7 HEMATO LOGY |e a raeBy Dr.Diaa Ahmed By Dr.Diaa Ahmed Zagazig University Zz Index ‘agazig University Introduction Anemia Iron deficiency anemi: Aplastic anemia..... Megaloblastic anemia Hemolytic anemias Thalassemia Re Anemia of chronic disease. Other types of anemia DISORDERS OF WHITE CELLS. Leukemia .. Acute leukemia Chronic myeloid leukemia. Chronic lymphocytic leukemia Lymphoma .. Hodgkin's lymphoma.. Non-Hodgkin's lymphoma. Generalized lymphadenopathy. Bleeding .. Purpura Coagulation disorders polycythemi Myeloproliferative syndrome: Multiple Myeloma. The Spleen... Blood transfusion ... Collections . Cases .. MCQ .. AnswersIn Capsule Series www. incapsuleseries.com Hematology Blood consists of : @ Red blood cells (RBCs ) . By DrDiaa Ahmed Zagazig University @ White blood cells. @ Platelets. @ Plasma. (The formation of blood cells ) > The hemopoietic system includes the bone marrow, liver, spleen, lymph nodes and thymus. > Liver & spleen are the chief sites of hemopoiesis from 6 weeks to 7 months , when the bone marrow becomes the main source of blood cells. The bone marrow is the only source of blood cells during normal childhood and adult life. 2 RBCs survive 120 days, platelets around 7 days but granulocytes only 7 hours. > Steps of hemopoiesis : Pluripotent stem cellIn Capsule Series www. incapsuleseries.com Hematology Erythropoiesis#y Pluri-potent stem cell 4 Uni-potent stem cell (CFU -E ) Colony Forming Unit - Erythrocyte By DrDiaa Ahmed y t si Zagazig University Pro-Erythroblast 4 Basophilic Erythroblast Precursor cell Polychromatic Erythroblast 4 Orthochromatic Erythroblast Reticulocyte + Erythrocyte ( Mature RBC ) Granulocytopoiesis Thrombocytopoiesis Pluri-potent stem cell Pluri-potent stem cell v Y CFU-G CFU - Mega + Y ‘Myeloblast Megakaryoblast 4 4 Pro Myelocyte Megakaryocyte ‘ + Myelocyte Platelets + Granulocyte ( PML )In Capsule Series www.ineapsuleseries.com Hematology Normal ranges (adults) © Hemoglobin : o 13.5-17.5gm/dL (8) © 115-155 gm/dL (2) © Haematocrit (PCV): the volume of packed RBCs in 100 ml blood © 40-52% ‘ © 36-48 % @Q) > RBCs indices © MCV (Mean Corpuscular volume ): 77 —95 fL. Ee F ™ RBCs count /emm ze = 90 femtolitre. o MCH (Mean Celf Hb) : 27-32 pg = Hb x10 — 15x10 _ F =Recscountjenm 7 ms seo escourem, o MCHC (Mean Cell Hb Concentration ) : 32 — 36 gm/dl _ Hb _ 15x 100 ~~ PCV sO 45 2D RDW (Red Cell Distribution Width): 11.5-14.5% RDW is a measure of the degree of anisocytosis (variation in RBC size). =33gm/dl Increased : Many types of anemia (iron deficiency, pernicious anemia , folate deficiency, thalassemia), liver disease. > Reticulocytes : 0.5-2.5 % > ESR : 2-12 mm/Ist hour . > WBC : 4000-11000 /cmm. o Neutrophils :50-70% © Lymphocytes : 20-45% inophils :1-59 © Eosinophils :1-5% By DrDiaa Ahmed -7% Zagazig, University © Monocytes © Basophils :0-1% 2 Platelets 150,000 ~ 400,000 /emm.In Capsule Series www incapsuleseries.com Hematology Anemia Scheme (Definition: Reduction in one of the following parameters : @ RBCs count — N: 4.5-6million\emm in 3. @ Hbconcentration — N: 15 gm%(13.5-175)ind. @ hematocrite value (packed cell volume) > N:45% Females are usually 1 to 2 gm Hb & about one million RBCs per Pathophysiology | 4 1. Hyperdynamic circulation > short circulation time & high cardiac output . 2. Tf Erythropoietin by the kidney > ++ RBCs 3. Tf O2 delivery to the tissue ( shift of O2 dissociation curve to the right ) : This is due to excess production of 2,3 DPG ( 23 diphosphoglycerate) which make the binding between O, & Hb very weak. 4. Redistribution of the blood : blood is shifted to the vital organs e.g. brain. (Clinical picture: 4 EYRRBISRE) (depend on the rate oF reduction rather than the absolute value of Hb) 1. General : Fatigue & lassitude. 2, CVS : manifestations of low cardiac output inspite of high Cop. 3. CNS— loss of concentration , headache & dizziness. 4. Genital : Impotence , menstrual irregularities. 4In Capsule Series www. incapsuleseries.com Hematology 1, Pallor. 2. Hyperdynamic circulation : Tachycardia , $1, gallop, hemic murmur. wo . lower limb edema "due to hyperdynamic circulation, hypoxia & heart failure " 4. papiledema and retinal hemorrhage due to + permeability. {Investigations} 4 Anemia is not a diagnosis, it is an abnormal clinical finding requiring an explanation for its cause. LCBC: > RBCs & HB — |{withalltypes © 2 WBCs & platelets — || with Megaloblastic , Aplastic anemia > Indices : * MCV, MCH, MCHC: eg. Normal in hemolytic & aplastic anemia. | in iron deficiency anemia. of in megaloplastic anemia except MCHC is normal U.Color index =1 (09-11) © except ° ° > Iron deficiency anemia < 1 > Megaloplastic anemia > 1 Ill.Bone marrow examinations < e.g. Erythroid hyperplasia in iron deficiency , aplasia in aplastic anemia ..... IV.Hepatic and renal investigationse.g. KFTs , LFTs. ffreatment; 4 1, Blood transfusion. 2. packed RBCs 3. Treatment of the cause e.g. > Fe — in iron deficiency anemia. 2 Folic acid & vitamin Bj, — Megaloblastic anemia. 4, Treatment of complications : as HF (and mention ©)In Capsule Series www.incapsuleseries.com Hematology I. Decreased production : © || Hb Synthesis : Iron Deficiency anemia , Thalassemia , Anemia of chronic disease. © || DNA Synthesis : Megaloblastic anemia. © || Stem Cell : Aplastic anemia. Il. Increased destruction : Hemolytic anemia. Ill. Increased RBCs loss: Acute-post-hemorrhagic anemia. SIGISSificationiofanemiaaaeeNSIZeR I. Microcytic hypochromic : © Iorn deficiency anemia : defect in haem synthesis. > Thalassemia : defect in globin synthesis. > Anemia of chronic disease : defect in haem synthesis. > Sideroblastic anemia : defect in haem synthesis. IL.Normocytic normochromic : > Hemolytic anemia, > Aplastic anemia. > Acute-post-hemorrhagic anemia. > Anemia of chronic disease, Ill. Macrocytic : > Vitamin B 2 deficiency. > Folic acid deficiency. > Myelodysplasia. > Myxedema. > Alcohol. > Chronic liver diseases.In Capsule Series www.incapsuleseries.com Hematology {the most common type} Etiology: 1. Chronic blood loss { the most common cause} eg. © Menorthagia. © Ancylostoma infection. o Esophageal varices , peptic ulcer. 2. | Iron intake. 3. | absorption of Iron : © Malabsorption syndrome. o Achlorhydria (4 HCL): notice that HCL is responsible for transformation of ferric form into ferrous to be absorbed. 4. t Demand for Iron e.g. pregnancy , puberty. {Compensatory mechanism: Iron deficiency leads to : a. Increase absorption from the intestine. b. Increase synthesis of transferrin ( iron carrying protein ). c. Decrease transferrin saturation ( from 33% to 10% ). 4In Capsule Series www.incapsuleseries.com Hematology icture;| as scheme plus General manifestations of anemia plus 1. Pica © Perverted appetite. 2. Nails © Brittle and spooning (koilonychias ) 3. Angular stomatitis & glossitis. 4. C/P of the cause : © Ancylostoma : GIT manifestations e.g. abdominal pain .... © Plummer - Vinson syndrome : Iron deficiency anemia with dysphagia.In Capsule Series www.incapsuleseries.com Hematology [Investigations :| as Scheme I. cBc: 6 ||RBCs,Hb. © @ || MCV, MCH, MCHC. (mcv | serum iron and serum ferritin & transferrin saturation. > 1 Total Iron Binding Capacity ( TIBC ). V.For the cause : @ Stool analysis for Ancylostoma : ova. Endoscope may be needed to detect the site of chronic blood loss eg, peptic ulcer. [Differential diagnosis Microcytic hypochromic anemia : Tron ‘Anemia of | Thalassemia Sideroblastic anemia deficiency | chronic trait (a oF f) disease Mc Reduced | Low normal | Very low for Low in inherited type or normal | degree of but often raised in anemia acquired type ‘Serum iron Reduced [Reduced | Normal Raised SerumTIBC | Raised | Reduced _| Normal Normal Serumferritin [Reduced | Normal or | Normal Raised raised Tron inmarrow | Absent __| Present Present Present, Tron in ‘Absent | Absent or | Present Ring forms erythroblasts reduced Details : see belowIn Capsule Series www.incapsuleseries.com Hematology Treatment 3 as scheme plus © Treatment of the cause e.g. ; Ancylostoma , peptic ulcer, menstruation ... © tron therapy : The response to iron therapy can be monitored using the reticulocyte count and Hb level ( Hb should rise by I gm% per week’) 1. oral: tab/8h zs Ferrous sulphate 200 mg tab zs Ferrous gluconate 300 mg tab ~. Vit C can be given to improve the absorption. za S/E : nausea, vomiting , abdominal pain , dark stool. 2. parental : > Indication: o Oral iron intolerance. o Malabsorption syndrome. © Gl disorders that may be aggravated by oral iron e.g. peptic ulcer. o Rapidiron loss. > Preparation: z= Iron-Dextran : 100 mg/d IM or IV vs. Iron-Sorbitol : 50 mg/d IM Sideroblastic anemia > Refractory anemia due to ineffective haem synthesis ( failure to incorporate iron into hemoglobin molecule ). > There is accumulation of iron in the mitochondri of ieneay By DrDiaa Ahmed 10 Zagazig UniversityIn Gapsule Series www. incapsuleseries.com Hematology EVER ECU cl (Definition: | Anemia due to Bone Marrow failure. [Etiology: 2 Primary: Idiopathic : probably autoimmune { the most common cause } > Secondary: 3M > Malignancy : Leukemia , Lymphoma > Myelofbrosis. > Myelosclerosis. 1) Irradiation. 2) Infection : Hepatitis , EBV 3) Immune : SLE 4) Iatrogenic: anyanti.. © > Anti biotics : Chloramphenicol > Antineoplastic : Azathioprine > Anti epileptic: Phenytoin. > AntiDM _: Chlorpropamide. > Anti thyroid + Carbimazole @ Anemia. @ Recurrent infections. Bleeding.In Capsule Series www. incapsuleseries.com Hematology investigations:| I. CBC: ©. The hallmark of aplastic anemia is pancytopenia. However, early in the evolution of aplastic anemia, only one or two cell lines may be reduced. © MCV, MCH, MCHC : normal. © Decreased reticulocytes. Il. Color index: normal (1) Ill. Bone marrow examination : Hypocellular , devoid of hematopoietic cells. Treatment supportive ttt plus A, B,C 6 Supportive treatment :red cell transfusion for anemia , antibiotics for infections , platelet transfusion for bleeding. © Androgen. (B.M. stimulant ) BM transplant: in severe cases , particularly in children. 6 Cause treatment. 2 Aplastic anemia ( and its causes ) 2 Megaloplastic anemia. 2 Hypersplenism ( e.g. portal HTN) 2 Myelofibrosis. 2 Myelosclerosis. 2 Subleukemic leukemia. > PNH. > SLE.In Capsule Series www. incapsuleseries.com Hematology Ieee N el CeCe beC Sete [Definition | It’s a hematological disorder characterized by Pancytopenia with 4 criteria: oa 1. Megaloplastic hyperplasia of the bone marrow. 2. Evidence of Macrocytosis . 3, Good response to vit. B12 & folic acid. 4, Neurological & G.LT manifestations. [Pathophysiology: 4 1. Arrest of the division : as vit. B12 & folic acid are essential for DNA synthesis. This will result in big cells ( megaloblasts ). 2. Ineffective erythropoesis : most of megaloblasts undego intra mdullary hemolysis. 3. Evidence of macrocytes : some megaloblasts can escape the bone marrow and appear in the blood as macrocytes. 4. Rapid hemolysis : macrocytes are rapidly sequestrated by the spleen. I. Vitamin By deficiency: 4 1. Diminished intake of vitamin B12 which is present in animal products. 2. Decreased absorption : © Pernicious anemia ( The most umon cause ) o Gasterectomy , chronic gastritis. © Malabsorption syndrome. o Ileal resection. 3. Chronic liver diseases : Body stores are Sufficient for 3yrs. 4. Transcobalamin I deficiency ( rare ) 13.Jn Capsule Series www.incapsuleseries.com Hematology Pernicious anemia ©. I think you know that intrinsic factor is necessary for absorption of vitamin B12 ok © Here in pernicious anemia , there is a deficiency in production of Ai abe lat ee Ss ins iu +3 II. Folic acid deficiency : 1. Decreased intake : lack of vegetables & fruits , alcoholism. 2. Decreased absorption : malabsorption syndrome. 3. Increased requirement : Pregnancy , malignancy. 4. Drugs : Methotrexate , phenytoin. MCQ > Anemia : see scheme > Neurological manifestations (3p) Vit B12 is an important co factor in the formation of myelin sheath. 1. Peripheral neuropathy. 2. Pyramidal tract lesion. 3. Posterior column — loss of deep sensations. 2 gastrointestinal manifestations (3 Atrophy ) 1, Atrophic glossitis. 2. Atrophic gastritis. 3. Atrophy in the intestine. 14 No NeurologicalIn Capsule Series www. incapsuleseries.com Hematology Investigations] As scheme plus I. CBC: > Pancytopenia : RBCs ,Hb, WBCs & platelets: | 2 MCV, MCH, MCHC: 1 except MCHC is normal. > Anisocytosis ( unequal size ) , Poikilocytosis ( abnormal shapes ) > Color index : >1 Il. Bone marrow examinations : Megaloplastic hyperplasia © Ill.Measurement of serum Biz & folic acid : + serumB,2: <100 pg/mL (N:> 200 pg/ml) + serum folate: <4 ng/ml (N:6-20 ng/ml) By DrDiaa Ahmed Zagazig University IV. Schilling test : ‘= Giving the patient vit. By: (100 ug IV ) to saturate body stores. ‘© Giving patient radioactive By (Iug) orally. = Collect patient urine /24 h and measure radioactive B12 ‘© Tfvitamin By, is absorbed , it will appear in urine. V. Therapeutic test : Giving small dose of vitamin B,2 or folic acid — Reticulocytosis. VI._Serological test : Anti parietal cell antibodies & anti intrinsic factor antibodies may be present in pernicious anemia. 1SIn Capsule Series www. incapsuleseries.com Hematology VII. FIGLU Test: +ve in folic acid deficiency. Oral loading with histidine is accompanied by high urinary excretion of Formin Ino GLUtamic acid, an intermediate metabolite in the conversion of L-histidine to L-glutamic acid. ( +ve FIGLU test). [Differential diagnosis | Other causes of macrocytic anemias : + Myelodysplasia = Myxedema. = Alcohol. © Chronic liver diseases. -eatment As scheme plus replacement therapy 1. Vitamin Bj deficiency : Vitamin By: ( Hydroxycobalamine ) : > Intramuscular injections of 1000 ug of vitamin B,2 : usually given daily for the first week, weekly for the first month, and then monthly for life. > Itis a lifelong disorder, and if patients discontinue their monthly therapy the vitamin deficiency will recur. 2. Folic acid deficiency : 2 Folic acid : 5 mg/day orally > Vitamin B1z is essential for the transformation of folic acid into the active form folinic acid , So large doses of folic acid may aggravate the manifestations of vitamin Biz deficiency especially neurological manifestations. Try to learn something about everything and everything about something. Thomas Henry HuxleyEn Capsule Series www. incapsuleseries.com Hematology Hemolytic anemias Anemias due to reduction of life span of RBCs ( increased rate of RBCs destruction ). NN: 120 days [Etiology ;| Hb defect DEnzyme defect 1- Immune: © Iso-immune: Antibodies cause destruction of RBCs after transfer to another person e.g. ABO , Rh incompatibility. © Auto-immune : Antibodies cause destruction of RBCs of the same person e.g. warm & cold type (see later) 2+ Infection : Malaria. 3- Toxic : Amphotericin B , Lead , Copper, snake venom , sulpha. 4- Trauma : Artificial valve , March hemoglobinuria , Micro- angiopathic hemolytic anemia e.g. vasculitis , DIC. 5- Hypersplenism.In Capsule Series www. incapsuleseries.com Hematology Pathophysiology : 1- Anemia occurs if life span < 15 days : As bone marrow has ability to T it's activity up to 8 times ( compensated hemolytic state ). 2- Hemolytic jaundice > T unconjugated bilirubin. 3- Intravascular hemolysis : in the circulation > Hemoglobinuria © tubular damage and dark urine. 4- Extravascular hemolysis : in the reticulo-endthelial system ( RES ) => HepatoSplenomegaly. General manifestations of anemia (sec before) Plus : 4 1+ Manifestations of hemolytic jaundice (see GIT...wait .see here © ) © Jaundice: mild (lemon yellow) © Urine: Normal , may be dark due to hemglobinuria. © Stool: dark 2- Intravascular hemolysis } Hemoglobinuria. © Tubular damage. © Dark urine. 3- Extravascular hemolysis ( in the reticulo-endthelial system, RES ) = HepatoSplenomegaly. 4- Hemolytic crisis : 1- Fever. 2- Rigor. 3- Deepening of jaundice. 4- Bone ache ~ due to hyperactivation of the bone marrow. 5- Kidney Loin pain. 6- Abdominal pain.In Capsule Series www.incapsuleseries.com Hematology © Megaloblastic crisis : due to development of folic acid deficiency. © Aplastic_crisis : viral infection = inhibition of BM + aggravation, of anemia without deepening of jaundice. = © Vaso-occlusive crisis (in sickle cell anemia + Occlusion Of Small Blood Vessels) Don’t forget features of certain types of hemolytic anemias| (see below ) iinvestigations { 1- CBC o |{RBCs,Hb © o Normal WBCs & platelets. o Normal MCV , MCH & MCHC. © #4 Reticulocytic count Except in Aplastic crisis. Reticulocytic count is the single test to detect hemolyticlanemia: 2- Color index = 1 3- BM examination : o Hypercellular to compensate for RBCs destruction. © Normoblasts. © Megaloplastic : in secondary folic acid deficiency 4- Investigations for hemolytic jaundice: © Inserum:® ‘unconjugated bilirubin. (Bilirubin never > Smg% as long as liver is normal ) © Instool :& | sterocobilinogen. (dark stool ) o Inurine: — Unconjugated bilirubin is water insoluble therefore NOT found in urine. (normal colored urine ) — § urobilinogen . 19In Capsule Series www. incapsuleseries.com Hematology 5- || RBCs life span : measured by isotopic methods. 6- Investigations for intravascular hemolysis : © Hemoglobinuria. © Diminished hemopexin & haptoglobin in plasma. (normal plasma proteins that bind and clear hemoglobin released into plasma ) 7-Investigations for certain types of hemolytic anemias : see below Coomb’s test * > A test for detection of antibodies against RBCs immune hemolytie anemia. > Positive in iad nh * The Coombs reagent is a rabbit IgM antibody raised against human IgG. The direct Coombs test is performed by mixing the patient's red blood cells with the ‘Coombs reagent and looking for agglutination, which indicates the presence of antibody on the red blood cell surface. 1- Fresh blood transfusion. 2- Splenectomy in some cases. 3- Treatment of the cause : if possible. Thave not failed. I've just found 10,000 ways that won't work. Thomas Edison 20In Capsule Series www.incapsuleseries.com Hematology Hereditary Spherocytos Hereditary spherocytosis is a disorder of the RBCs membrane in which there is a deficiency in spectrin protein in RBCs membrane . so the membrane becomes : i. Rigid: so the RBCs are trapped in the small capillaries & spleen & rapidly destroyed. (Normally, the red blood cell is a biconcave disk with a diameter of 7 mem. The red blood cells must be deformable to pass through capillaries 3 mcm in diameter ) ii. Highly permeable to Na & water : causing the RBCs to take the shape of sphere & early destruction occurs. ‘linical picture : © Features of hemolytic anemia ( see before ) o +e family history is usually +ve. © The onset is usually during childhood. Investigations :| The same as hemolytic anemias plus 1, Osmotic fragility : is increased , hemolysis occurs at dilution of 0.7% (normally RBCs hemolysis occurs at dilution less than 0.4 % ). 2. Blood film : spherocytes. 3. Increased MCHC : Hereditary spherocytosis is the only important disorder associated with microcytosis and an increased MCHC. Treatment ;| 1. Blood transfusion. 2. Splenectomy : Best avoided in patients < 10 years old due to risk of fatal infection postsplenectomy. Remember pre-splenectomy vaccines and post- splenectomy antibiotics. 3. Folic acid Img/d. 21In Capsule Series www.incapsuleseries.com Hematology Paroxysmal Nocturnal Hemoglobinurea (PNH)) Definition ;) Blood cells membranes are more sensitive to complement system . [Clinical picture | & Triad of 1- Chronic hemolytic anemic : particularly overnight 2- Pancytopenia : due to associated BM hypoplasia. 3- Thrombosis (e.g. Budd—Chiari syndrome). Complications ; €* May progress to more severe aplastic anemia. © Transforms to acute leukemia in 5%. 6 Serious thrombosis in up to 20%. Investigations ; > Ham test : +ve ( rapid hemolysis occurs if the serum is acidified ) > Flow cytometric assays may confirm the diagnosis ( absence of CD59 ) ffreatment_:| General supportive measures plus: 1- Steroid. 2- Oral anticoagulants for thrombosis. 3- BM transplant. Ce ee ety (Glucose 6 Phosphate Dehydrogenase deficiency ) © G6PD enzyme is essential for production of reduced glutathione (hrough Hexose monophosphate shunt ) which protects RBCs from oxidizing agents. © Inthe absence of reduced glutathione, hemoglobin may become oxidized. © Itis X-linked disease affects mainly 3. @ 22In Capsule Series www.incapsuleseries.com Hematology [Clinical picture | i. When patient is subjected to oxidizing stress — acute intravascular hemolysis occurs. ii. Oxidizing agents : — Drugs: ys. Anti-malarial : Primaquine , Chloroquine. = Antibiotics ; Sulphonamides (cotrimoxazole) , ciprofloxacin. vw. Aspirin. — Diet : Fava bean ( Favism ) — Infections. iii, Types: & 2 Type A : ( Negro type) : Enzyme defect in old RBCs only , so the hemolysis is not severe. > Type B : ( Mediterranean type ) Enzyme defect in all RBCs ( old, recent ) , so the manifestations are severe. > Favism : In Mediterranean populations — Hours/days after ingestion (or even smelling) of fava beans. — Beans contain oxidants e.g, vicine and convicine. — Itmay be fatal. — Investigations for hemolysis. (see before ) — Assay of the activity of G6PD enzyme. — Blood film : Heinz bodies. Treatment E — Avoid oxidizing agents. — Blood transfusion in severe attacks. 23In Capsule Series www.incapsuleseries.com Hematology Definition j an acquired anemia caused by auto-antibodies. es 3) Ine Extravascular RBC destruction by RES mediated by warm-reacting antibody. Etiology : © Most cases are idiopathic. (75% ) © Secondary : Lymphoma , leukemia , SLE , Drugs : & methyl dopa. Clinical picture : © Features of hemolytic anemia. o DIC Investigations : © Investigations for diagnosis of hemolysis: see before © Positive Coomb’s test : Detects antibodies on RBCs { IgG ) © Blood films : spherocytes. (when IgG attacks RBCs they become spherocytes ) © Immune thrombocytopenia may be associated (Evans's syndrome) Treatment : © Prednisone : 1mg/ke/d orally © Immunosuppressive drugs e.g. azathioprine, © Splenectomy . ISR ( Cold haemagglutinin disease ) Caused by RBC antibodies that reacts most strongly at temperatures < 37°C. Etiology : © Idiopathic. © Infectious Mononucleosis , Mycoplasma pneumonia , Paroxysmal cold haemoglobinuria. 24In Capsule Series www.incapsuleseries.com Hematology Clinical picture : © Hemolytic anemia on exposure to cold. o Raynaud’s phenomenon. Investigations : © General investigations for hemolysis. © Positive Coomb’s test. Treatment : © Avoid exposure to cold. By DrDiaa Ahmed Zagazig University o Cyclophosphamide. © Azathioprine. A Elam aot Causes : Idiopathic ~ Idiopathic o Lymphoma. © Infectious o Leukemia. Mononucleosis . o SLE. o Mycoplasma o Drugs( methyl pneumonia. dopa) © Paroxysmal cold haemoglobinuria.In Capsule Series www.incapsuleseries.com Hematology [Hemoglobinopathies Hemoglobin is composed of : © Haem : Iron - protoporphyrin complex. © Globin : protein consisting of 4 polypeptide chains. ‘Amount 85% 5-10% SON ERS Tenet) Definition ; - Hereditary disorder in which there is production of abnormal Hb (HbS) - In Hb S : valine replaces glutamic acid at position 6 on the f-globin chain. ~ It is of 2 types : 1) Homozygous ( sickle cell anemia ) : HbSS Leading to manifested anemia , sickling ( elongation ) may occur with mild hypoxia. 2) Heterozygous ( sickle cell trait ) : HbAS It is asymptomatic , sickling may occur with severe hypoxia. (Clinical picture ; > General manifestations of hemolytic anemia without splenomegaly > Vaso-occlusive crisis : abnormal sickling ¢ elongation ) of RBCs > vaso occlusion > Tissue infarction resulting in pain and/or tissue damage. > Brain: strokes. > Eye : retinal detachment. > Heart : myocardial infarction.= Capsule Series www.incapsuleseries.com Hematology Spleen : infarction > autosplenectomy ( No splenomegaly ) Kidney : infarction ( hematuria & chronic renal failure ) Bone : pain. > > > Abdomen : Mesenteric blood vessels occlusion > acute abdomen. > > Penis : priapism. > Leg ulcers. 2 Infections : pneumococci and salmonella. Investigations ;| = Investigations for diagnosis of hemolytic anemia. = Hb electrophoresis + HbS is high ( diagnostic ) © Blood film= sickle cells especially after inducing hypoxia by addition of Na metebisulphite. Treatment {| 1) Blood transfusion. 2) Symptomatic treatment : vs Analgesics. zs, O2 therapy. vw IV fluids z=. Exchange blood transfusion (if stroke or visceral damage) : Aim to | HbS to < 30%. zs Pneumococcal vaccination. 3) New lines of treatment : ~ Hydroxyurea : elevates HbF (HbF reduces HbS and hence sickling ) + BMI. © Gene therapy.In Capsule Series www.incapsuleseries.com Hematology Definition — Hereditary disorders characterized by reduction in the synthesis of globin chains (« or 8). — Reduced globin chain synthesis causes reduced hemoglobin synthesis and eventually produces a hypochromic microcytic anemia because of defective hemoglobinization of red blood cells. Types | 1- Alpha thalassaemia : > There is decreased production of « chains. > There are 4 o gene. The disease is caused by gene deletion as follow : a-Globin Genes Nar Ctcese ts pero Le im a. Thalassemia minor Ctrait ) "Mild Hypochromic microcytic gene deletion anemia. Usually diagnosed by exclusion (other causes of microcytic anemia are excluded e.g. iron deficiency). No splenomegaly. Requires no therapy. ‘4 gene deletion thalassaemia major | There is a major failure of o. chain Hb H& Hb Bart (ys): > 80% manufacture, death in utero results (Hydrops fetalis).= Capsule Series www.incapsuleseries.com Hematology 2- Beta thalassaemia : © There is decreased production of & chains which are replaced by gamma (7) or delta (5) chains leading to production of Hb F (czy) & HbA, (2252). o There are 3 types: 1) Thalassaemia major : ( Cooley's anemia ) > Hb Ais markedly reduced &Hb F is markedly increased ( 90%) > clini ifestations: ° Starts after the age of 6 months ( when hemoglobin synthesis switches from hemoglobin F to hemoglobin A ) . Severe anemia requiring lifelong blood transfusion. Hepatosplenomegaly , hypersplenism. Growth retardation : due to chronic anemia. Bony deformities : |. Flat bones , pathologic fractures. Il. Facial appearance : Y Protrusion of frontal & parietal bones. v Prominence of malar eminences & prognathism. Y Depressed nasal bridges. Hemochromatosis ( Cirrhosis, HF,DM...): see GIT p16 Itis due to transfusional iron overload. This problem develop because of the body's inability to excrete the iron from transfused red cells. 29In Capsule Series. www. leseries.com Hematology 2) Thalassaemia minor : ( Thalassaemia trait ) o HbA is slightly reduced with increase in both Hb F (5- 10% ) & Hb A: (5 - 10% ). It presents in adults by mild anemia & splenomegaly. © Usually requires no treatment. 3) Thalassaemia intermedia: variable Hb A . © NOT requiring regular blood transfusion. © more severe than thalassaemia trait but milder than thalassaemia major. Causes of death : 1. Congestive heart failure. {Investigations | 1) Peripheral blood examination : © RBCs &Hb:+ ° © Microcytic hypochromic anemia. (1 MCV, MCH, MCHC) © Target cells , Aniso- & poikilocytosis. 2) Hbelectrophoresis : diagnostic © Thalassemia major : Hb A is markedly reduced & Hb F is markedly increased (90%). @ Thalassemia minor : t Hb Az 3) X-ray: o Skull: Hair on end appearance. Long bones : thin cortex , wide medulla. 4) Serum iron & ferritin : Increased. 30In Capsule Series www. incapsuleseries.com Hematology Treatment 3 1. Blood transfusion : o Thalassaemia major : requiring lifelong blood transfusion. o Thalassaemia intermedia : NOT requiring regular blood transfusion. o Thalassaemia minor : Usually requires no treatment. Aim of blood transfusion: to keep Hb concentration Y >6 gmi/dl : simple transfusion. ¥ > 10 g/dl : hyper-transfusion, Y > 12 gnVdl: super-transfusion. 2. Avoid diet rich in iron. 3. Iron chelating agent : z= Desferrioxamine ( desferal ) : IM, SC. vs. Deferasirox : oral. 4. Folic acid : 1mg/d oral. 5. Antibiotics : for recurrent infections. 6. Splenectomy : may be indicated especially in a case of hypersplenism. 7. BM transplant : The most efficient. A doctor must work eighteen hours a day and seven days a week. If you cannot console yourself to this, get out of the profession. Martin H. Fischer By DrDiaa Ahmed Zagazig, University 31In Capsule Series www.incapsuleseries.com Hematology Anemia of chro: [Definition : It is a form of anemia seen in chronic illness e.g. chronic infection, chronic inflammation, liver disease, renal failure, or malignancy. {Incidence + te 2% most common type next to iron deficiency anemia physiology ;| (failure of iron utilization) o © Life span of RBCs o Failure of B.M to compensate is due to sequestration of iron in RES o © Erythropoietin is rarely an important factor except in renal failure. {Clinical picture @ Clinical picture of the cause 6 Clinical picture of anemia (see scheme and you may remember) > Serum iron: 11 > Transferrin saturation may be extremely low. > Tipc: 1) > Serum ferritin : normal or increased ( in contrast to iron deficiency) > For the cause : KFTs, LFTs, Tumor markers. ffreatment = In most cases no treatment is necessary as it is usually mild anemia ‘= Treatment of the cause. = Erythropoietin. Iron deficiency | Anemia of chronic disease MCV Reduced. Low normal or normal ‘Serum iron Reduced Reduced SerumTIBC | Raised Reduced Serum ferritin | Reduced Normal ar raised Iron in marrow | Absent Present 32Ea Capsule Series www. incapsuleseries.com Hematology One neat CS eCeaig This condition is attributed primarily to decreased erythropoietin production and may occur as the creatinine clearance declines below approximately 50 mL/min. Diagnosis : © CBC: Normocytic anemia. o Clinical picture & investigations of chronic renal failure. v= Erythropoietin. Adverse reactions : & Hypertension , seizures may occur. % Suboptimal responses may occur with coexisting iron deficiency so, many patients benefit from IV iron supplementation. Anemia in endocrine disease PITUITARY o Panhypopituitarism : is associated with normochromic, normocytic anemia , associated leucopenia may also occur. © Hypothyroidism : may produce a mild degree of anemia. Y Menorthagia occurs in hypothyroidism and can result in associated Fe deficiency. Y B12 levels should be checked because of the association with other autoimmune disorders (e.g. pernicious anemia). 33In Capsule Series www. incapsuleseries.com Hematology [ADRENAL > Hypoadrenalism : results in normochromic, normocytic anemia, the plasma volume is | which masks the true degree of associated anemia. The abnormalities are corrected by replacement mineralocorticoids. > Cushing’s : results in erythrocytosis with a typical net increase in Hb (by 1-2g/dL). Mechanism is unclear. PARATHYROD | > Hyperparathyroidism : may be associated with anemia from impairment of erythropoietin production, or in some cases from secondary marrow sclerosis. DIABETES MELLITUS } When poorly controlled may be associated with anemia; however, the majority of hematological abnormalities in diabetes mellitus result from secondary disease related complications e.g. renal failure. Any other type of Anemia (anemia of liver failure or pregnancy) Scheme + use your mind © By DrDiaa Ahmed Zagazig, University 34In Capsule Series www.incapsuleseries.com Hematology 50-70 % This is by far the commonest cause of Leucocytosis. Increased : A. Physiological : Severe exercise, last months of pregnancy, newborn, steroids. B. Pathological : = Bacterial infection. © Non-infective tissue damage : MI , pulmonary infarction , pancreatitis, burn . = Metaboli disorder : DKA, uremia, acute gout ‘= Myeloproliferative disorders. Decreased: a mild decrease is referred to as neutropenia; a severe decrease is called agranulocytosis. © Infection : viral , Typhoid , Brucella. © Immunological : SLE , Felty’s syndrome. § Iatrogenic : cytotoxic agents, phenothiazines, NSAIDs, anti-thyroid drugs. Aplastic anemia. Hypersplenism. qqa4q Benign familial neutropenia : is a feature of rare families , is associated with mild neutropenia but no propensity to infection. sophils :0Se Function : They combine with IgE causing release of histamine & other contents involved in acute hypersensitivity. Increased: ® Myeloproliferative disorders e.g. CML , polycythemia vera. ® Hodgkin disease. o> Rarely : recovery from infection or hypothyroidism. Decreased : Acute rheumatic fever, pregnancy , steroid therapy, thyrotoxicosis, stress. 35,In Capsule Series www.incapsuleseries.com Hematology 1-5% Increased: Allergy : Bronchial Asthma, Eczema. = Asthma. @ Addison disease. © Ankylostomiasis , Ascariasis. Decreased : Steroids, Cushing syndrome , Acute stressful conditions. 20-45 % Increased: = Viral infection : measles, mumps, smallpox, influenza, hepatitis, infectious mononucleosis). © Bacterial infection : TB , brucella , typhoid. = acute and chronic lymphocytic leukemia @ Lymphoeytosis is normal in infancy. Decreased: Normal in 22% of population. = Stress. = Steroids. = Suppression of BM after chemotherapy. © SLE. © Some viral infections e.g. HIV © Atypical Lymphocytosis : © Infectious mononucleosis , CMV , toxoplasmosis. © Viral hepatitis. = Leukemia & lymphoma. 3-7% They originate in the BM then circulate in the blood => to the tissue ( converted into tissue macrophages ). Increased : © Infection : TB, SBE, brucellosis, typhoid , infectious mononucleosis , malaria, © leukemia, Hodgkin disease. © Inflammatory bowel disease : ulcerative colitis. Decreased : Lymphocytic leukemia, aplastic anemia, steroid use. 36In Capsule Series www.incapsuleseries.com Hematology EMO SSO Definition : Malignant proliferation of immature WBCs primarily in bone marrow & then they circulate in peripheral blood & infiltrate other tissues. Classification of leukemia : I. Acute leukemia * Acute Lymphoblastic leukemia ( ALL ) ¢ Acute Myeloblastic leukemia (AML , ANEL ) II. Chronic leukemia. © Chronic myeloid leukemia ( CML) © Chronic Lymphocytic leukemia ( CLL) Etiology : Unknown but genetic & environmental factors may play a role: I. Genetic factor : © The incidence of leukaemia is increased in identical twins. © High incidence in certain chromosomal disorders : Down's syndrome, Klinefelter's syndrome. © Presence of chromosomal abnormalities in certain types of leukemia eg. Philadelphia chromosome in CML. Il. Environmental : © Radiation : Increased incidences in survivors of Hiroshima and Nagasaki and in patients treated with ionizing radiation. © Chemical and drugs : benzene, chlorambucil. o Viruses : Leukaemias are associated with human T cell lymphotropic virus (HTLV-1), which is found particularly in Japan and the Caribbean. IiLPre - existing hematologic disorders : Myelodysplastic syndromes. 37In Capsule. Series www.incapsuleseries.com Hematology Acute Leukem |. Acute lymphoblastic leukemia (ALL) : common in children ( 80% of the acute leukemias of childhood ). The peak incidence is between 3 and 7 years. ll. Acute myeloblastic leukemia (AML) : common in adults. 2 problems clinical picture jauBone Marrow pig: Blast cells proliferate in an uncontrolled fashion and replace normal bone marrow elements. > RBCs: Severe progressive anemia. > Platelets : purpura, menorrhagia, epistaxis & bleeding gums, rectal, retina. > WBCs: Fever & recurrent infections . © The most common pathogens are gram-negative bacteria (E coli, Klebsiella, Pseudomonas) or fungi (Candida, Aspergillus). © Common presentations include cellulitis, pneumonia, UTI and perirectal infections; death within a few hours may occur if treatment with appropriate antibiotics is delayed. m@Organ Infiltration 1. Bone marrow infiltration : bone pain , tender sternum. 2. Generalized lymphadenopathy especially in ALL ( e.g. Cervical , mediastinal , porta hepatis LN ) 3, Hepatosplenomegaly. 38In Capsule Series www.incapsuleseries.com Hematology 4. Other organs. affectic & > Infiltration. 2 Infection. > Infarction : due to leucostasis ( occlusion of the microcirculation leading to ischemia & hemorrhage ). © Kidney : Acute renal failure especially during treatment, pyelonephritis ° Skin: pruritis , nodules , chloromas ( soft tissue masses that may occur in AML), McQ © CVS: cardiomyopathy. © CNS: Paraplegia , meningitis , 1 ICT. © Lung-: Hemoptysis , infections. © Gum hypertrophy. © Testicular infiltration & penis priapism. Investigations: @ cBc: > WBCs : usually increased (up to 100,000/ emm ) , but WBCs may be low > RBCs: || normocytic normochromic anemia. > Platelets || > Blast Cells : +++ (lymphoblasts or myeloblasts ) > Cytochemical stains, immunological markers & cytogenetic analysis are necessary to differentiate AML from ALL. @ BM examination: > More than 20% blasts are required to make a diagnosis of acute leukemia, © Others: » Uric acid, LDH: T 39In Capsule Series www. incapsuleseries.com Hematology > Serum electrolytes may be affected due to diarrhea , vomiting or chemotherapy. > CT brain , CSF examination , renal function tests. How to differentiate between ALL & AML ? 2 Morphology : Myeloblasts look similar to lymphoblasts. Presence of Auer rods in the cytoplasm of blasts are diagnostic of AML. Mco > Cytochemical stains : Sudan black stain is +ve in AML , -ve in ALL. 2 Enzymes : t Deaminase in ALL , Muramidase enzyme in AML. 2 Immunological markers . French-American-British (FAB) Classification of AML : Norohalonial background MO: Undifferentiated leukemia. M1: Myeloblastic leukemia without maturation. M2: Myéloblastic leukemia with maturation. M3: Promyelocytic leukemia : often associated with DIC MCQ M4: Myelomonoeytic leukemia. Differential diagnosi: 1. Causes of fever with sore throat : Rheumatic fever , Infectious mononucleosis. 2. Bone marrow failure ( Aplastic anemia ) . 3. Causes of lymphadenopathy.In Capsule Series www.incapsuleseries.com Hematology 2 RBC and platelet transfusion will continue through treatment. > Antibiotics for infection. > Allopurinol to prevent hyperuricemia. 1. Induction of remission vap Aim : is to achieve a complete remission ( no evidence of leukaemia in the blood, a normal blood count & < 5% blasts in the bone marrow ). Vincristine: 1.8 mg/m*/week IV for about 4 weeks. @ Adriamycin: 40 mg/m*/week IV for about 4 weeks. Prednisolone : 40 mg/m?/d oral for about 4 weeks. Poor prognosis: MCQ - Age<2or> 10 years. - WBCs> 50,000. - CNS manifestations ~ Platelets <25000 - FAB classification : L3 2. CNS prophylaxis : © Cranial irradiation. @ Intrathecal methotrexate. 3. Consolidation : © Consolidation therapy is given after complete remission is achieved, to reduce the risk of relapse. © Itconsists of either the same drugs as those used in induction therapy or other cytotoxics. 4. Maintenance: for about 2-3 years @ Mercaptopurine ( daily ) © Methotrexate. (weekly ) @ Prednisolone (monthly ) 41In Capsule Series www.incapsuleseries.com Hematology 1. Induction of remission @ Cytosine arabinoside (ara-c) : 100 mg/m*/d for about I week. Adriamycin (poronbicn) : 45 mg/m? IV for 3 days. 2. CNS prophi is: Is NOT used in the treatment of adult AML. 3. Consolidation : It consists of either the same drugs as those used in induction therapy or other cytotoxics. 4. Maintenance therapy : In the treatment of AML, there is controversy over the use of maintenance therapy. (not thought to be of benefit in most patients with AML). Bone marrow transplantation is the treatment of choice. In general, the response to treatment and the prognosis are better in patients with ALL than in those with AML [Prognosis > Without treatment : Acute leukemia is fatal within few months. > Cure rate with chemotherapy : - ALL: © Children :90% o Adults : 60% - AML : 30% (over 60s do worse ) 1. Recurrent infections 2. Cerebral or internal hemorthage. 3. Multiple organ failure (MOF). 42In Capsule Series www incapsuleseries.com Hematology Chronic Myeloid Leukemia Definition J Chronic myeloid leukemia ( CML) is a myeloproliferative disorder characterized by overproduction of myeloid cells. (Clinical picture:| CML is more common in middle & old age males © > 30% asymptomatic at diagnosis; present after routine CBC. > Fatigue & weight loss. sf Organ Infiltration # The same as in acute leukemia but begin with splenomegaly. 2 Splenomegaly ( huge spleen) : o Dragging pain in the left hypochondrium. ° Stitching pain in the left hypochondrium due to splenic infarction. o The spleen is hugely enlarged , may be with multiple notches & splenic rub. > Generalized lymphadenopathy (e.g. Cervical, mediastinal, porta hepatis LN) may oceur. > Bone marrow infiltration ; bone pain , tender sternum. > Other organs affection : rare in CML > Infection. > Infiltration. > Infarction : due to leucostasis (occlusion of the microcirculation leading to ischemia & hemorrhage ). eg: © Kidney : Acute renal failure especially during treatment, pyelonephritis, © Skin: pruritis , nodules. © CVS: cardiomyopathy. © ENS: Paraplegia, meningitis , t ICT. © Lung :Hemoptysis , infections. © Gum hypertrophy. © Testicular infiltration & penis priapism. 43In Capsule Series www incapsuleseries.com Hematology Nm@Bone Marrow failure F > RBCs: anemia. > Platelets : purpura, menorrhagia, epistaxis & bleeding gums, rectal, retina. © WBCs : Fever & recurrent infections . im. FREESE - Patients may develop a transformation into acute myeloblastic leukemia. [Investigations @ CBC 1. WBCs : o The total white cell count is increased ( often > 100000/cmm ) © Itis mainly in the form of myelocytes & promyelocytes. © Myeloblasts is usually < 5% . Marked myeloblasts occur in blastic crisis. 2. RBCs : | but not as those in acute leukemia. 3. Platelets: initial rise but drop with the progress of disease. © B.M examination: 1. Hypercellular & full of myelocytes with few Myeloblasts. 2. Marked increase in Myeloblasts occurs in blastic crisis. The Philadelphia chromosome (Ph) : © It isa translocation between chromosomes 9 and 22. ©. It appears in all bone marrow derived cells except T cells. MCQ © Positive in most cases (> 90% ) ©. Philadelphia +ve patients have a better prognosis than Philadelphia -ve patients. Others: 1. Uric acid & LDH: t 2. Neutrophil alkaline phosphatase (NAP ): 4 aIn Capsule Series www.incapsuleseries.com Hematology Differential diagnosis J SM DD of huge splenomegaly : > Bilharziasis. > Malaria. > Chronic myeloid leukemia. > Hairy cell leukemia. > Thalassemia, > Polycythemia. > Myelofibrosis & Myelosclerosis. 2 > Marked Leucocytosis (50,000/emm) due to aggressive response of the bone marrow. > Causes : ©. Infection (severe, chronic, e.g.TB). © Severe hemolysis. o Paramalignant syndrome. > May be distinguished from chronic myeloid leukemia (CML) by measurement of the neutrophil alkaline phosphatase ( NAP ) : elevated or normal in leukemoid reactions, depressed in CML. ‘The same as acute leukemia > RBC and platelet transfusion. > Antibiotics for infection. ® Allopurinol to prevent hyperuricemia. > Leukapheresis : for leukostasis. 45In Capsule Series www. incapsuleseries.com Hematology 11. Ghemotnenapy: 1. Busulfan ( Myeleran ) : o 4-8 mg/d orally, The dose is reduced with reduction of TLC. o S/E: Aplastic anemia , vomiting , diarrhea , gonadal atrophy. 2. Hydroxyurea : o 1-6 gm/d orally , The dose is reduced with reduction of TLC. ©. Side effects: rash, mouth ulcers and diarrhea. IIT. [REGISFRELSPYEE Irradiation of spleen in cases of huge spleen. TV [IBBReNMGEROWETEONS plan : Option of choice in young & fit patient. V. ERR2GHMERAISAIPIGSHENERSISN! Similar to AML ( see above ) Other drugs recently used in CML: Interferon : 3 million units SC , 3 times weekly a Imatinib : tyrosine kinase inhibitor . dose : 400 mg/d orally. |In Capsule Series www. incapsuleseries.com Hematology Chronic Lymphocytic Leukemia [Definition ©. This is a malignant proliferation of small lymphocytes almost always (99%) B lymphocytes. © Commonest leukemia in adults (25-30% of all leukemia). (Clinical pictures > CLL is a disease of older patients : > 50 years. 3:Gratio~2:1 @ Often asymptomatic , lymphocytosis on routine CBC. Lymphadenopathy: painless, often symmetrical. splenomegaly & hepatomegaly ( 50% ) BM failure due to infiltration : v Anemia VVvVVVV ¥ Thrombocytopenia & bleeding tendency. Y Recurrent infection due to acquired hypogammaglobulinemia especially Herpes zoster. > Patients with advanced disease: weight loss, night sweats & malaise. Staging of CLL ;| (Rai modified staging) © stage : Lymphocytosis only. © stageI : Lymphocytosis plus lymphadenopathy. © stage Il : Lymphocytosis & organomegaly. © stage Il: Lymphocytosis & anemia. ©. stage IV: Lymphocytosis & thrombocytopenia. [nvestigations| 2: Ok @ CBC: 1. WBCs: ¥ The hallmark of CLL is isolated lymphocytosis . 47In Capsule Series www.incapsuleseries.com Hematology ¥ The white blood count : Tt and may be markedly elevated up to 1000000/emm . ¥ Usually 80% of the circulating cells are lymphocytes. v Lymphocytes appear small and mature. 2. RBCs and platelet count : v Usually normal at presentation. ¥ Autoimmune hemolysis or autoimmune thrombocytopenia may occur in late stage. BM examination : > 30% lymphocytes. Lymph node biopsy : Rarely required, appearances of lymphocytic lymphoma. ‘reatment Many patient with CLL require no treatment , Living at peace with their lymphocytosis to die of an unrelated complaint. @ supportive treatment : as usual (seeCML) specific treatment: I. Chemotherapy : Chlorambucil ( Leukeran ) : 6 - 10 mg/d orally. 2. Radiotherapy : Irradiation of LN & spleen. 3. Splenectomy : for massive splenomegaly or hypersplenism. Hairy Cell Leukem > It is a rare B-cell lymphoproliferative disorder associated with splenomegaly, pancytopenia and typical ‘hairy cells’ in blood and bone marrow. > Mostly in middle-aged males, with a male-to-female ratio of 5:1 > Treatment : © Cladribine ( 2- chlorodeoxyadenosine; CdA): intuion of 0.1mgold for 7 days ©. Splenectomy in severe cases. © Supportive treatment : as usual.In Capsule Series www. incapsuleseries.com Hematology MPHOMAS Lymphomas are divided into Hodgkin's & Non- Hodgkin's lymphoma based on the histological presence of Reed-Sternberg cells. Hodgkin's lymphoma] First described by Thomas Hodgkin in 1832 Hodgkin's disease is a malignant lymphoma characterized by Reed Sternberg cells. incidence J © Age: one major peak in the 20s and a second over age 50 years (Bimodal age incidence ) © Sex :higher incidenceing. © [Risk factors: @ EBV ( Epstein-Barr virus): T risk of HL in individuals with a history of infectious mononucleosis. 6 Positive family history. (Clinical picture; 1) LNenlargement: © Painless, non-tender , discrete , rubbery lymphadenopathy. © Frequently cervical ( 60 - 80%) , axillary in about 20% & inguinal in about 5%. © Mediastinal lymphadenopathy may produce local symptoms (c.g. bronchial or SVC compression) or direct extension (e.g. to pleura ). Pleural effusions in 20%. 2) Hepatosplenomegaly : palpable splenomegaly in 10%, hepatomegaly 5%. 3) Bone marrow involvement : rare (1 - 4%) © Anemia. © Bleeding tendency. 49In Capsule Series www.incapsuleseries.com Hematology 4) Systemic symptoms : 30% o Fever. ( Pel-Epstein fever , intermittent fever ) o Weight loss. © Night sweats. © Generalized Pruritus. By Dr-Diaa Ahmed A e Zaga © Alcohol-induced lymph node Pain. agazig University linical stages of Hodgkin’s lymphoma 3) (Ana Arbor classification ) Stage I Involvement of a single lymph node region. Involvement of lymph node regions on both sides of the diaphragm + involvement of spleen. Each stage is further subdivided into : > A: Absence of systemic symptoms. > B: Presence of systemic symptoms : fever, night sweats, weight loss Investigations; 1) The most important diagnostic test. > Presence of Reed-Sternberg cells surrounded by inflammatory cells. 2 Hodgkin's disease is histopathologically divided into 4 subtypes : McQ 1. Lymphocyte predominance : Best prognosis. 2. Lymphocyte depletion : Worst prognosis. 3. Nodular sclerosis : Most common in adult. 4. Mixed cellularity : Most common in children. 2) (BREaweteastess : may be necessary e.g. liver or bone marrow. 50In Capsule Series www.incapsuleseries.com Hematology BYR dioloricall = Chest X ray. © CT chest, abdomen and pelvis. = Isotope bone scan, MRI. may be necessary. ENB Hematological & biochemical finding > CBC: © Itmay be normal. © May show normochromic normocytic anemia. o Lymphopenia. © Neutrophilia , eosinophilia and thrombocytosis may be present. > Liver function tests : T transaminases may indicate liver involvement. > ESR,LDH,Ca:t ffreatment 3] I. Symptomatic treatment : e.g. blood transfusion , Antibiotics IL. Specific treatment : 2 Radiotherapy : for early stages (1, ITA ). > Chemotherapy : for later stages. Combination chemotherapy protocols : with or without radiotherapy. z. ABVD : Adriamycin, bleomycin, vincristine, and dacarbazine. TiL-Surgery : indicated in © Pressure manifestations. © Gastric lymphoma. 51In Capsule Series www.incapsuleseries.com Hematology lymphoma This includes all lymphomas without Reed-Sternberg cells. [Incidence ; © Age: old age ( 65 - 70 years ). By Dr.Diaa Ahmed © Sex : higher incidence ing. @ Zagazig University sk factors: @ Infection : ¥ EBV ( Epstein-Barr virus ) : Burkitt lymphoma. ¥ Helicobacter pylori : gastric MALT lymphomas. @ Immunodeficiency : immunosuppressive drugs, transplantation, HIV @ Connective tissue disorders : e.g. Sjogren’s syndrome. MCQ @ Chromosomal : transtocation between the long arms of chromosomes 8 and 14. (Clinical picture; As Hodgkin's disease but]: 1) The diseases is more aggressive than Hodgkin’s disease. 2) Hard lymphadenopathy. 3) Involved lymph nodes may be present also in the retroperitoneum, mesentery, and pelvis. 4) Abdominal pain & abdominal mass in Burkitt lymphoma. 5) Usually disseminated at the time of diagnosis. Hodgkin's lymphoma Non-Hodgkin's lymphoma Age Young Old Site Unicentric Multicentric Skin overlying | Normal Red — hot — dilated veins Consistency Hard Mobility i ‘Amalgamated ( confluent ) prognosis bad 52In Capsule Series www.incapsuleseries.com Hematology (Classification of NH. By DrDiaa Ahmed 1) Indolent lymphomas (Low grade NHL ). Zagazig University 2) Aggressive lymphomas (Intermediate grade NHL ). 3) Very aggressive lymphomas ( High grade NHL ). Indolent lymphomas (low grade) > Follicularlymphoma (grade! & II) 20% > MALT lymphoma. > ‘Small lymphocytic Burkittlymphoma: 3:9=2:1 @ Presents with bulky central nodal disease + extranodal involvement ( typically in the abdomen ), bone marrow and / or CNS involvement. Investigations :| As Hodgkin’s disease but no Reed-Sternberg cells. ffreatment 3 i, Low grade NHL: © Ifsymptomless and low grade, none may be needed. © Radiotherapy to involved nodal regions. © Single agent chemotherapy e.g. chlorambucil. ii, Intermediate & high grade NHL : © Combination chemotherapy : e.g. COPP (Cyclophosphamide, Oncovin, procarbazine , prednisolone ) ii, Lymphoblastic NHL : Treated as ALL (Acute lymphoblastic leukemia) 53In Capsule Series www.incapsuleseries.com Hematology Causes of generalized Lymphadenopathy > Viral : Infectious mononucleosis , Hepatitis. > Bacterial : TB , Brucellosis. > Protozoa : Toxoplasmosis 2 Fungal : Histoplasmosis. 2. Tumor: > Hodgkin's & Non- Hodgkin's lymphoma. > Leukemia : ALL , AML, CLL , CML. > Metastasis > SLE. > Sjogran syndrome. > Amyloidosis, Sarcoidosis £4 > Hyperthyroidism. > Drugs : phenytoin. Studying medicine without teacher is like sailing without a boat, and studying Internal medicine without Dr/Ahmed M.Mowafyis like not going to the sea at all. DR/Alsayed dawoudAn al) Chronic myeloi leukemia (CML) ‘Acute myeloid leukemia (AML) Sarcoidosis www.incapsuleseries.com Hematology Suggested by: anemia, splenomegaly, multiple lymph node enlargement. Confirmed by: histology showing Reed-Sternberg cells. ‘Suggested by: splenomegaly, variable hepatomegaly, bleeding, anemia. Confirmed by: presence of Philadelphia chromosome, tT WBC >100000/emm. "Suggested by: anemia, bleeding , tender sternum , hepatosplenomegaly. Confirmed by: T WBCs , Blast cells in blood r atl ‘Suggested by: dry cough, breathlessness, malaise, fatigue, weight loss, enlarged lacrimal glands, erethyma nodosum. Confirmed by: CXR appearances (e.g. bilateral lymphandenopathy), and tissue biopsy showing non-caseating granuloma. 5SIn Capsule Series www ineapsuleseries.com Hematology Figure; Ulasteating causes of Senatalized lymphadenopathyIn Capsule Series www incapsuleseries.com Hematology - Hemostasis means stopping of hemorrhage from injured blood vessels. - It needs : ( similar to building) . Blood all): (Base) > Immediate recoil & vasoconstriction of injured vessel. (Stones ) Factor IIT Factor V Factor VIII trix > Coagulation occurs through 2 pathways : see the figure 1- Extrinsic pathway : It is a rapid process , triggered by trauma © Release of tissue thromboplastin ( Factor III ) > activation of factor VII > to common pathway (activation of Factor X in presence of Ca ) @ Its specific diagnostic test is prothrombin time (PT ) N : 10- 14 sec. 2- Intrinsic pathway : © Its triggered by roughness of endothelium. It depends on factors XII , XI, IX & VIII Its specific diagnostic test is activated partial thromboplastin time (APTT),.N:30-40 sec, 57In Capsule Series www incapsuleseries.com Hematology Extrinsic pathway Intrensic pathway ry or trauma to roughness of blood vessel blood vessel activation of factor Xil activation of factor XI activation of factor VIII activation of factor VII ‘common pathway activation of factor il Prothrombin — Thrombin activation of factor | (it Stabilized fibrin (clot) 4 Factor Xill [we | inogen —* Fibrin) By DrDiaa Ahmed 58 Zag zig, UniversityIn Capsule Series www incapsuleseries.com Hematology 1, (ERE: ( Vascular purpura ) A) Acquired : > Immune: o Henoch-Schénlein ( Anaphylactoid purpura) ; see below o Vasculitis e.g. SLE > Infection : Meningitis , Typhoid , IE. > Iatrogenic : Steroids , Sulphonamide. > Idiopathic ( Purpura simplex ) : especially in females over limbs & trunk . It resolves without treatment. > Scurvy ( Vit C deficiency ). > Senile purpura. > Malignancy. > Menopause. B) Congenital : > Hereditary telangiectasia : Osler-Weber—Rendu syndrome Rare condition in which there are thin wall dilations in the wall of capillaries > recurrent haemorrhage and anemia. > Ehlers-Danlos syndrome : T skin elasticity & capillary fragility. 6 4 59In Capsule Series won incapsuleseries.com Hematology 0. due to defects in either platelet number or platelet function. a) Platelet number ( Thrombocytopenia ) : < 150,000/emm 1. Decreased production of platelets : © Bone marrow failure. © Bone marrow infiltration : e.g. leukemia. © Vitamin By, /folic acid deficiency. 2. Increased destruction of platelets : 4 I ( normal or 1 megakaryocyte) © Idiopathic ( Zmmune ) thrombocytopenic purpura : (ITP ) o Immune : SLE. © Infections : Epstein-Barr virus, HIV , Gram-negative septicemia © Hypersplenism © 3. Increased consumption of platelets : (normal or T megakaryocyte) © Disseminated intravascular coagulation ( DIC ) © Thrombotic thrombocytopenic purpura ( TTP ) b) Platelet function ( Thrombasthenia ) : 1. Hereditary : © Glanzmann’s disease : Platelets are unable to aggregate. ‘© von Willebrand’s disease : reduced production of vWF factor. 2. Acquired : © Chronic renal failure : unknown mechanism. © Chronic liver disease. ‘©. Vitamin C deficiency ( Scurvy ) © Tatrogenic : = Anti-platelet : Aspirin. 2s Heparin. > Antibiotics: penicillin and cephalosporins.In Capsule Series www. incapsuleseries.com Hematology I. a) Congenital : o Hemophilia A (classic hemophilia, factor VII hemophilia ) o Hemophilia B ( Christmas disease, factor 1X hemophilia ) © Afibrinogenemia & dysfibrinogenemia. b) Acquired : © Liver cell failure. © Vitamin K deficiency. o Disseminated intravascular coagulation ( DIC ). o Drugs: anti-coagulants. 1. Hess test : (capillary fragility test ) Detects vascular purpura. It may be +ve in other types of purpura. 2, Bleeding time : (2-7 minutes) obsolete investigation > Small incision is made & the wound is wicked with filter paper every 30 seconds until the fluid is clear. > Prolonged : in all types of purpura. 3. Clotting time : (5-10 minutes) > Indicator of the intrinsic pathway. > Not sensitive test as it take 4-5 minutes just to activate factor XII 4. Activated Partial Thromboplastin Time (aPPT , PTT): > Normal : 30 - 40 seconds. > Used to evaluate the intrinsic coagulation system. > Used to monitor heparin therapy. > Prolonged : Heparin , Defect in the intrinsic pathway e.g. Hemophilia , DIC , von Willebrand disease. 61In Capsule Series www incapsuleseries.com Hematology 5. Prothrombin Time (PT) : > Normal : 10 - 14 seconds > It is measured by adding tissue thromboplastin & Ca to the patient’s plasma to activate extrinsic pathway. > Used to evaluate the extrinsic coagulation system. > Used to monitor oral anticoagulant therapy. > Prolonged : Oral anticoagulants , liver diseases , | vit K , DIC > INR (Inwemational Normalized Ratio ) : o INR = patient /control PT © Normal : 0.8 - 1.2 © Therapeutic INR is 2-3 6. Thrombin Time (TT): > Normal : 10 - 14 seconds. > It is performed by adding thrombin to the patient’s plasma. > Measure of conversion of fibrinogen to fibrin. > Prolonged: Afibrinogenemia , Dysfibrinogenemia , DIC , Heparin. I know not with what weapons World War IT will be fought, but World War iV will be fought with sticks and stones. Albert Einstein 62In Capsule Series www.incapsuleseries.com Hematology Taal ge) je finit: Multiple spontaneous capillary bleeding in the skin & mucous membrane due to defect in platelets or in the wall of blood vessels. Etiology ; I. Vascular disorders. IL. Platelets disorders. is ical picture :| > Bleeding: spontaneous & of short duration. i, Skin: > Multiple petechiae , purpura. ¥ Without raised edge in platelet disorders. ¥ With raised edge in vascular disorders. > Small ecchymosis may occur. ii, Mucous membrane : gum bleeding. iii. Bleeding per orifices : epistaxis , menorrhagia , hematemesis. iv. Internal organs : cerebral , retinal hemorrhage. > Anemia. > Features of the cause. 63In Capsule Series www.incapsuleseries.com Hematology (Anaphylactoid purpura , Allergic purpura) [Definition 3 = Itis a type of small vessel vasculitis which occurs mainly in children. — This the most common cause of non thrombocytopenic purpura in children. — Age peak : 2-8 years. {Clinical picture :) The diagnosis of Henoch-Schénlein purpura depends on clinical findings and history. There is not a specific laboratory test for the disorder. 1) Skin: 100% Palpable Purpuric rash especially over buttocks & extensor surface of legs. 2) Joints : 75% © Migratory polyarthritis. ©. Particularly knees and ankles. 3) Abdominal pain & GIT bleeding due to mesenteric vasculitis. ? 4) Renal involvement : ( the worst prognosis ) © Focal glomerulonephritis. © Asymptomatic proteinuria & hematuria. Investigations | 1) All investigations of bleeding tendency are normal except +ve MCQ Hiss test may be 2) Platelet count and function are normal. 3) Elevated serum IgA level is suggestive. 4) Skin biopsy : IgA deposits. Treat: progn: Spontaneous resolution within a month is commonest outcome in children. — Chronic renal failure in 10% of cases. — Steroids may improve the joints & gastrointestinal manifestations. 64www incapsuleseries.com Hematology [Definition > Itis an autoimmune disorder in which there is a destruction of the peripheral platelets by IgG autoantibodies. ® It is the most common cause of thrombocytopenia. Types } 1. (GERMAN: Acute type > The condition is usually acute ( < 6months ). > Sex : equal. > Frequently precipitated by viral infection. > Usually self limited in most cases (90% ) > IgA level : normal. nL > The condition is usually chronic, with remissions and relapses. > It may be associated with other autoimmune disorders e.g. SLE. > Sex: 29> © > IgA: less than normal. (Clinical picture {| a) General manifestations of purpura: see before b) Spleen is not palpable & if enlarged never hugely enlarged. Sige [investigations ; platelet count < 150000/emm & may be <20,000/cmm in severe cases. 65In Capsule Series www.incapsuleseries.com Hematology Y Other counts are usually normal except for occasional mild anemia, which can be explained by bleeding or associated hemolysis. Y Platelet antibodies are present in most cases (65% of chronic cases ) v Bleeding time : prolonged Y Coagulation tests (CT , PT, APTT , TT): normal T- Ea : ¥ The most important diagnostic test. Y Normal or increased megakaryocytes with defective budding. By Dr.Diaa Ahmed Zagazig University Diagnostic criteria of ITP : ¥ Isolated thrombocytopenia. ffreatment ; 1) Most children do not require treatment as ITP is self limiting in most case. Just follow up for fear of intra-cerebral hemorrhage. o | Platelet antibody production and interferes with phagocytosis. © Dose : 2mg/kg/d orally for 2 weeks. o About 80% of patients will respond, and the platelet count will usually return to normal. © Splenectomy is a curative therapy for ITP as spleen is major site of platelet destruction.In Capsule Series www incapsuleseries.com Hematology o Indications : ¥ Who fail to respond to prednisone. Y Requiring high dose of prednisone. © Precautions :; Pneumococcal vaccine before & long acting penicillin after splenectomy. © e.g, Azathioprine , cyclophosphamide or vincristine. © Indication : ¥ Ifno improvement after Splenectomy. Y May be used with prednisolone to obtain an acceptable platelet count. 5) [EVGimmunGBTODUTEN TE] + e/efors or2 days © IVIg blocks surface receptor of platelets ( competitive inhibition of anti-platelets antibodies ) © Relatively non-toxic but expensive and the effect lasts only 1-2 weeks. o Indications : ¥ Refractory to other treatments. ¥ Who require an urgent improvement for surgery and pregnancy. 6 [Platelets ‘transfusion || © Use of platelets transfusion in ITP is a bad medicine as it destroyed by anti-platelets antibodies. © May be indicated in life threatening conditions. 7) (Danazol ;) co An androgen that increase platelet count. © May be used as alternative to prednisolone or in combination. o Dose : 400-800mg/d for 1-3 months. © Side effects: virilisation, weight gain and hepatotoxicity. 67In Capsule Series www incapsuleseries.com Hematology Coagulation disorders ‘Types | McQ 1, Hemophilia A : deficiency of factor VIII . Hemophilia B : deficiency of factor IX . Hemophilia C : deficiency of factor XI Rw nN . Parahemophilia : deficiency of factor V Goal — Congenital coagulation disorders caused by defective production of factor VIII. — Hemophilia is an X-linked recessive disease, and as a rule only males are affected. Ifa female carrier has a son, he has a50% chance of having hemophilia, and a daughter has a 50% chance of being a carrier. All daughters of men with hemophilia are carriers and the sons are normal. Do you understand anything ? ok... read it again & you may understand ... Degree | o Severe: factor VIII < 1% o Moderate : factor VIII 1-5% © Mild : factor VIII > 5%. {Clinical picture :| The disease affects only males © Bleeding : — Since birth usually by trauma e.g. during circumcision ( Factor VIII received from the mother is enough for just one week ). 68In Capsule Series www.incapsuleseries.com Hematology Ecchymosis ( either spontaneously or after minor trauma ) Intramuscular hematoma : following IM injections. Hemoarthrosis : spontaneous bleeding into joints ( knees > elbows > ankles > hips > wrists) — fibrosis & deformity. Internal organs : GIT , CNS bleeding. Orificial : Epistaxis , bleeding gum , hematuria , hematemesis. Excessive bleeding after minor surgical procedure ( tooth extraction ) Neuropathy may occur due to pressure from hematoma. M1 HBV, HCV and HIV may occur due to repeated blood transfusion. Investigations Reduced level or activity of factor VIIL. @ APTT : Prolonged . PT, bleeding time and vWF level are normal. Platelet count : normal. Radiological examination of joint : in hemoarthrosis. {Treatment : 1) General measures : Avoid anti-platelet drugs e.g. Aspirin. Avoid IM injections. @ Avoid trauma. @ Vaccinate against HBV. 2) Factor VIII concentrates are cornerstone of management. 3) Desmopressin (synthetic vasopressin) : increases the release of factor VIII. 4) Fresh blood transfusion in severe bleeding.In Capsule Series www. incapsuleseries.com Hematology Von Willebrand's disease (vWD) © VWE plays a role in platelet adhesion to damaged subendothelium as well as stabilizing factor VIII ) in plasma. ° So the deficiency of vWF results in a) Platelet dysfunction. b) Hemophilia © Laboratory diagnosis : Like hemophilia but bleeding time is prolonged & impaired platelet function tests. McQ ©. Treatment : like hemophilia. [Definition ; It is an acquired coagulopathy in which there is widespread fibrin formation , resulting in consumption of platelets/coagulation factors & activation of fibrinolysis. Etiology : I. Endothelial damage > activation of intrinsic pathway © Infection; Gram —ve bacteria (e.g. meningococcus), Gram +ve bacteria (e.g. pneumococcus), anaerobes, TB ,viruses , ... o Vascular : Malignant hypertension , MI. Il. Trauma © release of tissue factor > activation of extrinsic pathway © Obstetric complications : amniotic fluid embolism , retroplacental hemorrhage , IUED , pre-eclampsia. | Crush injury , Thermal injury. © Leukemia : especially acute promyelocytic leukemia (M3) MCO cal picture | DIC leads to both bleeding and thrombosis I. Clinical picture of the cause Il. Bleeding : (due to consumption of coagulation factors ) 70In Gapsule Series www. incapsuleseries.com Hematology © Ecchymosis, petechiae, oozing from venepuncture sites. © post-operative bleeding. Il. Thrombosis = Organ failure : © Renal dysfunction. © Cerebral dysfunction. o ARDS. o Skin necrosis. (Clinical types ! I, Acute (uncompensated) DIC : o Rapid and extensive activation of coagulation & fibrinolysis with depletion of coagulant factors. © Bleeding > thrombosis. Il. Chronic (compensated) DIC : © Slow consumption of coagulation factors. © Thrombosis > bleeding. © Prolongation of all coagulation times (PT , APTT , TT ) o Fibrin degradation products ( FDPs ) & D- dimers : high © Fibrinogen : | (Iris an important diagnostic laboratory feature, because only afew other disorders (congenital hypofibrinogenemia, severe liver disease) will lower the fibrinogen level ). © Platelet count: | especially in acute DIC. © Microangiopathic hemolytic anemia (25% of cases): fragmented RBCs. ffreatment ;| Highly Controversial 1) Treatment of the cause if possible : Antibiotics for infections. 2) Replacement therapy : Platelet transfusion , fresh frozen plasma. 3) Heparin : Its use is controversial , it may accelerate bleeding. 4) Antifibrinolytic ( epsilon-aminocaproic acid) : Its use is controversial , it may accelerate microvascular clotting. 1