Vitamin B12 deficiency deficiency Iron deficiency General Principles G6PD deficiency Hemolytic and aplastic anemia Sickle cell anemia • Anemia is a sign, not a . Coagulation Disorders • Anemia's are a dynamic process. Factor VIII disorders Factor IX disorders • It is never normal to be anemic. Factor XI disorders • Correct use of lab tests is paramount. for Board Review Idiopathic thrombocytopenic purpura • Concomitant causes of anemia are common. Thrombotic thrombocytopenic purpura Joe Schwenkler, MD Von Willebrand's disease • The diagnosis of iron deficiency anemia Medical Director Malignancies mandates further work‐up. UMDNJ‐ PA Program Acute/chronic lymphocytic June 7, 2013 Acute/chronic myelogenous leukema Lymphoma This image is a work of the National Institutes of Health Multiple myeloma MORPHOLOGIC APPROACH TO ANEMIA RBC Destruction/ Life Cycle • ‐> MCV<80 Reticulocyte Count – Reduced iron availability —severe iron deficiency, the anemia of chronic disease, copper deficiency • Normal life span about 120 days • Erythrocytes newly released from • Destroyed by phagocytes – Reduced heme synthesis —lead poisoning, • Contain small amount of RNA congenital or acquired – spleen, , bone marrow, lymph nodes – Reduced globin production — thalassemic states, • hemeÆ biliverdin Æ unconjugated (indirect) • Stain with methylene blue other bilirubin • Increase in response to erythropoietin (EPO) • ‐> MCV>100 • liver converts to conjugated (direct) bilirubin which – Megaloblastic anemias‐ Folic acid and Vitamin B12 enhances elimination from the body deficiency • globin and iron Æ recycled – alcohol abuse, liver disease, and hypothyroidism • RBC destruction in blood vessels Æ free Hb in http://en.wikipedia.org/wiki/Image:Hematopoiesis_%28human%29_diagram.png • urine (Hemoglobinuria vs. Hematuria which is whole red blood cells in urine due to kidney or – Anemia of chronic disease tissue damage) – Anemia of chronic renal failure KINETIC APPROACH TO ANEMIA Algorithm using Retic. count, WBC, IRON METABOLISM Decreased Production (Low Retic count) ƒ Low Retic count suggests poorly functioning  Lack of nutrients…iron, Vitamin B12, Folate bone marrow  Bone Marrow Suppression… Aplastic anemia ƒ Normal and WBC • Serum iron is free  Low levels of trophic factors…chronic renal disease ƒ Acute blood loss • Transferrin binds iron in circulation (low EPO), low , testosterone ƒ Renal disease  Anemia of chronic disease ƒ – TIBC is identical Increased destruction (High Retic count) ƒ Drugs – % Saturation is serum iron/TIBC  Hemolytic Anemias ƒ Low platelets and WBC • Ferritin stores iron in liver and Reticulo  Inherited…sickle cell, ƒ Leukemia  Acquired…idiopathic, drug‐induced, and myelodysplastic Endothelial System (RES) syndrome. ƒ Aplastic anemia ƒ Case One ƒ 76 yo female comes in c/o being “run down” for over a month ƒ Only med is daily ibuprofen for chronic LBP ƒ PMH unremarkable, no previous hosp. ƒ Denies extra stress, problems sleeping except for restless legs ƒ Recently has been craving ice to chew (Pagophagia) ƒ Physical exam unremarkable except angular stomatitis, , pale conjunctiva, 2/6 SEM at LUSB, and spoon nails as below Angular Stomatitis (Cheilosis) (from (From wikipedia commons) wikipedia commons) LAB RESULTS What is your next step? • Hgb 8.2 (12.3 – 15.3), Hct 27.4 (36 – 44) 1. Bone marrow • MCV 80.8 (80‐100) 2. Rx with vitamin B12 • RDW (12.7‐14.5) 14.6‐ Anisocytosis 3. Transfuse 2 units • Retic count (1.1‐2.1) 1.6 packed cells • Serum ferritin 11.2 (40‐200) 4. GI work‐up for • Serum iron 28.6 (30‐160) occult • TIBC (transferrin level) 376 (230‐400) Spoon nail (from wikepedia commons) 5. Treat with EPO • Transferrin saturation 10.2 (9.6‐29) Etiology of Iron deficiency Anemia What is your next step? Signs of iron deficiency anemia • Increased Requirements 1. Bone marrow • Microcytic anemia causing spoon nails – Bleeding from some GI source 74% – Menses 2. Rx with vitamin B12 (koilonychia). • Glossitis – Blood donation (one unit= 250mg iron) 3. Transfuse 2 units • esophageal web formation ( – Growth periods, pregnancy, lactation packed cells due to Plummer‐Vinson syndrome). – Infants fed cow’s milk suffer from reduced • Restless legs is often associated anemia, bioavailability iron and induced GI bleeding 4. GI work‐up for • Inadequate supply occult bleeding check ferritin! • Pica is unique to iron‐deficiency • Intestinal malabsorption‐ iron absorbed in duodenum 5. Treat with EPO syndrome. • Sprue, celiac, atrophic gastritis 7% 9% 7% • Gastric surgery bypassing duodenum (Rx high doses) 2% • Calcium inhibits GI absorption

12345 Fe deficiency Fe deficiency Severe Fe Normal without with mild deficiency with Treatment anemia anemia severe anemia Case Two Marrow iron 2+ to 3+ None None None • Ferrous sulfate 325mg b.i.d. Serum iron 60 to 150 60 to 150 <60 <40  47 yo male with 10 year h/o type 2 comes for PE – Beware Iron binding  Currently taking max doses metformin & glyburide capacity 300 to 360 300 to 390 350 to 400 >410 • Recheck blood tests 6 weeks later (transferrin)  BP 148/92, retinal exam shows cotton wool exudates Saturation  Diminished monofilament sensation on feet – Continue oral iron until serum ferritin normalizes (SI/TIBC), 20 to 50 30 <15 <10  Diabetes poorly controlled with A1c=10.6% (up to 6 months) percent Hemoglobin Normal Normal 9 to 12 6 to 7  Microalbumin 300 (<20), creatinine 1.4 Normal or Hypochromia • Iron salts not absorbed well if taken with food Red cell  CBC shows Hgb 9.1, MCV 85, normal platelets Normal Normal slight and morphology • Iron pills need to be given 2 hours before, or hypochromia microcytosis  Stool guiac negative x 3 Plasma or  Serum ferritin 170 (40‐200), Retic count .5% four hours after antacids 40 to 200 <40 <20 <10 serum ferritin  Serum iron 65 (60‐150), TIBC 320 (300‐360) Nail and • Vitamin C helps absorption Other tissue None None None epithelial changes changes What can cause elevated ferritin AND What can cause elevated ferritin AND What is the best treatment for this low serum iron low serum iron patient?

78% 1. Chronic inflammation 1. Chronic inflammation 1. EPO 2. Aplastic anemia 2. Aplastic anemia 2. Transfuse 2 units pc 3. Hemolysis 3. Hemolysis 3. Oral iron 4. Hemoglobinopathies 4. Hemoglobinopathies 4. Parenteral iron 5. Acute leukemia 5. Acute leukemia

7% 9% 7% 0%

12345 Diagnosis of Anemia of Chronic Disease is often complicated… ANEMIA OF CHRONIC DISEASE (ACD) What is the best treatment for this chronic iron (ANEMIA OF INFLAMMATION) patient? disease deficiency ƒ Second most common anemia after Iron serum iron 64% Deficiency 1. EPO ƒ Induced by inflammatory cytokines (IL‐6) 2. Transfuse 2 units pc ƒ Reduction in (RBC) production by TIBC BM (transferrin) 3. Oral iron ƒ Trapping of iron in macrophages 4. Parenteral iron ƒ reduced plasma iron levels making iron relatively iron 23% unavailable for new hemoglobin synthesis saturation ƒ Erythroid precursors are impaired 9% serum nL or 5% ƒ Interferons are potent inhibitors ƒ Blunted erythropoietin response ferritin

1234 ACUTE VARIANT Underlying causes of ACD DIAGNOSIS OF ANEMIA CHRONIC ANEMIA OF CRITICAL ILLNESS ( ) ƒ Acute and chronic infections DISEASE • Acute event‐related anemia ƒ TB ƒ Generally mild/moderate anemia (Hb 8‐10) – after surgery, major trauma, myocardial ƒ Endocarditis ƒ Normochromic, normocytic (may be slightly low) ƒ infarction, or sepsis Chronic UTI ƒ Low to normal count ƒ Malignancies • Secondary to tissue damage and acute ƒ Reduced serum iron and transferrin saturation ƒ Metastatic cancer inflammatory changes ƒ Leukemia ƒ Reduced or normal TIBC/transferrin levels • Shares many of the features of ACD ƒ Lymphoma ƒ Normal ferritin levels (acute phase reactant) – low serum iron ƒ Chronic arthritic conditions ƒ Need to exclude chronic renal failure, – high ferritin ƒ Chronic renal insufficiency hyperthyroidism, hypothyroidism – blunted response to EPO ƒ Hypothyroidism ƒ May have concomitant iron deficiency anemia ƒ ANY CHRONIC INFLAMMATORY CONDITION! TREATMENT OF ACD HEMOGLOBINOPATHIES Normal Adult Hemoglobins ƒ ‐ homozygous ƒ Erythropoietin (EPO) is most effective therapy ƒ Autosomal recessive disease Name of ƒ ƒ Substitution of the amino acid valine for glutamine Hemoglobin Distribution Structure Oral iron of little benefit unless also iron ƒ 8% to 10% of African Americans carry gene A 95%‐98% of adult Hb α β deficient ƒ ‐ heterozygotes 2 2 ƒ Transfusions only for short‐term if Hb<8 ƒ Splenic infarction can occur with hypoxia (altitude) A2 1.5%‐3.5% of Adult Hb α2δ2 ƒ Renal hematuria common ƒ Who to treat with EPO? F Fetal, 0.5%‐1.0% of α2γ2 ƒ Beware bacteruria during pregnancy adult Hb ƒ Hemoglobin <10 (pyelonephritis) ƒ Additional risk factors (pulmonary, CV, renal) ƒ Thalassemias‐ imbalanced synthesis of normal ƒ What is goal of therapy? globin chains ƒ Beta ƒ Hb 11 to 12 generally accepted ƒ Alpha Pathophysiology of SCD SICKLE CELL ANEMIA

• Chronic hemolysis of sickle cell disease is usually • On deoxygenation, hemoglobin associated with: S polymers form, causing cell – a mild to moderate anemia (hematocrit 20 to 30 sickling and damage to the percent) membrane – reticulocytosis of 3 to 15 percent (accounting for • Vasocclusive episodes result the high or high‐normal [MCV]) from a combination of vascular – unconjugated hyperbilirubinemia adhesion of young sickle cells – elevated serum lactate dehydrogenase and consequent trapping of • Red cells are normochromic unless there is coexistent dense sickle cells thalassemia or iron deficiency The elongated and crescent-shaped red blood cells seen on this smear represent circulating irreversibly sickled cells. Target cells • Functional asplenism • Hb electrophoresis high levels Hb F and a nucleated red blood cell are also seen. (Licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.) (From wikepedia commons) Acute Pain Episodes Sickle cell “crisis” Clinical manifestations of SCD Clinical manifestations (cont.) – Precipitated by weather, infection, stress • Hand & foot syndrome (dactylitis)‐ painful crisis in • Infections: Strep pneumonia and H. Influenza – Lasts 2 to 7 days hands/feet‐ common children under four • Gallstones – Often undertreated! • *Aplastic crisis can result from Parvovirus 19 infect. • Renal failure due to papillary infarcts – Low risk of narcotic addiction • Splenic sequestration with enlarging spleen – painless hematuria is common – Generate feelings of despair, depression • *Acute chest syndrome‐ major cause of death‐ • Chronic leg ulcers • Management – Fever, wheezing, chest pain, new pulmonary infiltrate • Priapism needs to be treated within 4 to 6 hours 9Hydration • *CVA risk increased if transcranial doppler slow • Aseptic necrosis in femoral and humeral heads 9Pain management (*Exchange transfusion indicated) • Chronic osteomyelitis (salmonelli typhi) 9Seek source of infection‐> Antibiotics? 9Hydroxyurea has promise‐> raises HbF levels Health Care Maintenance ß‐THALASSEMIAS ß‐THALASSEMIA MAJOR • (HOMOZYGOUS BETA)  Routine visits with primary provider Diminished production of ß‐globin chains – α ƒ severe anemia  Folic acid 1 mg daily causing unmatched ‐globin chains to accumulate and aggregate ƒ blood film  Transcranial doppler exam • ƒ pronounced variation in red cell size and shape (High RDW)  Detect patients that would benefit from regular transfusions to ß‐Thalassemia minor (ß‐thalassemia trait) ƒ pale red cells, target cells, basophilic stippling (ribosomal prevent CVA – Heterozygous condition precipitates), nucleated red cells, moderately raised retic count  Retina exam to look for proliferative changes • ß‐Thalassemia major (Cooley anemia) ƒ infants well at birth but develop anemia in first few  Strep pneumonia vaccine below age 5 both 7 and 23‐ – no ßchains are synthesized; only HbF and HbA2 months when switch occurs from gamma (HbF) to valent, then 23‐valent every 7 years – severe anemia that appears in the first year beta globin chains  H. flu, meningococcal, influenza starting age 6 months ƒ progressive ; iron loading; prone to  Daily prophylactic oral penicillin until age 5 infection ƒ Allogenic Bone Marrow transplantation Rx of choice Disorder Genotypic Abnormality Clinical Phenotype ß‐THALASSEMIA TRAIT (HETEROZYGOUS ΑLPHA THALASSEMIA SYNDROMES β‐Thalassemia Thalassemia major (Cooley's Homozygous β0‐ Severe hemolysis, ineffective CARRIER) anemia) thalassemia erythropoiesis, transfusion • α‐thalassemia‐2 trait (minima) dependency, iron overload – Loss of one of the four alpha globin genes Thalassemia intermedia Compound heterozygous Moderate hemolysis, severe anemia, • mild hypochromic microcytic anemia 0 + – No abnormalities of blood testing β ‐ and β ‐thalassemia but not transfusion dependent; main – HGB 9‐11 g/dL life‐threatening complication is iron • α‐thalassemia‐1 trait (minor) overload – MCV 50‐70 fL – loss of two of the four alpha globin genes Thalassemia minor Heterozygous β0‐ or β+‐ Microcytosis, mild anemia – MCH 20‐22 pg – MCV is often less than 80, but Hb electrophoresis is normal thalassemia α‐Thalassemia • Hemoglobin H disease • no clinical features, patients asymptomatic Silent carrier α‐/αα Normal – Hemoglobin H, composed of four beta chains (beta4) α‐Thalassemia trait αα/‐‐(α‐thalassemia 1) OR Mild microcytic anemia – three of the four alpha globin loci are nonfunctional • often diagnosed on routine blood count α‐/α‐ (α‐thalassemia 2) – chronic , due to the formation of inclusion • raised HbA2 level Hemoglobin H α‐/‐‐ Microcytic anemia and mild bodies in circulating red cells as Hb H precipitates hemolysis; not transfusion • Hydrops fetalis with Hb Barts dependent – none of the four alpha globin loci is functional Hydrops fetalis ‐‐/‐‐ Severe anemia, intrauterine anasarca from congestive heart failure; death in utero or at birth HEMOLYTIC ANEMIA NORMOCYTIC ANEMIAS Typical case of Hemolytic anemia ƒ Caused by premature breakdown of RBCs • Anemia of Chronic renal Insufficiency ƒ Intracorpuscular Defects‐ RBC membrane defects • EPO is effective treatment ƒ Heriditary Spherocystosis & Elliptocytosis • Acute onset from anemia • Acute blood loss ƒ Extracorpuscular Defects‐ • with high indirect bilirubin • Orthostatic Symptoms predominate ƒ Autoimmune Hemolytic Anemia • Resting and hypotension ƒ Positive coombs test • Increased serum LDH • Can take 24 hr. for Hct to fall ƒ Rx prednisone high dose and taper slowly • Reduced (or absent) serum • 3‐5 days reticulocytosis elevates MCV ƒ G6PD Deficiency • Anemia of liver disease multifactorial: ƒ Severity of anemia related to rate RBC destruction and • Increased • Remodeling of RBC membranes ability of bone marrow to produce reticulocytes • Positive coombs test if autoimmune etiology • Hypersplenism ƒ Free hemoglobin binds to haptoglobin • Folate deficiency ƒ Removed by RES unless exceeds capacity (low haptoglobin) • Co‐existing iron deficiency ƒ Excess filtered through kidney‐> dark urine GLUCOSE‐6‐PHOSPHATE DEHYDROGENASE DRUGS CAUSES HEMOLYSIS IN PATIENTS WITH G6PD DEFICIENCY (G‐6‐PD) Deficiency ƒ Forms spherocytic cells that are destroyed in ƒ antimalarials • RBCs depend on anaerobic metabolism spleen ƒ primiquine • First enzyme in pentose phosphate shunt ƒ ƒ pamaquine Present with jaundice and splenomegaly • Catalyzes conversion NADP+‐>NADPH ƒ Elevated retic count • RBCs deficient if G‐6‐PD susceptible to hemolysis ƒ analgesics ƒ Spherocytes on smear • 10% of male blacks in the U.S. are affected ƒ phenacetin ƒ Splenectomy often required • Gene carried on X‐chromosome ƒ acetyl salicylic acid • Hemolysis occurs after exposure to a drug or substance ƒ major risk is bacterial sepsis: pneumococcus, H. Flu, ƒ others that produces an oxidant stress meningococcus ƒ sulfonamides • Favism‐ Ingestion of, or exposure to, fava beans may ƒ especially in children younger than age 3 ƒ nalidixic acid cause a devastating intravascular hemolysis ƒ need to immunize prior to surgery ƒ APLASTIC ANEMIA Causes of Acquired Aplastic Anemia Main Causes of  Present with recurrent infections (due to profound Idiopathic MEGALOBLASTIC ANEMIAS ) Cytotoxic drugs and Radiation  Mucosal hemorrhage due to thrombocytopenia Gold ƒ  Fatigue and dyspnea Alcoholism frequently causes elevated MCV  , lack of reticulocytes NSAID ‐ ,indomethacin ƒ Vitamin B12 (cobalmin) deficiency due to: Sulfonamides  Marrow is profoundly hypocellular with a decrease in all ƒ Inadequate absorption due to Pernicious Anemia elements Antiepileptic drugs ‐  Rx options: Arsenicals ƒ Gastric Disease/Removal of terminal ileum  Hematopoietic cell transplantation if HLA compatible sibling ƒ Strict Vegan Lindane  Immunosuppressive regimens (cyclosporine) ƒ Folic Acid deficiency due to inadequate diet  Antithymocyte globulin (ATG)‐ selectively destroys T‐cells Glue vapors  Antiserum from animals immunized against human Non‐A, non‐B, non‐C and/or alcoholism thymocytes HIV infection ƒ Chemotherapeutic drugs can cause Epstein‐Barr virus Systemic lupus erythematosus Graft versus host disease DIAGNOSTIC WORK‐UP of B12 deficiency PERNICIOUS ANEMIA CLINICAL MANIFESTATIONS • Neurologic symptoms are related to lack of Cobalmin • Neuro symptoms often unrelated to degree of anemia ƒ Autoimmune gastritis ƒ Dementia or depression can be major symptom • Up to 50% have normal MCV and no anemia ƒ Autoimmune attack on gastric intrinsic ƒ 12% present with neuropathy but not anemia • If you treat with folate, only anemia improves factor(IF) ƒ Progressive cases develop peripheral neuropathy • B12 Serum levels are helpful if low, but can be ƒ 70% have elevated anti‐IF normal ƒ Ataxia, broad‐based gait, rhomberg, slow reflexes • Schilling Test rarely needed‐ measure absorption ƒ Increased risk gastric cancer ƒ Loss of position sense, vibration, reduced skin radioactive B12 ƒ Gastric carcinoid tumors sensation • Methylmalonic Acid high with cobalmin deficiency ƒ 25% have autoimmune thyroid disorders ƒ Treatment: • Homocysteine elevated in both B12 and folate ƒ Lab: RBC show (MCV>100) ƒ Old Rx: weekly 1000 micrograms cobalmin x 6 then deficiency monthly for lifetime ƒ Hypersegmented • Use tests for follow‐up to confirm successful therapy ƒ New Rx: daily high dose 1‐2mg daily. At least 2% is absorbed and results look superior to parenteral route Idiopathic Thrombocytopenia FOLIC ACID DEFICIENCY HEMORRHAGIC DISORDERS Purpura (ITP) • Most common cause is nutritional ƒ Platelet Abnormalities • Connected to alcohol abuse, malnutrition, faddism ƒ Thrombocytopenia due to decreased production ƒ Self‐limitted in children (post virus) in 70% • Clinical syndrome similar to pernicious anemia ƒ Aplastic anemia, drug reaction ƒ Petechial hemorrhage, mucosal bleeding, and • Diagnose with serum folic acid level ƒ Idiopathic Thrombocytopenic Purpura (ITP) thrombocytopenia, with counts often lower • Treat with 1mg daily supplement ƒ Thrombotic Thrombocytopenic Purpura (TTP) than 20,000/mcL • Homocysteine level is best way to monitor progress ƒ Drugs (heparin 3‐5%), Viruses, SLE ƒ Antiplatelet test‐?Useful (many false +) • Pregnancy increases demand for folic acid ƒ Sequestration in enlarged spleen ƒ Most clinicians prefer to treat children with – Helps to prevent fetal neural tube defects ƒ Common in advanced liver disease steroids or intravenous immunoglobulin (IVIG) if – All women of child‐bearing age daily .4 mg ƒ Coagulation Factor Deficiencies platelet counts < 10,000 • Prescription Prenatal vitamins have 1 mg*** Idiopathic Thrombocytopenic FEATURES OF ACUTE AND CHRONIC Platelet Defect vs. Clotting factor Purpura (cont.) ITP deficiency Clinical Clotting factor Features Acute ITP Chronic ITP Platelet defect ƒ Chronic in adults: treat if platelet count characteristic deficiency <10,000‐20,000 Peak age Children (2-6 yrs) Adults (20-40 yrs) Skin, mucous Female:male 1:1 3:1 membranes (gingivae, Deep in soft tissues Site of bleeding ƒ Steroids first choice x 4 weeks Antecedent infection Common Rare nares, GI and (joints, muscles) Onset of symptoms Abrupt Abrupt-indolent genitourinary tracts) Platelet count at presentation <20,000 <50,000 ƒ Intravenous Immunoglobulin (IVIG) Bleeding after minor Duration 2-6 weeks Long-term Yes Not usually cuts Spontaneous remission Common Uncommon ƒ Splenectomy causes remission in 60% Petechiae Present Absent ƒ Immunosuppressive agents Ecchymoses Small, superficial Large, palpable Hemarthroses, muscle Rare Common Bleeding after surgery Immediate, mild Delayed, severe Differential diagnosis of ITP The coagulation cascade LAB TESTS IN HEMORRHAGIC • Falsely low platelet counts DISORDERS – In vitro platelet clumping caused by EDTA‐dependent ƒ Bleeding Time (BT): measures platelet function agglutinins or giant platelets ƒ Platelet count: normal 150,000‐300,000 • Common causes of thrombocytopenia ƒ Prothrombin Time (PT): test of extrinsic system – Pregnancy (INR) • Gestational thrombocytopenia ƒ Partial Thromboplastin time (aPTT): intrinsic • Preeclampsia system – Drug‐induced thrombocytopenia: Heparin, Quinidine, ƒ Thrombin Time (TT): tests fibrinogen‐> fibrin , Sulfonamides, Gold ƒ Fibrinogen Level: DIC – Viral infections: HIV, infectious mononucleosis, ƒ D‐Dimer: specific to plasmin degradation seen in Hepatitis DIC , pulmonary embolus – Hypersplenism due to chronic liver disease VON WILLEBRAND DISEASE (VWD) THROMBOTIC THROMBOCYTOPENIC PURPURA TREATMENT OF VWD (TTP) ƒ Most common bleeding disorder (1‐3% population) ƒ Rare disease of unknown cause ƒ Majority asymptomatic ƒ Severe thrombocytopenia ƒ Autosomal dominant inheritance • DDAVP (deamino-8-arginine vasopressin) ƒ ƒ Von Willebrand factor (vWF) is defective/deficient Hemolytic anemia with schistocytes and helmet cells – ↑ plasma VWF levels by stimulating secretion from ƒ Large multimetric protein from chromosome 12 ƒ Neurologic abnormalities endothelium ƒ Forms adhesive bridge between platelets and endothelium ƒ Seizures – Duration of response is variable ƒ Carrier molecule for Factor VIII ƒ Clouded sensorium – Dosage 0.3 µg/kg q 12 hr IV an hour before surgery ƒ Lab mostly normal: ƒ Fever ƒ aPTT and bleeding time slightly elevated • Factor VIII concentrate ƒ Mild renal disease with creatinine <3.0 ƒ vWF levels are low ƒ Ristocetin‐induced platelet aggregation test – Contains large amount vWF ƒ Minimal changes in coagulation tests ƒ Rx large‐volume plasmapharesis Case Three What is the best treatment? What is the best treatment? • 26 yo female had a normal spontaneous vaginal delivery an hour ago 1. Heparin IV 1. Heparin IV 42% • Following the delivery the obstetrician had 2. Warfarin po 2. Warfarin po difficulty removing the entire placenta 3. Transfuse 2 units 3. Transfuse 2 units 33% • Patient now mildly hypotensive and confused packed cells packed cells • Oozing around IV site, increased bloody 4. DDAVP 4. DDAVP discharge from vagina 5. Vitamin K subQ 5. Vitamin K subQ 13% • Lab showed Hb 10.3, prolonged PT, aPTT, 9% Thrombin Time (TT ) and high levels of D‐dimer 2%

12345 Disseminated Intravascular DIC (cont.) Common manifestations of acute DIC Coagulation (DIC) ƒ Procoagulant substances trigger systemic ƒ Systemic disorder producing both: ƒ Bleeding (64 percent) activation of coagulation system ƒ ƒ Coagulation factors consumed faster than liver can ƒ Renal dysfunction (25 percent) ƒ Hemorrhage produce new factors ƒ Hepatic dysfunction (19 percent) ƒ Complicates about 1% hospital admissions ƒ Platelets are consumed faster than BM can cope ƒ Respiratory dysfunction (16 percent) ƒ Acute DIC results from: ƒ Acute form is often severe ƒ Blood exposed to large amounts of tissue factor ƒ Shock (14 percent) ƒ Massive generation of thrombin ƒ Chronic form associated with malignancies ƒ Thromboembolism (7 percent) ƒ Coagulation triggered in overwhelming fashion especially pancreatic ƒ Central nervous system involvement (2 ƒ Chronic DIC is low grade disorder ƒ Thrombotic complications (Trousseau syndrome‐ percent) migratory thrombophlebitis) Causes of DIC DIC Treatment Options HEMOPHILIAS Activation of both coagulation and fibrinolysis ƒ Sex‐linked recessive Triggered by: • Treatment of underlying disorder ƒ Genes on long arm of X chromosome • Sepsis • Obstetrical complications • Anticoagulation with heparin ƒ Hemophilia A affects one in 10,000 males – Meningococcemia – Amniotic fluid embolism – Gram + or ‐ – Abruptio placentae ƒ deficient or defective clotting factor VIII •Trauma • Vascular disorders • ƒ Hemophilia B‐ Factor IX Deficiency – Head injury – Fat embolism • Reaction to toxin (e.g. ƒ Factor XI Deficiency‐ Ashkenazi Jews snake venom, drugs) • Fresh frozen plasma • Malignancy ƒ Replacement therapy – Solid cancers (pancreas) • Immunologic disorders – Trousseau Syndrome- • Coagulation inhibitor concentrate (ATIII) ƒ Recombinant forms now available ($100,000/yr) • Migratory thrombophebitis – Severe allergic reaction – Transplant rejection ƒ Cryoprecipitate effective but risky Acute Chronic Leukemia CML Natural History • Acute Lymphocytic Leukemia (ALL) • Chronic Lymphocytic Leukemia • Chronic phase lasts 3 to 5 years – Peak incidence age 3‐5 – most common form of leukemia in adults in Western – Asymptomatic with high WBC counts – 20% adult leukemia, most childhood cases countries • Accelerated phase with increasing symptoms – median age at diagnosis is 62 years – Philadelphia chromosome 25% to 30% of – 10 to 20% blast cells on peripheral smear – therapy should be initiated only when indicated by • Blast crisis all adult cases one or more disease‐related symptoms, , or recurrent infections – Evolves to acute leukemia (2/3 AML, 1/3 ALL) – • Acute Myeloid Leukemia (AML) • Chronic Myelogenous Leukemia Death occurs within weeks to months Gleevec (imatinib) is new treatment – Peak incidence age 60 – caused by the transforming capability of the protein products resulting from the Philadelphia – 80% go into remission – Auer Rods formed by the aggregation of translocation (Ph Chromosome) – Lifelong Rx needed myeloid granules – Average survival 5 years (until new therapies) Clinical features of CML Lab findings in CML at diagnosis Multiple Myeloma ƒ raised WBC count (30‐400 X 109/L) ƒ fatigue • Accumulation of plasma cells in the bone ƒ differential marrow and, less often, soft tissues or visceral ƒ weight loss ƒ granulocytes at all stages of development organs ƒ sweating ƒ increased numbers of basophils and eosinophils ƒ blast (primitive) cells (maximum 0%) • Lytic bone lesions are most typical ƒ anemia ƒ never present in blood of normal people • Anemia, hypercalcemia, renal insufficiency ƒ easy bruising ƒ Hgb concentration may be reduced • Increased risk for life‐threatening bacterial ƒ splenomegaly with or ƒ RBC morphology usually unremarkable infections without ƒ nucleated RBC may be present – Encapsulated organisms like Strep. Pneum., H. Flu ƒ platelet count may be raised (300‐600 X 109/L) Diagnostic criteria for myeloma Lymphomas Hodgkin’s Disease

• >10% plasma cells in Bone Marrow or ƒ Higher incidence in men than in women plasmacytoma on biopsy • Lymphoma is the sixth most ƒ Occurs in a bimodal age distribution • clinical features of myeloma common type of cancer in the ƒ greatest peak in the third decade – bone pain, often in low back United States ƒ lesser peak in the seventh decade • plus at least one of: • 15% Hodgkin’s Lymphomas ƒ Increased incidence of Hodgkin lymphoma in persons with a history of infectious – serum paraprotein spike (IgG.30g/L; IgA>20g/L) • 85% Non‐Hodgkins lymphomas • Seen on serum electrophoresis (SPEP) mononucleosis – urine paraprotein (Bence Jones proteinuria) ƒ Neoplastic cell of Hodgkin lymphoma is – osteolytic lesions on skeletal survey‐ often cause almost always a B cell Hypercalcemia ƒ either the Reed‐Sternberg cell or one of its mononuclear variants Systemic Symptoms (B symptoms) Clinical Features Hodgkins vs. NHL Hodgkins Clinical Features • Drenching sweats at night, fever, and Hodgkins Disease Non‐Hodgkins • Most common presenting feature is painless unexplained weight loss. Lymphoma lymph node enlargement – Pel‐Ebstein fevers are intermittent Incidence Unchanged Increasing • Mediastinal lymphadenopathy is common at episodes of evening fevers that last for Age Median 29 years Incidence increases presentation. several days and alternate with afebrile with age periods. • Orderly spread from one lymph node region to Sites Mostly nodal: No predictable pattern contiguous nodal sites. • Total body pruritus Supradiaphragmatic • The spleen and the lymph nodes in the celiac • A unique feature is pain at sites of Clinical Mediastinal mass Nothing specific lymphadenopathy immediately after Features Pruritus axis are often the first sites of subdiaphragmatic Alcohol induces pain disease ingestion of alcohol. Prognoosis 70—80% cure Most incurable but very variable