Hemolytic Anemia

Question 1

Clinical symptoms of hemolytic anemia

Answer 1

Clinical Features (Symptoms and Signs)
Pallor: The patient may look pale, especially in the mucous membranes (inside of the mouth, eyes, etc.).

Jaundice: Mild, fluctuating yellowing of the skin and eyes due to increased breakdown of red blood cells.

Splenomegaly: The spleen (an organ involved in filtering blood) may be enlarged.

Urine Changes: There’s no bilirubin (a yellow compound) in the urine, but it may turn dark after standing due to excess urobilinogen, which turns into highly colored urobilin when exposed to light.

Gallstones: Pigment (bilirubin) gallstones can form as a complication.

Question 2

What’s aplastic crisis?
And it’s signs

Answer 2

Aplastic Crises

These are sudden worsening episodes of anemia, usually triggered by an infection with parvovirus, which temporarily stops red blood cell production. Signs of an aplastic crisis include:

A sudden drop in the number of red blood cells

A decrease in reticulocyte count (young red blood cells)

Question 3

Laboratory signs of hemolytic anemia

Answer 3

Features of Increased Red Cell Breakdown

These findings indicate that red blood cells are being destroyed faster than normal.

Serum Bilirubin Raised: Bilirubin levels in the blood are higher than normal. This bilirubin is unconjugated (not yet processed by the liver) and bound to a protein called albumin.

Urine Urobilinogen Increased: The levels of urobilinogen in the urine are higher. Urobilinogen is a product of bilirubin breakdown.

Serum Haptoglobins Absent: Haptoglobins, proteins that bind to hemoglobin released from destroyed red blood cells, are absent. This is because they become saturated with hemoglobin and are then removed from the bloodstream by certain cells in the immune system (RE cells).

2. Features of Increased Red Cell Production

These findings show that the body is trying to compensate for the increased destruction of red blood cells by producing more.

Reticulocytosis: There is an increased number of reticulocytes (immature red blood cells) in the blood. This indicates that the bone marrow is producing more red blood cells to replace the ones being destroyed.

Bone Marrow Erythroid Hyperplasia: The bone marrow shows an increased number of red blood cell precursors. Normally, the ratio of myeloid cells (another type of blood cell) to erythroid cells (red blood cell precursors) is between 2:1 and 12:1. In hemolytic anemia, this ratio is reduced to 1:1 or even reversed, indicating more red blood cell production.

3. Damaged Red Cells, Visualized by:

These findings show the physical signs of red blood cell damage.

Routine Blood Film Morphology: Under a microscope, damaged red blood cells can be seen. These may include:

Microspherocytes: Small, round red blood cells.

Elliptocytes: Elliptical or oval-shaped red blood cells.

Fragments: Pieces of red blood cells.

Flow Cytometry after Eosin-Maleimide (EMA) Staining: This is a lab test that uses a special dye (EMA) to stain red blood cells. Flow cytometry then analyzes these cells to detect abnormalities.

Specific Enzyme, Protein, or DNA Tests: These tests check for specific defects in enzymes, proteins, or DNA that could be causing the hemolytic anemia.

Question 4

What are the Main Laboratory Features of Intravascular Hemolysis

Answer 4

Haemoglobinaemia and Haemoglobinuria:

Haemoglobinaemia: Presence of free hemoglobin in the blood.

Haemoglobinuria: Presence of hemoglobin in the urine, indicating that the kidneys are filtering out excess hemoglobin.

Haemosiderinuria: Presence of haemosiderin (an iron-storage complex) in the urine, resulting from the breakdown of hemoglobin in the kidneys.

Methaemalbuminaemia: Formation of methaemalbumin, which is detected in the blood using a spectrophotometer.

Question 5

Consequences of intra vascular hemolysis?

Answer 5

Consequences:

Haemoglobinaemia and haemoglobinuria: Free hemoglobin is released into the plasma and urine, respectively.

Haemosiderinuria: Iron released from hemoglobin in the renal tubules appears as haemosiderin in urine.

Methaemalbuminaemia: Methaemalbumin, a product of hemoglobin breakdown, is detectable in the blood by spectrophotometry.

Question 6

What are the possible causes of intra vascular hemolysis?

Answer 6

Mismatched blood transfusions (especially ABO incompatibility)

G6PD deficiency with oxidant stress

Red cell fragmentation syndromes (such as microangiopathic hemolytic anemias)

Severe autoimmune hemolytic anemias

Certain drug- and infection-induced hemolytic anemias

Paroxysmal nocturnal hemoglobinuria (PNH)

March hemoglobinuria (hemolysis due to repetitive mechanical trauma)

Unstable hemoglobin disorders

Question 7

Mechanism: Red blood cells are phagocytosed and destroyed by macrophages, primarily in the spleen and liver.

What are the consequences of extra vascular hemolysis?

Answer 7

Consequences:

Iron recycled from hemoglobin is reused for erythropoiesis.

Bilirubin is produced from heme and excreted.

Question 8

What are the consequences of extra vascular hemolysis?

Answer 8

Causes: Typically involve conditions where red blood cells are prematurely destroyed due to membrane defects, enzyme deficiencies, or immune-mediated mechanisms.

Question 9

How can “G6PD deficiency” Cause intra vascular hemolysis?

Answer 9

G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency is a genetic disorder that affects the enzyme responsible for protecting red blood cells against oxidative stress. Here’s how G6PD deficiency can lead to intravascular hemolysis:

1. Role of G6PD in Red Blood Cells: G6PD enzyme plays a critical role in the pentose phosphate pathway within red blood cells. Its primary function is to generate NADPH, which is essential for maintaining adequate levels of reduced glutathione (GSH).
2. Protective Role Against Oxidative Stress: Reduced glutathione protects red blood cells from oxidative damage by neutralizing reactive oxygen species (ROS), such as hydrogen peroxide and superoxide radicals. These ROS can be generated from various sources, including metabolic processes within the cell and exposure to certain drugs or infections.
3. Deficiency and Oxidative Stress: Individuals with G6PD deficiency have reduced ability to produce NADPH and consequently lower levels of GSH. This deficiency makes red blood cells more susceptible to oxidative stress. When exposed to oxidative agents (oxidant stress), such as certain foods, drugs (like antimalarials, sulfa drugs), infections (like malaria), or even fava beans in some variants of G6PD deficiency, red blood cells can undergo hemolysis.
4. Intravascular Hemolysis Mechanism: During intravascular hemolysis in G6PD deficiency:
   
   • Oxidant stress triggers oxidative damage to the cell membrane of red blood cells.
   • This damage leads to the formation of membrane blebs and microspherocytes, which are more fragile and prone to rupture.
   • Ruptured red blood cells release hemoglobin directly into the bloodstream, causing hemoglobinaemia (free hemoglobin in plasma) and subsequently hemoglobinuria (hemoglobin in urine).
   • Additionally, hemoglobin breakdown products like bilirubin and hemosiderin may be detectable in urine and plasma, respectively.
5. Clinical Manifestations: Patients with G6PD deficiency may experience episodes of acute hemolytic anemia triggered by oxidative stressors. Symptoms can range from mild to severe depending on the extent of hemolysis and the individual’s level of enzyme deficiency.

In summary, G6PD deficiency predisposes red blood cells to oxidative damage, leading to intravascular hemolysis when exposed to oxidant stressors. Understanding this mechanism is crucial in managing patients with G6PD deficiency to prevent hemolytic crises triggered by known oxidative agents.

Question 10

What’s Hereditary spherocytosis (HS)?

Answer 10

Hereditary spherocytosis (HS) is a common genetic disorder characterized by defects in proteins that maintain the structural integrity of red blood cell membranes

Question 11

What’s the Pathogenesis of HS
It’s membrane defect
Loss of surface area
Spleen clearance

Answer 11

Membrane Protein Defects: HS primarily results from mutations affecting proteins involved in vertical interactions between the membrane skeleton (cytoskeleton) and the lipid bilayer of red blood cells.

Loss of Surface Area: Normally, red blood cells have a biconcave shape, which allows flexibility and optimal surface area for gas exchange. In HS, defective proteins lead to membrane instability. As a result, red cells lose fragments of their lipid bilayer, becoming spherical (spherocytes) due to a loss of surface area relative to volume.

Spleen Clearance: Spherocytes are less deformable and rigid compared to normal red blood cells. They are prone to premature destruction as they pass through the spleen, which selectively removes abnormal red cells. This process contributes to chronic hemolysis seen in HS.

Question 12

What are the clinical features of HS?

Answer 12

Inheritance: HS is usually inherited in an autosomal dominant manner with variable expressivity. Rarely, it can be autosomal recessive. About 25% of cases arise from spontaneous mutations without a family history.

Age of Onset: Symptoms can manifest at any age, from infancy to adulthood.

Jaundice: Fluctuating jaundice is a common feature due to increased bilirubin production from accelerated red blood cell breakdown. In individuals with concurrent Gilbert’s syndrome (a liver condition affecting bilirubin metabolism), jaundice may be more pronounced.

Splenomegaly: Enlargement of the spleen (splenomegaly) occurs in most patients due to increased red cell trapping and destruction within the spleen.

Question 13

What are the possible complications of HS

Answer 13

Complications:

Pigment Gallstones: Due to excessive bilirubin production and its subsequent precipitation in the bile.

Aplastic Crises: These are acute episodes of severe anemia triggered by infections, particularly by parvovirus B19. Infections can temporarily halt red cell production in the bone marrow, exacerbating anemia in individuals with HS.

Question 14

Diagnosis: Often confirmed by laboratory tests showing characteristic spherocytes on peripheral blood smear, increased osmotic fragility of red cells, and specific genetic testing.

Question 15

How can HS be managed?

& outcome

Answer 15

Management: Treatment aims to manage anemia and prevent complications. It may involve:

Folic acid supplementation.

Management of hemolytic crises with blood transfusions.

Splenectomy in severe cases to reduce hemolysis and improve anemia.

Monitoring for complications such as gallstones and ensuring vaccinations against infections.

Treatment:

Splenectomy: This is the primary treatment for HS, particularly in symptomatic cases with significant anemia or complications such as gallstones, leg ulcers, or growth retardation. Splenectomy removes the site of excessive red blood cell destruction, leading to a rise in hemoglobin levels. Laparoscopic splenectomy is preferred when clinically indicated, although it carries risks such as post-splenectomy sepsis, especially in young children.

Cholecystectomy: If symptomatic gallstones are present, cholecystectomy (removal of the gallbladder) is often performed concurrently with splenectomy.

Folic Acid Supplementation: Given to prevent folate deficiency, particularly in severe cases where there is increased red blood cell turnover.

Outcome:

Splenectomy in HS typically results in a significant improvement in hemoglobin levels, although microspherocytes formed in other reticuloendothelial (RE) system sites may persist.

Question 16

What are the Haematological Findings in Hereditary Spherocytosis (HS):

Answer 16

Anaemia: While not always present, anaemia is a common feature in HS. Its severity tends to be consistent among family members.

Reticulocytes: Typically, reticulocyte counts are elevated to compensate for the increased red blood cell destruction. They usually range from 5% to 20%.

Blood Film: Microspherocytes are characteristic findings on the blood film in HS. These are small, densely staining red blood cells with a diameter smaller than normal red cells.

Question 17

What are the Clinical and Laboratory Features of HE

Answer 17

Similarities to HS: HE shares clinical and laboratory features with hereditary spherocytosis (HS) but is generally milder in presentation.

Blood Film Appearance: Unlike HS, the blood film in HE shows elliptical or oval-shaped red blood cells rather than microspherocytes (Fig. 6.4b).

Haemolysis: Many patients with HE do not exhibit significant hemolysis, and the condition is often discovered incidentally on a blood film.

Genetic Basis: The primary defect in HE involves spectrin heterodimers, essential components of the red cell membrane skeleton.

Question 18

What are the severe forms of HE

What the treatment?/Management of HE

Answer 18

Severe Forms: Homozygous or doubly heterozygous forms of HE can present as hereditary pyropoikilocytosis, a severe hemolytic anemia more common in individuals of African descent.

Treatment: While most cases of HE do not require treatment, occasional patients with severe symptoms may benefit from splenectomy. Folic acid supplementation is also recommended in severe cases to support red blood cell production.

Question 19

Give an overview of Hereditary stomatocytosis

Answer 19

Hereditary stomatocytosis is a rare group of inherited red blood cell membrane disorders characterized by the presence of red blood cells with a mouth-like (stoma) slit in their center on a stained blood film. These cells have abnormal permeability to cations, leading to altered cell hydration. The condition can cause variable degrees of anemia due to the leakage of cations, resulting in either dehydration (xerocytosis) or overhydration (overhydrated stomatocytosis) of the red blood cells. The severity of anemia varies among individuals, and in some cases, it may occur as an artifact if blood films are improperly prepared

Question 20

What’s South-East Asian ovalocytosis & gone an overview of it

Answer 20

South-East Asian ovalocytosis is a hereditary red blood cell disorder commonly found in regions like Melanesia, Malaysia, Indonesia, and the Philippines. It is caused by a specific genetic mutation—a 9-amino acid deletion at the junction of the cytoplasmic and transmembrane domains of the band 3 protein.

This mutation results in red blood cells that are rigid and oval-shaped, which are resistant to invasion by malarial parasites. The blood film of individuals with this condition typically shows ovalocytes and stomatocytes. Most cases are asymptomatic and do not require treatment.

Question 21

Explain how Defective Red Cell Metabolism - Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency can cause hemolytic anemia

Answer 21

Metabolic Role: G6PD enzyme catalyzes the production of NADPH, essential for reducing glutathione and protecting red cells from oxidative stress.

Genetic Basis: Deficiency results from mutations in the G6PD gene, leading to vulnerability to oxidative stress.

Clinical Manifestations: Hemolytic episodes occur upon exposure to oxidative stressors such as infections, certain foods (like fava beans), and medications (like certain antibiotics).

Treatment: Management includes avoiding triggers of oxidative stress and supportive care during hemolytic episodes.

Question 22

G6PD deficiency
The condition is sex-linked, predominantly affecting males, while females carry the gene and show about half the normal G6PD activity.

Malaria Resistance: Female heterozygotes have resistance to Falciparum malaria.

Question 23

What are the Clinical Features of G6PD Deficiency

Answer 23

Clinical Features of G6PD Deficiency

Asymptomatic Between Attacks: Individuals are usually asymptomatic with a normal blood count between episodes of hemolysis.

Main Clinical Syndromes:

Acute Hemolytic Anemia: Triggered by oxidant stress from drugs, fava beans (containing the oxidant chemical divicine), or infections. This results in intravascular hemolysis with hemoglobinuria. Depending on the G6PD genotype, the anemia may be self-limiting or life-threatening.

Neonatal Jaundice: Occurs without hemolysis.

Congenital Non-Spherocytic Hemolytic Anemia: A rare chronic anemia caused by severe enzyme deficiency (<2% of normal).

Question 24

What are the Agents that may cause haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Answer 24

Infections and other acute illnesses (e.g. diabetic ketoacidosis)
Drugs
■ Antimalarials (e.g. primaquine, pamaquine, chloroquine,
Fansidar, Maloprim, quinine)
■ Sulphonamides and sulphones (e.g. co-trimoxazole,
sulfanilamide, dapsone, sufasalazine)
■ Other antibacterial agents (e.g. quinolones, nitrofurans, nalidixic acid, chloramphenicol)
■ Analgesics (e.g. aspirin); moderate doses are safe
■ Antihelminths (e.g. β-naphthol, stibophen)
■ Miscellaneous (e.g. vitamin K analogues, rasburicase, glibenclamide, naphthalene (mothballs), probenecid)

Fava beans

Chemical oxidants

Question 25

During an Acute Crisis:
What are the blood Film Findings in G6PD deficiency?

Answer 25

Diagnosis of G6PD Deficiency

Between Acute Crises:

Normal Blood Count: Except for rare cases of congenital non-spherocytic hemolytic anemia, the blood count remains normal.

Enzyme Assays: The deficiency is identified through screening tests or direct enzyme assays on red cells.

During an Acute Crisis:

Blood Film Findings:

Contracted and Fragmented Cells: Cells showing signs of damage.

‘Bite’ Cells and ‘Blister’ Cells: Result from the spleen removing Heinz bodies.

Heinz Bodies: These are oxidized, denatured, and insoluble hemoglobin precipitates within red cells, observable especially in the absence of a spleen.

Intravascular Hemolysis: Features indicative of red cells breaking down in the circulation.

Question 26

False Normal Levels in G6PD deficiency blood film

During Acute Hemolysis: Due to higher enzyme levels in young red cells, assays might show falsely normal G6PD levels.
Post-Crisis Assay: A subsequent assay will show the low G6PD level once the red cell population stabilizes to a normal age distribution.

Question 27

What are the ways for the Treatment of G6PD Deficiency

Answer 27

Discontinue Offending Drugs: Stop any medications triggering the hemolysis.

Treat Underlying Infections: Address any infections that could be causing oxidative stress.

Maintain High Urine Output: Ensure adequate fluid supplementation.

Blood Transfusion: Perform if necessary for severe anemia.

Neonatal Jaundice Management:
Phototherapy and Exchange Transfusion: Used in severe cases to manage jaundice, which is typically due to impaired liver function from G6PD deficiency rather than excess hemolysis.

Question 28

What are the related Conditions associated with G6PD deficiency

Answer 28

Glutathione Deficiency:

Pentose Phosphate Pathway Defects: Lead to similar syndromes as G6PD deficiency, particularly affecting glutathione production.

Glycolytic (Embden-Meyerhof) Pathway Defects:

Non-Spherocytic Hemolytic Anemia: These rare defects result in congenital anemia without spherocytosis.

Associated Systems: Some defects may involve other systems, such as causing myopathy.

Common Defects: Pyruvate kinase deficiency is the most frequently encountered defect in this pathway

Pyruvate Kinase Deficiency

Inheritance and Genetics:

Inherited as an autosomal recessive condition.

Question 29

Pathophysiology & clinical features of Pyruvate Kinase Deficiency

Answer 29

Pathophysiology:

Red cells become rigid due to reduced ATP formation.

Severity of anemia varies widely (hemoglobin levels between 40–100 g/L).

Symptoms are relatively mild due to a shift to the right in the oxygen dissociation curve, caused by increased intracellular 2,3-DPG.

Clinical Features:

Common Symptoms: Jaundice and frequent gallstones.

Physical Signs: Frontal bossing (protruding forehead) and leg ulcers.

Perinatal Complications: Includes hydrops (severe edema in the fetus), prematurity, neonatal jaundice, and anemia.

Question 30

What are the Blood Film Findings & Treatment for Pyruvate Kinase Deficiency

Answer 30

Poikilocytosis: Presence of abnormally shaped red blood cells.
‘Prickle’ Cells: Distorted cells, especially after splenectomy.

Diagnosis:

Direct enzyme assay is required to confirm the diagnosis.
Treatment:

Splenectomy: Can alleviate anemia but does not cure the condition. Indicated for patients requiring frequent transfusions.

Iron Loading Management: Caused by low serum hepcidin levels from increased ineffective erythropoiesis and blood transfusions.

AG-348: A small-molecule activator of pyruvate kinase, effective and in late-stage clinical trials.

Question 31

What are the/ List the Acquired haemolytic anaemias

Answer 31

Autoimmune Hemolytic Anemias (AIHAs)

Question 32

What are the mechanism & types of Autoimmune Hemolytic Anemia

Answer 32

Mechanism:

Caused by the body producing antibodies against its own red cells.

Characterized by a positive direct antiglobulin test (DAT), also known as the Coombs’ test.

Types:

Divided into ‘warm’ and ‘cold’ types based on the temperature at which the antibodies react more strongly with red cells:

Warm AIHA: Antibodies react more strongly at 37°C.

Cold AIHA: Antibodies react more strongly at 4°C.

Question 33

What’s the pathogenesis & clinical features of Warm Autoimmune Hemolytic Anemia

Answer 33

Pathogenesis:

Red Cell Coating: Red cells are coated with immunoglobulin, primarily immunoglobulin G (IgG), either alone or with complement.

Destruction Process: Coated red cells are taken up by macrophages in the reticuloendothelial (RE) system, particularly in the spleen, where they are destroyed.

Membrane Loss: The coated membrane is partially lost, leading to the formation of spherocytes, which are ultimately destroyed prematurely.

Clinical Features:

Onset and Demographics: Can occur at any age and in either sex.

Symptoms: Presents as a hemolytic anemia of varying severity.

Spleen: Often enlarged.

Disease Course: Tends to remit and relapse.

Question 34

What are the common associates of warm AIHA

Answer 34

Associations:

May occur alone or with other diseases like lymphoid malignancies, infections, and autoimmune disorders.

When associated with idiopathic thrombocytopenic purpura (ITP), it is called Evans’ syndrome.

Commonly secondary to systemic lupus erythematosus (SLE).

Question 35

What are the lab findings in warm AIHA

Answer 35

Laboratory Findings:

Blood Film: Shows spherocytosis, which are red cells that appear more spherical.

Direct Antiglobulin Test (DAT): Positive due to the presence of IgG, IgG and complement, or IgA on the cells. Antibodies are best detected at 37°C.

Rarely, cases may be DAT negative if the surface antibody titer is too low to detect.

About 5% of hospitalized patients may show a weakly positive DAT, usually due to complement on the red cell surface without hemolysis

Question 36

Warm AIHA involves the immune system attacking red blood cells, leading to their premature destruction mainly in the spleen. It can occur alone or in association with other diseases, often presenting with hemolytic anemia and an enlarged spleen. Diagnosis includes a positive DAT and the presence of spherocytes on a blood film. Evaluation for underlying conditions is crucial in idiopathic cases.

Question 37

Treatment of Warm AIHA involves?

Answer 37

Treatment of Warm AIHA involves removing underlying causes, using corticosteroids and rituximab, considering splenectomy for refractory cases(Used if other measures fail or before splenectomy.)
, and employing immunosuppressive agents if needed.

Supportive measures
include folic acid supplementation (Essential in severe and chronic cases to prevent deficiency.) ,
blood transfusions ( Necessary if anemia is severe and symptomatic) and
thrombosis prophylaxis.

Question 38

What’s the pathophysiology of cold AIHA

Answer 38

Pathophysiology

Autoantibody: In cold AIHA, the autoantibody involved is typically IgM.

Temperature Sensitivity: These antibodies attach to red cells primarily in the cooler peripheral circulation.

Complement Fixation: IgM antibodies are efficient at fixing complement, leading to both intravascular and extravascular hemolysis.

Clinical Severity: The severity depends on the thermal amplitude of the antibody; antibodies binding at higher temperatures are more pathogenic.

Question 39

What are the types and Laboratory Findings of Cold AIHA

Answer 39

Types and Associations

Primary Cold Hemagglutinin Syndrome: Usually associated with monoclonal IgM autoantibodies.

Secondary Cold AIHA: Often linked to lymphoproliferative disorders or transient polyclonal responses following infections like infectious mononucleosis or Mycoplasma pneumonia.

Laboratory Findings

Complement Factors: Only complement components can be detected on red cells, as IgM antibodies are eluted off in warmer parts of the circulation.

Cold Agglutinin Titre: High titres (>1:512) are typical, while low titres are common and not clinically significant.

Antigen Specificity: Antibodies generally target the ‘I’ antigen on red cells; in infectious mononucleosis, the target is the ‘i’ antigen.

Question 40

Summary

Cold AIHA involves IgM autoantibodies that bind to red cells in cooler parts of the body, leading to hemolysis through complement fixation. The severity is influenced by the temperature at which these antibodies are active. It’s essential to differentiate between primary and secondary causes, including underlying infections or lymphoproliferative diseases.

Question 41

Alloimmune Hemolytic Anemias

Mechanisms:

Transfusion Reactions: ABO-incompatible blood.

Hemolytic Disease of the Newborn: Rh disease.

Post-Allogeneic Transplantation: Antibodies from donor lymphocytes destroy recipient’s red cells.

Question 42

Drug-Induced Immune Hemolytic Anemias

Mechanisms:

Drug-Red Cell Membrane Complex: Antibody directed against this complex (e.g., penicillin, ampicillin).
Complement Deposition: Drug-protein-antigen complex deposits complement onto red cell surface (e.g., quinidine, rifampicin).
True Autoimmune Hemolytic Anemia: Role of the drug is unclear (e.g., fludarabine).
Resolution: Hemolytic anemia usually resolves upon discontinuation of the drug.

Question 43

Paroxysmal Cold Hemoglobinuria (PCH)
Rare Syndrome: Acute intravascular hemolysis after cold exposure.
Donath–Landsteiner Antibody: IgG antibody specific for P blood group antigens, binds at cold temperatures but causes lysis with complement in warm conditions.
Predisposing Factors: Often viral infections.
Course: Usually self-limiting, historically associated with advanced syphilis.

Question 44

Primary Cold Agglutinin Disease (CAD)

Pathophysiology

Chronic Hemolytic Anemia: Aggravated by cold exposure, often associated with intravascular hemolysis.

Clinical Features:
Jaundice: Mild.
Splenomegaly: Occasionally present.
Acrocyanosis: Purplish discoloration at the tips of the nose, ears, fingers, and toes due to red cell agglutination in small vessels.

Laboratory Findings
Similar to Warm AIHA: Except for less marked spherocytosis.
Cold Agglutination: Red cells agglutinate in the cold.
DAT: Shows complement (C3d) only on red cell surface.
Bone Marrow: Often shows nodules of a monoclonal population of B lymphocytes, distinct from lymphoplasmacytic lymphoma.

Treatment
Keeping Warm: Essential to prevent hemolysis.
Plasmapheresis: May be needed initially to treat hyperviscosity.
Rituximab: Best first-line therapy.
Combination Therapies:
Rituximab + Fludarabine or Bendamustine: Effective.
Bortezomib-based therapy: Also used.

Second-line Therapy:
Alkylating Drugs: Chlorambucil or cyclophosphamide.
Complement Inhibition:
Eculizumab: Inhibits complement C5 but is expensive.
Sutimlimab: Inhibits complement C1, promising in early trials.
Splenectomy: Not indicated unless massive splenomegaly is present.
Corticosteroids: Less effective than in warm AIHA.

Question 45

What’s Red Cell Fragmentation Syndromes?
Overview

Answer 45

These syndromes arise from physical damage to red cells, which can occur in various situations:

Abnormal Surfaces:

Artificial Heart Valves or Arterial Grafts: Mechanical damage to red cells.
Arteriovenous Malformations: Abnormal blood flow causing cell fragmentation.

Microangiopathic Hemolytic Anemia (MAHA):

Abnormal Small Vessels: Red cells are damaged when passing through.

Underlying Causes:

Fibrin Deposition: Often associated with disseminated intravascular coagulation (DIC).

Platelet Adherence: As seen in thrombotic thrombocytopenic purpura (TTP) or vasculitis (e.g., polyarteritis nodosa).

Question 46

Laboratory Findings of Red Cell Fragmentation

Peripheral Blood: Contains deeply staining red cell fragments.

DIC: Accompanied by clotting abnormalities and low platelet count.

Question 47

List the examples of Acquired causes of haemolytic anaemia

Answer 47

Warm or cold, auto- or alloantibodies to red cells
Red cell fragmentation syndromes
Infections
Toxins
Paroxysmal nocturnal haemoglobinuria

Question 48

March Hemoglobinuria
Cause: Physical damage to red cells between small bones of the feet, typically during prolonged marching or running.
Blood Film: Does not show red cell fragments.

Question 49

Infections

Precipitation of Hemolytic Crisis: In conditions like G6PD deficiency.
Microangiopathic Hemolytic Anemia: Caused by infections such as meningococcal or pneumococcal septicemia.

Malaria:
Extravascular Destruction: Parasitized red cells.
Intravascular Lysis: Direct destruction by the parasite.
Blackwater Fever: Acute intravascular hemolysis and renal failure due to Falciparum malaria.
Clostridium perfringens Septicemia: Causes intravascular hemolysis with marked microspherocytosis.
Tick-borne Illnesses: Babesiosis can enter red cells and cause hemolysis, though usually not as severe as malaria.

Question 50

Secondary Hemolytic Anemias
Systemic Disorders: Such as inflammatory bowel disease or rheumatological syndromes, can modestly shorten red cell survival and contribute to anemia.