Ch 13: Aplastic Anemia: Pathogenesis, Causes, and Related Disorders

What is aplastic anemia?

Aplastic anemia is characterized by pancytopenia due to the replacement of the bone marrow with fatty cellular depletion.

What leads to decreased production of blood cells in aplastic anemia?

The loss of functional hematopoietic stem cells (HSCs) leads to diminished production of one or all cell lines.

What are the criteria to define aplastic anemia?

1. Marrow cellularity of less than 25%. 2. At least two blood cytopenias: neutrophil count less than 500, platelets less than 20,000, or anemia with a corrected reticulocyte count of less than 1%.

What are the main causes of bone marrow failure in aplastic anemia?

Causes include decreased self-renewal of stem cells, cellular destruction, or disruption of the bone marrow microenvironment.

What percentage of aplastic anemia cases are acquired?

More than 95% of aplastic anemia cases are acquired.

What is the most common hereditary case of aplastic anemia?

Fanconi's anemia.

What are some chemical agents linked to aplastic anemia?

Benzene, trinitrotoluene, arsenic, insecticides, and weed killers.

How does benzene exposure relate to aplastic anemia?

Benzene inhibits DNA and RNA synthesis, leading to decreased proliferation and differentiation of marrow cells.

What is the effect of chloramphenicol on bone marrow?

Chloramphenicol can cause reversible bone marrow suppression or irreversible suppression weeks to months after exposure.

What role does ionizing radiation play in aplastic anemia?

Ionizing radiation has an acute destructive effect on rapidly dividing cells of the bone marrow, leading to aplastic anemia.

Which viral infections are associated with aplastic anemia?

Severe viral infections such as hepatitis, Epstein-Barr virus, and cytomegalovirus.

What are common clinical manifestations of aplastic anemia?

Symptoms include progressive fatigue, dyspnea, palpitations, bleeding, and infections.

What laboratory evaluations are typically done for aplastic anemia?

CBC showing pancytopenia, low reticulocyte count, bone marrow analysis, and tests for renal and hepatic function.

What is the typical bone marrow finding in aplastic anemia?

Bone marrow is hypocellular, often resulting in a dry tap during aspiration.

What is the prognosis for untreated aplastic anemia?

Untreated aplastic anemia has a very poor prognosis, with patients dying from bleeding and infections.

What is the preferred treatment for patients under 50 with aplastic anemia?

Bone marrow transplant is the preferred treatment, offering long-term survival rates.

What is the significance of lymphocytosis in aplastic anemia?

Lymphocytosis of 70 to 90% is observed due to decreased numbers of myeloid and monocytic cells.

What type of anemia is typically seen in aplastic anemia?

Aplastic anemia is usually normochromic and normocytic.

What is the relationship between aplastic anemia and autoimmune reactions?

Some cases are attributed to immune dysfunction or attack on bone marrow.

What are the effects of malnutrition on aplastic anemia?

Malnutrition can lead to stem cell necrosis and degenerative changes within the marrow stroma.

How long can suppression of bone marrow last due to acute infections?

Acute infections may suppress bone marrow for 10-14 days with little effect on blood counts.

What is the role of chronic infections in aplastic anemia?

Chronic infections may have a more significant impact on bone marrow function.

What is the impact of pregnancy on aplastic anemia?

Pregnancy can be associated with altered immunity and may contribute to aplastic anemia.

What are the common symptoms of aplastic anemia?

Common symptoms include fatigue, dyspnea, palpitations, and signs of bleeding.

What is the significance of a corrected reticulocyte count in diagnosing aplastic anemia?

A corrected reticulocyte count of less than 1% is one of the criteria for diagnosing aplastic anemia.

What is the effect of chemotherapeutic agents on bone marrow?

Chemotherapeutic agents can cause bone marrow suppression, which is often dose-dependent.

Why is early transplant preferred in aplastic anemia patients?

Transplant is less likely to work in patients who have received multiple transfusions.

What is immunomodulatory therapy in the context of aplastic anemia?

It involves using antithymocyte or antilymphocyte globulin, cyclosporine, or cyclophosphamide to inhibit the immune reaction.

What is Fanconi Anemia?

An autosomal recessive disorder characterized by physical abnormalities and progressive pancytopenia.

What are some physical abnormalities associated with Fanconi Anemia?

Skeletal defects, cutaneous hyperpigmentation, renal abnormalities, microcephaly, intellectual disability, and poor growth.

How does pancytopenia progress in Fanconi Anemia?

It progresses with age, with anemia and thrombocytopenia usually preceding leukopenia.

What genetic characteristics are associated with Fanconi Anemia?

Patients display genetic mutations or deletions in multiple genes, leading to unstable chromosomes and increased susceptibility to breakage.

What is the typical outcome for patients with Fanconi Anemia?

They often die from infection or hemorrhage secondary to cytopenia.

What is Dyskeratosis Congenita?

An X-linked disorder where about half of the affected patients develop aplastic anemia.

What are the clinical features of Dyskeratosis Congenita?

Abnormal skin pigmentation, dystrophic nails, and oral leukoplakia.

What is Pure Red Cell Aplasia?

An uncommon disorder where erythroid cells in the bone marrow are selectively destroyed, leading to severe anemia.

What distinguishes Pure Red Cell Aplasia from other anemias?

It only affects the red blood cell line, with normal WBC and platelet counts.

What is Diamond-Blackfan Anemia?

A congenital form of pure red cell aplasia characterized by chronic anemia that manifests early in infancy.

What is the most common mutation associated with Diamond-Blackfan Anemia?

A mutation involving a ribosomal protein on chromosome 11.

What are Congenital Dyserythropoietic Anemias (CDA)?

Disorders characterized by ineffective erythropoiesis and abnormal erythroblasts in the bone marrow.

What are the three types of CDA?

Type 1, Type 2, and Type 3, each with distinct clinical and genetic characteristics.

What is Paroxysmal Nocturnal Hemoglobinuria (PNH)?

A normocytic normochromic hemolytic anemia caused by a defect in cell membranes, making them susceptible to complement lysis.

What are the key symptoms of PNH?

Recurrent episodes of intravascular hemolysis, hemoglobinuria, and venous thrombosis.

What triggers the hemolysis in PNH?

It worsens during episodes of sleep (nocturnal hemolysis).

What is the significance of Thomas Ham's discovery related to PNH?

He discovered that PNH cells had increased sensitivity to complement, leading to their lysis when acidified.

What are the missing proteins in PNH stem cell membranes?

At least nine cell surface proteins including complement regulating proteins, membrane enzymes, and immune function proteins.

What is the role of decay accelerating factor (DAF) in PNH?

DAF accelerates the spontaneous decay of C3 convertase, helping to regulate complement activity.

What does MIRL (CD59) do in PNH?

MIRL protects the cell from the C5-C9 attack complex.

What are the three categories of PNH erythrocytes based on complement sensitivity?

1) PNH I: normal reaction with complement; 2) PNH II: low levels of MIRL and varying levels of DAF; 3) PNH III: completely or partially deficient in DAF and completely deficient in MIRL.

What are common clinical features of PNH?

Chronic hemolysis, periodic acute hemolytic episodes, bone marrow hypoplasia, and a tendency to develop thrombosis.

What triggers hemolytic episodes in PNH patients?

Infections (viral), surgery, menstruation, administration of iron, and various drugs.

What is hemosiderinuria?

A condition where iron lost in urine accumulates on renal tubule cells, common in PNH patients.

What is a major complication of PNH?

Formation of venous thromboses in hepatic, abdominal, cerebral, or subdermal veins.

What laboratory findings are characteristic of PNH?

Anemia, leukopenia, thrombocytopenia, elevated reticulocyte count, and decreased membrane acetylcholinesterase.

What is the significance of the Sugar Water Test in PNH?

It detects complement-sensitive cells by promoting lysis in a low ionic strength medium.

What does a positive Ham's Test indicate?

It confirms PNH diagnosis by demonstrating hemolysis of patient cells in acidified serum.

What is the role of flow cytometry in diagnosing PNH?

It uses monoclonal antibodies against GPI-anchored proteins to identify PNH cells.

What is the average survival rate after a PNH diagnosis?

Average survival is about 10 years.

What is the most common cause of death in PNH patients?

Thromboembolism.

What treatment is considered curative for PNH?

Allogenic bone marrow transplant, though it is limited to select patient populations.

What is Solaris (eculizumab) used for?

It is a treatment for PNH.

What are the symptoms of hemoglobinuria in PNH?

Hemoglobinuria may occur in the first morning specimen and can lead to renal failure.

What distinguishes hemoglobinuria from hematuria?

Hemoglobinuria is identified microscopically and can lead to hemoglobin casts in renal tubules.

What is the relationship between PNH and acute myelogenous leukemia?

PNH can occasionally develop into acute myelogenous leukemia, classifying it as a preleukemic syndrome.

What is the significance of decreased leukocyte alkaline phosphatase (LAP) in PNH?

It indicates decreased activity in granulocytes, ranging from zero to low normal.

What does the presence of spherocytes in PNH indicate?

Spherocytes can lyse in acidified serum due to low pH.

What is the role of the complement system in PNH?

The complement system is activated in PNH due to the deficiency of GPI-anchor proteins, leading to cell lysis.

What are the expected reticulocyte counts in PNH?

Reticulocyte counts are generally elevated.

What is the relationship between PNH and bone marrow hypoplasia?

Aplastic anemia may precede or coexist with PNH.

What is the typical hemoglobin level range in PNH patients?

Hemoglobin levels vary from normal to 26 g/dl.

What is the clinical presentation of PNH related to infections?

Patients often present with infections, headaches, and back pain.