L31: Anemias, Pt. 2 Flashcards
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)
Erythroid hyperplasia
Bone marrow responds to anemia by increasing erythropoiesis to replace RBCs lost (EPO-mediated)
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
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)
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
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
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
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)
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
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
Vertical hereditary membrane defect
Mutation in protein that disrupts the linkage b/w the transmembrane and cytoskeletal proteins
Horizontal hereditary membrane defect
Mutation in cytoskeletal protein that disrupts the cytoskeleton
Hereditary elliptocytosis
A horizontal membrane defect that causes shape change or fragmentation: elliptocytes, poikilocytosis
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
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)
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
Eculizumab
Anti-C5
A recent treatment for PNH
Inhibits complement from lysing cells
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
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
