Info
🌱 來自: Huppert’s Notes
RBC Disorders🚧 施工中
RBC Disorders
Anemia
• Definition: Low hemoglobin (Hg <13 g/dL in men, Hg <12 g/dL in women)
• Symptoms: Fatigue, shortness of breath, dizziness, bleeding, pallor
• Work-up:
- Check reticulocyte count
• Low retic count (reticulocyte index <2) → Decreased RBC production
• Normal/high retic count (reticulocyte index >2) → RBC loss or increased RBC destruction
- If underproduction, check MCV and help refine differential diagnosis. Review differential diagnosis for each category below and ask the patient relevant questions.
- Check peripheral blood smear, which can also help inform the differential diagnosis:
• RBC morphologies:
- Spherocytes = autoimmune hemolytic anemia (AIHA), splenomegaly, post-splenectomy, hereditary spherocytosis, hemoglobin C, hemoglobinopathies
- Schistocytes = disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), thrombocytopenic purpura (TTP), scleroderma renal crisis, vasculopathies, valvular heart disease, obstetric or hypertensive emergencies
- Burr cells (echinocytes) = renal disease, artifact
- Spur cells (acanthocytes) = liver disease
• Pancytopenia +/– blasts = aplastic anemia, myelodysplastic syndrome (MDS), leukemia
- Check additional studies based on differential diagnosis (e.g., macrocytic anemia – check folate, B12, TSH, ask about alcohol use, review the patient’s medication list, etc.)
Anemia due to decreased RBC production
Normal reticulocyte index (<2%). Think of three buckets: Microcytic, normocytic, macrocytic
1.Microcytic (MCV <80 fL)
• Iron deficiency anemia:
- Etiologies: Blood loss (e.g., menorrhagia, GI bleed), malabsorption
- Diagnosis: ↓Fe, ↓Ferritin,↑TIBC. Smear with hypochromia, anisocytosis (varied size), poikilocytosis (varied shaped)
- Treatment: PO or IV iron. Every other day PO iron dosing is preferred, take on an empty stomach
• Sideroblastic anemia:
- Etiologies: Hereditary (X-linked) or acquired (e.g., lead, alcohol use, vitamin B6 deficiency, isoniazid, chloramphenicol, INH, myelodysplastic syndromes)
- Diagnosis: ↑Fe, ↓TIBC. Ringed sideroblasts in marrow. Patient may have fatigue, insomnia, hypertension
- Treatment: Pyridoxine (B6). Stop culprit agent (e.g., lead chelation, stop medication)
• Anemia of chronic inflammation:
- Pathophysiology: Inflammatory states (e.g., infection, autoimmune disease, heart failure, liver disease) upregulate hepcidin, which is an acute phase reactant, and leads to the inability to utilize iron despite normal stores
- Diagnosis: ↓Fe ↑Ferritin ↓TIBC. Can be microcytic or normocytic
- Treatment: Treat underlying disease
2.Normocytic (MCV 80–100 fL)
• Iron deficiency: Can be normocytic in early stages. See information above.
• Anemia of chronic inflammation: Can be microcytic or normocytic. See information above.
• Decreased bone marrow RBC production: Bone marrow suppression can be due to medications, alcohol, toxins, etc. Also hematopoiesis is suppressed in low erythropoietin states (e.g., CKD, endocrine disorders).
• Aplastic anemia: Idiopathic, radiation, viral, medications. Diagnosis: Pancytopenia, hypoplastic bone marrow.
• Bone marrow invasion: Malignancy (e.g., MDS, myelofibrosis, multiple myeloma), deposition diseases (e.g., amyloidosis). Diagnosis: Pancytopenia with tear drop shaped RBCs, bone marrow biopsy.
3.Macrocytic (MCV >100 fL)
• Megaloblastic: Hypersegmented neutrophils
- Folate deficiency (↓folate, ↑homocysteine)
• The body typically has a 3-month store of folate. Folate is in fruits/veggies and flour is usually supplemented with folate in the United States, so it is uncommon for patients to become folate deficient unless they are experiencing extreme food insecurity.
• Treatment: Oral folate replacement
- Vitamin B12 deficiency (↓B12, ↑homocysteine, ↑methylmalonic acid)
• The body typically has a 3-yr store of vitamin B12. B12 is in meat/fish. It is more common for patients to be B12 deficient than folate deficient, especially if vegan.
• Differential diagnosis: Low B12 dietary intake, pernicious anemia (autoimmune destruction of parietal cells), decreased gut absorption (gastrectomy, Crohn’s, celiac)
• Treatment: Intramuscular B12 shots monthly vs. oral supplementation daily
• Non-megaloblastic:
- Liver disease (more lipoproteins), hypo/hyperthyroidism, alcohol use, medications (e.g., methotrexate, hydroxyurea, antiretrovirals), reticulocytosis, MDS, multiple myeloma
Anemia due to blood loss or increased RBC destruction
Elevated reticulocyte index (>2%); if due to hemolysis: ↑LDH, ↑Indirect bilirubin, ↓Haptoglobin. Think of three buckets: Blood loss, “bad RBC,” and “bad world.”
1.Blood Loss: GI bleed, retroperitoneal bleed
2.“Bad RBC”: Hemolytic anemia due to intrinsic RBC defects – hemoglobinopathy or enzyme deficiency
Hemoglobinopathies:
• Thalassemia:
- Pathophysiology: Inherited blood disorder characterized by decreased hemoglobin production. There are two main types, alpha and beta thalassemia. Either alpha globin or beta globin genes are missing, causing an abnormal ratio of α–β chains. The unpaired chains precipitate, causing destruction of RBC precursors in the bone marrow and leading to intravascular hemolysis.
• Alpha thalassemia: There are 4 α-globin genes
- Clinical features: Clinical phenotype depends on the number of α globin genes that are lost. 1 gene lost = silent (asymptomatic); 2 genes lost = thalassemia trait; 3 genes lost = HbH significant anemia; 4 genes lost = hydrops fetalis (incompatible with live birth)
• Beta thalassemia: There are 2 β-globin genes
- β-minor: Typically causes mild anemia; no treatment needed
- β-major: Typically causes severe anemia; often associated with extramedullary hematopoiesis (skull spike, hepatosplenomegaly), risk aplastic crisis
- Diagnosis: Microcytic anemia (↓↓MCV 60–75 fL), MCV/RBC<13 (Mentzer index), normal iron studies, target cells on smear. Diagnosis with hemoglobin electrophoresis.
- Treatment: RBC transfusions; hydroxyurea (induces HbF)
• Sickle cell anemia:
- Pathophysiology: Autosomal recessive genetic disorder; HbS replaces HbA. HbS sickles when low oxygen → hemolysis and microvascular occlusion. Symptoms may start as early as age 6 months when HgF is replaced with HgS.
- Clinical features:
• Hemolytic anemia, pigmented gallstones, extramedullary hematopoiesis (hepatosplenomegaly), aplastic crisis with parvo B19 infection, increased risk of infection with encapsulated organisms due to functional asplenia (e.g., Salmonella osteomyelitis)
• Vasoocclusion: Pain crisis, dactylitis (painful swelling of the hands, more common in children), acute chest syndrome, avascular necrosis, priapism, stroke, renal papillary necrosis with painless hematuria
- Diagnosis: Sickle cells on smear, hemoglobin electrophoresis
- Treatment:
• Early vaccination for H. influenzae, S. pneumoniae, N. meningitidis
• Folic acid supplement, hydroxyurea
• Treat pain adequately
• If concern for acute chest syndrome or stroke: Consult hematology, consider exchange transfusion
• Hemoglobin C disease:
- Pathophysiology: Beta-globin chain mutation. Heterozygous = benign carrier state. Homozygous = mild hemolysis and mild to moderate anemia.
- Diagnosis: ↑MCV. No sickling. Smear: Target cells.
RBC Membrane Defects:
• Hereditary spherocytosis:
- Pathophysiology: Autosomal dominant mutation in spectrin which disrupts the vertical connections between the RBC membrane and the cytoskeleton
- Clinical features: Hemolytic anemia, jaundice, splenomegaly, bilirubin gallstones, risk of aplastic crisis
- Diagnosis: Osmotic fragility test. Smear: Spherocytes.
- Treatment: Splenectomy
• Hereditary elliptocytosis:
- Pathophysiology: Disruption of the horizontal connections between the RBC membrane and the cytoskeleton
- Clinical features: Spectrum of asymptomatic to severe hemolytic anemia
- Diagnosis: Elliptocytes on smear
- Treatment: No treatment needed typically
• Paroxysmal nocturnal hemoglobinuria (PNH):
- Pathophysiology: PIGA mutation (on X chromosome), which encodes an enzyme essential for the synthesis of glycosylphosphatidylinositol (GPI) anchors
- Clinical features: May present as hemolytic anemia, aplastic anemia, or thrombus (e.g., Budd-Chiari)
- Diagnosis: Flow cytometry of CD55/59 or FLAER for GPI anchor.
- Treatment: Bone marrow transplant, eculizumab or ravulizumab (monoclonal antibody that inhibits complement activation), +/– glucocorticoids (limited evidence)
• G6PD deficiency:
- Pathophysiology: X-linked recessive disorder; common in people of Mediterranean descent. ↓ATP so RBC is susceptible to oxidative stress. Can be triggered by medications (TMP/SMX, dapsone, sulfa), infection, fava beans.
- Clinical features: 2–4 days after oxidative stress, develop back pain, jaundice, dark urine
- Diagnosis: Smear with Heinz bodies, bite cells. G6PD levels often normal during hemolytic episode (cells with low G6PD levels already hemolyzed) → repeat labs 3 months after attack.
- Treatment: Hydrate, stop causative agent
• Pyruvate kinase deficiency:
- Pathophysiology: Autosomal recessive disorder. ↓ATP → Stiff RBC → Splenic trap.
- Clinical features: Hemolytic anemia
- Treatment: Folic acid, splenectomy
3.“Bad World”: Hemolytic Anemia Due to Factors External to RBC
• Autoimmune Hemolytic Anemia (AIHA): Auto-antibodies coat RBC surface and lead to hemolysis. Always evaluate for an underlying cause that has resulted in secondary AIHA.
- Diagnosis: Direct antiglobulin test (DAT, aka a Coombs test) to detect auto-antibodies
- IgG = warm. IgG binds RBC in body (warm) causing extravascular hemolysis.
• Causes: SLE, CLL, medications
• Treatment: Prednisone, folic acid, IVIG, splenectomy
- IgM = cold. IgM binds RBCs in extremities (cold) causing intravascular hemolysis. Peripheral sludge: Cyanosis, pain, gangrene.
• Causes: Mycoplasma pneumonia, mononucleosis, medications
• Treatment: RBC transfusions if needed, avoid cold, consider rituximab or eculizumab (no steroids or splenectomy)
• Mechanical:
- Prosthetic heart valve
- Microangiopathic hemolytic anemia (MAHA)
• Terminology: Thrombotic microangiopathy (TMA) describes specific pathological lesions in which abnormalities in the arteriole and capillary vessel walls lead to microvascular thrombosis. Not all MAHA is caused by TMA, but most TMAs cause MAHA.
• Pathophysiology: Non-immune (Coombs negative) hemolysis resulting from intravascular abnormalities or mechanical shear (i.e., prosthetic heart valve)
• Diagnosis: Smear with schistocytes, helmet cells, negative DAT
• Other: Medications, burns, toxins (snake bite, brown recluse spider), infections (Malaria, Clostridium, Babesia)