Sickle Cell Anemia (SCA) and Aplastic Anemia, Thalassemia😍

SKULL XRAY PATTERN APPROACH

RBC Inclusions

Inclusion	Composition	Seen in
Howell–Jolly bodies	• DNA remnants	• Post-splenectomy • Megaloblastic • Sickle cell disease (NOT THALASSEMIA) • Dyshematopoiesis • Hemolytic anemia
Reticulocytes	• Residual RNA (bluish network)	• Hemolysis • Blood loss • Response to therapy
Basophilic Stippling	• Ribosomal RNA	• Coarse → Lead poisoning • Fine → Thalassemia, Megaloblastic Anemia • Also seen in 5’ Pyrimidine nucleotidase
Heinz bodies	• Hb denaturation • Stained by Crystal Violet stain • (Supravital stain)	• G6PD
Pappenheimer Bodies	• Iron granules	• Sideroblastic anemia • Post-splenectomy
Cabot Rings	• Arginine-rich • Mitotic spindle remnants • Figure of eight/loop	• Severe anemia • Megaloblastic anemia • Sideroblastic anemia
Hemoglobin H inclusions	• β4 tetramers • (precipitated Hb H)	• α-thalassemia (Hb H disease)
Siderotic Granules	• Iron • In Prussian blue stain	• Sideroblastic states
Target cells	ㅤ	• Thalassemia • Iron deficiency anemia • Liver disease • Post-splenectomy • Hemoglobin C disease
Dohle bodies	• ER remnant	• Bacterial sepsis
Perinuclear hof	• Golgi apparatus	• Plasma cells

Hemoglobinopathies

Sickle Cell Anemia (SCA)

Genetic defect:

• Inheritance: Autosomal recessive.

• Most common Structural Hemoglobinopathy.

• A point mutation in the 6th codon of the β-globin gene in chromosome 11
• forming HbS.
• Non-conservative missense mutation
• Replacement of polar (glutamic acid) with a non-polar (valine)

• Sickle cells alias: 
• Drepanoocytes.

• Property: 
• Sticky, cause occlusion.

• Deoxygenated HbS polymerizes.
• Triggers:
• Low O₂ (e.g., high altitude, acidosis).
• High HbS concentration (e.g., dehydration).

• Results in sickling of RBCs → crescent-shaped RBCs → vaso-occlusion.

• Target cells, Hb crystals → seen in HbSC homozygotes.

Pathophysiology:

• HbS formed has different physiochemical properties.

• Microvascular obstruction leads to ischemia & tissue damage.

Sickle Cell Trait

• Heterozygotes have malaria resistance.

Clinical Finding: 

• Anemia;
• Pallor, generalized weakness.

• Usually presents after 6 months of age.

• Most common cause of death - infections.

• MCC of osteomyelitis in Sickle cell disease is Salmonella.
• Normal : Staph Aureus

• Fishmouth vertebra

• "Crew cut" skull X-ray → marrow hyperplasia.
• Also seen in thalassemia.

• Newborns
• Asymptomatic at birth.
• Due to ↑ HbF, ↓ HbS.

• ↑ risk of infection by encapsulated organisms.
• e.g., Salmonella osteomyelitis.

Ischemia

• CNS: Stroke.

• Retinopathy.

• Hand - Dactylitis.

• Priapism in males.

• Pulmonary
• Acute chest syndrome:
• Respiratory distress.
• New infiltrates on CXR.
• Commonest cause of death.
• Pulmonary artery hypertension.

• Renal
• Sickling in medulla → renal papillary necrosis.
• Causes hematuria (also in sickle cell trait).
• Hyposthenuria → inability to concentrate urine.

• Splenic infarct/sequestration crisis:
• Splenomegaly due to red pulp congestion.
• Auto splenectomy due to repeated splenic infarcts.
• Due to repeated infarctions.
• Leads to Howell-Jolly bodies.

Crisis in SCD

• Painful crises:
• Dactylitis → painful swelling of hands/feet.

• Aplastic Crisis
• Caused by Parvovirus B19.
• Leads to transient arrest of erythropoiesis.

• Vaso occlusive crisis:
• Painful Ischemia.

• Hemolytic crisis.

• Splenic sequestration.

• Acute chest syndrome.

Other Crises

• Priapism.

• Leg ulcer.

• Growth retardation.

• Retinopathy.

H shaped vertebra

• H-shaped Appearance or Lincoln Log Vertebrae.
• Seen in Sickle Cell Anemia.

• Depressed end plate, predominantly in the center.
• Lateral part is flat.

• In later stages: Fish mouth vertebra.

Tests:

Peripheral Smear:

• Sickle cells.
• Evidence of hemolysis, Sickle cells, Howel Jolly bodies

Sickling test: 

• Adds 2% sodium metabisulfite or dithionate
• induces sickling of RBCs if HbS is present.

Hb Electrophoresis:

• Migration (Anode to Cathode): 
• A FAT SANTA CLAUSE

• HbS is less mobile compared to regular Hb
• Negatively charged Polar Glutamate is replaced by non polar valine
• → Poorly attracted to anode

Investigation	Finding
Hb Electrophoresis	↓ HbA, ↑ HbF, ↑ HbS
Peripheral Smear	- Sickle cells - Howell-Jolly bodies (autosplenectomy) - Target cells, Hb crystals in HbS carrier

• Hb Electrophoresis to detect HbS peak.

Spleen biopsy:

• Gamma Gandy bodies.

Gold Standard: 

• HPLC (High-Performance Liquid Chromatography).

Treatment: 

• Maintain hydration.

• Avoid infections & immunization of the child.

• Infections
• Treat with appropriate antibiotics.

• Acute painful crisis: Analgesia with NSAIDs.

• Blood transfusion.

• Hydroxyurea
• ↑↑ HbF levels and
• ↓↓ the requirement for blood transfusions.

• Regular blood transfusion is the mainstay of the treatment.

• Hematopoietic stem cell transplant and gene therapy.

• Progestrone ↓ sickling crisis

Newer drugs:

• Voxelotor to increase oxygen affinity and reduce HbS polymerization.

• L-glutamine to reduce vaso-occlusion.

• Crizanlizumab also ↓↓ vaso-occlusion.

Aplastic Anemia

• Inherited/acquired condition +
• pancytopenia with hypo / acellular bone marrow.

• Clinical features:
• Pancytopenia:
• Anemia: Pallor, easy fatiguability.
• Thrombocytopenia: Bleeding manifestations.
• Leukopenia: Fever, recurrent infections.
• No lymphadenopathy.
• No hepatosplenomegaly.

Hemoglobin C Disease

• Genetic defect:
• Beta-globin gene, Glutamate → Lysine at beta-6 position.

• Peripheral Smear:
• Characteristic HbC crystals inside RBCs.

Thalassemia

• Genetic disorders:
• Decreased production of globin chains.
• Autosomal recessive.

• Chromosome 16 del → α Thalassemia

• Chromosome 11 splicing → β Thalassemia

• Osmotic Fragility: 
• Low fragility (tough), graph shifts left.

Alpha Thalassemia:

Cause:

• Alpha gene deletion (Normal: 4 alpha genes).

Alpha gene deletion	Condition	Key Features
1 gene AA/A-	Asymptomatic carrier	No symptoms
2 genes AA/—	Alpha thal trait	- Can be α⁺ (cis) or α⁰ (trans) - Mild anemia Mnemonic: 2 trait
3 genes A-/—	HbH disease	- Formation of β₄ tetramers (HbH) - Golf ball inclusions Mnemonic: He (HbH) is Playing Golf (Golf ball) at 3am in the morning (bcz gf left him)
4 genes —/—	Hb Bart's disease	- Formation of γ₄ tetramers (Hb Bart's) - Causes hydrops fetalis- Intrauterine death Mnemonic: - Barr barr (bart) fetus - Gaya fetus (γ)

SKULL XRAY PATTERN APPROACH

Beta Thalassemia:

• Cause: Beta globin gene mutation ("badlna").

Most common mutation (India):

• Splicing mutation
• IVS 1-5 G→C.
• Common Mutations in India:
• IVS 1-5 G→C.
• IVS 1-1 G→T.
• Codon 41/42.

Splice site mutations

• B-thalassemia, Marfan, Gaucher's

• β Thala () Got () spliced in a fan ()

• Frameshift occurs
• +8/9
• +41/42

Only possible deletion: 

• 619 base pair deletion.

Beta Thalassemia Major (Koul's Anemia):

Transfusion dependent.

• Iron overload from repeated transfusions.

• Severe anemia (Hb 3-5 g).
• Palar, jaundice, splenomegaly.

Diagnosis Gold Standard:

• HPLC.
• HbF elevated (>90%).

Peripheral Smear:

• Hemolytic anemia:
• Low Hb, low MCV, low MCH (thalassemia major).
• Microcytic-hypochromic anemia.
• Target cells/ Codocytes
• Howell jolly bodies.
• Poikilocytosis.
• Increased LDH.
• Increased unconjugated bilirubin.

Beta Thalassemia Minor:

• Mild/asymptomatic
• Hb > 8 g
• normal iron studies

• Microcytic hypochromic.

Differentiation from IDA:

• Mentzer Index



• Formula: (MCV / RBC count) x 100.

• Interpretation:
• <13: Thalassemia minor
• Mnemonic: Tha Lessemia → < 13
• >13: Iron Deficiency Anemia

• RDW:

N: 11.5 - 14.5 %	Conditions	Notes
↑ RDW	• B12 Deficiency • IDA • Hemolytic Anemia	• Due to fluctuating raw material
Normal RDW	• Thalassemia Trait	• Microcytic Hypochromic Anemia

• Coombs test:
• Negative

Confirmation:

• Elevated HbA2 levels (>3.5%) by HPLC.

• Hb HPLC (High performance liquid chromatography) / Hb electrophoresis:





• Hb A (α2 β2) decreased.
• Hb A2 (α2 δ2) increased.
• Beta thalassemia trait:
• Hb A2 : 3.5%-7%.
• HbF (α2 γ2) increased.

Definitive diagnosis:

• Globin gene mutation
• helps in prenatal diagnosis in the next pregnancy.

Osmolar fragility:

• (NESTROFT — Naked Eye Single Red Tube Cell Osmotic Fragility Test).
• Decreased

• Thalassemia cells (tough) in saline:
• Lines absent behind tube.
  (Thal Assemia, Absent lines).

• Normal cells (break):
• Lines visible.

Treatment of Thalassemia:

• Regular Blood Transfusions (PRBC):
• To maintain pretransfusion Hb level between 9-10.5 g/dL.

• The only curative treatment:
• Hematopoietic stem cell transplantation (HSCT).

• Iron Chelation Therapy:
• Desferrioxamine/Deferoxamine
• Injectable
• DOC for acute Iron poisoning
• When Iron level > 500 Microgram/dl
• Monitor for hypotension, pulmonary toxicity.
• Oxygen → acute → IV → but BP falls and Lung injury
• Deferiprone
• Oral
• Used for chronic Iron overload
• Agranulocytosis
• needs weekly blood monitoring
• Best for cardiac iron;
• Chronic Ferry Pirates (Feripirone) → oral
• Prone (Deferiprone) Close (Clozapine) Car (Carbamazepine) → Agranulocytosis

Haemophilia A

• Basic defect: Deficiency of factor VIII.

• Inheritance:
• X-linked recessive

• Family h/o maternal uncles being affected.

Classification:

• Mild (factor VIII >5%).

• Moderate (factor VIII 1-5%).

• Severe (factor VIII <1% factor level).

Clinical features:

• H/o joint swelling following trauma (Ankle>knee joint).

• Deep bleeding.

Investigation:

• Prolonged aPTT
• but normal PT, BT, and platelet counts.

• Low factor VIII levels.

Treatment:

• Factor VIII replacement is TOC

• If not available —use fresh frozen plasma (FFP).

• Cryoprecipitate.

• Avoid contact sports.

• Precautions during immunization
• Compress the site of injection to prevent the formation of a hematoma.

Cancer-Associated Thrombosis (CAT)
Management

Low Molecular-Weight Heparin vs. Oral Anticoagulants:

• CLOT trial

• All recent guidelines now favor LMWH for cancer-associated thrombosis

LMWH

• Preferred due to bioavailability,

• Lack of need for anticoagulant monitoring

• Long t1/2

• Tinzaparine - used for maintainence

Unfractionated Heparin (UFH):

• Can be used in patients with renal failure