L31: Anemias, Pt. 2 Flashcards by Preethi Gov

What are the 2 main causes of decreased RBC survival in circulation?

Intrinsic causes: problems with RBCs (most inherited)

Extrinsic causes: problems outside of RBC (acquired)

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Erythroid hyperplasia

Bone marrow responds to anemia by increasing erythropoiesis to replace RBCs lost (EPO-mediated)

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Briefly differentiate extravascular hemolysis and intravascular hemolysis

Extravascular hemolysis: macrophage-mediated; RBCs hemolyzed in macrophage in spleen, liver; get spherocytes in PB

Intravascular hemolysis: fragmentation; RBCs hemolyzed in peripheral blood; get schistocytes in PB

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What is evidence of RBC regeneration in diagnosis of hemolytic anemia?

BM: erythroid hyperplasia (in chronic hemolysis, BM may compensate for RBC loss, and no anemia develops)

PB: ~3 days after hemolytic event; ↑ retics (polychromasia on blood smear); NRBCs if anemia severe; ↑ MCV from baseline (due to retics/NRBCs which have larger volume)

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What is evidence of hemolysis in diagnosis of hemolytic anemia?

↑ unconjugated bilirubin (not immediate, takes 2 - 3 days to see increase after a hemolytic event)

↓ haptoglobin (precautions in interpretation: acute phase reactants are increased in inflammation and infections; also, is produced in liver so it decreases in liver disease)

Hemoglobinuria in intravascular hemolysis (when haptoglobin and hemoplexin are depleted and the amount of Hb in glomerular filtrate exceeds amount that can be reabsorbed)

↑ lactate dehydrogenase: released from RBCs; not specific for hemolysis; found in almost all cells and increases in cell tissue/damage, lymphoma, testicular and other cancers

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How can intravascular and extravascular hemolysis be differentiated in lab findings in hemolytic anemia?

Free plasma hemoglobin increases in intravascular

Serum haptaglobin is greatly decreased in intravascular hemolysis and somewhat decreased in extravascular

There is urine hemoglobin and urine hemosiderin in intravascular hemolysis

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What are manifestations of acute hemolysis?

Brown urine: methemoglobinuria found in intravascular hemolysis (oxidation or red hemoglobin in urine to brown methemoglobin); urine pos from blod but few or no RBCs microscopically

Malaises, aches, fever, vomiting, abdominal pain

Esophageal spasm, dysphagia, erectile dysfunction, platelet activation/thrombosis (in intravascular hemolysis, free Hb rapidly removes nitric oxide)

Renal failure (flank pain), shock, death

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Differential diagnosis for patient with brown urine

Acute hemolysis OR rhabdomyolysis (myoglobin released from damaged muscle cells is excreted in urine and appears as a brown color)

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What are manifestations of chronic hemolysis?

Fatigue, pallor

Jaundice pre-hepatic (yellow skin, sclera); ↑ unconjugated bilirubin

Cholelithiasis: gallstones due to ↑ bilirubin in bile

Kernicterus in newborns: due to diffusion of unconjugated bilirubin past the blood-brain barrier

Splenomegaly: chronic macrophage-mediated hemolysis

Bone deformities in children: due to excessive erythropoiesis

Iron overload: especially if anemia is transfusion-dependent

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What are intrinsic causes of hemolysis?

Membrane defects: mutation in transmembrane or cytoskeletal protein

Enzyme deficiencies: mutation in RBC enzyme

Hemoglobinopathies: mutation in polypeptide chain of hemoglobin

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Vertical hereditary membrane defect

Mutation in protein that disrupts the linkage b/w the transmembrane and cytoskeletal proteins

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Horizontal hereditary membrane defect

Mutation in cytoskeletal protein that disrupts the cytoskeleton

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Hereditary elliptocytosis

A horizontal membrane defect that causes shape change or fragmentation: elliptocytes, poikilocytosis

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Hereditary spherocytosis (HS)

Mutation in membrane protein (ankyrin, spectrin, others)

Vertical membrane defect

Spherocytes trapped in spleen causes extravascular hemolysis

Anemia, jaundice, splenomegaly

Mild - moderate aenmia

↑ Retics, unconjugated bili, osmotic fragility

Asplastic crisis (parovirus B19 infection)

Treatment: splenomegaly in severe cases to reduce hemolysis

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What conditions other than HS cause spherocytes?

Other inherited membrane defects

Acquired conditions that damage RBC membrane

Burns (microspherocytes and shistocytes due to thermal damage to RBC membrane for first 24 hours after thermal injury)

Microangiopathic hemolytic anemia (microspherocytes and schistocytes due to rupture of RBCs passing through small blood vessels partially blocked by thrombi)

Immune hemolytic anemia (antibody binding to RBC membrane causes membrane damage and membrane loss)

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What causes paroxysmal noctural hemoglobinuria (PNH)

Acquired membrane defect causing chronic intravascular hemolysis

Hematopoietic stem cell acquires somatic mutation in the PIGA gene on the X chromosome (absence of glycosylphosphatidylinositol or GPI anchored proteins on cell surface; affects RBCs, WBCs, and PLTs

2 GPI-anchored proteins, CD55 and CD59, protect RBC from complement lysis

Loss of CD55 and CD59 makes RBCs susceptible to complement lysis

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Eculizumab

Anti-C5

A recent treatment for PNH

Inhibits complement from lysing cells

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Features of PNH

Episodic hemoglobinuria and hemosiderinuria (not nocturnal pattern)

Venous thrombosis in unusual locations

Diagnosis: absence of CD59, CD55, and other GPI-linked proteins on cell surfaces (flow cytometry)

Triad: hemolytic anemia,pancytopenia, venous thrombosis

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What causes G6PD deficiency? What does this result in?

X-linked mutation in G6PD gene located on X chromosome

Most asymptomatic

Develop acute hemolytic anemia (within hours or days) when challenged with an oxidant stress (some drugs, infections, fava beans)

G6PD is needed to detoxify oxidants; it protects hemoglobin from oxidation and denaturation

In oxidant stress, hemoglobin is oxidized to methemoglobin (Fe3+); oxidized hemoglobin denatures and precipitates as Heinz bodies; RBCs with Heinz bodies have decreased survival and hemolytic anemia develops

What drugs cause G6PD deficiency

G6PD is PAIINS

Primaquine

Aspirin

Ibuprofen

Isoniazid

Nitrofurantoin

Sulfonamides, etc.

What are features of G6PD deficiency?

Acute hemolytic anemia after oxidant stress

↓ HGB, HCT, hemoglobinuria, hemoglobinemia

↓ haptoglobin and ↑ LD

Blood film: schistocytes, bite cells, polychromasia, NRBCs, spherocytes

Supravital stain: Heinz bodies adhere to inner membrane of RBC

Pyruvate kinase (PK) deficiency

ATP depletion in RBC leads to rigid RBCs

Hemolysis in RBCs and their precursors in BM

May see burr cells (projections on membrane) on smear

Chronic hemolytic anemia with varying clinical presentations

What are extrinsic causes of hemolysis?

Non-immune:
Microangiopathic hemolytic anemia (MAHA)
Macroangiopathic
Infectious agents
Direct injury by drugs, chemical, venoms, burns

Immune:
Autoimmune hemolytic anemia
Transfusion reactions (alloimmune)
Hemolytic disease of fetus and newborn (alloimmune)

MIcroangiopathic hemolytic anemia (MAHA)

Thrombi (platelets with or without fibrin)

RBCs are fragmented as they are pushed through thrombus in blood vessel; get schistocytes

↓ platelets (consumed in thrombi)

Found in: thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC)

Macrovascular hemolytic anemia

Anemia, schistocytes, PLTs normal Traumatic cardiac hemolytic anemia (prosthetic heart valve, aortic stenosis) Exercise-induced hemoglobinuria (rare)

Microorganisms causing hemolytic anemia

Malaria (plasmodium species, intracellular parasite) Babesia (intracellular parasite) C. perfringens sepsis (alpha-toxin hydrolyses RBC membrane phospholipids) Bartonella

Autoimune hemolytic anemia

Patient makes antibody to own RBC antigen Warm-reactive antibodies to RBCs (IgG) - CLL, SLE, drugs Cold-reactive antibodies to RBCs (IgM - cryoglobulins) - CLL, mycoplasma pneumoniae infection, infectious mono Drug-induced antibodies

Alloimmune hemolytic anemia

Patient makes antibody to RBC antigens of other cells Hemolytic transfusion reaction Hemolytic disease of the fetus and newborn

How is immune hemolytic anemia identified?

Lab: positive direct antiglobulin test (DAT) Blood film: polychromasia, may see spherocytes

When would you use DAT or IAT?

DAT if you want to see if there is antibody on cells IAT if you want to see if there are peripheral antibodies

What causes bone marrow failure?

Destruction of HSCs Ineffective hematopoiesis due to stem cell mutations or vitamin B12 or folate deficiency Disruption of BM microenvironment Deficiency of hematopoietic growth factors Infiltration of BM with abnormal cells Inherited mutations in HSCs cuasing premature aginga nd apoptosis

What can bone marrow failure lead to?

Neutropenia: infections, fever Anemia: fatigue, shortness of breath, cardiovascular abnormalities Reticulocytopenia: inability of BM to replace RBCs Thrombocytopenia: bleeding

What is aplastic anemia (AA)?

Refractory bone marrow failure affecting all cell lines: not responsive to growth factors, vitamin B12 and folate therapy

How does the bone marrow appear in aplastic anemia?

Hypocellular Hematopoietic stem cells depleted

How can aplastic anemia be acquired?

Idiopathic or primary Secondary: dose dependent (cytotoxic drugs, benzene, radiation, alcohol), idiosyncratic drugs and chemical reaction, viruses (hepatitis, parovirus B19, etc.), miscellaneous (PNH, autoimmune diseases, pregnancy)

Acquired aplastic anemia

Autoimmune T-cell mediated reaction against hematopoietic stem cells (and stromal cells) Responsible antigens not known Symptoms: Fatigue, shortness of breath, pallor (due to anemia) Fever due to bacterial or fungal infections (due to prolonged neutropenia) Petechiae, brusing, epistaxis, gum bleeding, retinal or intracranial bleeding (due to thrombocytopenia)

How is acquired aplastic anemia diagnosed?

Pancytopenia (initially only 1 or 2 cell lines may be affected) ↓ Retics (no polychromasia on peripheral blood film) MCV ↑ or normal BM cellularity ↓

Fanconia Anemia (FA)

Inherited bone marrow failure Pt inherits mutation in one of the DNA repair genes Affects HSCs and all cell lines with symptoms usually appearing at 5 - 10 years of age Variable congenital abnormalities, skin pigmentation, short stature ↑ risk of leukemia and solid tumors CBC and BM finding same as acquired AA

Diamond-Blackfan Anemia (DBA)

Pt inherits a mutation in one of the ribosomal protein genes Can have physical abnormalities Severe anemia: ↓ retics (appears < 1 yrs old) Bone marrow: ↓ in erythroid precursors only WBCs and PLTs normal

Myelophthisic anemia

Infiltration of bone marrow by abnormal cells (malignant and non-malignant); destruction of stem, progenitor, stromal cells ↓ RBC MCV normal Teardrop RBCs Leukoerythroblastic NRBCs/immature myeloid cells; abnormal cells

Anemia of chronic renal disease

↓ EPO production ↓ RBC suvival Chronic inflammation ↓ Iron availability ↓ RBCs ↓ Retics MCV normal EPO used for treatment

What is polychythemia? What are the causes?

↑ RBCs, HGB, HCT Polcythemia vera, secondary polycythemia, relative polychythemia

Polycythemia vera

Myeloproliferative neoplasm (mutation in HSC or progenitor cell; uncontrolled proliferation) ↑ in all lineages Splenomegaly >95% have JAK2 mutation

Secondary polycythemia

Conditions with ↓ O2 tension and ↑ EPO (e.g. pulmonary disease, high altitudes, congenital heart disease, smoking) Paraneoplastic polycythemia due to inappropriate ↑ EPO production

Relative polycythemia

↓ plasma volume (fluid loss, dehydration) RBC mass is normal