clumped ribosomes and RER.Enter the blood streamFully mature with in 2 days as their contents are degraded by intracellular enzymes.Count = 1-2% of red cellsProvide an index of rate of RBC formation
drpankajyadav05@gmail.com
Proerythroblast or
pronormoblast
Basophilic erythroblast
or Early
Normoblast
Polychromatophilic (or intermediate)Erythroblast or
Normoblast
DividingPolychromatophilic
Erythroblast orNormoblast
Orthochromatic(Acidophilic) erythroblast
OrLate
Erythroblast
Orthochromatic erythroblast
ExtrudingNucleus
Reticulocyte
Reticulocyte(brilliant cresyl
blue dye)
drpankajyadav05@gmail.com
Duration
Differentiation phase- from pronormoblast to reticulocyte phase- 5 days
Maturation phase: from reticulocyte to RBC- 2 days
drpankajyadav05@gmail.com
Factor needed of Erythropoiesis
1. Erythropoietin ( Released in response to Hypoxia)2. Vitamin B 6 (Pyridoxine)3. Vitamin B 9 (Folic Acid)4. Vitamin B 12 (Cobolamin)
Essential for DNA synthesis and RBC maturation
5. Vitamin C Helps in iron absorption (Fe+++ Fe++)6. Proteins Amino Acids for globin synthesis7. Iron & copper Heme synthesis8. Intrinsic factor Absorption of Vit B 129. Hormones
drpankajyadav05@gmail.com
Hormonal factors:Androgens: increase erythropoiesis by stimulating the production of
erythropoietin from kidney.Thyroid hormones: Stimulate the metabolism of all body cells including the bone marrow cells,
thus, increasing erythropoiesis. Hypothyroidism is associated with anemia while hyperthyroidism is
associated with polycythaemia.
Glucocorticoids:
Stimulate the general metabolism and also stimulate the bone
marrow to produce more RBCs.
In Addison’s disease (hypofunction of adrenal cortex) anemia
present, while in Cushing’s disease (hyperfunction of adrenal
cortex) polycythaemia present.
Factor needed of Erythropoiesis
drpankajyadav05@gmail.com
Factor needed of Erythropoiesis
Hormonal factors
Pituitary gland: Affects erythropoiesis both directly
and indirectly through the action of several
hormone.
Haematopoietic growth factors: Are secreted by
lymphocytes, monocytes & macrophages to
regulate the proliferation and differentiation of
proginator stem cells to produce blood cells.
drpankajyadav05@gmail.com
Factor needed of Erythropoiesis
State of liver & bone marrow
Liver - Healthy liver is essential for normal erythropoiesis because the liver is the main site for storage of vitamin B12 , folic acid, iron & copper. In chronic liver disease anemia occurs.
Bone marrow - When bone marrow is destroyed by ionizing irradiation or drugs, aplastic anemia occurs.
drpankajyadav05@gmail.com
Regulation of erythropoiesis
Tissue Oxygenation
drpankajyadav05@gmail.com
Erythropoietin
• Glycoprotein with 165 amino acids, 4 oligosaccharide chains and molecular weight of 34,000
• Production- 85% by peritubular capillary bed interstitial cells(Kidney) and 15% by perivenous hepatocytes( Liver)
• Also seen in brain, salivary glands, uterus, oviducts• Site of Action: BONE Marrow
drpankajyadav05@gmail.com
Factors increasing erythropoietin secretion:(i) Hypoxia(ii) Androgens(iii) Growth Hormone(iv) Catecholamines(v) ProstaglandinsFactors inhibiting erythropoietin secretion:(vi) Estrogen(vii)Theophylline
drpankajyadav05@gmail.com
Action of Erythropoietin:1. Formation of Pronormoblast from stem cell2. Speeds up the differentiation through various
stages of erythropoiesis
Mechanism of Action:• Formation of ALA synthetase• Activation of Adenylyl Cyclase• Synthesis of transferrin receptors
drpankajyadav05@gmail.com
Maturation factors
Vitamin B12 and Folic acid:– Essential for DNA synthesis (Thymidine triphosphate)– Abnormal and diminished DNA– Failure of division and maturation– Macrocytic / Megaloblastic anemia
Other factors– Cobalt– Copper – Vitamin C
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
HEMOLYTIC ANEMIA
Hemolytic anemia = reduced red-cell life span
drpankajyadav05@gmail.com
HAEMOLYTIC ANAEMIAS
•The normal red cell life is 110-120 days after which the senile cells are removed by bone marrow and splenic macrophages.•Reduced red cell survival leads to increased red cell production due to erythropoietin drive that can compensate for the reduced red cell life and maintain a normal Hb level.•The mean red cell life is affected by molecular changes in either the red cell membrane or haemoglobin.
drpankajyadav05@gmail.com
• A haemolytic state exists when the in vivo survival of the RBC is shortened.
• Anaemia occurs if the onset of haemolysis is sudden with no time for marrow compensation or in severe chronic haemolysis when the mean red cell life is very short.
• The usual marrow response in acute hemolytic anemia is reflected by a reticulocyte index of 2–3, whereas in long-standing chronic hemolysis, the increase in erythropoiesis is approximately 6-fold.
drpankajyadav05@gmail.com
Correcting Retic Count
Retic Index = Retic % x Patient Hct Normal Hct
Absolute Retic = Retic % x RBC/mm3
Retic Production Index = Retic Index Days in circulation
drpankajyadav05@gmail.com
CLINICAL FEATURES
Jaundice: generally mild and often not noticed by the patient.
Anaemia: recent onset = acquiredlong-standing = possibly congenital.
Haemoglobinuria: intravascular haemolysis.Urobilinogenuria: increased Hb catabolism.
Splenic pain: spenomegaly or splenic infarction.
Leg ulcers: intrinsic red cell disorders, e.g. sickle cell disease.
Skeletal hypertrophy: severe congenital haemolytic anaemias and thalassaemias.
CLASSIFICATION OF HEMOLYTIC ANEMIAS
The course of the disease
acute chronic
The place of RBC distraction
intravascular extravascular
The whence acquired inherited
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
Haemolytic anaemia Intravascular vs. Extravascular
Intravascular• red cells lyse in the
circulation and release their products into the plasma fraction.
• Anemia• Decreased Haptoglobin• Hemoglobinemia• Hemoglobinuria• Urine hemosiderin• Increased LDH
Extravascular• ingestion of red cells by
macrophages in the liver, spleen and bone marrow
• Little or no hemoglobin escapes into the circulation
• Anemia• Decreased Haptoglobin• Normal plasma
hemoglobin• Increased LDH
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
Evidence of Hemolysis
• Low RBC survival with chromium tagging study
• Unconjugated bilirubin• Plasma Hb• Decreased serum haptoglobin
drpankajyadav05@gmail.com
Evidence of Erythropoiesis
• Polychromasia• Increased reticulocyte• “Shift” macrocytosis• Hypercelluar BM
drpankajyadav05@gmail.com
HEMOLYTIC ANEMIA
• INTRACORPUSCULAR HEMOLYSIS– Membrane Abnormalities– Metabolic Abnormalities– Hemoglobinopathies
• EXTRACORPUSCULAR HEMOLYSIS– Nonimmune – Immune
drpankajyadav05@gmail.com
Membrane Defect
• Hereditary spherocytosis• Hereditary elliptocytosis• Hereditary pyropoikilocytosis• PNH (sensitivity to complement lysis --
sugar water test, Ham’s test)• Hereditary stomatocytosis (possibly Rh
null)
drpankajyadav05@gmail.com
Metabolic Defect(enzyme deficiency)
• G6PD deficiency– Hexose monophosphate shunt– Most common RBC enzyme defect, >50
variants– X-linked– Low glutathione due to low NADPH– Oxidative lysis, Heinz bodies, spherocytic– Primaquine, fava beans
• Pyruvate kinase deficiency– Glycolysis– Low RBC ATP level– Non-spherocytic
• B12 and folate deficiency– Macrocytic– HJ bodies
• Hemoglobinopathies– Poikilocytosis– Abnormal Hb
drpankajyadav05@gmail.com
Hemoglobin Abnormalities
• Unstable hemoglobin disease • Sickle cell anemia • Other homozygous hemoglobinopathies
(CC, DD, EE; Chapter 52)• Thalassemia major • Hemoglobin H disease • Doubly heterozygous disorders (such as
hemoglobin SC disease and sickle thalassemia)
drpankajyadav05@gmail.com
HEMOLYTIC ANEMIA - IMMUNE• Drug-Related Hemolysis
PENICILLIN,CEFTRIAXONE,CEFOTETAN,QUINIDINE,ALPHA-METHYLDOPA,LEVODOPA,PROCAINAMIDE,SULFA DRUGS
• Alloimmune Hemolysis– Hemolytic Transfusion Reaction – Hemolytic Disease of the Newborn
• Autoimmune Hemolysis– Warm Autoimmune (WAIHA)70-80%– Cold Autoimmune (CAIHA) 20-30%– Mixed 7-8%– Paroxysmal Cold Hemoglobinuria - rare
drpankajyadav05@gmail.com
Warm vs. Cold Auto
WARM• Reacts at 37 degC• Insidious to acute• Anemia severe• Fever, jaundice frequent• Intravascular not common• Splenomegaly• Hematomegaly• Adenopathy• None of these
COLD• Reacts at room temperature• Often chronic anemia• 9-12 g/dL (less severe)• Autoagglutination• Hemoglobinuria, acrocyanosis and raynaud’s with cold
exposure• No organomegaly
drpankajyadav05@gmail.com
EXTRACELLULAR DEFECTS
• Fragmentation Hemolysis– DIC, TTP, HUS – Extracorporeal membrane oxygenation– Prosthetic heart valve– Burns—thermal injury– Hypersplenism– Venom - Snake, Spider, Bee
drpankajyadav05@gmail.com
Plasma Factors
• Liver disease (Spur-cell )• Hypophosphatemia • Vitamin E deficiency in newborns• Abetalipoproteinemia• Infections
– Malaria– Babesia– Clostridium– Gram negative endotoxin
• Wilson Disease
drpankajyadav05@gmail.com
Etiologic and Pathogenetic Classification of the Hemolytic
DisordersI. Inherited Hemolytic Disorders A. Defects in the erythrocyte membrane
1. Hereditary spherocytosis D. Deficiencies of enzymes involved in the pentose phosphate
pathway and in glutathione metabolism 1. Glucose-6-phosphate dehydrogenase (G6PD)
E. Defects in globin structure and synthesis1. Unstable hemoglobin disease 2. Sickle cell anemia 3. Other homozygous hemoglobinopathies (CC, DD, EE; Chapter
52)4. Thalassemia major 5. Hemoglobin H disease 6. Doubly heterozygous disorders (such as hemoglobin SC disease
and sickle thalassemia)
drpankajyadav05@gmail.com
Etiologic and Pathogenetic Classification of the Hemolytic
Disorders
II. Acquired Hemoltyic AnemiasA. Nonimmune: due to
1. Traumatic and microangiographic hemolytic anemias 2. Infectious agents 3.Chemicals, drugs, and venoms 4. Physical agents 5. Hypophosphatemia 6. Spur-cell anemia in liver disease 7. Vitamin E deficiency in newborns
drpankajyadav05@gmail.com
Etiologic and Pathogenetic Classification of the Hemolytic
DisordersII. Acquired Hemoltyic AnemiasB. Immunohemolytic anemias 1. Iso (allo) immune:
transfusion of incompatible bloodHemolytic disease of the newborn
2. Heteroimmune:Virus, bacterial infections, chemical, Drug-induced
3. Autoimmune hemolytic anemia Idiopathic (the essential cause is unknown)Secondary or symptomatic (in case of lymphoma, chronic lymphocytic leukemia, Other malignant disease, Immune-deficiency states, Systemic lupus erythematosus and other autoimmune disorders, Virus and mycoplasma infections)
Autoimmune hemolytic anemia caused by warm-reactive antibodies (Coomb’s positive).
Autoimmune hemolytic anemia caused by cold-reactive antibodiesCold hemagglutinin disease
Paroxysmal cold hemoglobinuria
drpankajyadav05@gmail.com
Etiologic and Pathogenetic Classification of the Hemolytic
Disorders
II. Acquired Hemoltyic AnemiasC. Paroxysmal nocturnal hemoglobinuria
drpankajyadav05@gmail.com
The Three Primary Measures
Measurement NormalRange
A. RBC count (RCC) 4- 5.7 million
B. Hemoglobin 12 to 17
Hematocrit (PCV) 38 to 50
A x 3 = B x 3 = C - This is the rule of thumb
Check whether this holds good in a given result
If not -indicates micro or macrocytosis or hypochro.
drpankajyadav05@gmail.com
The Three Derived Indicies
Measurement NormalRange
A. RCC 4 to 5.7
B. Hemoglobin 12 to 17
C. Hematocrit 38 to 50
MCV C ÷ A x 10MCH B ÷ A x 10MCHC (%) B ÷ C x 100
drpankajyadav05@gmail.com
Hemolytic Anemia
Anemia of increased RBC destruction
– Normochromic, normocytic anemia
– Shortened RBC survival
– Reticulocytosis – due to ↑ RBC destruction
Will not be symptomatic until the RBC life span is
reduced to 20 days – BM compensates 6 times
drpankajyadav05@gmail.com
Findings in Hemolytic Anemia
Reticulocyte count and RPI Increased
Serum Unconjugated Bilirubin Increased
Serum LDH 1: LDH 2 Increased
Serum Haptoglobin Decreased
Urine Hemoglobin Present
Urine Hemosiderin Present
Urine Urobilinogen Increased
Cr 51 labeled RBC life span Decreased
drpankajyadav05@gmail.com
Tests to define the cause of hemolysis
1. Hemoglobin electrophoresis
2. Hemoglobin A2 (βeta-Thalassemia trait)3. RBC enzymes (G6PD, PK, etc)4. Direct & indirect antiglobulin tests
(immune)5. Cold agglutinins6. Osmotic fragility (spherocytosis)7. Acid hemolysis test (PNH)8. Clotting profile (DIC)
drpankajyadav05@gmail.com
Peripheral smear
spherocytes
- hereditary spherocytosis
- acquired hemolytic anemia (e.g. AIHA)
- physical or chemical injury
- heat
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
elliptocytes
- heredirary elliptocytosis
- iron def. anemia- myelofibrosis with
myeloid metaplasia
- megaloblastic anemia
- sickle cell anemia
- normal (<10% of cells)
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
Elliptocytosis
drpankajyadav05@gmail.com
StomatocytesSlit like central pallor in RBC
1. Liver Disease
2. Acute Alcoholism
3. H Stomatocyosis
4. Malignancies
drpankajyadav05@gmail.com
Stomatocytes
acanthocytes(irregular surface spicules)
irregularly spiculated cells
with bulbous/rounded ends of spicules
- abetalipoproteinemia
- liver disease
drpankajyadav05@gmail.com
echinocytes(crenated cells, burr cells)
regularly contracted cells with smooth surface undulation
- uremia
- artifact
- hyperosmolarity
- discocyte-echinocyte transformation
(may be associated with reduced ATP of RBCs)drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
EchinocytesEvenly distributed spicules > 10
1. Uremia
2. Peptic ulcer
3. Gastric Ca
4. PK-D
Called Burr Cells
bite cells
Removal (“bites”) of membrane by splenic macrophages
- G6PD deficiency
drpankajyadav05@gmail.com
Heinz bodies
denatured hemoglobin
- G6PD deficiency
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
Heinz body preparation with Crystal violetUnstable hemoglobin
drpankajyadav05@gmail.com
drepanocytes(sickle cells)
- sickle cell anemia
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
basophilic stippling
irregular basophilic granules
(remnants of RNA)
fine stippling:•increased production of RBCs (reticulocytosis)
coarse stippling:•lead poisoning•impaired Hgb syntheisis•megaloblastic anemia•other sever anemias
drpankajyadav05@gmail.com
dacrocytes(teardrop cells)
- thalassemia
- myelofibrosis
drpankajyadav05@gmail.com
leptocytes(target cells)
- liver disease (obstructive jaundice)
- post splenectomy
- hemoglobinopathies (hypochromic anemias)
thalassemia
Hgb C disease
Hgb H diseasebeta thalassemia
relative increase of cell membrane --> “target” formation drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
rouleaux
lined up RBCs in a row
- multiple myeloma
drpankajyadav05@gmail.com
sideroblast/siderocyte
inorganic iron-containing granules (Pappenheimer bodies)
- sideroblastic anemiaabnormally trapped iron in mitochondria forming a ring around nucleus
- post splenectomy
ring sideroblasts
intermediate sideroblast
siderocytedrpankajyadav05@gmail.com
Howell-Jolly body
remnant of nuclear chromatin
single:•megaloblastic anemia•hemolytic anemia•post splenectomy
multiple:•megaloblastic anemia•other abnormal erythropoiesis
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
Acanthocytes5-8 spikes of varying length, irregular
intervals
Called Spur Cells, Occur in A H A
schistocytes(cell fragments)
indication of hemolysis
- megaloblastic anemia
- severe burns
- traumatic hemolysis
- microangiopathic hemolytic anemia
(helmet cells, triangular cells)“helmet
cell”drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
Shistocytes
1. MAHA
2. Prosthetic valves
3. Uremia
4. Malignant HT
Fragmented, Helmet or triangle shaped RBC
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
MAHA Micro Angiopathic Hemolytic
Anemia
drpankajyadav05@gmail.com
TRAUMATIC HEMOLYSIS
drpankajyadav05@gmail.com
Malaria
Schistocytes
drpankajyadav05@gmail.com
Normal BM High Power
E : G = 1 : 3
drpankajyadav05@gmail.com
drpankajyadav05@gmail.com
Bone marrow
drpankajyadav05@gmail.com
Hyperactive BM – SkullHemolytic Anemia
Recommended