Red Cells and Bleeding Disorders

Red Cells and Bleeding Disorders Amer Akmal, MD Anemia Reduction in the total number of red blood cells, amount of hemoglobin or circulating RBC mass Men- Hct < 41% ( Hb < 13.5 g/dl) Women Hct < 37% (Hb < 12g/dl) As such, is not a diagnosis but a sign of underlying disease Relative anemia: increased plasma, normal RBC number Pregnancy, macroglobulinemia Decreased plasma volume masks decrease in RBC number, as in dehydration Diagnosis Approach SYMPTOMS OF ANEMIA Fatigue Shortness of breath Dizziness Palpitations Diagnosis Approach (cont.) SIGNS OF ANEMIA Skin and mucous membranes • • • • Pallor- non-hemolytic anemia Scleral icterus- hemolytic anemia Smooth tongue- pernicious anemia, iron def anemia Petechiae- thrombocytopenia and bone marrow replacement Lymph nodes • Lymphadenopathy- lymphoma and leukemia Heart • Tachycardia, postural hypotension • Cardiac diltation, murmurs- severe anemia Diagnosis Approach (cont.) SIGNS OF ANEMIA ……. • Abdomen  Splenomegaly- lymphoma and leukemia, infectious mononucleosis  Massive in chronic myelogenous leukemia and myelofibrosis  Hepatosplenomegaly with ascitis- liver disease • CNS  Spinal cord degenration- pernicious anemia  Delayed tendon reflexes- hypothyroidism  Gum hyperplasia- acute monocytic leukemia Diagnosis Approach (cont.) LAB FINDINGS Complete Blood Count (CBC) • Hemoglobin (Hb) • Hematocrit (Hct) • Mean Cellular Volume (MCV)  80-100 m3  Normocytic, microcytic, macrocytic • Reticulocyte count  O.8-2.5% (M), 0.8-4.0%(W)  Measures bone marrow status indirectly • Mean Corpuscular Hemoglobin Conc (MCHC)  Normochromic, hypochromic, hyperchromic Diagnosis Approach (cont.) • Red cell Distribution Width (RDW)  Measure of anisocytosis  Generally speaking  Increased in deficiency states  Normal in genetic or primary bone marrow defect Chemistry • LDH increased in hemolysis • Haptoglobin decreased in hemolysis  Normal initially Diagnosis Approach (cont.) Peripheral Blood Smear (PBS) Poikilocytosis (change in shapes) • Sickle cells, schistocytes, helmet cell, target cell Inclusion • Heinze bodies, Howell-Jolly bodies, malarial parasites Leukemia Bone Marrow Aspiration (BMA) Erythroid aplasia or hyperplasia Megakaryocytes decreased or increased Morphology Splenomegaly Extra Medullary Hyperplasia (EMH) Anemia Of Blood Loss Clinical and morphological features depend upon Rate of hemorrhage-acute or chronic Blood loss internal or external ACUTE BLOOD LOSS Body reacts to loss of blood volume rather than loss of Hb Water shifts from interstitial compartment to restore volume Increased erythropoeitin compensate with increased erythropoiesis 10-15% bllod loss will increase reticulocytes count after 7 days Anemia Of Blood Loss (cont.) Internal blood loss allows recycling of iron In external blood loss iron deficiency can limit compensatory erythropoiesis CHRONIC BLOOD LOSS Etiology- GI, GYN bleeding. Cancers with occult bleeding. Anemia appears only when blood loss exceeds compensatory mechanisms Hemolytic Anemia DEFINATION Premature destruction of RBCs (normal life span-120 days) Accumulation of Hb breakdown products Increased erythropoiesis in bone marrow Hemolytic Anemia (Cont.) EXTRAVASCULAR HEMOLYSIS Takes place in spleen  splenomegaly • because the rbc have deformed shapes or coated with antibody Lab findings • • • • • Decreased Hb  bilirubin and urobilin PBS: reticulocytes, spherocytes BMA:  normoblast Severe cases leads to EMH, hemosiderosis, gallstones Hemolytic Anemia (Cont.) INTRAVASCULAR HEMOLYSIS Takes place in the blood vessels Etiology; thrombus, mechanical cardiac valve, complement fixation, exogenous toxic factors Lab findings • • • • • • •  Bilirubin and urobilin Decreased haptoglobin Hemoglobinuria, Methemalbuminemi  red brown urine Hemosiderinuria PBS: reticulocytes, shistocytes BMA:  normoblast Severe cases leads to EMH, hemosiderosis, gallstones Hereditary Spherocytosis Intrinsic defect in rbc skeleton, resulting in spheroidal shape. Less deformable and more vulnerable to splenic squeeze Molecular defect: deficiency of spectrin, from 6090% in these cells Degree of deficiency correlates with the severity of the disease Northern Europeans effected mostly, 1: 5000 Autosomal dominant in 75% Autosomal recessive, more severe Hereditary Spherocytosis (cont.) LAB FINDINGS CBC:  MCHC PBS: Spherocytes (not pathognomic) Osmotic fragility: 2/3 pts manifest osmotic hemolysis • Induced by putting RBC in hypotonic solution CLINICAL FEATURES Most have chronic hemolytic anemia, 20-30% are asymptomatic • Minority presents at birth with severe jaundice Complication: Aplastic crisis, marked by disappearance of retics • Mostly remits spontaneously TREATMENT: splenectomy G6PD Deficiency Glucose-6-phosphate dehydrogenase deficiency Enzyme def leads to increase vulnerability to oxidative stress and results in hemolysis Several hundred variants of G6PD def G6PD B : most common G6PD A-: 10% of American Africans, cause significant hemolysis G6pd Mediterranean: in middle east, cause significant hemolysis • Protects against plasmodium falciparum malaria G6PD Deficiency (cont.) X-linked disease, caused by mutant gene • In both G6PD A- and G6pd Mediterranean, the mutation impair the stability of the enzyme, rather than the the synthesis. • Reticulocytes have normal enz activity, but the older cells are deficient Hemolytic attacks are usually triggered by oxidative stress Infections, especially viral hepatitis, pneumonia, typhoid fever Drugs: antimalarials, sulfonamides, nitrofurantoins Favisms, by eating fava beans Idiopathic G6PD Deficiency (cont.) LAB FINDINGS (only during the attack) PBS • Heinz bodies (crystal violet) • Bite cells • both EVH and IVH findings CLINICAL FEATURES Episodic and self limited hemolysis Lab findings appear after 2-3 days G6pd Mediterranean is more severe Sickle Cell Disease Hb is a tetramer of four globulin chains, comprising 2 pairs of similar chains Adult Hb is composed of • 96% HBA (22) • HbA2 (22 ) • HbF (22 ) In HbS , globin gene mutation substitute valine for glutamic acid at the sixth position in the beta chain. It is a QUALITATIVE disorder of Hb synthesis Sickle Cell Disease (cont) 85 of American blacks are HbS heterozygous 40% of Hb is sickleed 30% of African blacks are heterozygous Slight protection against Falciparum malaria PATHOGENESIS On deoxygenation, HbS  polymerize into crystals deformation of rbc + secondary membrane damage • Secondary membrane changes are present even in normal appearing cell and play an important role in microvasculature occlusion Sickling initially is reversible with oxygenation Sickle Cell Disease (cont) Factors affecting the rate and degree of sickling • Amount of HbS in the cell • Amount of other Hb , which have anti-sickling properties  HbF, HbC, HbD  Increased HbF in newborn, therefore disease is not maifested until 5-6 months • MCHC  Lower MCHC decreases disease severity  By hydration, concomitant alpha thalasemia • Acidosis (fall in pH) increases sickling Consequences of sickling • chronic hemolytic anemia  RBC life span reduced to 20 days • erythrpstasis microvascular occlusion  initiated by non-sickled cells Sickle Cell Disease (cont) LAB FINDINGS CBC: normocytic, normochromic, inc RDW PBS: sickle cells, Howell-Jolly bodies (after splenectomy) Hb electrophoresis. Principal test to differentiate b/w different Hb Sickling test. A reducing agent will induce sickling BMA: hyperplastic BM Sickle Cell Disease (cont) CLINICAL FEATURES Chronic hypoxia leads to decrease generalized growth and development Initially splenomegaly, later autosplenectomy • vulnerability to encapsulated bacteria, pneumococci and Haemophilus influenza • splenomegaly can lead to ‘sequestration crisis’ in kids New bone formation (crew haircut on skull x-rays) Sickle Cell Disease (cont) Microvascular occlusion leads to ‘painful crisis’. • leg ulcers  hand-foot syndrome in kids • • • • • pulmonary infarct ( acute chest syndrome) stroke and seizures kidney function impairment retinal function loss priapism Aplastic crisis Survival. 90% upto 20 years, 50% beyond 50 years Thalasemia syndromes QUANTITATIVE deficiency of  or  globin chain - Thalasemias TYPES QUANTITATIVE deficiency of  globin chain •  0-Thalasemia- total absence of -globin chain • +-Thalasemia- reduced synthesis of -globin chain PATHOGENESIS point mutation in the globin gene on chromosome 11 Decreased -globin   Hb  hypochromic anemia ( MCHC) unpaired  globin chains precipitate  cell membrane damage  death in BM or destruction later in spleen Erythroid hyperplasia ( ineffective erythropoiesis)   bone growth, EMH unused iron  secondary hemochromatosis - Thalasemias (cont.) LAB FINDINGS CBC • Hb. 2.5-6.5 g/dl (anemia is more severe than sickle cell anemia) • MCV- Severe micocytosis • Normal to slightly increased RBC count PBS • • • • • microcytes target cells basophilic stippling reticulocytes inc less than expected erythroblastosis- normoblast with poor Hb content - Thalasemias (cont.) BMA • erythroid hyperplasia Hb electrophoresis • HbA - none or decreased • HbF- increased • HbA2 - nml or increased or decreased DNA analysis- for prenatal Dx Morphology • erythroid hyperplasia  BM expansion and new bone formation  crew cut appearance on x-ray • marked splenomegaly (1500 gm) • hemosiderosis and secondary hemochromatosis  heart, liver, pancrease - Thalasemias (cont.) CLINICAL FEATURES • THALASEMIA MAJOR  most common in Mediterranean countries, SE Asia and part of Africa  sign symptoms appear at 6-9 months (HbF HbA)  growth retardation and early death if untreated  facial bone enlargement and distortation (erythroid hyperplasia)  Maintenance treatment - life long blood transfusion  decrese anemia and secondary erythropoiesis  further increase iron load, need treatment by iron chelators  Curative treatment- BM transplant from HLAidentical sibling - Thalasemias (cont.) CLINICAL FEATURES…….. • THALASEMIA MINOR       more common than T. major same ethnic gps asymptomatic or mild symptoms HbA2 characteristically increased to 4-8% PBS findings are same should be Dx for  genetic counseling  D/D from Fe deficiency anemia  -Thalasemias - globin genes are on chromosome 16 normally , 4 - globin chains most common cause of  - thalasemias is gene deletion less severe than - thalasemias non-  chains are more soluble and less toxic • newborn-  4- tetramers form Bart Hb • adults- 4- tetramers form HbH  -Thalasemias (cont.) SILENT CARRIER STATE ( -  /  ) totally asymptomatic - THALASEMIAS TRAIT less chances of HbH disease from mating of the African type (-  / - ) than from the Asian type ( - -/  ) HEMOGLOBIN H DISEASE ( - - / - ) Mainly in Asians HbH has high affinity for oxygen moderate severe anemia HbH inclusions seen by incubation with Brilliant Crystal Blue • RBC look like golf ball  -Thalasemias (cont.) HYDROPS FETALIS (- - / - -) Bart Hb have very extremely high oxygen affinity • intrauterine death • generalized edema • massive splenomegaly Paroxysmal Nocturnal Hemoglobinuria The only acquired disorder of defect in the cell membrane Mutation in the phosphatidylinositol glycan A gene ( PIGA gene)  impaired synthesis of anchor proteins GPI  Normal function is to inactivate complement The mutation affects pluripotent stem cells  RBC, WBC, platelets are effected renders cells unusually sensitive to hemolysis by endogenous complement mixture of normal and abnormal cell Paroxysmal Nocturnal Hemoglobinuria (Cont.) LAB FINDINGS CBC, PBS and BMA not characteristic • decreased reticulocytosis Screening tests • Sucrose Hemolysis test  promotes globulins aggrgation on cell  facilitates complement action • Test for urine hemosiderine Confirmatory test • Acid Hemolysis Test ( Ham’s test )  Complements lyse PNH cells at slightly acidic pH, normal cells do not. Paroxysmal Nocturnal Hemoglobinuria (Cont.) CLINICAL FEATURES paroxysmal and nocturnal hemolysis only in 25% • dark urine in the morning most have irregular episoder precipitated by infections, surgery or blood transfusions Hemosiderine  iron deficiency anemia Platelet defect  bleeding episodes, venous thromboses WBC  leukopenia sometimes evolves into aplastic anemia, leukemia median survival- 10 yrs Immuneohemolytic Anemia hemolysis by anti-RBC antibodies, demonstrated by Coomb’s antiglobulin test. Types Alloimmune- e.g. transfuion reactions autoimmune Drug induced- penicillin, cephalosporins, quinidine Hemolysis occur in spleen (EVH) spherocytes moderate splenomegaly Immunehemolytic Anemia (cont.) AUTOIMMUNE HEMOLYTIC ANEMIA most common in the clinical practice Warm type- clinically more significant • cause hemolysis • interfere with alloantibody detection  Anti-Rh specificity more common Caused by • lymphoma, leukemias • autoimmune disorders -SLE, RA • Drugs- methyl dop Immunehemolytic Anemia (cont.) COLD AGGLUTININ TYPE hemolysis of variable severity vascular obstruction Raynaud phnomenon COLD HEMOLYSIS HEMOLYTIC ANEMIA acute inermittent hemolysis after exposure to cold Donath-Landsteiner antibody Follows syphilis, measles, mumps, mycoplasma pneumonia etc Hemolysis Secondary To Trauma To RBC physical trauma to red cell  intravascular hmolysis schistocytes, helmet cell microangiopathic hemolytic anemiaDIC, TTP, SLE, malignant hypertention mechanical heart valve malaria Megaloblastic Anemia Def of vitamin B12 and folic acid  defect in DNA synthesis Failure of nuclear maturation  megaloblast (RBC, WBC, Plt) RNA and cytoplasmic maturation is not effected Anemia caused by Ineffective erythropoiesis Increased hemolytic destruction of megaloblasts, intra and extra medullary Megaloblastic Anemia (cont.) LAB FINDINGS CBC MCV >120 m, MCHC normal,  retic count Leucopenia thrombocytopenia PBS Macrocytes, ovalocytes, nucleated RBC Large and hypersegmented neutrophils with 5-6 lobed nuclei Megaloblastic Anemia (cont.) BMA Hypercellular, Myeloid/ Erythroid ratio is 1:1 (nml 3:1) Giant normoblast with nuclear-cytoplasmic asynchony Giant bands and metamelocytes Giant megakaryocytes with multilobate nuclei  methylemalonic acids in urine Schilling Test Detects different causes of vitamin B12 def (malabsorption, bacterial overgrowth) Test not done these days because of better aternatives Anemia Vitamin B12 Deficiency Normal requirement 2-3 mg Animal products are the only osurce Large reserve therefore def takes years to appear Intrinsic Factor must for vitamin B12 absorption Secreted by parietal cell of gastric fundus (also secrete HCL) vitamin B12 is absorbed in ileum Anemia Vitamin B12 Deficiency (cont.) Biochemical effects of vitamin B12 def folic acid deficiency • Def of tetrahydro folate needed for DNA synthesis •  methionine sybthesis  polyglutamte forms of folates def  methylemalonate  abnormal fatty acids  myelin breakdown  neural complication Folic acid supplement cures anemia but not the neural complications Anemia Vitamin B12 Deficiency (cont.) PERNICIOUS ANEMIA Destruction of gastric mucos  chronic atrophic gastritis • Achlorhydria even after histamin stimulation all races, more in scandiniians and English speaking Autoimmune disease • 3 types of antibodies- Morphology • Atrophic glossitis • Atrophic gastritis, intestinal metaplasia   gastric cancer risk  Because of autoimmune process, not vit def • Myelin degeneration of dorsal and lateral tracts  spastic paraparesis, sensory atxia, paraesthesia Anemia Vitamin B12 Deficiency (cont.) Clinical features • Insidious onset • marked anemia at presentation • Anemia and peripheral neurological symptoms respond to parenteral vitamin B12 • Gastric mucosa not responsive to vitamin B12 Anemia Of Folic Acid Deficiency 50-200 mg daily requirement Green vegetables (spinach, broccoli), fruits ( banana, melons), meats Sensitive to heat, destroyed by 5-10 min frying Absorbed in proximal jejunum Def appears within months LAB FINDINGS CBC, PBS, BMA same as vitamin B12 D/D from vitamin B12 anemia •  folate levels in serum or RBC •  FIGlu (formiminoglutamic acid) in urine Iron Metabolism DAILY REQUIREMENT daily requirement= daily loss I mg/ day must be absorbed in serum Only 10-15% of oral intake is absorbed Daily oral requirement • Men-5-10 mg • Women-15-20 mg Average oral intake in the Western world- 1520 mg Iron Metabolism (cont.) ABSORPTION all along GI but most in duodenum Heme (meats) iron is much more absorbable-25% Non-heme (vege) iron absorption- 1-2 % • Also effected by tea, carbonates BLOOD TRANSPORT By Transferrin, a protein synthesized in liver Serum iron meaures transferrin-bound iron Total Iron Binding Capicity (TIBC) is a measure of transferrin conc • Normal- 33% saturation Iron Metabolism (cont.) BODY STORAGE Ferritin- protein-iron complex • Normal levels- 10-500 g/L  Largest quantities in liver, spleen, bone marrow and muscles  Serum level very low normally • Serum levels are BEST indicator of body iron stores  < 12 g/L in iron def anemia  >5000 g/L in iron overload Hemosiderine • represent aggregate of iron in cytoplasm, when ferritin store is saturated  Golden-yellow granules in H&E stain  Blue-black in Prussian blue stain Iron Deficiency Anemia ETIOLOGY Dietary lack: Poor, elderly, infants Impaired absorption • Chronic diarrhea, intestinal steatorrhea, gastrectomy • Plummer-Vinson syndrome  Atrophic glossitis+ esophageal webs+ hypochromic microcytic anemia Increased requirements • Growth spurts, pregnancy • Chronic blood loss- MOST IMPORTANT CAUSE IN WETERN WORLD  GI, GY, GU diseases  In West, iron def in adult men and post-menopausal women should be considered to be caused by GI loss until proven otherwise Iron Deficiency Anemia (cont.) LAB FINDINGS CBC-  MCV,  MCHC  serum iron,  ferritin,  TIBC PBS (not required for Dx) • Microcytes, hypochromia BMA ( not required for Dx) • Decrease stainable iron CLINICAL FEATURES Specific iron def signs (in severe cases) • Koilonychia, Alopecia • Tongue and gastric atrophy • Intestinal malabsorption Anemia Of Chronic Disease Most common cause of anemia in hospitalized pts in USA Anemia starts 1-2 months after the onset of chronic disease ETIOLOGY Chronic inflammatory diseases- RA, SLE, Sarcoidosis Chronic infections- TB, pyelonephritis, osteomyelitis, fungal inf, endocarditis Neoplasm- malignant lymphoma, carcinomas Anemia Of Chronic Disease (cont.) PATHOGENESIS chronic disease cytokines released   erythropoietin  anemia Defect is in utilizing available iron • Decreased RBC survival LAB FINDINGS  serum iron,  TIBC ( like iron def) Increased ferritin (unlike iron def) CBC and PBS- normocytic, normochromic to microcytic hypochromic anemia • Low retic count BMA-increased storage iron Aplastic Anemia Failure or supprssion of multipotent stem cell, effecting all 3 cell lines PATHOGENESIS Immune injury Intrinsic stem cell defect LAB FINDINGS CBC & PBS: normochromic, normocytic anemia. no reticulocytes • Leucopenia, thrombocytopenia BMA: dry tap is diagnostic • Fibrous stroma with only lymphoplasmacytic infiltrate Aplastic Anemia (cont.) CLINICAL FEATURES Gradual or sudden onset Splenomegaly is characteristically absent Persistent minor infections, bleeding disorders Occasionally can transform to Leukemia Prognosis variable TREATMENT• Antithymocyte globulin and cyclosporin • Bone marrow transplantation Other Anemias of Diminished Erythropoiesis Fanconi’s Anemia Inherited form of aplastic anemia Autosomal recessive disorder Defect in DNA repair Also show hypoplasia of kidney, spleen and bone (thumbs, radii) Pure Red Cell Aplasia Caused by thymoma, large granular lymphocytic leukemia Only erythropoiesis is effected Other Anemias of Diminished Erythropoiesis (cont.) Myelophthistic Anemia Space-occupying lesions destroy bone marrow and replace by fibrosis • Lymphoma, leukemia, myeloms, carcinoma Leukoerythroblastosis is characteristic • Immature red and white cells in peripheral smear Diffuse Liver Disease Folate def and GI bleed due to varices also contribute Chronic Renal Disease Anemia is multifactorial • Decrease erythropoietin • Chronic bleeding leading to iron def Polycythemia Increase in the RBC number, relative or absolute Polycythemia vera- a neoplastic disorder involving all 3 lines DIAGNOSIS • Major criteria  Elevated red cell mass  Normal arterial oxygen saturation (>92%)  Splenomegaly • Minor criteria     Plt count > 400,000/mm3 Wbc.12,000/ Increased leukocyte alkaline phosphatase level Increased vit B12 level Polycythemia (cont.) LAB FINDINGS • CBC:  RBC, WBC and platelets, normal retic count • PBS: normochromic, normocytic • BMA: panhyperplasia, dec iron stores CLINICAL FEATURES • Middle age • S/S due to  blood vol, thromboembolic phenomenon or hemorrhage • Splenomegaly (not in non-neoplastic polycythemia). Classification of Anemias NORMOCYTIC ANEMIAS • Sickle cell anemia • Aplastic anemia • Hereditary spherocytosis MICROCYTIC ANEMIAS (MCV < 70) Iron deficiency anemia Anemia of chronic disease Thalassemias MACROCYTIC ANEMIAS ( MCV > 100) Megaloblastic anemia (MCV > 125) Immune hemolytic anemia Alcohol, liver disease Bleeding Disorders: Hemorrhagic Diathesis CAUSES Blood vessel disorder Platelet disorder Coagulation disorder Tests For Evaluations Of Bleeding Disorders • BLEEDING TIME (BT)  Measure in vivo platelet response to minimal vascular injury  Nml-2-9 min • PLATELET COUNT  150,000-450,000/mm3 • PROTHROMBIN TIME (PT)  Test the adequacy of extrinsic and common pathway  Factors VII (extrinsic)  Factors V,X, prothrombin, fibronogin  Nml-10-16 seconds • PARTIAL THROMBOPLASTIN TIME (PTT)  Test the adequacy of intrinsic and common pathway  All factors except VII  Nml- 25-45 sec Blood Vessels Disorders Petechiae and purpura in skin and mucous membranes If severe hemorrhage into deeper tissues Platelet count, BT, PT, PTT are usually normal ETIOLOGY • Infections: meningococcemia, endocarditis, Scurvy, EhlersDanlos syndrome: collagen defect • Henoch-Schonlein purpura • Systemic hypersensitivity • Hereditary hemorrhagic telangiectasia • Amyloidosis of blood vessels • Drugs Thrombocytopenia Reduction in platelet number Nml count- 150,000-450,000/mm3 <100,000/mm3 is considered thrombocytopenia However count alone does not predict bleeding. Influenced by fever, infections, drugs or any other stress In absence of any other stress Spontaneous bleeding occurs only at < 20,000/ mm3 Post traumatic bleeding occurs at < 20-50,000/ mm3 Thrombocytopenia (cont.) Type of bleeding Spontaneous bleeding from small vesselspetechiae • mucous membrane oozing • Skin and GI, GU • Intracranial bleeding in severe cases Prolonged bleeding from superficial cuts Idiopathic Thrombocytopenic Purpura (ITP) Autoimmune destruction of platelets Acute and chronic type ITP is a diagnosis of exclusion • R/O SLE, HIV, drugs, viral infection etc PATHOGENESIS • Autoantibodies- usually IgG, against platelet membrane glycoproteins  GP IIb-IIIa or Ib-IX • Autoantibodies present in serum as well as on platelets • Antibody covered platelet are destroyed in spleen (like hemolytic anemia) • Splenectomy improves plt count in 75-80%  Spleen is also the major site of the antibody synthesis ITP (cont.) LAB FINDINGS Bleeding time- increased PT, PTT- normal Large platelets in PBS MORPHOLOGY- is non-dignostic BMA • Increased megakaryocytes, some with immature nuclei SPLEEN • lymphoid proliferation with germinal centers • Sinusoidal congestion • Megakaryocytes within sinusoides, usually ITP (cont.) CLINICAL FEATURES Females (3:1), 40 H/O easy bruising, bleeding from minor trauma Petechiae, echymoses particularly at the dependent areas Melena, hematuria, menorrhagia No splenomegaly or lymphadenopathy TREATMENT Steroids IVIG Splenectomy Acute Idiopathic Thrombocytopenic Purpura Disease of childhood Equal frequency in both sexes Onset abrupt after a viral illness Self limited- 20% develop chroni ITP Drug-induced Thrombocytopenia Immune mediated Heparin, penicillin, quinidine, thiazide diuretics Heparin Induced Thrombocytopenia 5% of recipients TYPE I thrombocytopenia • Immediate onset after therapy • Moderately severe • Clinically insignificant TYPE II thrombocytopenia • After 5-14 days • Immune reaction against heparin-plt factor4 complex  Deplete and activate platelets • Life threatening venous and arterial thrombosis HIV-Associated Thrombocytopenia Most common hematological manifestation of HIV HIV infects megakaryocytes , thus suppressing production Also form antibody against GP IIb-III, thus promoting peripheral destruction Thrombotic Thrombocytopenic Purpura (TTP) A syndrome characterized by Fever Thrombocytopenia Microangiopathic hemolytic anemia Transient neurologic deficit Renal failure Affects adult women Etiology unknown- immune? Infection? TTP (cont.) PATHOGENESIS Endothelial injury platelet and fibrin aggregate intravascular thrombosis in the microvasculatur  microangiopathic anemia LAB FINDINGS  LDH  platelets- 5,000-10,000 in severe cases  creatinine PT, PTT are normal (unlike DIC) PBS: schistocytes TTP (cont.) PROGNOSIS: 90% fatal without treatment TREATMENT Platelet transfusion is CONTRINDICATED Plasma exchange- 90% survival Splenectomy HEMOLYTIC UREMIC SYNDROME (HUS) Same disease as TTP except Onset in childhood Renal symptoms more dominent than neurological symptoms Association with E.coli 0157:H7 Defective Platelet Function Disorders Normal platelet count,  bleeding time ETIOLOGY CONGENITAL • Bernard-Soulier syndrome  Autosomal recessive  Def of GP Ib-IX complex (receptor for vWF) defective adhesion • Thrombasthenia  Autosomal recessive  Def of GP IIb- IIIa (fibronogen receptor)  defective platelet aggregation • Storage pool disease  Defect in release of prostaglandins and ADP Defective Platelet Function Disorders (cont.) ACQUIRED • Aspirin- suppress prostaglandin • Uremia • Drugs Disorders Of Clotting Factors Caused by deficiency of single or multiple factors ACQUIRED: Vitamin K def -II, VII, IX, X Severe liver disease- most factors synthesized in liver DIC HEREDITARY DISORDERS Typically involve a single clotting factor Hemophilia A & B Disorders Of Clotting Factors (cont.) Bleeding type Spontaneous bleeding rare Mucosal bleeding is minimal Bleeding from superficial cuts rare Deep hematomas and hamarthroses characteristic Plasma Factor VIII-Vwf Complex vWF Secreted by endothelium and megakaryocytes forms 99% of the complex Major functions• adhesion of platelet to subendothelial collagen  GP Ib-IX- major receptor for vWF • Carrier of factor VIII and stabilizes it  Without vWF, VIII half-life is six times less Factor VIII Liver is the major source Converts X into Xa- starts clotting cascade von Willibrand Disease Incidence-1%- most common inherited disorder of bleeding More than 20 variants Autosomal dominant disease, in most cases CLINICAL FEATURES Compound defect involving both platelet function and clotting factor deficiency. • The later manifest only in severe cases Usually mild disease Spontaneous mucosal oozing and bleeding Excessive bleeding from wounds, menorrhgia von Willibrand Disease (cont.) TYPES TYPE 1 • Reduced circulating vWF • 70% of the cases • Mild disease TYPE 3 • Severely reduced circulating vWF • Autosomal recessive • Severe disease TYPE 2 • Qualitative defect in vWF, several variants • 25% of the cases • Mild to moderate disease von Willibrand Disease (cont.) LAB FINDINGS Increased bleeding time with normal platelet count Decreased vWF assay by ristocetin aggregate test Secondary decrease in VIII  increased PTT Hemophilia A Most common hereditary disease with severe bleeding Caused by deficiency of factor VIII X-linked recessive disease Manifest in males and homozygous females only 30% have no family history • New mutations Hemophilia A (cont.) CLINICAL FEATURES Wide range of clinical severity, correlating with the VIII level • < 1% of the normal activity  severe • 2-5% moderate • 6-50% mild Easy bruising and massive hemorrhage after trauma Deep hemarthroses  deformities Petechiae are typically absent LAB FINDINGS Prolonged PTT Normal PT, BT, platelet count Decreased VIII levels Hemophilia A (cont.) TREATMENT Human factor VIII • 15% develop antibodies • Viral transmission Recombinant factor VIII HEMOPHILIA B ( CHRISMAS DISEASE) Caused by factor IX deficiency X-linked recessive disease Clinical and lab findings are similar to hemophilia A Only diagnostic difference is factor IX level Disseminated Intravascular Coagulation (DIC) Acquired thrombohemorrhagic disorder Acute, subacute or chronic Imbalance of procoagulant and anticoagulant factors PATHOGENESIS Initiated by multiple and interrelated factors Activation of intrinsic/extrinsic coagulative pathway  thrombin deposition  widespread microvascular fibrin thrombosis  consumption of platelets and coagulation factors  hemorrhage • Microvascular occlusion  microangiopathic hemolytic anemia in 25% DIC (cont.) LAB FINDINGS Increased PT, BT ( PTT not always increased) Low platelets hypofibronogenemia Increased fibrin degradation products (FDP) • D-dimer is most sensitive PBS- schistocytes MORPHOLOGY Microthrombi and microinfarcts • Lung-hyaline membrane • Adrenals- massive adrenal hemorrhage (WaterhouseFriderichsen Syndrome) • Pituitory gland- Sheehan postpatrtum necrosis DIC (cont.) CLINICAL FEATURES Bleeding sign far more common than thrombosis • Spontaneous oozing at venipuncture sites Thrombosis manifests as digital ischemia and gangrene 50 % are OB patients 30 % are cancer patients PROGNOSIS Highly variable, depends on the underlying disorder Fatal without immediate treatment DIC (cont.) TREATMENT Primary focus: treatment of the underlying cause Symptomatic treatment • • • • Heparin for thrombosis Platelet transfusion Fresh frozen plasma (FFP) Fibronogen replacement ( cryoprecipitate)