Anemia

Anemia of chronic disease:

• Mediated by IL-6

  • Promotes hepcidin expression → decreased intestinal absorption and storage of ferritin in macrophages

    • Transferrin downregulated

    • Erythropoiesis becomes iron restricted (since iron not accessible) 

    • May eventually lead to iron deficiency due to lack of GI absorption

Hemolytic anemia (Separate section below)

Iron deficiency anemia (Separate post "Iron Metabolism and Diseases")

Iron refractory iron deficiency anemia (IRIDA):

• Inherited order of systemic iron balance in which both absorption and utilization of iron is impaired

• Significant microcytosis (MCV 45-65) and anemia (Hb 6-8)

• Associated with TMPRSS6 gene

Atransferrinemia/ Hypotransferrinemia:

• Autosomal recessive

• Causes iron overload and microcytic/hypochromic anemia

• Treatment: FFP infusion, iron chelation

Paroxysmal Nocturnal Hemoglobinuria (PNH):

• Acquired mutation in PIGA gene → loss of GPI anchored cell surface proteins (which help attach other surface proteins, such as CD55/CD59)

  • RBCs lacking CD55/CD59 → complement activation + IgG against P antigen on RBCs → intravascular hemolysis + venous and/or arterial thrombosis (common cause of death)

• Associated with paroxysmal cold hemoglobinuria (PCH)

• Typically only develop symptoms or requirement treatment with PNH clones >30% of blood cells

  • AA may have small PNH populations ~1%

• HSCT is the only cure

• More commonly treated with complement inhibitors

  • Patients need meningococcal+pneumococcal vaccination before starting complement inhibitors

  • Lifelong therapies, expensive

  • Eculizumab: C5 inhibition, blocks intravascular hemolysis

    • (IV) Weekly loading x 4, followed by q2 week maintenance

  • Ravulizumab: C5 inhibition, blocks intravascular hemolysis

    • (IV) q2 week loading x 2, followed by q8 week maintenance

  • Pegcetacoplan: C3 inhibition, blocks intravascular and extravascular hemolysis (PEGASUS)

    • Increases baseline Hb 

    • SQ injection, patient administered, q2 weeks

Sideroblastic anemia:

• Presence of ringed sideroblast in bone marrow

• Most patients have iron overload

• Respond to Vitamin B6

Erythropoietic Porphyria:

• Subtypes:

  • Congenital erythropoietic porphyria (CEP)

  • Erythropoietic protoporphyria (EPP)

• (Porphyria is discussed in a separate lecture "Iron Metabolism and Diseases")

Myelonecrosis/Serous Atrophy:

• Associated with anorexia/ Cachexia, HIV or autoimmune diseases.

• Causes hypoplasia, fat atrophy, gelatinous transformation of bone marrow

• Treat underlying cause, generally reversible

Nutritional Deficiency/Excess:

• Folate deficiency

• B12 deficiency:

  • Associated with megaloblastic/macrocytic anemia, hypersegmented neutrophils

  • Due to dietary deficiency or poor GI absorption (pernicious anemia)

  • Low retic count

  • Can be associated with metformin

    • Due to metformin’s interaction with Ca dependent membrane action

    • Treat with Vit B12 +/- calcium supplementation

• Copper/ceruloplasmin deficiency:

  • Necessary to convert iron from ferric to ferrous

  • Common after gastric bypass

  • Associated with neurotoxicities and neutropenia

  • BMbx shows vacuoles in RBC precursors/Ringed sideroblasts/can mimic MDS

  • Labs can look like iron deficiency

• Excessive zinc:

  • Found in a lot of over the counter supplements

  • Mechanism: Zinc competes with copper for absorption → copper deficiency, microcytic anemia

Abnormal oxygen affinity hemoglobin:

• Diagnosed with p50 (normal is 26mmg Hg)

  • High affinity/low p50 (<24 mmHg) → Hb not dropping off oxygen to tissues → polycythemia

  • Low affinity/high p50 (>30 mmHg) → Hb is dropping off excess oxygen to tissues → anemia (feedback loop)

Acute megaloblastosis:

• Typically young patient using recreational drugs or N2O (nitrous oxide) → inactivates B12

• Can causes neurological defects (like B12 deficiency)

• Treat with b12/folate

VEXAS syndrome:

• Vacuolization in marrow cells

• E1 ubiquitin activating enzyme (encoded by UBA1 gene)

• X-linked

• Autoinflammatory 

• Somatic mutation

• Sign/Symptoms:

  • Anemia, rash, cartilaginous structures affected, lungs, joints, vasculature

Loxoscelism:

• Severe reaction to a Brown recluse spider bite

• Causes hemolysis and skin necrosis

Hemolytic Anemia

Premature destruction of red blood cells:

• Numerous mechanisms:

  • Immune vs. non-immune mediated

  • Hereditary vs. acquired

  • Intravascular vs. extravascular

  • Intrinsic vs. Extrinsic

• Membrane shedding and activation of coagulation complexes can increase risk of thrombosis

Labs:

• low haptoglobin (binds free Hb), high LDH, high indirect bili, elevated retic count/polychromasia

• Urine hemosiderin (usually with intravascular hemolysis)

Intrinsic Hemolytic Anemia

• PNH

• Hemoglobinopathy (Separate post "Red Cell Disorders"):

  • Sickle cell disease

  • Thalassemia

  • Hemoglobin C (beta chain)

  • Hemoglobin E (beta chain) 

  • Hemoglobin Lepore (beta chain)

  • Hemoglobin M

• Enzymatic defects:

  • G6PD deficiency:

    • More common in mediterranean (more severe) or african descent

    • X-Linked (typically male patient)

    • Enzyme defect in the pentose phosphate pathway → generation of reducing agents in cells

    • Coombs negative/ non-immune mediated

    • Triggers which cause hemolysis:

      • Food: Fava beans

      • Medications: Sulfa drugs, Rasburicase, Dapsone, Nitrofurantoin, Primaquine

      • Infectious: hepatitis, CMV, enterovirus, dengue, coronavirus, bacterial infections

    • Treatment is supportive

    • DO NOT test for G6PD deficiency during acute episode (can be falsely normal)

      • Send the test (direct gene sequencing) after 1-2 weeks

  • Pyruvate kinase deficiency:

    • Autosomal recessive

    • Caused by mutations in the PKLR gene

    • Lack of pyruvate kinase → depletion of ATP → disturbs cation gradient, loss of H2O and potassium → cell dehydration → echinocytes (Buzzzz word)

    • Signs and symptoms: splenomegaly, jaundice, gallstone, leg ulcers

    • Treatment:

      • Red cell transfusions 

      • Mitapivat (Pyruvate kinase activator)

      • Splenectomy (historical, in severe cases)

• Membrane abnormalities:

  • Spherocytosis:

    • Mild anemia, gallstones

    • Diagnosed with Eosin-5-maleimide testing

      • Osmotic fragility test is outdated and not routinely used

    • Direct antiglobulin test (DAT) negative/ non-immune mediated

    • Most mutations are in ankyrin, spectrin, Band 4.2

    • Managed with splenectomy

  • Elliptocytosis:

    • Autosomal dominant

    • Most mutations in spectrin

    • Pyropoikilocytosis is more severe form (MCVs in 30-50s)

  • Acanthocytosis:

    • Associated with McLeod Syndrome

      • X-linked

      • Lack of Kell expression on RBCs

  • Echinocytes:

    • Associated with uremia, liver disease, and hyperlipidemia

Extrinsic Hemolytic Anemia

• Immunologic

  • Diagnosed with Coombs test/DAT

    • Detects IgG and/or complement (C3) on surface of RBC

  • Warm Agglutinin Disease:

    • Associated with autoimmune diseases, viruses and Evan’s syndrome

    • IgG Ab weakly activate complement, but do not agglutinate spontaneously

      • Typical pattern is IgG++, C3+/-

    • Mostly extravascular hemolysis (in spleen)

    • Treatment (in order of preference):

      • Glucocorticoids ± Rituximab

        • Prednisone 1-2 mg/kg for 2-3 weeks and then slow taper dose

        • Rituximab weekly x 4 doses

      • Glucocorticoids and/or IVIG

      • Splenectomy

      • Azathioprine, cyclosporine A, cyclophosphamide, MMF

  • Cold Agglutinin Disease:

    • Primary clonal B cell disorder (Waldenstrom Macroglobulinemia, lymphoma) vs. secondary to underlying condition (EBV, mycoplasma, autoimmune diseases)

      • Consider imaging or BMBx to find underlying cause

    • Smear shows RBC clumping

    • IgM Ab agglutinate RBCs at lower temperatures (0-30 degrees) and activate complement (fixes C3 onto red cells)

      • Typical pattern is IgG- and C3+

    • Targets the I or i antigen on RBC surfaces

    • Mostly intravascular hemolysis, liver (not spleen) removes the C3b coated RBCs

    • Treatment: 

      • Treat underlying cause (steroids, antibiotics, antivirals)

        • Bendamustine/Rituximab

        • Fludarabine/Rituximab

        • Rituximab alone

        • Sutimlimab (Ab that targets C1s protein)

      • Consider PLEX in acute setting if urgent (ACS, stroke)

      • Splenectomy is not helpful (Liver is the organ of RBC destruction)

    • Cryoglobulin is a cold antibody (cold reacting IgM, IgG, or IgA) but cryoglobulinemia is a vasculitis (may present with purpura) and is not typically associated with hemolysis

      • Usually underlying process: hepatitis C, HIV, autoimmune, lymphoma, vaccination

  • Medication induced hemolysis:

    • Various mechanisms:

      • Alteration of antigen on normal membrane

      • Hapten reactions

        • Medication (Penicillins, cephalosporins, tetracyclines) binds to RBC membrane (now is a part of the antigen) → antibody reacts → RBC destruction

  • Infectious hemolysis:

    • Malaria:

      • Associated with anopheles mosquito (female)

      • Treatment: chloroquine, hydroxychloroquine, quinine, atovaquone, doxycycline

    • Babesia (Babesiosis):

      • Associated with tick bite (incubation 1-4 weeks)

      • Previous history of splenectomy causes more severe cases

      • Associated with “maltese cross” seen on RBC smear

      • Treat with atovaquone/azithromycin with RBC exchange

  • Mechanical hemolysis:

    • Microangiopathic hemolytic anemia (MAHA)

      • Small vessel platelet microthrombi

      • Some medications can cause TTP-HUS

        • Quinine, gemcitabine, oxaliplatin, bactrim, quetiapine

    • Valve hemolysis (typically mechanical aortic valve)

      • Mild hemolysis is normal due to shearing

      • Severe hemolysis may be associated with paravalvular leak

      • Schistocytes seen on smear, urine hemosiderin

  • Chemical hemolysis:

    • Lead poisoning → acquired deficiency of pyrimidine-5-nucleotidase → accumulation of pyrimidine-containing nucleotides in RBCs → chronic hemolysis + basophilic stippling