McCance 29 - Aplastic and Hemolytic Anemia

Aplastic Anemia (AA)

• Hematopoietic failure means reduced production of mature cells in bone marrow.
• Leads to pancytopenia (deficiency of all three blood cell types).
• Causes can be acquired like immune-mediated, chemical/physical agents, viral infections.
• Causes can be inherited like Fanconi anemia or telomerase defects.
• Idiopathic AA is the most common type.
• Symptoms include insidious onset, related to bone marrow destruction rate.
• Hypoxemia, pallor, weakness, fever, dyspnea, and hemorrhaging are symptoms.
• Diagnosis involves blood tests, showing diminished erythrocytes, leukocytes, and platelets.
• Bone marrow biopsy confirms the diagnosis.
• Treatment includes bone marrow transplant, immunosuppression using antithymocyte globulin and cyclosporine, plus supportive care.

Hemolytic Anemia

• Characterized by premature destruction of erythrocytes, either episodically or continuously.
• Can be congenital, including red cell membrane defects, enzyme deficiencies, or hemoglobin synthesis defects.
• Can be acquired, including immune hemolytic anemias or mechanical injury.
• Extravascular hemolysis occurs within phagocytes in lymphoid tissue.
• Intravascular hemolysis occurs within blood vessels due to mechanical injury, complement fixation, or toxic factors.
• Warm autoimmune hemolytic anemia is caused by IgG antibodies binding to erythrocytes at body temperature.
• Cold agglutinin autoimmune hemolytic anemia is mediated by IgM antibodies that bind to erythrocytes at colder temperatures.
• Cold hemolysin autoimmune hemolytic anemia (paroxysmal cold hemoglobinuria): Exposure to cold initiates acute intravascular hemolysis.
• Drug-induced hemolytic anemia comes from allergic reactions against foreign antigens or autoantibodies.
• Symptoms vary with the degree of anemia and hemolysis.
• Jaundice may be present.
• Diagnosis involves clinical manifestations, bone marrow studies, and blood tests.
• Treatment involves removing the cause, corticosteroids, splenectomy, rituximab, eculizumab, fluid and electrolyte replacement, transfusions, and folate.

Myeloproliferative Red Blood Cell Disorders

• Characterized by overproduction of cells in one or more hematopoietic lines.
• Polycythemia is excessive red blood cell production.
• Relative polycythemia results from hemoconcentration due to dehydration.
• Absolute polycythemia can be primary (Polycythemia Vera), which results from abnormal regulation of hematopoietic stem cells.
• Absolute polycythemia can be secondary, resulting from increased erythropoietin secretion in response to chronic hypoxia.

Polycythemia Vera (PV)

• Chronic neoplastic condition with overproduction of red blood cells, often with increased white blood cells and platelets, and splenomegaly.
• Most individuals have a JAK2 mutation.
• Symptoms include enlarged spleen, abdominal pain, increased blood viscosity, plethora, headache, visual disturbances, and aquagenic pruritus.
• Diagnosis involves increased red blood cells and total blood volume, high hemoglobin and hematocrit.
• Bone marrow examination and JAK2 mutation analysis are also used to diagnose it.
• Treatment includes phlebotomy, low-dose aspirin, hydroxyurea, radioactive phosphorus, interferon-alpha, and JAK2 inhibitors.

Iron Overload

• Can be primary (hereditary hemochromatosis) or secondary (anemias with inefficient erythropoiesis, dietary iron overload, repeated transfusions).

Hereditary Hemochromatosis (HH)

• Autosomal recessive disorder with increased gastrointestinal iron absorption and tissue iron deposition.
• Caused by mutations in the HFE gene (C282Y and H63D).
• Symptoms include fatigue, malaise, abdominal pain, arthralgias, hepatomegaly, bronzed skin, altered glucose homeostasis, and cardiac dysfunction.
• Diagnosis involves elevated serum iron, transferrin saturation, and ferritin levels, plus genetic testing.
• Treatment includes phlebotomy, avoidance of iron and vitamin C supplements, and moderation of alcohol consumption.

Thrombocytopenia

• Defined as a platelet count less than 150,000 platelets/mm3.
• Hemorrhage risk increases significantly below 50,000/mm3.
• Pseudothrombocytopenia is an in vitro artifact due to platelet agglutination.
• Causes include decreased platelet production, increased consumption, congenital conditions, or acquired conditions.

Heparin-Induced Thrombocytopenia (HIT)

• Immune-mediated drug reaction caused by IgG antibodies against heparin-platelet factor 4 complex, leading to platelet activation.
• Symptoms include thrombocytopenia and risk for venous or arterial thrombosis.
• Diagnosis involves dropping platelet counts after heparin treatment and tests for heparin-platelet factor 4 antibodies.
• Treatment is to withdraw heparin and use alternative anticoagulants such as thrombin inhibitors.

Immune Thrombocytopenic Purpura (ITP)

• Thrombocytopenia is secondary to increased platelet destruction caused by autoantibodies against platelet-specific antigens.
• Acute ITP is often seen in children, usually resolves.
• Chronic ITP is more common in adults, tends to worsen progressively.
• Symptoms include petechiae, purpura, and hemorrhage from mucosal sites.
• Diagnosis includes history of bleeding, physical examination, CBC, and peripheral blood smear.
• Treatment includes glucocorticoids, intravenous immunoglobulin (IVIG), anti-Rho(D) immune globulin, romiplostim, eltrombopag, and splenectomy.

Thrombotic Thrombocytopenic Purpura (TTP)

• Characterized by thrombocytopenia and thrombotic microangiopathy, leading to platelet aggregation and occlusion of arterioles and capillaries.
• Familial TTP is rare, chronic, relapsing.
• Acquired TTP is more common, acute, and severe.
• Most cases are related to decreased or dysfunctional ADAMTS13, an enzyme responsible for digesting large vWF molecules.
• Symptoms include thrombocytopenia, intravascular hemolytic anemia, ischemic signs (CNS involvement), kidney failure, and fever.
• Diagnosis involves blood smear reveals fragmented red cells (schistocytes), high LDH levels.
• Treatment includes plasma exchange, steroids, rituximab, and caplacizumab.

Thrombocythemia

• Platelet count greater than 450,000/mm3.
• Secondary (reactive) thrombocythemia occurs after splenectomy, infections, or inflammatory conditions.
• Essential (primary) thrombocythemia (ET) is a chronic myeloproliferative disorder with excessive platelet production due to a defect in bone marrow megakaryocyte progenitor cells.

Essential Thrombocythemia (ET)

• Thrombocythemia happens secondary to increased plasma thrombopoietin levels resulting from defects in the thrombopoietin receptor.
• Symptoms include microvasculature thrombosis such as erythromelalgia, headache, paresthesias, arterial or venous thrombosis.
• Diagnosis requires a sustained platelet count of at least 450 × 109/L, bone marrow biopsy, and exclusion of other myeloproliferative disorders.
• Treatment includes hydroxyurea, interferon, anagrelide, and aspirin.

Qualitative Platelet Function Alterations

• Increased bleeding time with normal platelet count.
• Congenital alterations are rare, affect platelet-vessel wall adhesion, platelet-platelet interactions, platelet granules and secretion, arachidonic acid pathways, and membrane phospholipid regulation.
• Acquired disorders are more common, caused by drug effects, systemic inflammatory conditions, and hematologic conditions.

Disseminated Intravascular Coagulation (DIC)

• Acquired syndrome with widespread activation of coagulation, leading to fibrin clot formation in small vessels with consumption of platelets and clotting factors.
• Causes include sepsis, trauma, malignancy, obstetric complications, and blood transfusion.
• Pathophysiology involves excessive exposure of tissue factor (TF).
• Symptoms include hemorrhage such as oozing from puncture sites, ecchymoses, thrombosis, and shock.
• Diagnosis involves clinical symptoms and laboratory tests such as thrombocytopenia, prolonged clotting times, presence of fibrin degradation products.
• Treatment involves eliminating the underlying pathology, controlling ongoing thrombosis with heparin, and maintaining organ function via fluid replacement.

Thromboembolic Disease

• Spontaneous clot formation within blood vessels.
• Thrombus is a stationary clot attached to the vessel wall.
• Embolus is a thrombus that detaches and circulates.
• Virchow triad: Injury to vessel endothelium, abnormalities of blood flow, and hypercoagulability of blood.

Hypercoagulability (Thrombophilia)

• Increased risk for thrombosis.
• Primary (hereditary) causes: Defects in proteins involved in hemostasis, such as Factor V Leiden and Prothrombin mutation.
• Secondary (acquired) causes: Clinical disorders or conditions, such as Antiphospholipid syndrome.

Anemia Overview

• Anemia is characterized by either a reduction in the total circulating red cell mass, or a decrease in the quality or quantity of hemoglobin
• Results in reduced oxygen-carrying capacity of the blood and tissue hypoxia.
• Anemias can be classified based on the underlying mechanism or by changes affecting erythrocyte size or hemoglobin content.
• Terms ending in "-cytic" refer to cell size, while "-chromic" refers to hemoglobin content.
• Additional descriptors include anisocytosis (various sizes) and poikilocytosis (various shapes).

Classification of Anemia by Underlying Mechanism

• Blood Loss
  • Acute blood loss, such as from trauma, leads to posthemorrhagic anemia.
  • Chronic blood loss, such as from gastrointestinal lesions or gynecologic disturbances, can cause iron deficiency.
• Increased Red Cell Destruction (Hemolysis)
  • Can be inherited or acquired.
  • Inherited causes include red cell membrane disorders, enzyme deficiencies, and hemoglobin abnormalities.
  • Acquired causes include antibody-mediated destruction, mechanical trauma, infections, toxic or chemical injury, and membrane lipid abnormalities.
• Decreased Red Cell Production
  • Can be inherited or acquired.
  • Inherited causes include defects leading to stem cell depletion or affecting erythroblast maturation.
  • Acquired causes include nutritional deficiencies, erythropoietin deficiency, immune-mediated injury, inflammation, primary hematopoietic neoplasms, space-occupying marrow lesions, and infections.

General Symptoms and Manifestations of Anemia

• Symptoms vary depending on the body’s ability to compensate.
• Common symptoms include shortness of breath (dyspnea), rapid heartbeat (palpitations), dizziness, and fatigue.
• Physical signs include pallor of the skin and mucous membranes.
• In hemolytic anemia, the skin may turn yellowish due to accumulation of hemolysis products.
• Severe or acute anemia can cause peripheral blood vessel constriction, salt and water retention, and decreased blood volume.
• Chronic conditions trigger the movement of interstitial fluid into the intravascular space and cause a hyperdynamic circulatory state.

Anemias of Blood Loss

• Acute Blood Loss (Posthemorrhagic Anemia)
  • Normocytic-normochromic anemia caused by acute blood loss.
  • Volume loss reduces mean systemic filling pressure, decreasing venous return.
  • Initial treatment involves restoring blood volume with intravenous fluids; large losses may require transfusion.
  • Within 24 hours, plasma is replaced by mobilizing water and electrolytes.
• Chronic Blood Loss
  • Occurs when blood loss exceeds bone marrow replacement capacity, leading to iron deficiency anemia.

Anemias of Diminished Erythropoiesis

• These anemias result from ineffective erythrocyte DNA synthesis, often due to nutritional deficiencies of vitamin B12 or folate.
• Megaloblastic Anemias
  • Characterized by abnormally large erythroid precursors (megaloblasts) in the marrow that mature into large erythrocytes (macrocytes).
  • Caused by vitamin B12 (cobalamin) or folate (folic acid) deficiencies.
  • Pernicious Anemia (PA)
    • Caused by vitamin B12 deficiency, often associated with end-stage type A chronic atrophic (autoimmune) gastritis.
    • Autoimmune gastritis impairs the production of intrinsic factor (IF), required for vitamin B12 uptake.
    • Symptoms include weakness, fatigue, paresthesias, difficulty walking, loss of appetite, abdominal pains, weight loss, and a sore tongue.
    • Neurologic manifestations may result from nerve demyelination.
    • Treatment involves lifelong vitamin B12 replacement.
  • Folate Deficiency Anemia
    • Results in megaloblastic anemia due to impaired DNA synthesis.
    • Symptoms include cheilosis, stomatitis, painful ulcerations, and gastrointestinal issues.
    • Treatment includes daily oral administration of folate.

Microcytic-Hypochromic Anemias

• Characterized by abnormally small erythrocytes with reduced hemoglobin.
• Iron Deficiency Anemia (IDA)
• The most common nutritional disorder worldwide.
• Caused by dietary deficiency, impaired absorption, increased requirement, and chronic blood loss.
• Symptoms include fatigue, weakness, shortness of breath, and pale earlobes, palms, and conjunctivae.
• Advanced symptoms include brittle nails (koilonychia), glossitis, and angular stomatitis.
• Treatment involves identifying and eliminating blood loss sources and iron replacement therapy.

Anemia of Chronic Disease (ACD)

• A mild to moderate anemia resulting from decreased erythropoiesis and impaired iron utilization in individuals with chronic systemic disease or inflammation.
• Commonly noted in hospitalized individuals and those with congestive heart failure.
• Pathophysiology
  • Decreased erythrocyte lifespan.
  • Suppressed erythropoietin production.
  • Ineffective bone marrow erythroid progenitor response to erythropoietin.
  • Altered iron metabolism and iron sequestration in macrophages.
• Characterized by abnormal iron metabolism with low circulating iron levels and high total body iron storage.
• Treatment involves alleviating the underlying disorder.

Aplastic Anemia (AA)

• Hematopoietic failure characterized by a reduction in the effective production of mature cells by the bone marrow, causing pancytopenia.
• Mechanisms include immune-mediated destruction of hematopoietic stem cells.
• Causes include chemical agents, physical agents, inherited factors, or unpredictable exposures.
• Treatment may include bone marrow transplantation.

This resource covers aplastic and hemolytic anemia. It explores hematopoietic failure, pancytopenia, causes, and symptoms of aplastic anemia. It also highlights the premature destruction of erythrocytes in hemolytic anemia.