Hematolymphoid Disorders

Notes by: Dr. Amit Sharma

1. What is Blood?
– Fluid that carries oxygen to the tissues of the body and waste material and carbon dioxide
away from the tissues away from the body.

2. What is Hemoglobin?
– The red, iron-rich protein that gives blood its red color. It allows red blood cells to carry
oxygen from the lungs to all parts of the body.

3. What are Erythrocytes (RBC's)?

– Erythrocytes (RBC's) = red blood cells that contain hemoglobin.
– They are made from special stem cells in the spongy red bone marrow of the larger bones in
the body (erythropoesis).
– They normally live about 120 days, then are removed from the blood so they can be replaced
by new, immature RBCs called a reticulocyte

4. What is anemia?
– Anemia is where the number of RBC's is lower than normal or where the RBC's don't contain
enough hemoglobin.
– Anemia results in less oxygen to body tissues.
– Anemia is not a specific disease but is a symptom of some other diseases or conditions

Red Blood Cell Indices

● Red blood cell indices are calculations that provide information on the physical
characteristics of the RBCs:
– Mean corpuscular volume (MCV) is a measurement of the average size of RBCs.
– Mean corpuscular hemoglobin (MCH) is a calculation of the average amount of oxygen-
carrying hemoglobin inside a red blood cell.
– Mean corpuscular hemoglobin concentration (MCHC) is a calculation of the average
percentage of hemoglobin inside a red cell. In contrast to MCH, MCHC correlates the
hemoglobin content with the volume of the cell.
Iron Studies

Serum ferritin
- Soluble iron-binding storage protein.

Serum iron
– Iron that is bound to transferrin .
– Transferrin is the binding protein of iron and is synthesized in the liver.

Serum total iron-binding capacity (TIBC)

– Correlates with the concentration of transferrin.
– Decreased ferritin stores leads to increased liver synthesis of transferrin and vice versa.

Iron saturation (%)

 – Percentage of binding sites on transferrin that are occupied by iron.
– Formula for calculating iron saturation: Iron saturation (%) = serum iron/ TIBC × 100

Classification of Anaemias
– Anaemias are classified based on
. The cause of anaemia (aetiological classification)
. The morphology of red cells (morphological classification)

● Aetiological classification of anaemia

(a) Anaemia of blood loss (may be acute or chronic):

(i) Acute: Trauma, major surgical procedures and postpartum bleeding
(ii) Chronic: Hookworm infestation, bleeding peptic ulcer, carcinoma colon, haemorrhoids and
excessive menstrual loss

(b) Decreased production of red cells:

(i) Nutritional deficiency:
– Iron (affects haemoglobin synthesis),
– Vitamin B12 and folate (affect DNA synthesis)

(ii) Inherited genetic defects:-

– Fanconi anaemia (Defects leading to stem cell depletion)
– Thalassaemia syndromes (Defects affecting erythroblast maturation)

(iii) Erythropoietin deficiency: Renal failure and anaemia of chronic disease

(iv) Immune-mediated injury of progenitors:

– Hypoplastic or aplastic anaemia
– Pure red cell aplasia

(v) Marrow invasion: Leukaemia, lymphoma, secondary carcinoma and granulomatous disease
(vi) Inflammatory iron sequestration: Anaemia of chronic disease.
(vii) Unknown mechanisms:
– Endocrine disorders (Hypothyroidism, hypoadrenalism and hypopituitarism) and hepatic
disease

(c) Due to excessive destruction of red cells (haemolytic anaemias):

(i) Genetic disorders: Red cell membrane, enzyme abnormalities, haemoglobinopathies, like
(i) Genetic disorders: Red cell membrane, enzyme abnormalities, haemoglobinopathies, like
sickle cell disease and thalassaemias
(ii) Acquired disorders: Immune, toxic, mechanical and infectious causes

● Morphological classification of anaemia

(a) Microcytic hypochromic anaemia

(b) Macrocytic normochromic anaemia
(c) Normocytic normochromic anaemia
Symptoms of Anaemia
Acute:
– Shortness of breath, organ failure and shock
Chronic:
. General symptoms(due to tissue hypoxia)
– Fatigue, lassitude, dyspnoea, palpitations, dizziness, headache, syncope, tinnitus and vertigo
– Irritability, sleep disturbances, lack of concentration and paraesthesias
– Anorexia, nausea and bowel disturbances
– Symptoms of cardiac failure
– Amenorrhea and polymenorrhea

. With haemolysis:
– Skeletal abnormalities (due to expansion of marrow), growth retardation, jaundice and
gallstones

. With defective erythropoiesis: Iron overload leading to heart and endocrine failure

Signs of Anaemia
• Pallor of skin and mucous membranes, nail beds and conjunctivae
• Tachycardia with a wide pulse pressure
• Cardiac dilatation and later, signs of cardiac failure
• Oedema

Iron-deficiency anaemia (IDA)

– IDA is the most common type of anaemia met with in clinical practice.
– Iron deficiency anemia develops when body stores of iron drop too low to support normal red
blood cell (RBC) production.

Causes
– Pathological blood loss: Peptic ulcer, haemorrhoids, carcinoma stomach and colon,
hookworm infestation, haematuria, repeated epistaxis, haemoptysis and pathological
uterine bleeding.
– Increased physiological demand: Growing children and women in reproductive age
group
– Inadequate intake
– Nutritional deficiency
– Impaired absorption: tropical sprue, celiac disease.
• Plummer–Vinson (Paterson–Kelly) syndrome:
– Syndrome complex of chronic iron deficiency, dysphagia due to postcricoid web and
glossitis

Clinical Features

– Anaemia: Lassitude, weakness, fatigue, dyspnoea, palpitations, angina, CCF and pallor
– Nails: Thin, lusterless, brittle, koilonychia (spoon-shaped nails)
– Tongue: Atrophy of papillae, shiny or glazed tongue, glossitis
– Pica: This is defined as a craving to eat substances like dirt, clay, salt, hair and is a
typical manifestation of iron deficiency.
– Recurrent infections: Iron deficiency induces defective lymphocyte-mediated immunity
and impairs bacterial killing by phagocytes leading to impaired immunity and recurrent
infections.

Laboratory Diagnosis
1. General blood parameters
(a) Hb: Decreased
(b) RBC count: Decreased
(c) RBC indices: Reduced/low

2. Peripheral smear
(a) Microcytic hypochromic cells (red cells are smaller than normal and have increased
central pallor)
(b) Anisocytosis or variation in cell size
(c) Poikilocytosis or variation in cell shape
(d) Tear drop cells, pencil-shaped cells and target cells (common in severe anaemia)
(e) Normal, increased or decreased platelet count and unremarkable WBCs

3. Reticulocyte count
– Normal or decreased (in post-haemorrhagic anaemia reticulocyte count may be mildly
raised)

4. Iron studies
(a) Decreased serum iron
(b) Decreased Percentage saturation = serum iron/TIBC
(c) Decreased Serum ferritin
(d) Increased Serum total iron-binding capacity (TIBC)

Megaloblastic Anaemia

– A megaloblast is so labelled when a large erythroid cell shows nuclear-cytoplasmic

asynchrony (maturation of nucleus lags behind maturation of cytoplasm due to
impaired DNA synthesis caused by the deficiency of vitamin B12 and folate).

Causes of Megaloblastic Macrocytosis

1. Deficiency of vitamin B12 and/or folate
2. Resistance to B12 or folic acid therapy due to metabolic inhibitors of DNA synthesis or
folate metabolism

Causes of Vitamin B12 Deficiency

• Decreased intake: Nutritional deficiency (vegans, breastfed infants of vegan mothers)
• Impaired absorption:
• Gastric causes: Pernicious anaemia, destruction of gastric mucosa or gastric bypass
surgery • Intestinal causes: Malabsorption due to enteritis, celiac disease or tropical sprue,
competition
for vitamin B12 in fish tapeworm (Diphyllobothriumlatum) infestation
• Drug-induced malabsorption

Causes of Folate Deficiency

• Inadequate intake: Young persons on junk food diets, elderly and terminally ill people
• Inappropriate cooking methods
• Excess utilization: Pregnancy, haemolysis and tumours
• Alcoholism: Reduces serum folate levels
• Impaired absorption: Celiac disease and tropical sprue

Clinical Features of Vitamin B12 Deficiency

● General signs and symptoms of anaemia:
– Weight loss, angular cheilosis, dermatitis, osteomalacia, pallor, icterus (lemon tint), low-
grade fever (in severe anaemia), mucocutaneous bleeding (with thrombocytopenia)
● Neurological manifestations:
– Vitamin B12 deficiency causes peripheral neuropathy (leading to paraesthesias and
numbness) and cerebral changes (leading to dementia, psychosis or personality
changes).
● Splenomegaly and hepatomegaly
● Gastrointestinal symptoms: Weight loss and poorly localized abdominal pain
● Glossitis: Loss of papillae leading to a smooth beefy red tongue
● Skin and hair changes: Premature greying of hair and melanin pigmentation of skin
with sparing of mucosa
● Infertility: Reversible with correction of deficiency

Clinical Features of Folate Deficiency

– Folate deficiency mainly manifests with megaloblastic anaemia and glossitis.
– Subacute combined degeneration is not seen and peripheral neuropathy is rare.

Laboratory Diagnosis of Megaloblastic Anaemia

• General blood parameters
– RBC count and haemoglobin levels are decreased.
– MCV is increased and MCH is decreased
– Reticulocyte count is normal.
• Peripheral smear
– Red cells show anisopoikilocytosis with the presence of macrocytes and
macroovalocytes (large oval RBCs).
– Also present are Howell–Jolly bodies (nuclear remnants left after the nucleus is
extruded) and Cabot rings (abnormal histone synthesis causes arginine-rich histones to
accumulate as rings in red cells).
– Neutrophil hypersegmentation is seen

• Biochemical tests
– Serum vitamin B12 levels <200 pg/mL indicate vitamin B12 deficiency (normal 200–900
pg/mL)
– Serum folate levels <6 ng/mL indicate folate deficiency (normal 6–12 ng/mL).
– There are two methods to measure serum B12—microbiological and radioisotope assay.
– Schilling test: Schilling test is useful for diagnosing intrinsic factor deficiency, as in
classic pernicious anaemia. It measures absorption of free radiolabelled vitamin B12.

Thrombocytopenia
– Platelets (thrombocytes) are colorless blood cells that help blood clot.
– Platelets stop bleeding by clumping and forming plugs in blood vessel injuries.
– Thrombocytopenia is a condition in which you have a low blood platelet count.

Causes of Thrombocytopenia

● Disorders of decreased production

– Bone marrow failure syndromes
– Hereditary
– Marrow infiltration
– Chemotherapy induced
– Radiotherapy induced

● Disorders of Increased destruction

– Immune thrombocytopenic purpura (ITP)
– Disseminated intravascular coagulation (DIC)
– Hemolytic uremic syndrome (HUS)
– Thrombotic thrombocytopenic purpura (TTP)
– Heparin induced thrombocytopenia
– Pregnancy (HELLP syndrome)
 ● Others
– Splenic sequestration in hypersplenism
– Medications

Haemophilia
– Haemophilia is a frequently fatal haemorrhagic diathesis affecting male children
characterized by a deficiency of clotting factors .
– Hemophilia A (Factor VIII Deficiency) - Most comman
– Hemophilia B (Christmas disease, Factor IX Deficiency)

Clinical Manifestations
– Excessive haemorrhage from a trivial injury
– Haemarthrosis most common and debilitating manifestation
– Haemorrhage -> organization and inflammation n chronic proliferative synovitis ->
chronic haemophilic arthropathy (may lead to fibrous or bony ankylosis)
– Pain, muscle spasm and limitation of mobility
– Subcutaneous, intramuscular haematomas and retroperitoneal haematomas
– Gastrointestinal and genitourinary bleeding
– Splenomegaly (40% patients)

Laboratory Diagnosis
– Prolongation of aPTT due to an abnormality of the intrinsic coagulation pathway.
– Normal bleeding time, platelet count, and PT
– Factor VIII-specific assays are required for diagnosis.
– Anaemia with neutrophilia
– Megakaryocytes are normal or increased in number

Leukemia and Lymphoma

Leukemia is a term used to describe the widespread involvement of the bone marrow
accompanied with large number of cancer cells in the peripheral blood whereas Lymphoma is a
term used for proliferation of lymphoid cells arising as discrete tissue masses.
Etiology of Leukemia
• Heredity
• Infections: Human T cell leukaemia-lymphoma virus 1 (HTLV-1)
• Environmental factors
– Ionising radiation
– Chemical carcinogens
– Certain drugs.
• Association with diseases of immunity:
– Immunodeficiency diseases like AIDS
– Iatrogenic immunosuppression induced by chemotherapy or radiation

Classification of Leukemia
Classification of Lymphoma

Hodgkin Lymphoma (HL)

● Classic type
– Lymphocyte rich
– Mixed cellularity
– Lymphocyte depleted
– Nodular sclerosis
● Nodular lymphocyte-predominant type

Non-Hodgkin Lymphoma
● B-cell
– Small lymphocytic lymphoma
– Precursor lymphoblastic lymphoma
– Mantle cell lymphoma
– Lymphoplasmacytic lymphoma
– Diffuse large B-cell lymphoma
– Burkitt lymphoma
– Marginal zone lymphoma
– Follicular lymphoma
 – Hairy cell leukemia
– Plasma cell neoplasm

● T-cell
– Mycosis fungoides
– Precursor lymphoblastic lymphoma
– Anaplastic large T-cell lymphoma
– Natural killer cell lymphoma

Causes of Lymphadenitis
● Malignancies
– Kaposi sarcoma
– Leukemias
– Lymphomas
– Metastases
Skin neoplasms Infections

● Bacterial:
– Tuberculosis
– Brucellosis
– Primary and secondary syphilis
– Cat-scratch disease (Bartonella)
– Cutaneous infections (staphylococcal or streptococcal)

● Granulomatous:
– Histoplasmosis
– Berylliosis
– Cryptococcosis
– Silicosis

● Viral:
– Adenovirus
– Cytomegalovirus
– Hepatitis
– Herpes zoster
– Human immuno-deficiency virus
– Infectious mononucleosis (Epstein-Barr virus)
● Other:
– Fungal
– Helminthic
– Lyme disease
– Rickettsial
– Scrub typhus
– Toxoplasmosis

● Autoimmune disorders
– Rheumatoid arthritis
– SjOgren syndrome
– Systemic lupus erythematosus

● Miscellaneous/unusual conditions
– Castleman disease
– Kawasaki disease
– Kikuchi lymphadenitis
– Kimura disease
– Sarcoidosis

● latrogenic causes
– Medications
– Serum sickness