Hemoglobin Disorders Quiz

Hereditary Spherocytosis

• Autosomal dominant disorder characterized by mutations in ankyrin, band 3, protein 4.2, and spectrin.
• Results in defective red blood cell membrane structure causing spherocyte formation.
• Spherocytes lose membrane surface relative to cell volume, leading to increased fragility and dehydration.
• Increased Mean Corpuscular Hemoglobin Concentration (MCHC) due to high hemoglobin concentration.
• Symptoms include aplastic crisis, splenomegaly, and pigmented gallstones.
• Diagnosis involves EMA binding test, decreased mean fluorescent RBCs, osmotic fragility test, and typical blood tests showing decreased MCV and abundant RBC count.
• Treatment typically involves splenectomy.

Paroxysmal Nocturnal Hemoglobinuria

• Caused by a mutation in haematopoietic stem cells.
• Impaired synthesis of GPI anchors due to PIGA gene mutation leads to absence of protective protein attachment on cell membranes.
• Red blood cells are susceptible to complement-mediated intravascular hemolysis, notably at night.
• Symptoms include pain, pink/red urine in the morning, and possible venous thrombosis.
• Diagnosis confirmed through flow cytometry on RBCs.
• Managed with eculizumab, targeting terminal complement protein C5.

G6PD Deficiency

• X-linked recessive condition leading to a defect in G6PD enzyme.
• G6PD is crucial for maintaining NADPH levels, which aid in regenerating reduced glutathione—important for protecting RBCs from oxidative damage.
• Deficiency causes oxidative stress hemolysis, especially triggered by specific drugs or substances like fava beans.
• Symptoms include back pain and hemoglobinuria developing a few days post-oxidant exposure.
• Diagnosis through blood smear revealing Heinz and bite cells; G6PD activity may appear normal during acute hemolysis.

Pyruvate Kinase Deficiency

• Autosomal recessive disorder affecting pyruvate kinase enzyme in glycolysis.
• Lack of ATP production leads to increased RBC rigidity and vulnerability to extravascular hemolysis.
• Compensatory rise in 2,3-bisphosphoglycerate reduces hemoglobin’s oxygen affinity, enhancing oxygen release in active tissues.
• Primarily presents as hemolytic anemia in newborns.
• Diagnosis includes blood smear indicating burr cells.

Hemoglobin C Disease

• Result of glutamic acid-to-lysine mutation in the β-globin gene leading to an autosomal recessive disorder.
• More severe manifestation occurs in homozygous HbC carriers; mild forms in heterozygous states with HbS gene.
• Hemoglobin SC disease results from a combination of the sickle cell trait and hemoglobin C.
• Diagnosis via blood smear displays hemoglobin crystals inside RBCs and target cells.

Autoimmune Hemolytic Anemia

• Etiology can be idiopathic or related to conditions like SLE and certain drugs.
• Warm variant involves IgG antibodies leading to RBC destruction (extravascular hemolysis).
• Cold variant mediated primarily by IgM antibodies triggers agglutination and hemolysis upon cold exposure.
• Symptoms commonly include acute anemia.
• Diagnosis through blood smear showing spherocytes; treatment for warm variant includes steroids and rituximab, while cold variant focuses on avoidance and rituximab.

Drug-Induced Hemolytic Anemia

• Triggered by various medications including antibiotics, antitubercular drugs, chemotherapy, and NSAIDs.
• Mechanism involves both antibody-mediated destruction and oxidative injury from drug metabolism.
• Diagnosis might reveal spherocytes indicating immune hemolysis or bite cells suggesting oxidative hemolysis in a blood smear.

Extrinsic Hemolytic Anemia

• Microangiopathic forms include conditions like DIC, TTP, HUS, SLE, and HELLP syndrome.
• Macroangiopathic forms include hemolysis related to prosthetic heart valves or aortic stenosis.
• Infection-related hemolysis noted in conditions such as malaria and Babesia.
• Diagnosis through blood smear commonly shows schistocytes indicative of extrinsic mechanisms.

Hereditary Spherocytosis

• Inherited condition primarily caused by autosomal dominant mutations.
• Mutations affect proteins like ankyrin, band 3, protein 4.2, and spectrin, resulting in abnormal red blood cell shapes (spherocytes).
• Spherocytes exhibit increased fragility and dehydration due to altered membrane structure, leading to elevated MCHC (Mean Corpuscular Hemoglobin Concentration).
• Common manifestations include splenomegaly, abdominal pain, and risk of aplastic crisis during parvovirus B19 infections.
• Diagnosis involves tests like the Eosin-5 maleimide binding test, osmotic fragility test, and evaluation of RBC count and MCHC.
• Treatment primarily consists of splenectomy to reduce hemolysis.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Caused by mutations in hematopoietic stem cells, particularly affecting the PIGA gene.
• PIGA mutations lead to impaired synthesis of GPI anchors, crucial for protective proteins (CD55, CD59) that prevent complement-mediated hemolysis.
• This results in intravascular hemolysis, especially during sleep, leading to symptoms like pink or red urine and pancytopenia.
• Patients may also develop venous thrombosis like Budd-Chiari syndrome and are at risk of aplastic anemia or acute leukemia.
• Diagnosis confirmed via flow cytometry to assess RBC surface proteins.
• Treatment with eculizumab targets terminal complement protein C5.

G6PD Deficiency

• An X-linked recessive condition resulting from a defect in glucose-6-phosphate dehydrogenase (G6PD) enzyme.
• G6PD deficiency leads to decreased NADPH production, impairing the regeneration of reduced glutathione, which protects RBCs from oxidative stress.
• Vulnerable RBCs can undergo hemolysis after exposure to oxidative agents (sulfa drugs, antimalarials, fava beans), causing symptoms like back pain and hemoglobinuria.
• Diagnosis involves blood smear analysis showing Heinz and bite cells, while G6PD activity may appear normal during acute hemolysis.
• Management focuses on removing oxidative stressors and treating hemolysis.

Pyruvate Kinase Deficiency

• An autosomal recessive disorder stemming from defective pyruvate kinase, crucial for glycolysis.
• Insufficient ATP production from this defect leads to increased RBC rigidity and extravascular hemolysis.
• A compensatory rise in 2,3-bisphosphoglycerate (2,3-BPG) reduces hemoglobin's oxygen affinity, aiding oxygen release, but may compromise oxygen delivery to less active tissues.
• Hemolytic anemia is often evident in newborns, marked by distinctive presentation.
• Diagnosis includes blood smear observation for burr cells.
• Treatment revolves around managing hemolytic anemia.

Hemoglobin C Disease

• Result of a mutation in β-globin, causing alterations in hemoglobin structure and leading to hemolysis.
• Various forms exist, with HbSC disease being milder than sickle cell disease (HbSS).
• Patients can present with varying symptoms depending on the severity of the condition.
• Diagnosis typically involves a blood smear showing hemoglobin crystals and target cells.
• Management primarily targets alleviating hemolytic anemia symptoms.

Autoimmune & Drug-induced Hemolytic Anemia

• Autoimmune hemolysis can be idiopathic or triggered by warm and cold autoimmune mechanisms.
• Drug-induced hemolysis often involves antibiotics like penicillins and cephalosporins.
• Conditions causing extrinsic hemolytic anemias include mechanical RBC damage from heart valves or infections such as malaria and Babesia.
• Diagnosis and treatment vary based on the underlying cause and severity of hemolytic anemia.

Hereditary Spherocytosis

• Aetiology involves mutations in genes for ankyrin, band 3, protein 4.2, and spectrin.
• Pathophysiology characterized by defective vertical interactions of RBC membrane proteins, leading to reduced surface area and increased spherical shape.
• Spherocytes are fragile and prone to hemolysis.
• Signs include aplastic crisis, especially after parvovirus B19, splenomegaly, and pigmented gallstones.
• Diagnosis includes EMA binding test, osmotic fragility test, and examination of RBC morphology; elevated MCHC and abundant RBC count noted.
• Treatment involves splenectomy, improving RBC lifespan.

Paroxysmal Nocturnal Haemoglobinuria

• Caused by a mutation in haematopoietic stem cells.
• Critical for GPI anchor biosynthesis, impacting cell membrane integrity.
• Symptoms include hemolysis at night, pain, and venous thrombosis.
• Diagnosed using flow cytometry, revealing negative results on RBC.
• Treatment with eculizumab, targeting complement protein C5.

G6PD Deficiency

• Inherited in an X-linked recessive manner.
• Results in decreased NADPH, weakening RBCs against oxidative stress.
• Symptoms include back pain and hemoglobinuria following oxidant exposure.
• Diagnosis features blood smear showing Heinz and bite cells.
• Treatment focuses on avoiding triggers to prevent hemolysis.

Pyruvate Kinase Deficiency

• An autosomal recessive disorder affecting ATP production in RBCs.
• Secondary increase in 2,3-bisphosphoglycerate, impacting oxygen delivery.
• Hemolytic anemia is evident, particularly in newborns.
• Diagnosis found through blood smear showing burr cells.

Hemoglobin C Disease

• Involves a mutation where glutamic acid is replaced by lysine in β-globin.
• Leads to structural hemoglobinopathy, potentially causing sickle cell disease when homozygous.
• Hemolytic anemia primarily presents in newborns.
• Diagnosis through blood smear shows hemoglobin crystals and target cells.

Autoimmune Haemolytic Anaemia

• Aetiologies include warm and cold autoimmune conditions, often idiopathic.
• Antibodies, mainly IgG, target and destroy RBCs via extravascular hemolysis.
• Symptoms feature acute anemia.
• Diagnosed with a blood smear exhibiting spherocytes and agglutinated RBCs.
• Treatment includes corticosteroids and rituximab for refractory cases.

Drug-Induced Haemolytic Anaemia

• Associated with various antibiotics, antituberculous drugs, and chemotherapy.
• Mechanisms include antibody-mediated destruction and oxidative injury from free radicals.
• Presents as rutin anemia.
• Diagnosis via blood smear displaying spherocytes and bite cells.

Extrinsic Haemolytic Anaemia

Microangiopathic Haemolytic Anaemia

• Causes include DIC, TTP, HUS, SLE, hypertensive emergencies, and HELLP syndrome.
• RBCs experience damage when traversing narrowed or obstructed vessels.
• Diagnosis involves blood smear showing schistocytes.

Macroangiopathic Haemolytic Anaemia

• Typically caused by prosthetic heart valves or aortic stenosis.
• These conditions mechanically destroy RBCs.
• Diagnosis via blood smear showing spherocytes.

Haemolytic Anaemia Due to Infection

• Caused by pathogens such as malaria and Babesia.
• Results in direct destruction of RBCs.