Hematology chapter 13

• Bone marrow syndromes encompass disorders with bone marrow abnormalities, the primary site of blood cell production.
• These syndromes can manifest in various ways, affecting the production of one or more blood cell types, leading to a range of clinical consequences.
• Cytopenia, is a common feature, characterized by a reduction in the number of one or more blood cell types in the circulation.
• Cytopenias can result from decreased production, increased destruction, or sequestration of blood cells.

General Characteristics of Bone Marrow Syndromes

• Bone marrow syndromes are a diverse group of disorders affecting the bone marrow's ability to produce blood cells effectively.
• These syndromes can be congenital (present at birth) or acquired (developing later in life).
• Underlying causes can include genetic mutations, exposure to toxins or radiation, infections, autoimmune disorders, and certain medications.
• One of the hallmark features of bone marrow syndromes is cytopenia.
• Cytopenia can affect red blood cells (anemia), white blood cells (leukopenia), and/or platelets (thrombocytopenia).
• The severity of cytopenia can range from mild to severe, and the clinical consequences depend on the specific type and degree of blood cell deficiency.
• Bone marrow syndromes can be associated with other abnormalities such as changes in cellularity, dysplastic features, and fibrosis.
• Bone marrow examination, including aspiration and biopsy, is essential for diagnosing and classifying bone marrow syndromes.
• These procedures allow for the evaluation of bone marrow cellularity, morphology, and the presence of any abnormal cells or infiltrates.
• Genetic testing and cytogenetic analysis may also be performed to identify underlying genetic abnormalities that contribute to the development of bone marrow syndromes.

Diagnoses Associated with Cytopenias and Hypocellular Bone Marrow

• Several diagnoses are commonly associated with cytopenias and hypocellular bone marrow (a condition characterized by a reduced number of hematopoietic cells in the bone marrow)

Aplastic Anemia

• Aplastic anemia is a bone marrow failure syndrome characterized by pancytopenia and hypocellular bone marrow.
• It can be caused by autoimmune destruction of hematopoietic stem cells, exposure to toxins or drugs, viral infections, or inherited genetic mutations.
• The diagnosis of aplastic anemia typically requires a bone marrow biopsy showing hypocellularity with a paucity of hematopoietic cells.

Myelodysplastic Syndromes (MDS)

• MDS are a group of clonal hematologic disorders characterized by dysplastic changes in one or more myeloid cell lines and ineffective hematopoiesis.
• MDS can present with cytopenias in one or more cell lines, and the bone marrow may be normocellular, hypercellular, or hypocellular depending on the subtype of MDS.
• Hypocellular MDS is a specific subtype characterized by hypocellular bone marrow and dysplastic features.
• The diagnosis of MDS requires a bone marrow examination showing dysplasia in at least one cell line and excluding other causes of cytopenia.

Pure Red Cell Aplasia (PRCA)

• PRCA is a rare disorder characterized by a selective deficiency of red blood cells, resulting in anemia.
• The bone marrow in PRCA typically shows a marked reduction or absence of erythroid precursors, while other cell lines are usually normal.
• PRCA can be caused by autoimmune mechanisms, viral infections (such as parvovirus B19), thymoma, or certain medications.
• The diagnosis of PRCA requires a bone marrow examination showing a selective absence of erythroid precursors.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• PNH is a rare acquired disorder characterized by the absence of certain surface proteins (GPI-anchored proteins) on blood cells, making them susceptible to complement-mediated destruction.
• PNH can present with hemolytic anemia, thrombosis, and cytopenias.
• The bone marrow in PNH may be normocellular or hypocellular, and some patients may develop aplastic anemia or MDS as a complication of PNH.
• The diagnosis of PNH is based on flow cytometry analysis showing the absence of GPI-anchored proteins on blood cells.

Inherited Bone Marrow Failure Syndromes

• Several inherited genetic disorders can cause bone marrow failure and cytopenias.
• These include Fanconi anemia, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome.
• Fanconi anemia is characterized by pancytopenia, congenital abnormalities, and an increased risk of developing leukemia.
• Diamond-Blackfan anemia is characterized by selective red blood cell deficiency, while Shwachman-Diamond syndrome is characterized by pancreatic insufficiency and bone marrow failure.
• The diagnosis of these inherited bone marrow failure syndromes requires genetic testing to identify the underlying genetic mutation.

Other causes of hypocellular bone marrow

• In addition to the above diagnoses, other conditions can also be associated with cytopenias and hypocellular bone marrow.

• These include:

  • Infections (e.g., HIV, parvovirus B19)
  • Medications (e.g., chemotherapy drugs, immunosuppressants)
  • Autoimmune disorders (e.g., systemic lupus erythematosus)
  • Nutritional deficiencies (e.g., vitamin B12, folate)
  • Exposure to toxins or radiation

• In summary, bone marrow syndromes encompass a diverse range of disorders characterized by abnormalities in the bone marrow and often presenting with cytopenias.

• Hypocellular bone marrow is a common finding in many of these syndromes, and the underlying causes can be varied.

• Accurate diagnosis requires a thorough evaluation of the patient's medical history, physical examination, and laboratory findings, including a bone marrow examination and genetic testing.

Acquired Aplastic Anemia (AAA)

Major Characteristics

• AAA is characterized by the gradual or sudden onset of pancytopenia.
• It is typically caused by an immune-mediated destruction of hematopoietic stem cells.
• The bone marrow is hypocellular, with a significant reduction in all hematopoietic cell lines.
• There are no abnormal or malignant cells present in the bone marrow.
• Cytogenetic abnormalities are typically absent, helping to distinguish it from myelodysplastic syndromes (MDS).
• The remaining hematopoietic cells are usually morphologically normal.

Clinical Features

• Patients with AAA may present with a variety of symptoms related to pancytopenia.
• Anemia can cause fatigue, weakness, pallor, and shortness of breath.
• Thrombocytopenia can lead to easy bruising, petechiae, nosebleeds, and prolonged bleeding after injuries.
• Leukopenia, particularly neutropenia, increases the risk of bacterial and fungal infections.
• Infections may be severe or recurrent due to the impaired immune response.
• Some patients may experience bleeding complications, which can be life-threatening.
• In severe cases, patients may require frequent blood transfusions and platelet transfusions to manage the cytopenias.
• Splenomegaly and lymphadenopathy are typically absent, which helps distinguish AAA from other bone marrow disorders.
• Untreated severe AAA can be fatal due to infections or bleeding.

Iatrogenic Causes of Acquired Aplastic Anemia

• Iatrogenic refers to a condition or illness caused by medical examination or treatment.

• Three substances that can cause acquired aplastic anemia are:

  • Chemotherapy drugs
  • Immunosuppressants
  • Certain antibiotics

• APA refers to antiphospholipid antibody syndrome, an autoimmune disorder characterized by blood clots and/or pregnancy complications, in association with antiphospholipid antibodies.

• Viral infections have been implicated as potential triggers for the development of antiphospholipid antibodies (aPL) and subsequent APA.

• Four virus infections associated with APA include:

Cytomegalovirus (CMV)

• CMV is a common herpesvirus that infects a large proportion of the population.
• CMV infection has been linked to the transient production of aPL in some individuals.
• In certain cases, CMV infection may trigger persistent aPL production and the development of APA manifestations.
• The mechanisms by which CMV induces aPL are not fully understood, but molecular mimicry and immune activation are thought to play roles.
• Molecular mimicry refers to the similarity between viral antigens and certain phospholipids or phospholipid-binding proteins, leading to the production of cross-reactive antibodies.
• Immune activation during CMV infection can also result in the release of cytokines and other inflammatory mediators that promote aPL production.

Epstein-Barr Virus (EBV)

• EBV is another common herpesvirus that causes infectious mononucleosis and is associated with various autoimmune diseases.
• EBV infection can induce the production of aPL, which may be transient or persistent.
• The association between EBV and APA has been reported in several studies.
• EBV can activate B cells, leading to the production of aPL.
• Molecular mimicry between EBV antigens and phospholipid-binding proteins may also contribute to aPL production.
• EBV can induce epigenetic changes that promote the expression of genes involved in autoimmunity.

Hepatitis C Virus (HCV)

• HCV is a bloodborne virus that causes chronic liver infection and is associated with several extrahepatic manifestations, including autoimmune disorders.
• HCV infection has been linked to the development of aPL and APA.
• The prevalence of aPL is higher in individuals with HCV infection compared to the general population.
• Cryoglobulinemia, often associated with HCV infection, can contribute to aPL production.
• HCV can directly infect B cells and stimulate aPL production.
• Molecular mimicry between HCV antigens and phospholipid-binding proteins may also play a role.

Human Immunodeficiency Virus (HIV)

• HIV is a retrovirus that infects immune cells and causes acquired immunodeficiency syndrome (AIDS).
• HIV infection has been associated with the development of aPL and APA.
• The prevalence of aPL is increased in HIV-infected individuals, particularly those with advanced disease.
• Several mechanisms may contribute to aPL production in HIV infection.
• HIV can directly infect B cells and stimulate aPL production.
• Immune activation and chronic inflammation associated with HIV infection can also promote aPL production.
• Molecular mimicry between HIV antigens and phospholipid-binding proteins may also play a role.

Antiphospholipid Antibodies (aPL)

• The immune process implicates the development of antiphospholipid syndrome (APS), leading to the production of aPL.
• APS is characterized by thrombosis (blood clots) and/or pregnancy complications in individuals with aPL.
• aPL are a diverse group of antibodies that bind to phospholipids and phospholipid-binding proteins.
• The most commonly tested aPL include lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-β2 glycoprotein I (anti-β2GPI) antibodies.
• These antibodies are not typically found in healthy individuals but are present in those with APS.

Mechanisms of aPL-Mediated Thrombosis

• aPL can induce thrombosis through multiple mechanisms, affecting various components of the coagulation system, platelets, and endothelial cells.

Activation of the Coagulation Cascade

• aPL, particularly LA, can interfere with phospholipid-dependent coagulation assays, leading to an overestimation of clotting time in vitro.
• In vivo, aPL can enhance thrombin generation, a key enzyme in the coagulation cascade that converts fibrinogen to fibrin, leading to clot formation.
• aPL can bind to prothrombin, enhancing its activation to thrombin on cell surfaces.

Platelet Activation

• aPL can bind to platelets, causing their activation and aggregation. The activation leads to the release of prothrombotic factors, such as thromboxane A2 and platelet-derived microparticles, further promoting clot formation
• aPL can also increase the expression of adhesion molecules on platelets, facilitating their interaction with other cells and the vessel wall.

Endothelial Cell Activation

• Endothelial cells line the inner surface of blood vessels and play a critical role in maintaining vascular homeostasis
• aPL can bind to endothelial cells, causing their activation and dysfunction
• This activation leads to increased expression of adhesion molecules, such as E-selectin and VCAM-1, which promote the recruitment of inflammatory cells.
• aPL-mediated endothelial cell activation can also result in increased production of tissue factor, a potent initiator of the coagulation cascade and decreased production of anticoagulant molecules like thrombomodulin and protein C.

Complement Activation

• The complement system is a part of the innate immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells.
• aPL can activate the complement system, leading to the generation of pro-inflammatory and prothrombotic mediators.
• Activation of the complement cascade results in the formation of the membrane attack complex (MAC), which can damage endothelial cells and promote thrombosis
• Complement activation also leads to the release of anaphylatoxins, such as C3a and C5a, which recruit and activate immune cells, further amplifying the inflammatory response.

Role of β2 Glycoprotein I (β2GPI)

• β2GPI is a plasma protein that binds to negatively charged phospholipids
• It acts as a cofactor for many aPL, particularly aCL and anti-β2GPI antibodies.
• aPL binding to β2GPI on cell surfaces can induce intracellular signaling, leading to cell activation and the production of prothrombotic mediators
• β2GPI can also inhibit the intrinsic coagulation pathway, and aPL binding can interfere with this anticoagulant function.

Mechanisms of aPL-Mediated Pregnancy Complications

• aPL can lead to various pregnancy complications, including recurrent miscarriage, preeclampsia, and fetal growth restriction.
• These complications are thought to arise from impaired placental development and function.

Impaired Trophoblast Function

• Trophoblasts are cells that form the outer layer of the blastocyst, which provides nutrients to the embryo and develops into a large part of the placenta.
• aPL can directly bind to trophoblasts, interfering with their differentiation, invasion, and function
• This impaired trophoblast function can lead to inadequate placental development and reduced blood flow to the fetus.

Inflammation at the Maternal-Fetal Interface

• aPL can induce inflammation at the maternal-fetal interface, leading to the release of cytokines and chemokines that disrupt normal placental function.
• Activation of immune cells, such as macrophages and NK cells, can contribute to placental damage and fetal loss.

Complement Activation in Pregnancy

• Complement activation plays a critical role in aPL-mediated pregnancy complications
• Activation of the complement cascade at the maternal-fetal interface can lead to inflammation and placental damage, contributing to adverse pregnancy outcomes.

Other Factors

• Genetic and environmental factors also play a role in the development of APS.
• Certain HLA alleles and infections have been associated with an increased risk of developing aPL and APS.
• Environmental triggers, such as infections and certain medications, can also induce aPL production in genetically predisposed individuals.

Laboratory Findings in APA

• Diagnosis of APA requires laboratory confirmation of aPL presence.

• Laboratory tests for aPL include:

  • Lupus anticoagulant (LA) assays: These detect the presence of antibodies that interfere with phospholipid-dependent coagulation reactions
  • Anticardiolipin antibodies (aCL): Measured by ELISA, these detect antibodies against cardiolipin
  • Anti-β2 glycoprotein I (anti-β2GPI) antibodies: Also measured by ELISA, these detect antibodies against β2GPI

• For a diagnosis of APA, the aPL must be present on at least two occasions, at least 12 weeks apart, to rule out transient aPL positivity associated with infections

• Other associated lab findings can include thrombocytopenia, which occurs due to aPL-mediated platelet activation and destruction

Manifestation of APA After Acute Radiation Exposure

• Acute radiation exposure can lead to bone marrow suppression, resulting in cytopenias, including lymphopenia.
• Radiation-induced immune dysregulation can potentially trigger or exacerbate autoimmune conditions such as APA in predisposed individuals.
• Post-radiation, aPL may appear or increase, leading to a higher risk of thrombotic events.
• Thrombocytopenia may also worsen due to both direct radiation effects on megakaryocytes and aPL-mediated platelet destruction.
• Monitoring for aPL and thrombotic events is important in individuals exposed to significant radiation, especially those with pre-existing autoimmune conditions or a genetic predisposition.
• The combined effect of radiation and APA can lead to severe complications, including bone marrow failure, infections, and bleeding disorders.

Fanconi Anemia

• Etiology: Genetic mutations affecting DNA repair pathways.
• Pathophysiology: Impaired DNA repair leads to genomic instability, bone marrow failure, and increased cancer risk.
• Laboratory Findings: Pancytopenia, chromosomal breakage on diepoxybutane (DEB) or mitomycin C (MMC) testing.

Familial Aplastic Anemia

• Etiology: Inherited genetic defects affecting hematopoietic stem cells.
• Pathophysiology: Reduced numbers or impaired function of hematopoietic stem cells lead to bone marrow failure.
• Laboratory Findings: Pancytopenia, hypocellular bone marrow.

Dyskeratosis Congenita

• Etiology: Mutations affecting telomere maintenance.
• Pathophysiology: Shortened telomeres lead to bone marrow failure, abnormal skin pigmentation, nail dystrophy, and increased cancer risk.
• Laboratory Findings: Pancytopenia, short telomeres, abnormal skin and nail findings.

Pure Red Cell Aplasia (PRCA)

• Etiology: Autoimmune, viral infections (e.g., parvovirus B19), or idiopathic.
• Pathophysiology: Selective destruction or suppression of erythroid precursors in the bone marrow, leading to anemia.
• Laboratory Findings: Anemia with reticulocytopenia, normal white blood cell and platelet counts, absence of erythroid precursors in bone marrow.

Dyserythropoietic Anemia

• Etiology: Genetic mutations affecting erythroid differentiation or hemoglobin synthesis.
• Pathophysiology: Ineffective erythropoiesis leads to anemia with abnormal erythroblasts in the bone marrow.
• Laboratory Findings: Anemia, elevated bilirubin, abnormal erythroblasts (e.g., multinucleated) in bone marrow.

Shwachman-Diamond Syndrome

• Etiology: Mutation in the SBDS gene.
• Pathophysiology: Ribosomopathy affecting multiple organ systems, including bone marrow, pancreas, and skeleton.
• Laboratory Findings: Neutropenia, pancreatic insufficiency (low fecal elastase), skeletal abnormalities.

Congenital Amegakaryocytic Thrombocytopenia (CAMT)

• Etiology: Mutations in the MPL gene (thrombopoietin receptor).
• Pathophysiology: Impaired megakaryocyte development leads to severe thrombocytopenia and eventual bone marrow failure.
• Laboratory Findings: Severe thrombocytopenia, reduced or absent megakaryocytes in bone marrow.