Hematology
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| How is blood count? | First investigation done (but overdone), three main components (RBC count (important to look at) and HB, Total |
| What are the roles of eosinophils and basophils? | Eosinophils against parasites, allergic responses. Basophils unclear role |
| What are the roles of eosinophils and basophils? | Eosinophils against parasites, allergic responses. Basophils unclear role |
| How are reticulocytes? | They are RBC nucleated, they carry alot of RNA and can be detected by supravital staining live 2-3 days, 2% of RBCs, number of reticulocytes is useful in clinical test (increased ->marrow more active than normal, decreased ->production problem) They come from pronormoblast, which gives normoblasts, that differentiate into reticulocyte which loses its nucleus to become RBC |
| How is blood composition? | Volume (70ml/kg), composed of cells circulating in plasma 55% plasma, 45% RBCs, <1% WBCs and platelets. Serum is coagulated blood, plasma we added anti-coagulant like Ca citrate. |
| How is hemopoiesis occurring? | In bone marrow, stem cells give pluripotent stem cells, which divide into lymphoid progenitor and CFU-GEMM Lymphoid progenitor gives T cells (IL12), B cells (IL6) and NK cells CFU (colony forming unit)-GEMM (IL3) gives CFU-GM (gives monocyte and neutrophil ~ G-CSF [myeloid cell]), Basophil progenitor gives basophil, eosinophil progenitor gives eosinophil (IL5), Megakaryocyte progenitor gives megakaryocyte (TPO) and thus platelets, erythroid progenitor gives erythrocytes (EPO) |
| What are hemopoietic stem cells? | Rare subtype of cells in bone marrow, gives all blood cells, expresses CD34+, exists in stem cell niche of bone marrow, supported by cells surrounding, distributed in a range of conditions. |
| What are red cells? | 1,000 times more common than WBC, no nucleus live 120 days, carry oxygen to tissues, flexible shape allows migration through capillaries. Regulated by EPO Normal cells are 7 microns, highly flexible, biconcave shape Contain hemoglobin, consists of 4 protein chains each w/ a pocket for heme, and 4 iron (heme) |
| What are lymphocytes? | Cells mediate immune function, can survive for many years and circulate around blood and through lymphoid tissues (so in blood transfusion it is important to irradiate the blood to not get and WBC to acceptor). Two subtypes T and B cells B cells make Ab, T cells regulate immunity, help B cells and can kill virally infected cells 95% are found w/in lymphoid tissue, enter through lymph nodes or high endothelial venules and leave nodes through lymphatic vessels into blood Most are found in MALT (colon, tonsils, bronchus...) |
| What are neutrophils? | Play a role in bacterial and fungal infections, released from bone marrow and survive 2-3 days, ingest bacteria and cells that have been covered w/Ab, kill using toxic enzymes and oxygen radicals They have multilobed nucleus, contain granules destroy bacteria, then undergo phagocytosis (PAMP recognition/Ab attachement/ Complement) |
| What are monocytes? | Cells migrate to tissues and become macrophages, ingest bacteria, play a role in triggering immune response Help ingest pathogens, link innate immunity to adaptive |
| What are platelets? | Fragments of cytoplasm which bud off megakaryocytes in bone marrow, can stick to areas of damage w/in blood vessel and trigger formation of a blood clot. |
| How is bone marrow structure? | Almost all bones of children are hemopoietic bone marrow, in adults it is in vertebra and proximal long bones, stem cells are found in niche w/in bone marrow. |
| How is structure of spleen? | Areas of red pulp and white pulp, blood system has a unique open pattern not contained w/in capillaries. Spleen has hemopoietic and immune functions |
| How are reticulocytes? | They are RBC nucleated, they carry alot of RNA and can be detected by supravital staining live 2-3 days, 2% of RBCs, number of reticulocytes is useful in clinical test (increased ->marrow more active than normal, decreased ->production problem) They come from pronormoblast, which gives normoblasts, that differentiate into reticulocyte which loses its nucleus to become RBC |
| How is the regulation of erythropoiesis? | By EPO, if the kidney detects hypoxia it releases EPO, which stimulates increased production of red cells. Also EPO are elevated in people who live in high altitudes or who have lung disease (due to low O2) |
| How is O2 dissociation curve for Hb? | Hb releases O2 easier than myoglobin to allow tissue transfer of O2, at pO2 = 100mmhg SaO2=100% (arterial), 75% in 40 mmHg (venous). 2,3-DPG shifts dissociation curve to right as it increases, so does CO2 increase, H+ increase, and temperature increase |
| How is CO2 transport by Hb? | Carbonic anhydrase generates H2CO3 (carbonic acid) from CO2, which dissociates into bicarbonate and H+, where protons are buffered by Hb into HbH+ |
| What are the roles of eosinophils and basophils? | Eosinophils against parasites, allergic responses. Basophils unclear role |
| How is hx in pt w/blood disorders? | Depends on clinical problem RBC (anemia, fatigue, SoB), WBC (unusual prolonged infections, if excess lumps and swellings), platelets (bruising and bleeding) |
| How is examination of pt w/blood disorders? | Broad general exam, nails, skin mucus membranes may suggest anemia (glossy tongue = iron deficiency), lymph node exam may suggest leukemia/ lymphoma, bruising suggest platelet disorder. |
| How is blood count? | First investigation done (but overdone), three main components (RBC count (important to look at) and HB, WBC count, and platelet count) Normal RBC (4-6 * 10^12), Hb (13.5-17.5 male and -2 for females), MCV (80-95 normal, less microcytic and more macrocytic) White cells (normal 4-7 *10^9, decrease leukopenia, increase leukocytosis, may be lymphocyte or neutrophil alone) Platelets (normal 150-400 * 10^9, low thrombocytopenia seen in poor production and increased destruction and high cytosis increase risk of blood clot) |
| What is blood film? | Used to prepare for microscopic analysis for properly prepared smears, may be thin film or thick film (for malaria) |
| How is assessment of blood clotting done? | Two major tests, Activated partial thromboplastin time (APTT) and prothrombin time (PT) test different components of clotting cascade |
| How is examination of bone marrow done? | We take a specimen of bone marrow and inspect it, may be aspiration or biopsy, usually done from pelvis (posterior iliac spine) or sternum (usually only aspiration not biopsy since very painful and risky) We see cytosis of bone marrow and fat tissue, w/ age fat predominates and cytosis is decreased, important to know in order to see any disorder according to the age of presentation |
| What additional investigation techniques that may be used in hematology? | Genetic analysis (karyotype, WBC DNA, mutation analysis) US (liver/ spleen for splenomegaly in cytosis for example) CT , MRI (for brain and neuromuscular imaging no X ray use) PET (radiolabeled glucose taken up by tumor cells, see lymphoma tx) |
| What are red cell disoders? | Reduced number or Hb concentration (Anemia) body gets O2 deprived and SoB that is due to either decrease in production or increase in loss Decreased production (by nutritional deficiency (B12, iron, folate), reduced erythroid cells by malignancy, ineffective red cell formation in case of thalassemia and chronic disease/ kidney problem) Increase in red cells (polycythemia) causes problems like thick blood, increased risk of clot, may be natural response to hypoxia high EPO, but can occur due to clonal expansion of red cell precursors (polycythemia vera) EPO normal or low |
| How is size of red cell useful in dx of red cell disorder? | Microcytic hypochromic cells (MCV and MCH low, iron deficiency/ thalassemia) Normocytic (acute blood loss, hemolysis, chronic disease, marrow infiltration) Macrocytic (MCV high, megaloblastic anemia/ vitamin deficiency) |
| What are white cell disorders? | Deficiency (increases risk of infection) like neutropenia (caused by drugs/ infection, very risky if below 0.5) Lymphopenia is rare from immune deficiency. Increase in WBC more common, called leukemia, 4 major types: Acute leukemia (rapid) chronic (slow), lymphoid or myeloid Tx specific for each type Lymphoma (malignant WBC accumulate in lymphoid tissues not blood, may be hodgkins (Reed-Sternberg cells in biopsy/ non-hodgkins) May be myeloproliferative disease (increased production) or myelodysplastic syndromes (active marrow dysfunctional cells) Myeloma (malignant disease of plasma cells) |
| What are disorders of platelets? | Deficiency (thrombocytopenia) leads to bruising and bleeding, caused by autoimmune/ drugs Increased (thrombocytosis) cause clots and bleeding Sometimes function impaired (use of aspirin) Deficiency in proteins of clotting can be inherited disorder or later in life (Hemophilia A deficiency in factor VIII most imp) Acquired can be severe infection/ complication after birth. Clot problems are more important than bleeding disorders (increased susceptibility for clotting) and risk increases w/bed rest/ surgery/ arrhythmia, so use of anti-thrombotics is very widely seen |
| How are red cell disorders? | Some of the most common diseases, anemia can result from many conditions (iron deficiency, Hbpathies, chronic infection) Hemolytic anemia occurs w/red cell lifespan is reduced, increased nb of red cells are seen in polycythemia (myeloproliferative disease in response to hypoxia) Anemia is very common worldwide |
| What is anemia? | Reduction in Hb levels in blood, must take into consideration age and gender (above 18 males normal [13,14.5], females [12,14], under 18 each age group has values at birth high, decreases at 1 months, and starts increasing after 2 months) Symptoms of anemia (tiredness, SoB, poor concentration, palpitations, pallor) |
| How are classifications of anemia by MCV? | Microcytic (MCV<80) seen in iron deficiency, thalassemia. Normocytic (80-95) seen in chronic infection, renal disease, marrow disease Macrocytic (MCV>95) seen in hemolytic anemia, vitamin B12 and folic acid deficiency |
| How is iron physiology? | Metabolism (absorption regulated highly preventing toxicity, no pathway of excretion of excess iron, can be toxic in excess damage DNA) Body iron compartments (Hb (Males 2.5g, females 1.9g), myoglobin less (300mg), enzymes less (180mg), transferring much less (2.7mg), ferritin and hemosiderin (800 mg male 300 mg female), total in female 2.7g in male 3.8g) 70% stored in Hb, 25% in reticuloendothelial system (ferritin, hemosiderin), 5% myoglobin, cytochromes, enzymes and <1% transferrin in plasma Absorption is in upper small intestine (after gastric secretion convert them into Fe2+), most are not absorbed, some go in intestinal mucosa make ferritin and are excreted after shedding 1mg iron, only iron needed for erythropoiesis is absorbed into blood by hepatocyte 1mg/day bound to transferrin. |
| How is iron absorption in small bowel regulated? | Enhanced absorption (seen in iron deficiency, increase erythropoiesis, dietary factors are ascorbic acid (Vit C) and heme vs. nonheme Fe) Inhibited absorption (seen in increased iron stores, cause inflammation, dietary factors are tannins (tea) and phytates (bran)) Regulation of metabolism by hepcidin (which increases Fe storage in macrophages and decrease it in blood and absorption by hepatocytes by binding ferroportin on macrophages and enterocytes degrade them, increased activity in case of inflammation and increased Fe, decreased in case of increased hemopoiesis and Fe deficiency |
| How is heme biosynthesis by immature red cells? | In mitochondria (glycine and succinyl CoA acted on by ALA synthase and vitamin B6 to form ALA, which will become protoporphyrin, which combines w/ iron from ferritin or transferrin coming from cytosol to become Heme) In cytosol (Globin chains are formed by translation, combines w/ heme to make hemoglobin tetramer) |
| What is iron deficiency? | Most common finding in people around the globe, major cause is chronic blood loss through menstruation, GI blood loss (malignancy/inflammation), if no obvious cause of bleed check other causes (dietary insuff, malabsorption) Tx (oral iron, IV iron can be given for intolerant people/ malabsorption cause) |
| What is sideroblastic anemia (SA)? | Group of inherited and acquired anemia, iron accumulates in mitochondria of erythrocyte precursors. Inherited (X recessive, more in males, abnormality synthesis of protoporphyrin decreased Hb, iron accumulated cause ring sideroblast, iron laden mitochondria ring around nucleus of RBC precursor in bone marrow, basophilic stippling in peripheral smear (no2at)), Acquired (alcoholism, B6 deficiency, lead poisoning, Cu deficiency, age>74) |
| What is thalassemia? | Other major cause of microcytic anemia, imbalance of a and b globin, a deficiency in a (deletion), b defect b chain (mutation), tx blood transfusion. a thalassemia (more in asian, maybe minor (2/4 alleles affected mild microcytic anemia), HbH disease (3/4 affected, cause chronic hemolytic anemia, lead to beta tetramer (HBH) and Bart'sHbG increase in electrophoresis), hydrops fetali (4/4 alleles affected, total body edema fetal, barts Hgb high) Beta thalassemia (more in MENA, required at six months (may be minor (asymptomatic, decreased HbA increased A2 and normal F, tx avoid oxidative stress) or major (anemia at six months, no HbA, increased A2 and F, splenectomy tx, folate supplement, transfusion , may die due to transfusion iron overload) We see decreased Hb and MCV and normal or increased RBC count (Mentzer ratio= MCV/RBC if less than 13-> thalassemia if more iron deficiency or inflammation. |
| What are some findings in thalassemia? | Skull radiography of child w/beta thalassemia we see massive expansion of hemopoiesis w/in bone marrow (even skull) so leads to hair on end appearance on skull Xray. We may see hepatosplenomegaly due to extramedullary hemopoiesis. If regular transfusions are given iron chelation is a must to avoid iron poisoning. |
| What is normocytic anemia? | Chronic inflammation (iron sequesters in macrophages, reduce iron levels w/no increase in iron binding capacity, tx of underlying disease) could be renal disease (kidney produce EPO suppressed by kidney damage, so give EPO injection for CKD pt) Could be bone marrow disease (reduced RBC, WBC and platelets, can't produce normal cells, infiltration w/leukemia, myeloproliferative disease, infiltration w/carcinoma/aplastic anemia) |
| What is macrocytic anemia? | Large erythroblasts (megaloblast), multilobed nuetrophils, due to deficiency of vitamin B12 or folate Pernicious anemia (autoimmune Ab against gastric parietal cells and intrinsic factor prevent B12 absorption in terminal ileum, neuropathy can occur lead to numbness and if severe blindness or dementia, tx vitamin B12 PRL) Folate deficiency (when we have excess need for folate like pregnancy/hemolytic anemia, give folic acid tablets |
| What is hemolytic anemia? | Shortened half life lead to increasing reticulocytes, which are larger than RBC (increase MCV), lifespan may go below 15 days then develop anemia. Classified into inherited (Red cell mmb, cytoskeleton, Red cell enzymes, Hb) and acquired (autoimmune, PNH, infection...) |
| What is hereditary spheocytosis? | Abnormality in gene of spectrin (ankyrin protein band 3.0 and 4.1) Red cell is smaller and more dense than usual, tx folic acid and when necessary splenectomy, other examples are hereditary elliptocytosis (mutation in spectrin/ankyrin/band 3/band 4.1/4.2 defects impair elastic deformability of RBC lead to spherocytic shape of RBC (not biconcave disc) We see MCHC >36 (CBC), smear see spheocytes and some polychromatophilia (reticulocytosis), increased LDH and bilirubin, decreased haptoglobin, elevated reticulocyte count (in hemolysis testing), Coombs test negative (not autoimmune) Confirmatory test (EMA binding (eosin-5-maleimide, binds membrane proteins of RBC), or osmotic fragility test (OFT) |
| What is pre-splenectomy vaccination done for HS? | Immunization for encapsulated organisms should be given (vaccine for pneumococcal disease, hemophilus influenza, meningococcal diseases) |
| What is G6PD deficiency? | More common in MENA, since if heterozygous provide protection against malaria, Xlinked (avoid oxidants), other examples Pyruvate kinase. Lack of sufficient G6PD leads to oxidation damaging RBC due to inadequate NADPH (prevents oxidative stress by reducing glutathione by glutathione reductase). HMP shunt is the way of producing NADPH, leading to reduced glutathione, detoxify peroxidase and free radicals w/in RBC preserving RBC membrane integrity. So in G6PD deficiency we see hemolysis, and reticulocytes appear w/in 5-10 days, and have G6PD activity to compensate the loss, so ends the anemia w/in a week (self limited) Tx (remove inciting agent of hemolysis, maybe aggressive hydration for acute intravascular hemolysis/transfusion for severe anemia), chronic hemolysis give folic acid Test (first resolve hemolysis then test, used for people in need for oxidant drug |
| What is pyruvate kinase deficiency? | Caused by gene mutation affecting activity of pyruvate kinase (last enzyme in glycolysis turning phosphoenol pyruvate to pyruvate making ATP) Auto recessive, intrinsic to RBC, extravascular (spleen), since no pyruvate kinase, 1,3-bisphosphoglycerate will transform to 2,3-DPG which offsets anemia by right shifting the oxygen saturation curve |
| How is pathophysiology of pyruvate kinase deficiency? | RBC only glycolysis (no mitochondria), PK deficiency little or no ATP/NADH production, ATP deficiency affects Na+/K+ ATPase leading to osmotic instability and misshapes RBCs clear them in spleen (extravascular hemolysis). NADH deficiency decrease reducing power required to convert methemoglobin (Hb-Fe3+ to Fe2+) because of distal block, 2,3-DPG is increased, binds to Hb and alters its conformation (shifts OSC to right) |
| How is dx of pyruvate kinase deficiency? | In childhood as chronic hemolytic anemia, serum methemoglobin increased, rare disease Echinocytes are RBCs that had their membranes damaged due to dysfunctional Na+/K+ ATPase seen in microscopy |
| What is sickle cell anemia? | Point mutation in beta globin gene leading to sickle hemoglobin, inherited group of disorders characterized by presence of hemoglobin S (sickle cell anemia/beta thalassemia/SC disease..) Auto recessive, hallmarks are vaso-occlusive phenomena and hemolytic anemia. Valine (GTG) for glutamic acid (GAG) 6th amino acid substitution in beta globin, the resulting tetramer becomes poorly soluble when deoxygenated |
| How is manifestation of sickle cell anemia? | Acute manifestations Infection, anemia and vaso-occlusion (life-threat) Infection (encapsulated bacteria), acute vasooclusion pain may be accompanied with other complications (stroke, renal infarction, acute chest syndrome, priapism, bone infarct, osteomyelitis (salmonella) Complications related to pregnancy. Chronic manifestations chronic organs ischemia and infarction exacerbated with iron overload Chronic pain, seizure disorder, pulmonary HTA, asthma, hypoxemia, renal impairment and HTA, osteoporosis (bone infarct), cardiamyopathy (diastolic), hepatic injury, delayed puberty, reduced growth, chronic leg ulcers, proliferative retinopathy Spleen frequently affected (infarcted in childhood (autosplenectomy) recommended Abx and vax |
| How is sickle cell disease dx? | HPLC, Hgb electrophoresis (cellulose acetate, citrate agar), DNA testing may be useful |
| How is tx of SCD? | Pain management, preventive measures (vax, BP control, nutritional), hydroxyurea (hydroxycarbamide), transfusion, stem cell transplant, iron chelating agent (iron overload) |
| What is polycythemia? | Increase in hemoglobin concentration makes blood more difficult to pump around the body, more viscous and complications include blood clot, tiredness, lethargy, and pruritis |
| How is classification of polycythemia? | Primary polycythemia (myeloproliferative disorder w/increased RBC mass (clonal proliferation)) Secondary (increase in erythropoietin [lung disease, smoking, attitude, tumor producing alot of erythropoietin]) Relative polycythemia (Hemoconcentration, elevation of Hb/Hct due to decrease in plasma volume alone. |
| What is Polycythemiavera polycythemia? | Splenomegaly, thrombocytosis/leukocytosis, thrombotic complications, erythromelalgia/pruritis. EPO level decrease, JAK2 V617F mutation +ve |
| How is management of PV? | Phlebotomy, hydroxycarbamide or JAK2 inhibitors. Secondary PV is best treated by correcting the underlying cause and using phlebotomy if needed |
| What are hemolytic anemia types? | Warm autoimmune hemolytic anemia (AIHA), paroxysmal cold hemoglobinuria, cold agglutinin disease, hemoglobinopathies, drug-induced hemolytic anemia, RBC membrane defects, RBC enzymatic defects, microangiopathic hemolytic anemia (MAHA) (TTP) (HUS) (DITMA) Hemolysis associated with blood transfusion, paroxysmal nocturnal hemoglobinuria (PNH) |
| What are causes of hemolysis? | Intrinsic or extrinsic to RBCs (intracorpuscular vs. extracorpuscular defects), inhertited or acquired, acute or chronic, immune destruction (AB) or non-immune mechanism, intravascular vs extravascular (in vasculature or in reticuloendothelial macrophages in liver and spleen), most of inherited conditions are intracapsular and most of hemolysis by an immune mechanism is extravascular. Reticulocytosis requires adequate iron and vitamins (B12, folate) for RBC production. Normally functional bone marrow and adequate EPO production |
| What is autoimmune hemolytic anemia (AIHA)? | Due to presence of warm agglutinins, almost always due to IgG react w/protein antigens on the RBC surface at body temperature, for this reason they are called warm agglutinins (seldom directly agglutinate RBCs) |
| What are etiologies of AIHA? | Most cases unknown, minority of cases associated with other disorder include (viral infection [children], autoimmune disorders [SLE], lymphoproliferative diseases [chronic lymphocytic leukemia], disorders of immune deficiency/regulation [common variable immunodeficiency], drugs [penicillin, methyldopa], allogenic blood transfusion/ABO-incompatible hematopoietic cell transplantation |
| What are clinical manifestations of AIHA? | Small amount may be asymptomatic/slightly anemic. If severe hemolysis and sudden onset, symptoms may be those of severe degrees of cardiac compensation including heart failure, arrhythmia, chest pain, medical emergency. Physical exam reveals pallor, jaundice, moderate splenomegaly |
| What are labs of AIHA? | • Complete blood count with red blood cell indices (eg, MCV, MCH, MCHC), reticulocyte percentage, and examination of the peripheral blood smear • Tests for hemolysis, including indirect bilirubin, lactate dehydrogenase, and haptoglobin • Direct antiglobulin (Coombs) testing, including testing for both IgG and C3 on the red cell surface • Testing for specificity of the antibody for antigens identified on red blood cells • Anemia may be severe,↑MCHC (spherocytosis), ↑MCV (reticulocyte) • ↑indirect bilirubin, ↑lactate dehydrogenase, and ↓haptoglobin. • The peripheral blood smear; spherocytes, polychromatophilic (retic) • DAT, direct antiglobulin test (Coombs); 97- 99 % of pt will exhibit apositive result with anti-IgG, anti-C3, or both (on the surface of RBC). |
| How is treatment of AIHA? | Initial tx of symptomatic start GCs, acute onset of severe hemolysis w/symptomatic anemia in pt with cardiac disease, immediate red cell transfusion may be needed Second-line treatment for symptomatic pt not responding to GCs is elective splenectomy/rituximab |
| What is cold agglutinins AIHA? | IgM antibodies recognize RBC antigens at temperatures below normal core body temperature. Infections (mycoplasma pneumonia and EBV (mono)), autoimmune disorders and lymphoid/plasma cell malignancies (B cell NHL, CLL, Waldenstrom macroglobulinemia) |
| How is dx of cold agglutinins AIHA? | • Evidence of hemolysis (eg, high reticulocyte count, high LDH, high indirect bilirubin, low haptoglobin) • Positive direct antiglobulin (Coombs) test for C3d • Cold agglutinin titer of ≥64 at 4°C • Blood smear, RBC agglutination |
| How is management of AIHA? | • Cold-induced symptoms –avoidance of cold temperatures, if hospitalized (keep things warm) IVF fluid, blood transfusion etc.. • Anemia –if severe or symptomatic anemia, transfusions can be given. • Underlying disorders –individualized according to the specific disorder and patient's clinical status. If lymphoproliferative disorder (clonal) Rituximab • Glucocorticoids and splenectomy are not effective in the majority of patients |
| What is paroxysmal cold hemoglobinuria? | • Donath-Landsteiner hemolytic anemia • Autoantibody (IgG) binds to the red blood cell (RBC) P antigen in the cold and fixes complement. • Upon warming, the antibody dissociates and complement lyses the RBCs, leading to intravascular hemolysis. • Induced by acute infections (often viral), chronic syphilis, or states of immune dysregulation |
| What is presentation of paroxysmal cold hemoglobinuria? | • Signs and symptoms related to intravascular hemolysis (back or abdominal pain, weakness, nausea or vomiting, fever or chills, and/or dark or red urine), typically are self-limited and correlate with cold exposure. • Positive direct Coombs test for complement. Initial testing will show anemia, low haptoglobin, high (LDH) and bilirubin, and free hemoglobin in serum and urine. • Patients with these findings can be tested for the Donath-Landsteiner antibody |
| How is management of paroxysmal cold hemoglobinuria? | • Management of the acute episode is supportive. • It is important to avoid all cold exposures including cold ambient temperature, cold surfaces, ingestion of cold foods or beverages, and infusion of cold substances (fluids, blood transfusions). • Some individuals may require transfusions for severe anemia and/or hydration to prevent acute kidney injury |
| What is drug-induced hemolytic anemia? | • Immune (antibody-mediated) hemolysis, which can be drug dependent or drug-independent • Oxidative damage and Methemoglobinemia • Thrombotic microangiopathy (TMA) In drug-dependent reactions, the drug binds to the RBC surface and becomes part of the antigen with which the antibody interacts • Penicillin type, drug remains on RBC, and is required for antibody binding • Immune complex type, the drug causes formation of immune complexes that bind to the RBCs and cause complement activation • Passive absorption administration of antibody preparations introduces antibodies that can react with the recipients RBCs. eg IVIG • In drug-independent, It can cause immune hemolysis several weeks to months after drug initiation. drug alters RBC membrane |
| What is paroxysmal nocturnal hemoglobinuria (PNH)? | • Clonal deficiency in glycosyl phophatidyl inositol (GPI-linked protiens on RBCs, neutrophils, and platelets) GPI-linked proteins; which neutralize complements attached to RBC, neutrophils, and platelets - DAF, decay-accelerating factor (CD55) - MIRL, membrane-inhibitor reactive lysis (CD59) - In the absence of this protein, RBCs are susceptible to complementmediated intravascular hemolysis |
| How is the presentation of PNH? | • Episodic (paroxysmal) hemolysis when complement is activated by mild acidosis: - Respiratory acidosis during sleep (nocturnal) - Lactic acidosis during exercise • Can lead to IDA (iron deficiency anemia) from chronic blood loss • Hepatic vein – Hepatic vein thrombosis (Budd-Chiari syndrome) in the setting of a hemolytic episode • Inferior vena cava, portal and splenic veins: Thrombosis of other intra-abdominal vessels • Dermal veins – discrete areas of erythema, swelling, and pain or as a syndrome resembling purpura fulminans • Hemolysis: related to anemia/hemolysis such as smooth muscle dystonia, pulmonary hypertension, and renal insufficiency. • Thrombosis: is the leading cause of death in PNH. It is relatively rare as a presenting symptom but eventually occurs in up to 40 percent of patients, if not treated. • Pancytopenia: could overlap with bone marrow disorders; eg.aplastic anemia (AA) or occasionally MDS. Other factors include iron deficiency and hypersplenism |
| What are labs of PNH? | • Laboratory: - hemolytic anemia with Coombs-negative - loss of glycosylphosphatidylinositol (GPI)-anchored proteins. - findings of organ damage from hemolysis and/or thrombosis. • Bone marrow examination; if significant pancytopenia • imaging for thromboses: in patients with intractable headache or severe abdominal pain. |
| How is dx of PNH? | - Flow cytometry- to look for CD59 (MIRL) and CD55 (DAF), absence or reduced expression of both CD59 and CD55 on RBCs is diagnostic. - FLuorescent AERolysin (FLAER) a reagent derived from the bacterial toxin aerolysin, which binds directly to the GPI anchor - PNH leukocytes have a low leukocyte alkaline phosphatase (LAP) score, which is similar to that of CML |
| What is micro/macroangiopathic hemolytic anemia? | Mechanical damage to RBC (due to stenotic/mechanical heart valve [waring blender effect] or malignant HTA) Diseased endothelium (microthrombus formation, DIC, TTP [thrombotic thrombocytopenia purpura], and HUS. |
| What is thrombocytopenia purpura? | Inhibition of vWF-cleaving protease (ADAMTS-13) idiopathic/autoimmune form, lack of enzyme activity prevents breakdown of vWF. Excess circulation multimers of vWF promote adhesion of plt to endothelium, causes formation of microthrombi, leading to thrombocytopenia. secondary/acquired (cancer, pregnancy, bone marrow transplant, immunosuppressants, HIV-1 we get no ADAMTS-13 suppression) Inherited (Upshaw-Schulman syndrome) Classic pentad (fever, thrombocytopenia, microangiopathic hemolytic anemia, renal failure, altered mentation) fatal if not treated, treatment is plasma exchange (remove offending Abs and replaces ADAMTS-13) may use corticosteroids |
| What is HUS? | Hemolytic uremic syndrome, caused by sepsis (mainly E.coli O157:H7, bacterial toxins cause endothelial damage, leading to formation of plt microthrombi and thrombocytopenia Mostly in children, similar to TTP but more renal involvement/failure. Tx supportive dialysis until renal function returns (most recover w/in few weeks, some develop chronic renal failure) |
| What is DIC? | • Sepsis, especially E.coli and Neisseria meningitis • Malignancy- any cancer especially APL (promyrlocytic leukemia) M3 • Obstetrical complications (eg eclampsia) • Trauma- especially crush injury and burns • Snake bites • Activation of coagulation system • Leading to extensive thrombus formation in the microvaculature resulting in: • Obstruction of flow → tissue hypoxia • Consumption of clotting factors and plt → risk of bleeding • Activation of the fibrinolytic system → production of FDP/D-dimer |
| How is dx and tx of DIC? | Diagnosis is based on clinical history + • ↑ PT/INR and PTT, • Thrombocytopenia (↓plt) • Fibrinogen N ↓ • ↑ D-dimer • Microangiopathic hemolytic anemia (schistocytes) • Signs of bleeding, petechiae, purpura, mucosal bleeding, etc. • Treatment is supportive, Rx underlying disease (may use FFP, plt, or cryoprecipitate transfusion) • Poor prognosis |
| What is PF? | Proliferation of abnormal clone of hematopoietic stem cell in bone marrow and other sites results in fibrosis. Myelofibrosis is a form of myeloid metaplasia, which refers to a change in cell type in the blood forming tissue of bone marrow, progressive scarring or fibrosis of bone marrow occurs, results in extramedullary hematopoiesis. Anemia, with enlarged spleen the blood film with leukoeryt |
| What is acute leukemia? | Disease of neoplastic leukocytes, predominance of immature forms especially blasts (myelo/lymphoblasts)- disease defined by >20% blasts in bone marrow. Symptoms due to marrow failure secondary to leukemia infiltration causing pancytopenia (anemia, leukopenia, and thrombocytopenia) |
| What are etiologies of acute leukemia? | Chromosomal abnormalities (down syndrome) ionizing radiation, chemical exposures, topoisomerase agents (chemotherapy), age. |
| What are subtypes of acute leukemia? | Acute myeloid leukemia (disease of immature granulocytes, seen in young to middle-age adults (15-60 yrs). Acute lymphocytic leukemia (disease of immature lymphocyte [pre-B and pre-T ALLs], typically seen in children [0-15 yrs] number 1 leukemia of this age) |
| How is pathogenesis of acute leukemia? | Recurrent cytogenetic abnormalities (t(15;17) - acute promyelocytic leukemia [M3] t(8;21) - acute myelobastic leukemia w/maturation [M2], 11q23 abnormalities Genetic abnormalities lead to defects in stem cell maturation and clonal expansion of leukemic blasts |
| How is morphology of cells in acute leukemia? | Abnormal myeloid blasts (large nuclei and prominent nucleoli, APL (M3) [cytoplasmic granules w/occasional Auer rods, Azurophilic granules stain w/Ab against MPO] |
| How is the classification of AML? | M0 (undifferentiated) M1 (AML w/out maturation) M2 (w/maturation) M3 (acute premyelocytic leukemia APL) M4 (myelomonocytic) M5 (moncytic/monoblastic - show gingival hypertrophy) M6 (erythroleukemia) M7 (megakaryoblastic leukemia) |
| What are symptoms of AML? | Weakness, pallor, fatigue [normocytic anemia], infection susceptibility [leukopenia], easy bleeding/bruising [thrombocytopenia], bone pain [marrow infiltration]. Clinical pathology of M3 (APL) associated with DIC can be effectively treated with all-trans retinoic acid (ATRA) |
| What is tx of acute myeloid leukemia? | Intensive chemo, induction chemo w/AraC and daunorubicin, consolidation therapy [2-3 courses of intensive chemo given each time blood count recovers]. Stem cell transplantation [high-risk disease pt, or if there is disease relapse] |
| How is pathogenesis of ALL? | Defective maturation of lymphocyte precursors, pre-B or pre-T ALL, can be extramedullary (lymphoblastic lymphoma), metastasizes to CNS/testicles |
| How is morphology in ALL? | >20% lymphoblasts, smaller than myeloblasts w/large nuclei and scant, basophilic cytoplasm |