Blood elements
□ Blood consist of 3 elements , erythrocytes ( red cells ) , leukocytes ( white cells ) & thrombocytes ( platelets ) . All are suspended in the plasma□ Site of blood cell formation• 1st 2 month ( intrauterine ) : in the yolk sack• 2-7 month ( intrauterine ) : in the liver• Bone marrow start at the 5th month ( intrauterine ) - take over after birth ErythropoiesisHemoglobin ( Hb ) composition Hb Molecule Is Composed Of 4 Heme Groups ( Containing Ferrous Iron ) Attached To 4 polypeptide chains which define the type Of Hb
Anemia Definition : decrease of Hemoglobin or hematocrit concentration below the normal value for age . Range At birth 15-20gm /dl 2-3 month : decrease to 10 gm/dl Rise gradually with age to 15 gm at 15years
Causes ( classification ) of Anemia 1- Decreased RBCs production
2-Increased RBCs destruction 1- Hemolysis2- Hypersplenism : leading to pancytopenia 3- Blood loss ( haemorrhagic anemia ) - Acute : trauma ,accidents , surgery - varices - operative ( circumcision in hemophilics) - Chronic : feto - maternal transfusion - ankylostoma - bilhariziasis - meckel's diverticulum
Iron metabolism
Dietary requirements 1 mg of iron must be absorbed / day . ( intake of 10mg of iron / day ) . iron is absorbed 2-3 times more from human milk than from cow's milk absorption Luminal border of duodenal mucosa : iron is absorbed in the ferrous form . Inside duodenal mucosa : it is oxidized to the ferric form and becomes attached to an iron free protein called apoferritin , to form ferritin . When the available apoferritin is fully saturated with iron absorption by the duodenal mucosa stops . Distribution In the plasma : combined with transferrin as ferric iron . The iron binding capacity = 250-350mg / 100 ml . Storage : iron is then delivered to the liver , spleen and bone marrow . Iron deficiency Anemia Incidence : the most common cause of anemia in infancy Causes : A- Diminished stores : Anemic mother with deficient iron supplementation Premature and twinsB- Deficient dietary iron : Prolonged breast feeding Cow milk Protein energy malnutrition C- Diminished absorption : chronic diarrhea - malabsorption D- Blood loss : chronic hemorrhage - ankylostoma - schistosomiasis - cow milk allergy E- Increased requirements : in ( adolescent specially girls - acute hemorrhage ) Clinical features : - Onset : above 6 month ( more common between 9-24month ) - General symptoms of anemia : pallor ( nail bed - palm - lids ) - tachycardia - murmurs heart failure - dyspnea - easy fatigability - Atrophic glossitis - Poor appetite - Poor concentration and behavioral abnormalities - Spooning of the nail - Pica : ( geophagia ) eating unusual substances as dirt and mud - Palpable spleen in 15% of causes Investigation : Blood pictures: Low Hb . microcytic hypochromic anemia : MCHC < normal & microcytic MCV < normal ] Reticulocyte count is normal , it show mild increase with therapy .
Blood chemistry : Low serum iron < 50mcg % ( normal 90-150micg/dl) Low serum ferritin < 10ng ( normal 30 - 150 ng ) Increased iron binding capacity ( normal : 250 - 350 micg / dl ) Detect the cause Stool analysis : ankylostoma - blood in stool - bithariziasis Endoscopy : to exclude peptic ulcer .
D.D from other causes of hypochromic microcytic anemia :
Diseases
c/p
Iron deficiency anemia
pica
B- Thalassemia trait
No response to iron
Chronic infection
picture of infection
Sideroblastic anemia
improve with Vit . B6
Lead poisoning
manifestations of lead toxicity
Prevention : 1- Adequate supply of iron to pregnant female 2- Making powdered formula well - fortified with iron 3- Prophylactic iron therapy to premature 4- Proper weaning by supplying iron containing foods 5- Treatment of cause
Treatment :
Iron therapy : Oral therapy : ferrous sulfate or gluconate 6 mg / kg / day / 3 doses in between meals for 2 month . ( new preparations ( no teeth stain - minimal GIT upset ) , e.g. sodium iron edetate . Parenteral therapy : I.M. iron dextran dose : 50 - 100 mg daily for 5 days I.V. iron hydroxide in severe cases Diet : rich in iron ( meat , liver , green vegetables ) and vitamin C . packed RBCs transfusion Treatment of causePathophysiology :■ In Hemolysis : RBC life span shorten ( 120 day down to few days )■ Bone marrow compensate to 8 fold ( more rapid Hemolysis will manifest) Chronic Hemolytic Anemia
Organomgaly and disfigurement :■ Hepatosplenomegaly with minimal lymphadenopathy :1- Destruction of abnormal RBCs .2- Formation of new RBCs ( extra medullary hematopoiesis )3- Deposition of iron overloads ( hemosidrosis )□ N.B. : splenomegaly will result in Hypersplenism with more severe anemia and pancytopenia■ Macrocephaly : of face due to compensatory bone marrow action .- Prominent zygoma , forehead , maxilla with [ depressed nasal bridge - prominent upper central incisor - separation of teeth ]■ Dilated heart & heart failure : due to tachycardia - relative hypoxia ( anemia ) cardiomyopathy due to hemosidrosis Investigations :■ To prove anemia : CBC shows low Hemoglobin■ To prove Hemolysis :Blood film : reticulocytosisBlood chemistry : elevated serum indirect bilirubin , serum iron , serum ferritin , decreased iron binding capacity Increased urinary urobilinogen X ray finding : of poor value : bone marrow expansion ( wide diploid space of the skull - rarefaction of the other table -increased trabecular pattern
Complications :• Complication of long term blood transfusion :■ Hemosidrosis■ 10% of causes show antibodies with difficulty to find compatible blood■ Infection ( HBV - HCV - HIV - Malaria )■ Complication of venous access ( infection and bleeding )• Anemic heart failure :• Gall bladder stones :• Crises : aplastic , hemolytic , sequestration - ( VOC in SCA )• Deposition of iron in tissues ( hemosidrosis ):Each 500ml of blood deliver 200mg of iron- Endocrinal disturbances : delayed puberty - pituitary dysfunction diabetes mellitus- Liver cirrhosis and liver failure- Pulmonary hemosidrosis- Cardiomyopathy- Arthropathy- Neuropathy• Easy fracture of bones• Growth retardation and delayed puberty• Hypersplenism ( mainly in thalassemia mainly )• Autosplenectomy in SCA
ThalassemiaIncidence : β - thalassemia is the commonest chronic hemolytic anemia common in the Mediterranean area , while a - thalassemia is rare . Inheritance : autosomal recessive disease Genetics :
- Defective synthesis of one of the globin chains ( the gene is absent or non - functioning ) :
If the defect in ɑ chain production : a thalassemia If the defect in β chain production : β thalassemia - β thalassemia : 2 genes on chromosome 11 2 gene mutation ( homozygous ) : thalassemia major ( Cooley's anemia ) 1 gene mutation ( heterozygous ) : thalassemia minor Thalassemia intermedia : moderate severity
Beta thalassemia major ( Cooley’s anemia )PathogenesisThe bodies try to switch to Hb A at the age of 3 - 5 months but the gene of B chain is defective ( production of restricted amount of Hb A )Then the body try to reproduce Hb F but also its production will be defective free ɑ chain become insoluble and precipitate inside RBC ( Hemolysis )Clinical picture■ onset : by 2nd half of the 1st year■ The Course is sever with frequent blood transfusion■ most liable for early complications and early development of Hypersplenism
investigations : prove anemia & Hemolysis blood film : microcytosis - anisocytosis - target cells - poikilocytosis . Hemoglobin electrophoresis : in the affected child : Hb F is markedly elevated (90% ) - reduced Hb A parents : increased of Hb A2 > 4 % ( normal : 3 % )
differential diagnosis□ from other causes of chronic hemolytic anemia Thalassemia minor
Most cases are asymptomatic The condition is suspected when a patient with microcytic hypochromic anemia Fails to respond to iron therapy Blood picture : microcytic hypochromic anemia - obvious signs of hemolysis Hemoglobin electrophoresis : increased Hb A2
Prevention : Genetic counseling , carrier detecting & prenatal diagnosis Treatment :1- supportive treatment : restrict iron in diet / folic acid 1mg / day . hepatitis B vaccine . calcium and vitamin D2- Repeated packed RBCs transfusions :• 10-15 ml /kg every month to keep Hb level at 10-12 mg /dl ( hyper transfusion )• Value : good activity - better growth - reduce Organomgaly & disfigurement3- Iron chelating agents :Desferroxamine ( desferal ) : 20 - 40 mg / kg by s.c. pump over 10 hours , 5days / week .Deferiprone : oral chelating agent ( 100 mg / day divided by 3 times )Deferasirox : oral - effective ( 10 - 20 /kg / day )
4- Spleneectomy : indications : huge splenomegaly or Hypersplenism ( avoid before the age of 4 years )Splenectomy care :- Before Splenectomy : vaccination ( pneumococci - meningococci - H . influenza )- After Splenectomy : long acting penicillin prophylaxis till the age of 18 years .5- Bone marrow transplantation :Prepared from bone marrow from a HLA match It is curative ( best below 3 years )6- Gene therapy : introduction of a functioning gene ( under trials )7- Induction of fetal Hemoglobin synthesis :- Hydroxyurea can stimulate Hb F productionTreatment of complications :■ Gall bladder stone : cholecystectomy■ Diabetes : insulin therapy■ Short stature : growth hormoneSickle cell anemiaDefinition : formation of abnormal globin chain ( abnormal B chain )Incidence : common in black race Genetics :■ Defect in B chain gene show mutation that result in replacement of amino acid number 6 in the chain ( glutamic by valine )Heterozygous : sickle cell trait : only 20-40 % Hb S. only it present with vaso - occlusive crisis with severe hypoxia and resistant to infection with falciparum malaria Homozygous ( Hb SS ) : sickle cell anemia
Pathogenesis :
A single amino acid substitution in beta chain result in different Hemoglobin ( Hb S ) which is less soluble than Hb A . with hypoxia , deoxygenated Hb S polymerize inside RBCs , distortion of shape ( sickle shaped ) result in easy destruction & occlusion of blood vessels Clinical pictureOnset : by the2nd half of the 1st year . the course is less severe than thalassemia Complication : no Hypersplenism but Autosplenectomy usually develop Investigation Prove anemia & Hemolysis Blood film : sickling characteristic sickle RBCs in blood film under low O2 tensions Hb electrophoresis : Hb S is present ( > 90% ) no Hb A Genetic study of the affected gene Parents : Hb S 20-40% Hb A 60-80%
Crisis in chronic Hemolytic anemiaSequestration crisis■ Cause : for unknown cause , large amount of blood become acutely pooled in spleen■ Clinical picture : shock , marked enlargement of spleen and liver & acute anemia■ Treatment : I .V fluids - packed RBCs transfusion - Splenectomy for recurrent cases
Hyper- hemolytic crisis❖ Cause : patient with sickle cell anemia who have in addition G6PD deficiency❖ Clinical picture : acute anemia , Hemoglobinuria ( dark urine )❖ Investigation : reticulocytosis - enzyme assay later on❖ Treatment : packed RBCs transfusionAplastic crisis❖ Cause : infection with parvovirus B19 result in failure of erythroid serious❖ Clinical picture : severe anemia that last for 3-4 weeks❖ Investigation : reticulocytopenia Treatment : packed RBCs transfusion once in twice over 4 weeksVaso - occlusive crisis■ Definition : painful crisis peculiar to sickle cell anemia . it may be the only presentation in sickle cell trait■ Causes :Hypoxia - infections - dehydration - acidosis all deoxygenate Hb SHbS polymerizes within red blood cells result in sicklingErythrocytes express a number of adhesion molecules and adhere to the vascular endothelium resulting in obstruct blood vessels Clinical picture : Bony pains : hand - foot syndrome which may be the 1st presentation of SCA with severe pain & swelling ( ischemia of the metacarpal and metatarsal bones ) recurrent strokes : neurological defect and poor school performance acute chest syndrome : acute chest pain & fever due to pulmonary infarction GIT ischemia : acute abdominal pain - ischemic nephropathy , priapism : fibrosis and impotence . spleen : splenic infarctions ( Autosplenectomy ) : so spleen is enlarged early then regress gradually .
Infection crisis
In patients S.C.A due to Autosplenectomy infection mainly by capsulated organisms Treatment of sickle cell anemia : as thalassemia• Supportive• Blood transfusion and chelation . ( less frequent )• No need for Splenectomy• Treatment of VOC : Oxygen IV and fluid - antibiotics for infection - analgesics for pain . Bicarbonate for acidosis . blood transfusion if ( Hb is < 6 g/dl ) Complete rest in bed . exchange transfusion ( acute chest syndrome - stroke - priapism ) .Hereditary spherocytosis Genetics : autosomal dominant form of chronic hemolytic anemia ( 25% new mutation ) Incidence : more common in Europe Pathogenesis : A defect in spectrin or Ankyrin of the RBC membrane increases Na permeability . this increases water influx so that RBCs become spherical shape , less deformable with premature destruction in the spleen . Clinical features :
• Onset : may present with neonatal jaundice and anemia• May present later in infancy or childhood• Less incidence of complications
Acute Hemolytic Anemia
Definition :■ It is anemia caused by acute ( sudden ) and rapid destruction of the RBCs in peripheral blood and in the spleen .Glucose - 6 - phosphate dehydrogenase deficiency Incidence :■ The most common cause of Hemolysis■ Geography : in middle east and middle Africa - far east■ It is commonest RBC enzymopathyEtiology :■ X linked recessive ( more common in males )■ Heterozygous female : 50% of enzymatic activity ( appear normal )■ Female may be affected ( If homozygous or with lionization )Pathogenesis :■ G 6PD is the rate limiting enzyme in synthesis of NADPH & reduced glutathione.■ NADPH & glutathione provide H + protect Hemoglobin against oxidation■ G6PD deficiency result in deficiency in NADPH & glutathione■ If exposure to oxidants , Hemoglobin become oxidized to met - Hemoglobin and precipitate as Heinz bodies leading to Hemolysis ( mainly intravascular )Clinical picture :■ History of neonatal jaundice . ( mild to very severe )■ History of exposure to oxident . infection or drugs and chemicals : analgesics : aspirin in high dose - novalgin , antibiotics : chloramphenicol - sulphonamides - quinolones
Antimalarial : primaquine - chloroquine - quinine . naphthalene . naphthalene Acute pallor with palpitation - dyspnea - irritability or drowsiness
Acute jaundice
Acute dark urine ( hemoglobinuria ) indicating high rate of Hemolysis
Complications : acute heart failure Investigation :
■ CBC : anemia ( normocytic normochromic ) ■ Reticulocytosis in blood film ( Hemolysis ) ■ Chemistry : unconjugated hyperilirubinemia - hemoglobinemia - Hemoglobin in urine ■ Blood film show fragmented & Heinz bodies ■ Estimation of enzyme activity after 2 weeks of hemolytic attack , because immediately after Hemolysis , bone marrow release new RBCs and reticulocytes with normal enzyme level giving misleading normal result . Treatment :■ Urgent packed red cell transfusion ( 10 ml/kg ) is life saving in very severe Hemolysis■ Prevention of subsequent attacks : a list containing oxidants materials must be offered to parents DD of the cause of acute Hemolysis
Disease
Specific clinical picture
Specific investigations
G - 6 - PD - D
History of first intake of beans ( G6PD deficiency )
Heinz bodies G6PD assay
AIHA
Drug intake - infection 2 weeks ago associated arthritis - skin rash
+ Ve coombs test
HUS
History of severe gastroenteritis acute renal failure
Thrombocytopenia elevated renal function
Infection ( malaria )
Traveling to endemic area pattern of fever
Blood film is diagnostic
sepsis
Toxic patient ( septicaemia ) purpuric eruption
CBC ( leukocytosis , shift to Lt ) , increased CRP , ESR )
APLASTIC ANEMIA
Definition : A plasia of blood precursors in the bone marrow that result in pancytopenia in the peripheral blood . Clinical picture : Anemia Purpura Fever : persistent fever resistant to treatment - persistent oral fungal infection specific picture of the cause Investigation : Blood picture : pancytopenia Bone marrow examination : hypocellular bone marrow Causes : A- Congenital : Fanconi anemia : most common Dyskeratosis congenital : with dysgenesis in skin & nails B- Acquired : 1- Idiopathic : the most common ( 70% ) 2- Secondary to : - Chemicals : like benzene - Chemotherapy - Infection ( EBV - HBV ) - Exposure to radiation - Exposure to toxins - Drugs : chloramphenicol - sulfaD.D. of aplastic anemia : Leukemia - ITP
Fanconi Anemia
■ Autosomal Recessive■ Onset of bone marrow failure : after the age of 3 years ( average 6-8 years )■ Skeletal association in 50% of cases■ Skeletal anomalies : microcephaly , short stature absent thumb , absent radius■ Mental retardation Skin pigmentation , renal malformation , and micro-ophthalmia.Investigations : Karyotyping : increased chromosomal breaks Skeletal survey - abdominal U/S Acquired aplastic anemia Clinical features : onset : at any ago ( acute onset ) after certain event or idiopathic Treatment of aplastic anemia : Supportive therapy : ( controlling anemia - infection - bleeding ) Fanconi anemia : Prolong survival by androgen and corticosteroid therapy Bone marrow transplantation ( BNT ) is the treatment of choice Acquired : Mild cases : anti - thymocyte globulin ( ATG ) or cyclosporine Severe cases : bone marrow transplantation ( BNT ) is the treatment of choice from HLA matched sib . If not available immunosuppressive therapyPlatelets Megakaryocytes of the bone marrow , release platelet by budding ( fragmentation ) of the cytoplasm of mature Megakaryocytes Platelet are non-nucleated cell fragments ( short half-life 7-10days ) Function of Platelets Adhere and aggregate to seal points bleeding Platelet plays a role in initiation of coagulation and in clot retraction .
Platelet count Normal Platelet count : Mild thrombocytopenia : Moderate thrombocytopenia : Severe thrombocytopenia :
150 - 450 x 103 / mm3 50 - 150 x 103 / mm3 20-50 x 103 / mm3 > 20 x 103 / mm3
PURPURA
Definition : minute bleeding due to platelet or vascular defect characterized by purple petechie and ecchymosis Thrombocytopenic Purpura : ( low platelets ) A- Increased Platelet destruction ( normal megakaryocytes ) Immune : - Idiopathic thrombocytopenia Neonatal Isoimmune thrombocytopenia Maternal ITP - Systemic Lupus Erythematosus. Non immune : - DIC - Hemolytic uremic syndrome - Hypersplenism - Drug induced B- Decreased Platelet Production ( Low Megakaryocytes ) Congenital : - Thrombocytopenia with absent radius ( TAR syndrome ) - Constitutional pancytopenia ( Fanconi anemia ) - Thrombopoietin deficiency
Acquired :- Megakaryocytic aplasia ( idiopathic or 2ry to drugs )- Aplastic anemia ( idiopathic - drugs - toxin - irradiation )- Marrow infiltration ( leukemia - lymphoma - metabolic disorders )Non - thrombocytopenic Purpura : ( normal platelets )A- Platelet dysfunction :- Drugs as aspirin- Uremia- Inherited abnormal Platelets e.g. giant Platelet syndromeB- Vascular Purpura :■ Infections as meningococcemia■ Vitamin C deficiency ( Scurvy )■ In hearted : Ehlar Danlos syndrome - marfan syndrome■ Immune vasculities ( HSP)Immune Thrombocytopenic PurpuraDefinition : acquired generalized hemorrhagic state due to destruction of circulating platelets due to autoantibodiesIncidence : the most common cause of PurpuraAcute : 85 - 90 % usually by nonspecific viral illness or rubellaIt is characterized with autoantibodiesChronic : 10-15% persistence of clinical and laboratory findings > 12months . it is related to autoimmune disease . hereditary factors may be present .
Intravenous immunoglobulin (IVIG) : dose 0.8.1mg /kg/day for 2 days . duration for 2 days action it causes rapid rise of platelet count . ( block the phagocytic activity ) C- In Severe Cases : ( severe muco-cutaneous hemorrhage or intra-cranial hemorrhage ) I.V. methyl prednisolone 20mg/kg/day--,5days Platelet transfusion +/- fresh whole blood is needed IVIG. Plasmapheresis : ( transient effect ) ( only when others fail) Emergency Splenectomy : final solution D- In chronic cases ( > 12 month ) : Careful evaluation for associated disorders ( E.g. SLE: frequent of screening of autoantibodies ) Prednisone & IVIG Splenectomy (75% curative ) immunosuppressive therapy ( e.g. azathioprine - cyclosporine ). Prognosis : acute serious hemorrhage occur in the acute phase (1-2weeks ). 75 % of cases recover in < 3 month
PHASE I : thromboplastin is formed through successive activation of coagulation factors in the presence of phospholipids . Assessed by partial thromboplastin time ( normal value = 25-40 seconds ) It measure clotting factors ( XII,XI.IX and VIII ) PHASE II : Thrombin is Formed by factor II ( prothrombin ) in the presence of thromboplastin complex . This phase can be assessed by prothrombin time ( normal value 11-14 sec ) It evaluate factors II, V, VII and X PHASE III : fibrin is formed by splitting of fibrinogen ( factor I ) in the presence of thrombin assessed by thrombin time ( normal value = 15-20 seconds ) it assess the fibrinogen level
Coagulation defects Hemophilia A ( Classic Hemophilia )Genetics : X linked recessive disease with reduced factor VIII cone . ( more in male ) Incidence : 1/14000 male – 80% 0f cases of hemophilia .Clinical features : bleeding in the neonatal period [ circumcision bleeding – prolonged bleeding from heal stick or venipuncture from umbilical stump .Extensive bruising . hematoma and bleeding with minor trauma on ambulation hemoarthrosisThe hallmark of hemophilia With trauma or spontaneous If repeated : degenerative joint changes and fibrosis ( ANKYLOSIS ) with unstable fixed joint
Spontaneous bleeding from orifices : epistaxis or hematuria in severe cases
Internal organs : intracranial hemorrhage . intramuscular hemorrhage ( e.g. psoas hemorrhage )Complications :
Intracranial hemorrhage Psoas hemorrhage may be fatal Complication of treatment
• Blood born infection ( HBV - HCV - HIV - CMV ) • Development of antibodies against transfused factor 8 ( 5-20% ) This result in resistance & effect of treatment
The condition required higher dose of plasma or bypassing agent ( a f VII )
• Complication of vascular access [ difficult cannulation - thrombosis or infection ] Investigation :
1- Phase I coagulation defect ( prolonged PTT )
2- Specific factor VIII assay ( reduced below normal )
Normal > 60 %
Carrier 30-60% ( female )
5-30% : mild hemophilia ( bleeding with trauma or surgery )
1-5% : moderate ( bleeding with minor trauma )
>1% : severe ( spontaneous joint bleeding )
Prevention :
Avoid trauma - aspirin - give HBV - physiotherapy prevent ankylosis power Treatment :
■ Cold compress minimize bleeding in mild cases ■ Replacement ( essential severe cases )
I.V. infection of cryoprecipitate ( plasma concentrate Of factor VIII ) ( dose : 25 - 50 unit / kg every 12 hours ) . I.V infusion of purified factor VIII concentrateRecombinant factor 8. prophylactic F VIII in severe hemophilia ( 2times per week )■ Desmopressin : in mild hemophilia A it increase endogenous release of FVIII ( ineffective in hemophilia B ) Physiotherapy : Specially after immobilization to prevent muscle wasting and joint contractureHemophilia B ( Christmas disease ) factor IX deficiency Genetics : X linked recessive -15% of all hemophilia due to factor IX deficiency Clinical features : like hemophilia a but with ( delayed onset ) - milder bleeding Treatment : fresh frozen plasma or factor IX concentrate ( once or every 24 hours ) Von willebrand disease ( vascular hemophilia ) Genetics : autosomal dominant defect in the production of VW protein Pathogenesis : Von- willebrand protein play 2 roles - Facilitate platelet adhesion and - Protect factor VIII from breakdown ( act as carrier protein ) - If reduced , it reduced factor activity & defective platelet adhesion
Clinical features : Mild bleeding tendency : mainly epistaxis , bleeding gums bruising , menorrhagia & bleeding with surgery Spontaneous hemorrhage is extremely rare
1- Normal platelet count but defective platelet adhesion ( prolonged bleeding time ) 2- Prolonged PTT 3- Reduced level of vw protein & factor 8 .
Treatment :
• I.V Infusion Of Fresh Frozen Plasma , cryoprecipitate or vw factor• Desmopressin can help in mild cases Differential diagnosis of hemophilia in general :■ Acquired coagulation defects as liver failure■ Disseminated intravascular coagulation (DIC) Investigation :