Aplastic A

Question 1

What’s Pancytopenia

Answer 1

Pancytopenia refers to a condition where there is a reduction in the counts of all three major types of blood cells

Question 2

What are the major Causes of Pancytopenia

Answer 2

Pancytopenia can be caused by:

Decreased bone marrow production: The bone marrow is not producing enough blood cells. This could be due to conditions like aplastic anemia.

Increased peripheral destruction: Blood cells are being destroyed faster than they can be produced

Question 3

What’s aplastic Anemia

Answer 3

Aplastic anaemia is defined as pancytopenia resulting from hypoplasia of the bone marrow

It occurs when the bone marrow becomes hypoplastic, meaning it doesn’t produce enough new blood cells.

Question 4

Aplastic anaemia can be categorized into?

Answer 4

Primary: Either congenital (present at birth) or acquired (develops later).

Secondary: Caused by external factors like certain drugs, radiation, or infections.

Question 5

In aplastic anemia, there is a significant reduction in the number of which stem cell?

Answer 5

haemopoietic pluripotential stem

The remaining stem cells may not function properly due to an inherent defect or an immune response against them.

Question 6

List examples of Congenital Marrow Failure Syndromes

Answer 6

: Fanconi Anemia
DKC
SDS
Diamond–Blackfan Anemia (DBA):
Severe Congenital Neutropenia:
Amegakaryocytic Thrombocytopenia:
Thrombocytopenia with Absent Radii:

Question 7

What’s fanconi anemia?

Answer 7

Anemia

Fanconi anemia (FA) is a genetic disorder with an autosomal recessive inheritance pattern, meaning a child must inherit two defective genes (one from each parent) to develop the condition.

Question 8

What are the Characteristics and Symptoms of Fanconi Anemia

Answer 8

Physical abnormalities:

Growth retardation.

Congenital defects in bones (e.g., small head, missing radius bones or thumbs).

Renal tract abnormalities (e.g., abnormal kidney shapes like pelvic or horseshoe kidneys).

Skin pigmentation changes (areas of darker or lighter skin).

Intellectual ability: Generally normal, though learning disabilities can occur.

Question 9

What are the genetical basis of FA?

Answer 9

FA involves mutations in at least 16 different genes (FANC A–Q).

FANCD1 is identical to BRCA2, which is known for its role in breast cancer susceptibility.

The proteins produced by these genes work together in a pathway important for DNA repair. This pathway includes the ubiquitination of the FANCD2

dimer, a crucial step in protecting cells from genetic damage.

Question 10

Cells from FA patients are prone to ______ breakage.

Answer 10

spontaneous chromosomal breakage

Question 11

What’s the Age of Presentation of GA

What are the possible Complications: of FA

Answer 11

FA typically presents in children aged 3–14 years, but it can also be diagnosed in adults.

Around 10% of FA patients develop myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). MDS and AML are types of blood cancers that affect the bone marrow and blood cell production

Question 12

What are the possible treatment of FA & side effects

Answer 12

Androgens:

Androgens are male hormones that can help improve blood counts.

Side effects, especially in children, can include virilization (development of male characteristics such as deep voice and facial hair) and liver abnormalities.

The improvement in blood counts usually lasts less than 2 years.

Stem Cell Transplantation (SCT):

SCT can potentially cure the bone marrow failure.

However, FA patients have an increased risk of developing epithelial cancers (cancers of the tissues lining organs).

SCT does not address growth retardation or other congenital defects.

Because FA patients are highly sensitive to DNA damage, the conditioning regimens (preparatory treatments) for SCT are mild, and radiation is avoided.

Question 13

Myelodysplastic Syndromes (MDS)
What is MDS?

MDS is a group of disorders caused by poorly formed or dysfunctional blood cells.
It occurs when something goes wrong in the bone marrow, leading to the production of abnormal blood cells.
Characteristics:

Ineffective hematopoiesis: The bone marrow produces blood cells that are immature or abnormal.
Cytopenias: Low counts of one or more types of blood cells (red cells, white cells, platelets).
Dysplasia: Abnormal shape and appearance of blood cells.
Symptoms:

Anemia: Fatigue, weakness, paleness.
Neutropenia: Increased risk of infections due to low white blood cell counts.
Thrombocytopenia: Increased risk of bleeding and bruising due to low platelet counts.
Progression:

MDS can remain stable for years or progress to acute myeloid leukemia (AML).

Question 14

Acute Myeloid Leukemia (AML)
What is AML?

AML is a type of cancer that starts in the bone marrow but often moves quickly into the blood.
It involves the rapid growth of abnormal white blood cells.
Characteristics:

Blasts: The bone marrow produces a large number of immature white blood cells (blasts) that do not function properly.
Crowding out: These blasts crowd out normal blood cells, leading to deficiencies.
Symptoms:

Anemia: Fatigue, weakness, shortness of breath.
Neutropenia: Frequent infections.
Thrombocytopenia: Easy bruising, bleeding, petechiae (small red spots under the skin).
Other symptoms: Bone pain, swollen gums, weight loss.
Progression:

AML progresses rapidly and requires prompt treatment.

Question 15

Why FA Patients are at Risk
FA patients have a genetic predisposition that affects DNA repair mechanisms.
This predisposition increases the likelihood of developing mutations in the bone marrow cells, which can lead to MDS or AML.

Question 16

What are the possible causes of Decreased Bone Marrow Function which is a sign of pancytopenia

Answer 16

Decreased Bone Marrow Function (with cellular marrow):

This means the bone marrow is still active but not functioning properly.

Examples:

During an acute infection: The body may temporarily reduce blood cell production.

Aplastic anemia: The bone marrow fails to produce sufficient blood cells.

Acute leukemia and myelodysplastic syndromes (MDS): Blood cancers that disrupt normal blood cell production.

Infiltration: Conditions where other cells invade the bone marrow, like lymphoma, myeloma, metastatic solid tumors, and tuberculosis.

Megaloblastic anemia: A condition often caused by vitamin B12 or folate deficiency, leading to large, dysfunctional red blood cells.

Paroxysmal nocturnal hemoglobinuria (PNH): A rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells.

Myelofibrosis: A disorder in which scar tissue forms in the bone marrow.

Hemophagocytic lymphohistiocytosis (HLH): A severe systemic inflammatory syndrome

Question 17

What are the possible causes of Increased Peripheral Destruction: which is a cause of pancytopenia

Answer 17

Blood cells are being destroyed faster than they are produced.
Example:
Microangiopathic processes: Conditions like thrombotic thrombocytopenic purpura (TTP) where small blood clots form in vessels and destroy blood cells.
Splenomegaly: Enlargement of the spleen which can sequester and destroy blood cells excessively.

Question 18

What are the characteristics of Dyskeratosis Congenita (DKC)

& its associated risk

Answer 18

Description:

DKC is a rare genetic disorder with a classic triad of symptoms:

Nail dystrophy: Abnormal growth and appearance of nails.

Lacy reticular pigmentation: A net-like pattern of pigmentation on the upper chest and neck.

Oral leukoplakia: White patches inside the mouth.

Associated Risks:

DKC patients are at high risk for:

Pulmonary fibrosis: Scarring of lung tissue.

Cirrhosis: Scarring of the liver.

Osteoporosis: Weak and brittle bones.

Marrow failure: The bone marrow fails to produce enough blood cells.

Epithelial cancers: Includes cancers of the oral cavity, esophagus, and uterine cerv

Question 19

What are the genetic basis of DKC

Answer 19

Genetic Basis:

DKC is associated with mutations in genes like DKC1, TERC, TERT, which are involved in telomerase function. Telomerase helps maintain the length of telomeres (protective caps on chromosomes).

Milder forms of telomere shortening may cause some syndrome features without the nail and skin abnormalities.

Question 20

So how do you diagnose DNC & it’s treatment

Answer 20

Diagnosis:

Telomere length measurement: Typically done in lymphocytes (a type of white blood cell).

Genetic testing: Looks for mutations in telomere complex genes.

Treatment:

Androgens:

Can improve blood counts and potentially lengthen telomeres.

Stem Cell Transplantation (SCT):

Can cure bone marrow failure but doesn’t eliminate the risk of epithelial cancer, cirrhosis, or pulmonary fibrosis.

Question 21

Imagine a book (chromosome) with protective covers (telomeres) that prevent the pages (genetic material) from getting damaged. In DKC, these covers are too short, making the book prone to wear and tear. Treatments like androgens can temporarily strengthen the cover, while SCT replaces the book’s content but doesn’t address the fundamental issue of weak covers

Question 22

So what’s DKC?

Question 23

What’s Shwachman–Diamond Syndrome (SDS) & it’s features

Answer 23

Description:

SDS is a rare autosomal recessive genetic disorder. Key features include:

Cytopenia: Low levels of various blood cells, especially neutropenia (low neutrophils, a type of white blood cell).

Exocrine pancreatic dysfunction: The pancreas doesn’t produce enough digestive enzymes.

Skeletal abnormalities, hepatic impairment, and short stature are also common.

Question 24

What are the associate risk of SDS

Answer 24

Associated Risks:

SDS patients have a propensity to develop myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).

Question 25

What are the genetic basis of SDS

Answer 25

Genetic Basis:

Caused by mutations in the SBDS gene, which plays a role in ribosome assembly (essential for protein synthesis).

Question 26

List Other Inherited Bone Marrow Failure Syndromes:

Answer 26

Diamond–Blackfan Anemia (DBA): Characterized by anemia due to failure to produce red blood cells.

Severe Congenital Neutropenia:
Low neutrophil counts leading to increased infection risk.

Amegakaryocytic Thrombocytopenia:
Low platelet counts due to the absence of megakaryocytes in the bone marrow.

Thrombocytopenia with Absent Radii:
Low platelet counts and missing radius bones in the forearms.

Question 27

What’s the most acquired aplastic anemia

Answer 27

Idiopathic Acquired Aplastic Anemia

This is the most common type of acquired aplastic anemia, accounting for at least two-thirds of cases

Question 28

What’s Idiopathic acquired aplastic anemia

Answer 28

Idiopathic acquired aplastic anemia is a condition where the bone marrow fails to produce enough blood cells due to an unknown cause.

Idiopathic acquired aplastic anemia: Mainly an autoimmune disorder where immune cells attack bone marrow, with treatment aimed at modulating the immune response.

Question 29

Short not on Idiopathic acquired aplastic anemia

Answer 29

In idiopathic acquired aplastic anemia, we recognize that the bone marrow failure is due to an autoimmune process, but the exact reason why this autoimmune process started is unknown

Autoimmune Mechanism:

The immune system (specifically cytotoxic CD8+ T cells) attacks the bone marrow.
This attack leads to a reduction in the production of all types of blood cells (pancytopenia).

This immune attack can be triggered by factors like infections or genetic mutations affecting immune pathways, such as the STAT3 signaling pathway.

Clonal Hematopoiesis:

In about half of the cases, some bone marrow cells acquire additional mutations and continue to survive and produce blood cells. This process is called clonal hematopoiesis.

These surviving cells have mutations in specific genes (like PIGA, BCOR, ASXL1, etc.) that help them endure in the failed bone marrow environment.

Question 30

Challenges in Diagnosis:

It’s sometimes difficult to differentiate idiopathic acquired aplastic anemia from late-onset congenital forms of aplastic anemia or from hypoplastic myelodysplastic syndromes (MDS), a related bone marrow disorder.

Question 31

What’s the treatment of idiopathic acquired aplastic anaemia

Answer 31

Treatment:

Treatments that suppress the immune system are often effective. These include:

Anti-lymphocyte globulin (ALG) and anti-thymocyte globulin (ATG): These treatments target and reduce the activity of the immune cells attacking the bone marrow.

Cyclosporine: A medication that suppresses the immune system to prevent further attacks on the bone marrow.

Question 32

What are the Secondary Causes of Aplastic Anaemia? & examples

Answer 32

Drug-induced Aplastic Anaemia:

Mechanism: Certain medications can directly damage the bone marrow where blood cells are produced.

Examples:

Antimetabolite drugs: Such as methotrexate and mitotic inhibitors like daunorubicin cause temporary aplasia (cessation of blood cell production).

Viral Hepatitis:

Association: Aplastic anaemia can develop during or shortly after viral hepatitis infections, even when standard hepatitis viruses are not detected.

Chemical Exposure:

Implicated Agents: Chemicals such as benzene are known to potentially cause aplastic anaemia.

Leukaemia and Myelodysplastic Syndromes (MDS):

Rare Presentations: Aplastic anaemia can rarely manifest as an initial symptom of acute lymphoblastic or myeloid leukaemia, especially in children.

Hypoplastic MDS: Myelodysplastic syndromes can also present with a hypoplastic bone marrow, making it challenging to distinguish from aplastic anaemia.

Question 33

What are the clinical features of Secondary Causes of Aplastic Anaemia

Answer 33

Clinical Features

Age Distribution: Aplastic anaemia can onset at any age but shows peak incidences around 10-25 years and over 60 years.

Geographical Variations: It’s more common in certain regions like Asia (e.g., China, Vietnam) compared to Europe or the Americas.

Symptoms: Presentation can be insidious (gradual onset) or acute, with symptoms related to low blood counts:

Anaemia: Fatigue, weakness.
Neutropenia: Increased susceptibility to infections, especially oral and throat infections.

Thrombocytopenia: Easy bruising, bleeding gums, nosebleeds, and heavy menstrual bleeding in women.
Additional Features: Retinal hemorrhage may affect vision, and infections can become life-threatening due to compromised immunity.

Physical Examination: Enlarged lymph nodes, liver, or spleen are typically absent. A thorough history and examination are crucial to rule out inherited forms or bone deformities.

Question 34

What are the possible lab findings in aplastic anaemia

Answer 34

Hemoglobin Levels: Typically below 100 g/L.

Red Blood Cell Characteristics:

Color: Normochromic (normal color), normocytic (normal size), or macrocytic (larger than normal).

Mean Cell Volume (MCV): Often in the range of 95-110 fL.

Reticulocyte Count: Usually extremely low relative to the degree of anaemia, indicating reduced production of new red blood cells.

Neutropenia:

Neutrophil Count: Less than 1.5 × 10^9/L.

Severe Neutropenia: Defined as neutrophils less than 0.5 × 10^9/L. Very severe cases may have neutrophils less than 0.2 × 10^9/L.

Thrombocytopenia:

Platelet Count: Less than 50 × 10^9/L.

Severe Thrombocytopenia: Defined as platelets less than 20 × 10^9/L.

Question 35

What does Bone Marrow Examination look like in aplastic anaemia

Answer 35

Bone Marrow Examination:

Hypoplasia: The bone marrow shows reduced cellularity with significant loss of hematopoietic (blood cell-producing) tissue. Fat cells may occupy more than 75% of the marrow space.

Reduced Cellularity

Question 36

What’s the general treatment of aplastic anaemia

Answer 36

General Management:

Supportive Care: Includes blood transfusions, platelet concentrates, and infection prevention and treatment.

Blood Product Precautions: All blood products should be leukodepleted (removal of white blood cells) and irradiated to reduce risks.

Antifibrinolytic Therapy: Drugs like tranexamic acid may be used to control bleeding in severe thrombocytopenia.

Granulocyte Transfusions: Rarely used but may be considered for severe bacterial or fungal infections not responding to antibiotics.

Antimicrobial Therapy: Oral antibiotics and antifungal drugs may be prescribed to prevent infections.

Question 37

List specific treatment of aplastic anaemia

Answer 37

Androgens

Mechanism: Improve blood counts but do not improve survival.

Side Effects: Significant side effects with chronic use, including virilization, salt retention, and liver damage.

Management: Discontinue if no response within 4-6 months; gradual withdrawal if there is a response.

Stem Cell Transplantation (SCT)

Cure Potential: Offers a chance of permanent cure, especially in young patients with severe aplastic anaemia and a matching sibling donor.

Conditioning: Typically involves cyclophosphamide without irradiation to prepare the bone marrow for transplant.

Sources: Marrow grafts preferred over peripheral blood due to lower risk of graft-versus-host disease (GVHD).

Non-myeloablative Transplants: Used in older patients or those with less severe disease.

Risk Reduction: In vivo T cell depletion and high-dose cyclophosphamide post-infusion reduce GVHD risk.

Haemopoietic Growth Factors

G-CSF: May produce minor responses but does not lead to sustained improvement.

Limited Efficacy: Other growth factors besides eltrombopag have not proven helpful in aplastic anaemia treatment.

Iron Chelation Therapy

Indication: Needed in patients requiring regular red cell transfusions to manage iron overload.

Question 38

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Question 39

What’s Paroxysmal nocturnal haemoglobinuria & it’s clinical triad

Answer 39

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired disorder characterized by a clonal mutation affecting marrow stem cells.

*“Paroxysmal nocturnal haemoglobinuria (PNH)** is a rare blood disorder where stem cells in the bone marrow have a genetic mutation. This mutation leads to a lack of certain proteins on the surface of red blood cells, making them prone to destruction by the body’s immune system.
This causes ongoing red blood cell breakdown (haemolysis), leading to symptoms like dark urine due to released haemoglobin, fatigue, and a higher risk of blood clots. PNH can also cause bone marrow failure, affecting the production of other blood cells. Treatment includes medications to suppress the immune system, prevent blood clots, and newer drugs that target the underlying genetic problem.

Clinical Triad:

Chronic Intravascular Haemolysis: Due to increased sensitivity of red blood cells to complement-mediated destruction.

Venous Thrombosis: Can occur in various venous distributions (e.g., portal, hepatic, mesenteric veins) and occasionally in arteries (e.g., strokes, myocardial infarctions).

Bone Marrow Failure: Often presents as hypoplasia or even aplastic anaemia due to the clonal expansion of PNH stem cells.

Question 40

What’s the clinical manifestation of Paroxysmal nocturnal haemoglobinuria

Answer 40

Clinical Manifestations:

Haemosiderinuria: Results in iron deficiency, exacerbating anaemia.

Symptoms: Include abdominal pain from mesenteric vein thrombosis, dysphagia, erectile dysfunction, and pulmonary hypertension due to nitric oxide depletion.

Laboratory Findings: Absence of haptoglobins, continuous haemolysis (despite the name), and evidence of chronic intravascular haemolysis.

Question 41

Possible treatment of Paroxysmal nocturnal haemoglobinuria

Answer 41

Iron Therapy: Used to manage iron deficiency resulting from chronic haemolysis.

Anticoagulation: Long-term use of warfarin may be necessary to prevent thrombotic complications.

Immunosuppression: Can be beneficial, particularly in cases with concurrent bone marrow failure.

Stem Cell Transplantation: Offers a potential cure, especially in severe cases or those progressing despite other therapies.

Question 42

What’s Red Blood Cell Aplasia?

Answer 42

Red cell aplasia refers to a group of rare syndromes characterized by anemia, normal white blood cell and platelet counts, and a significant reduction or absence of erythroblasts (immature red blood cells) in the bone marrow

Question 43

What are the forms of red cell Aplasia

Answer 43

Chronic Forms:

Congenital (Diamond–Blackfan anaemia): Inherited as a recessive condition typically diagnosed in early childhood, often associated with physical abnormalities. It results from mutations in genes that encode ribosomal proteins.
Treatment includes corticosteroids as the first-line therapy, with stem cell transplantation (SCT) considered curative. Androgens may also help, but they can have severe side effects on growth. Iron chelation therapy is necessary with frequent transfusions

Acquired: Can occur without a known cause (idiopathic) or be associated with autoimmune diseases (especially systemic lupus erythematosus), thymoma, lymphoma, or chronic lymphocytic leukemia. Treatment involves immunosuppressive therapies such as monoclonal antibodies like rituximab (anti-CD20). In severe cases, SCT may be considered.

Transient Form:

Parvovirus B19 infection: Infects red cell precursors, causing a transient (5–10 days) red cell aplasia. This infection can lead to sudden severe anemia, especially in individuals with conditions like sickle cell disease or hereditary spherocytosis, who already have shortened red blood cell survival. Transient red cell aplasia can also occur in association with certain drug therapies or in normal infants and children following a viral infection.

Question 44

What’s Congenital dyserythropoietic anaemias (CDAs) & it’s clinical features

Answer 44

Congenital dyserythropoietic anaemias (CDAs) are a group of rare inherited disorders characterized by ineffective erythropoiesis and abnormalities in red blood cell development. Here are the key points about CDAs:

Clinical Features:

Patients typically present with refractory anemia, often noticed in infancy or childhood.

Jaundice may be present due to increased bilirubin levels, and there is often bone marrow expansion.

White blood cell and platelet counts are usually normal.

Despite increased marrow cellularity, the reticulocyte count is low relative to the degree of anemia.

Question 45

What’s the complications & management of Congenital dyserythropoietic anaemias (CDAs)

Answer 45

Complications and Management:

Iron overload may develop due to chronic transfusion therapy.

Splenomegaly (enlarged spleen) is common.

Treatment strategies may include supportive care with blood transfusions and iron chelation therapy to manage complications.

For some types, hematopoietic stem cell transplantation (SCT) offers a potential cure by replacing the defective bone marrow with healthy stem cells.