eac-hema

Pediatric HematologyPediatric Hematology

EDWIN V. RODRIGUEZ, MDEDWIN V. RODRIGUEZ, MDPediatrician – Pediatric HematologistPediatrician – Pediatric Hematologist

Red Blood CellsRed Blood Cells

Hemoglobin carriersHemoglobin carriers

Hemoglobin - main protein for oxygen deliveryHemoglobin - main protein for oxygen delivery

RED CELL MORPHOLOGYRED CELL MORPHOLOGY

AnemiasAnemias

Reduction of the RBC volume of hemoglobin concentration Reduction of the RBC volume of hemoglobin concentration below the range of values occurring in healthy individualsbelow the range of values occurring in healthy individuals

Critical cut off: < 7 g/ dL of hemoglobinCritical cut off: < 7 g/ dL of hemoglobin

Below this level, pallor in the skin and mucous membranes Below this level, pallor in the skin and mucous membranes become evidentbecome evident

Anemia: Signs and SymptomsAnemia: Signs and Symptoms

GENERALGENERAL pallorpallor anorexia; tirednessanorexia; tiredness circulatory adaptationcirculatory adaptation susceptibility to susceptibility to

infectioninfection

SPECIFICSPECIFIC hepatomegalyhepatomegaly splenomegalysplenomegaly jaundice/hematuriajaundice/hematuria hemorrhagehemorrhage

Pathogenesis of AnemiaPathogenesis of AnemiaIron, folic acid, proteins . . .

Bone MarrowI (Deficiency Anemia)

II (Marrow Failure)

Circulation

III (Blood Loss) IV (Hemolysis)

Acute Chronic Intravascular Extravascular

AnemiasAnemias

Classification of anemia based on RBC mean corpuscular Classification of anemia based on RBC mean corpuscular volume (MCV): microcytic, macrocytic, normocyticvolume (MCV): microcytic, macrocytic, normocytic

Classification of anemia according to pathophysiology: Classification of anemia according to pathophysiology: impaired production (nutritional deficiencies, bone marrow impaired production (nutritional deficiencies, bone marrow failure), increased destruction (hemolysis) and massive failure), increased destruction (hemolysis) and massive blood loss (injuries, parasitism)blood loss (injuries, parasitism)

Classification according to duration: acute, chronic, Classification according to duration: acute, chronic, recurrent (compensated)recurrent (compensated)

Microcytic AnemiaMicrocytic Anemia

POSSIBLE ETIOLOGIESPOSSIBLE ETIOLOGIESIron deficiency anemia (IDA)Iron deficiency anemia (IDA)ThalassemiaThalassemiaSideroblastic anemiaSideroblastic anemiaAnemia of chronic disorder (ACD)Anemia of chronic disorder (ACD)Lead poisoningLead poisoning

HYPOCHROMIA, MICROCYTOSISHYPOCHROMIA, MICROCYTOSIS

Macrocytic AnemiaMacrocytic Anemia

POSSIBLE ETIOLOGIESPOSSIBLE ETIOLOGIESMegaloblastic process (ovalocyte)Megaloblastic process (ovalocyte)Reticulocytosis (bleeding, hemolysis)Reticulocytosis (bleeding, hemolysis)Liver diseaseLiver diseasePost-splenectomyPost-splenectomyChemotherapyChemotherapyHypothyroidismHypothyroidism

ANISOCYTOSISANISOCYTOSIS

POIKILOCYTOSISPOIKILOCYTOSIS

(ACANTHOCYTOSIS, ECHINOCYTES)(ACANTHOCYTOSIS, ECHINOCYTES)

Physiologic Anemia of InfancyPhysiologic Anemia of Infancy

Physiologic Anemia of InfancyPhysiologic Anemia of Infancy Normal newborns have HIGHER hemoglobin and hematocrit Normal newborns have HIGHER hemoglobin and hematocrit

levels and LARGER red blood cells.levels and LARGER red blood cells. Occurs during the first 6-8 weeks of lifeOccurs during the first 6-8 weeks of life Hemoglobin drops to 9-11 g/ dLHemoglobin drops to 9-11 g/ dL ““physiologic adaptation to extrauterine life”physiologic adaptation to extrauterine life” Premature infants have more extreme dips in hemoglobin levels Premature infants have more extreme dips in hemoglobin levels

(7-9 g/dL) occurring within the first 3-6 weeks of life(7-9 g/dL) occurring within the first 3-6 weeks of life Requires NO therapyRequires NO therapy Diet must have adequate folic acid and ironDiet must have adequate folic acid and iron PRBC transfusion if hemoglobin < 6.5 g/ dL. Give 10-15 mL/kg PRBC transfusion if hemoglobin < 6.5 g/ dL. Give 10-15 mL/kg

Anemia During the Neonatal PeriodAnemia During the Neonatal Period

Hemorrhage: Hemorrhage: Post-natal blood lossPost-natal blood loss

External: bleeding from umbilicus, GUTExternal: bleeding from umbilicus, GUT Internal: cephalhematoma, ruptured spleenInternal: cephalhematoma, ruptured spleen

Intranatal blood lossIntranatal blood loss Umbilical cord abnormalitiesUmbilical cord abnormalities Placental abnormalitiesPlacental abnormalities

Prenatal blood lossPrenatal blood loss Transplacental fetomaternal Transplacental fetomaternal Intraplacental and retroplacentalIntraplacental and retroplacental Twin-to-twin transfusionTwin-to-twin transfusion


HemolysisHemolysis Congenital erythrocyte defectsCongenital erythrocyte defects Acquired erythrocyte defectsAcquired erythrocyte defects

Rh isoimmunizationRh isoimmunization ABO isoimmunizationABO isoimmunization Late onset anemia in immune hemolytic anemiaLate onset anemia in immune hemolytic anemia Non-immune hemolytic anemiaNon-immune hemolytic anemia Vitamin E deficiencyVitamin E deficiency


Failure of Red Cell ProductionFailure of Red Cell Production congenitalcongenital Acquired: viral diseasesAcquired: viral diseases


Anemia of PrematurityAnemia of Prematurity Nadir of hemoglobin level: 7 g/ dl at 4-8 weeksNadir of hemoglobin level: 7 g/ dl at 4-8 weeks Reduced bone marrow erythropoietic activityReduced bone marrow erythropoietic activity Low erythropoietin (Epo) levelsLow erythropoietin (Epo) levels Low hemoglobin due to:Low hemoglobin due to:

Decreased RBC productionDecreased RBC production Shorter RBC life spanShorter RBC life span Increased blood volume with growthIncreased blood volume with growth

TREATMENT: recombinant human Epo, supplemental iron, PRBC TREATMENT: recombinant human Epo, supplemental iron, PRBC transfusion if neededtransfusion if needed


Acute Blood LossAcute Blood Loss Acute distress: pallor, shallow breathing, tachycardia, shockAcute distress: pallor, shallow breathing, tachycardia, shock Low venous pressureLow venous pressure Hemoglobin may be normal initially then drops quickly within 24 Hemoglobin may be normal initially then drops quickly within 24

hourshours RBC: normochromic, macrocyticRBC: normochromic, macrocytic Normal serum ironNormal serum iron Prompt treatment of anemia necessary to prevent deathPrompt treatment of anemia necessary to prevent death Treatment: NSS, PRBC, ironTreatment: NSS, PRBC, iron


Chronic Blood LossChronic Blood Loss Marked pallor disproportionate to the evidence of distress, CHF, Marked pallor disproportionate to the evidence of distress, CHF,

hepatomegalyhepatomegaly Normal or elevated venous pressureNormal or elevated venous pressure Hemoglobin low at birthHemoglobin low at birth RBC: hypochromic, microcytic, anisopoikilocytosisRBC: hypochromic, microcytic, anisopoikilocytosis Low serum iron at birthLow serum iron at birth Course generally uneventfulCourse generally uneventful Treatment: iron therapyTreatment: iron therapy


Isoimmune Hemolytic Anemia due to Rh IncompatibilityIsoimmune Hemolytic Anemia due to Rh Incompatibility Frequency: Frequency: unusualunusual Occurrence in firstborn: Occurrence in firstborn: 5%5% Predictably severe in subsequent pregancies: usuallyPredictably severe in subsequent pregancies: usually Stilbirth or hydrops: Stilbirth or hydrops: occasionaloccasional Pallor: Pallor: markedmarked Jaundice:Jaundice: marked marked Hepatosplenomegaly:Hepatosplenomegaly: marked marked Incidence of late anemia:Incidence of late anemia: common common


Rh IncompatibilityRh Incompatibility Mother’s blood type:Mother’s blood type: Rh (-)Rh (-) Infant’s blood type:Infant’s blood type: Rh (+)Rh (+) Antibody type:Antibody type: Incomplete (IgG)Incomplete (IgG) Coomb’s test:Coomb’s test: (+)(+) Hemoglobin:Hemoglobin: very lowvery low Serum bilirubin:Serum bilirubin: markedly elevatedmarkedly elevated RBC:RBC: nucleated RBC’snucleated RBC’s


Rh IncompatibilityRh Incompatibility Need for antenatal management:Need for antenatal management:YesYes Exchange transfusion:Exchange transfusion: YesYes


IsoimmuneHemolysis due to ABO IncompatibilityIsoimmuneHemolysis due to ABO Incompatibility Frequency:Frequency: commoncommon Occurrence in firstborn:Occurrence in firstborn: 40-50%40-50% Predictably severe in subsequent pregnancies: noPredictably severe in subsequent pregnancies: no Stillbirth/ hydrops:Stillbirth/ hydrops: rarerare Pallor:Pallor: minimalminimal Jaundice:Jaundice: minimal (< 24 hours)minimal (< 24 hours) Hepatosplenomegaly:Hepatosplenomegaly: minimalminimal Incidence of late anemia:Incidence of late anemia: uncommonuncommon


ABO IncompatibilityABO Incompatibility Blood type, mother:Blood type, mother: O(+)O(+) Blood type, infant:Blood type, infant: A or B or ABA or B or AB Antibody type:Antibody type: immune (IgM)immune (IgM) Coomb’s test:Coomb’s test: usually positiveusually positive Hemoglobin level:Hemoglobin level: moderately lowmoderately low Serum bilirubin:Serum bilirubin: Variable elevatedVariable elevated RBC morphology:RBC morphology: spherocytesspherocytes


ABO IncompatibilityABO Incompatibility Need for antenatal management:Need for antenatal management:nono Exchange transfusion:Exchange transfusion: nono

Iron Deficiency AnemiaIron Deficiency Anemia Iron deficiency anemia (IDA)Iron deficiency anemia (IDA)

Etiology: lack of sufficient iron for synthesis of hemoglobinEtiology: lack of sufficient iron for synthesis of hemoglobin Most common hematologic disease of infancyMost common hematologic disease of infancy Clinical manifestations:Clinical manifestations:

PALLOR: most important cluePALLOR: most important clue Blue scleraBlue sclera IrritabilityIrritability Pagophagia: desire to ingest unusual substances (ice, dirt)Pagophagia: desire to ingest unusual substances (ice, dirt) AnorexiaAnorexia TachychardiaTachychardia Cardiac dilationCardiac dilation Systolic (high output) hemic murmursSystolic (high output) hemic murmurs

Iron Deficiency AnemiaIron Deficiency Anemia

Iron deficiency anemiaIron deficiency anemia Laboratory findingsLaboratory findings

Mild IDA: Hemoglobin 9-10 g/ dLMild IDA: Hemoglobin 9-10 g/ dL Moderate IDA: Hemoglobin 6-8 g/ dLModerate IDA: Hemoglobin 6-8 g/ dL Severe IDA: Hemoglobin < 5 g / dLSevere IDA: Hemoglobin < 5 g / dL Stages of Iron Deficiency AnemiaStages of Iron Deficiency Anemia

Iron depletionIron depletion Iron deficiency without anemiaIron deficiency without anemia Iron deficiency anemiaIron deficiency anemia

Iron Deficiency Anemia(hypochromic, microcytic red

cells)

IRON DEFICIENCY ANEMIA

Iron Deficiency AnemiaIron Deficiency Anemia Iron Deficiency AnemiaIron Deficiency Anemia

TreatmentTreatment Oral ferrous salts (sulfate, gluconate, fumarate): 6 mg/ kg/ day in 3 divided Oral ferrous salts (sulfate, gluconate, fumarate): 6 mg/ kg/ day in 3 divided

doses for 2-3 months doses for 2-3 months Iron rich diet (red meat, green leafy vegetables, eggs)Iron rich diet (red meat, green leafy vegetables, eggs) Limited milk intake: 500 mL/ day or lessLimited milk intake: 500 mL/ day or less Blood transfusion RARELY needed. Only when anemia is VERY SEVERE Blood transfusion RARELY needed. Only when anemia is VERY SEVERE

(hemoglobin < 4 g/ dL) or when superimposed infection interferes with (hemoglobin < 4 g/ dL) or when superimposed infection interferes with expected responseexpected response

RETICULOCYTOSIS increases within 72-96 hours after iron RETICULOCYTOSIS increases within 72-96 hours after iron administration (so a high or normal RETICULOCYTE COUNT on day 3 of administration (so a high or normal RETICULOCYTE COUNT on day 3 of treatment is predictive of adequate response)treatment is predictive of adequate response)

Response of Anemia to Iron Response of Anemia to Iron SupplementationSupplementation

= most reliable indicator of iron-deficiency anemia.

= therapeutic dose should be calculated in terms of

elemental iron.

= 3 - 6 mg /kg /day in three divided doses

= duration is 6 - 8 weeks after hemoglobin level is

restored back to normal.

Response to Iron Therapy in Iron Deficiency AnemiaResponse to Iron Therapy in Iron Deficiency Anemia

12-24 hours12-24 hoursreplacement of intracellular iron enzymes; subjective replacement of intracellular iron enzymes; subjective improvement; decreased irritability; increased appetiteimprovement; decreased irritability; increased appetite

36-48 hours36-48 hoursinitial bone marrow response; erythroidinitial bone marrow response; erythroid hyperplasiahyperplasia

48-72 hours48-72 hoursreticulocytosis; peaking at 5-7 daysreticulocytosis; peaking at 5-7 days

4 – 30 days4 – 30 daysiincrease in hemoglobin levelncrease in hemoglobin level

1-3 mos1-3 mosrepletion of storesrepletion of stores

Hemolytic AnemiasHemolytic Anemias

Definitions and Classification:Definitions and Classification:

HEMOLYSIS: premature destruction of RBC’s, shortened RBC HEMOLYSIS: premature destruction of RBC’s, shortened RBC survival, increased BMA activity and increased reticulocyte survival, increased BMA activity and increased reticulocyte percentage and numberpercentage and number

If the rate of RBC destruction > rate of RBC production = anemiaIf the rate of RBC destruction > rate of RBC production = anemia

SUSPECT HEMOLYTIC ANEMIA if the reticulocyte count is HIGH SUSPECT HEMOLYTIC ANEMIA if the reticulocyte count is HIGH in the absence of bleeding or administration of hematinicsin the absence of bleeding or administration of hematinics

Hemolytic AnemiasHemolytic Anemias

Definition and Classfication:Definition and Classfication:

ClassificationClassification CELLULAR: intrinsic abnormalities of the membranes, enzymes or CELLULAR: intrinsic abnormalities of the membranes, enzymes or

hemoglobinhemoglobin EXTRACELLULAR: antibodies, mechanical factors, plasma factorsEXTRACELLULAR: antibodies, mechanical factors, plasma factors

Most of the cellular causes of hemolytic anemia are INHERITED Most of the cellular causes of hemolytic anemia are INHERITED while most of the extracellular causes are ACQUIRED.while most of the extracellular causes are ACQUIRED.

Hereditary SpherocytosisHereditary Spherocytosis Hereditary SpherocytosisHereditary Spherocytosis

Common in the newborn and may present as ANEMIA and Common in the newborn and may present as ANEMIA and HYPERBILIRUBINEMIA requiring phototherapy or exchange HYPERBILIRUBINEMIA requiring phototherapy or exchange transfusionstransfusions

May remain ASYMPTOMATIC into adulthoodMay remain ASYMPTOMATIC into adulthood Clinical manifestations: severe anemia with pallor, jaundice, easy Clinical manifestations: severe anemia with pallor, jaundice, easy

fatigability, exercise intolerancefatigability, exercise intolerance SPLENOMEGALY happens usually after infancySPLENOMEGALY happens usually after infancy PIGMENTARY (BILIRUBIN) GALLSTONES appear as early as 4-5 PIGMENTARY (BILIRUBIN) GALLSTONES appear as early as 4-5

years oldyears old HIGH susceptibility to APLASTIC and HYPOPLASTIC crises HIGH susceptibility to APLASTIC and HYPOPLASTIC crises

(parvovirus and other infections)(parvovirus and other infections)

Hereditary SpherocytosisHereditary Spherocytosis

Autosomal dominant inheritanceAutosomal dominant inheritance Primary defect is membrane instability due to dysfunction or Primary defect is membrane instability due to dysfunction or

deficiency of a red cell skeletal proteindeficiency of a red cell skeletal protein Ankyrin mutations (50-67%), alpha and beta spectrins, protein Ankyrin mutations (50-67%), alpha and beta spectrins, protein

4.2, and band 34.2, and band 3 Vertical defect in RBCS Vertical defect in RBCS progressive loss of membrane lipid progressive loss of membrane lipid

and surface -and surface - loss of surface area - loss of surface area - spherocytes spherocytes


DiagnosisDiagnosis History and PEHistory and PE CBC platelet countCBC platelet count Red cell indices: Low MCV, high MCHC, high RDWRed cell indices: Low MCV, high MCHC, high RDW Reticulocyte count (3-15%)Reticulocyte count (3-15%) PBS: microspherocytes (high surface/ volume ratio)PBS: microspherocytes (high surface/ volume ratio) Osmotic Fragility Test (incubated): spherocytes lyse in higher Osmotic Fragility Test (incubated): spherocytes lyse in higher

concentrations of NSS than normal RBCs)concentrations of NSS than normal RBCs) Elevated total and indirect bilirubinElevated total and indirect bilirubin Obstructive jaundice due to elevated direct bilirubin (gallstones)Obstructive jaundice due to elevated direct bilirubin (gallstones)


Hereditary SpherocytosisHereditary Spherocytosis Laboratory Findings:Laboratory Findings:

EVIDENCE OF HEMOLYSIS: reticulocytosis and hyperbilirubinemiaEVIDENCE OF HEMOLYSIS: reticulocytosis and hyperbilirubinemia Hemoglobin: 6-10 g/ dLHemoglobin: 6-10 g/ dL Reticulocyte count: 6-20% (mean 10%)Reticulocyte count: 6-20% (mean 10%) MCV: normalMCV: normal MCHC: increasedMCHC: increased Morphology: polychromatophilic reticulocytes and spherocytesMorphology: polychromatophilic reticulocytes and spherocytes

Hereditary SpherocytosisHereditary Spherocytosis Treatment:Treatment:

Folic acid supplement (1 mg/ dau)Folic acid supplement (1 mg/ dau) Leukocyte depleted PRBC for severe erythroblastoopenic crisisLeukocyte depleted PRBC for severe erythroblastoopenic crisis SplenectomySplenectomy

ComplicationsComplications Hemolytic crisisHemolytic crisis Erythroblastopenic crisisErythroblastopenic crisis Folate deficiencyFolate deficiency GallstonesGallstones HemochromatosisHemochromatosis

TARGET CELLS WITH SOME SPHEROCYTESTARGET CELLS WITH SOME SPHEROCYTES

RETICULOCYTOSISRETICULOCYTOSIS

NORMOBLASTEMIANORMOBLASTEMIA


Hereditary SpherocytosisHereditary Spherocytosis TreatmentTreatment

SupportiveSupportive SPLENECTOMY for children > 5 years oldSPLENECTOMY for children > 5 years old

Risk of Overwhelming Post-Splenectomy Infection is HIGH in children < 5.Risk of Overwhelming Post-Splenectomy Infection is HIGH in children < 5. Indications for splenectomyIndications for splenectomy

Very severe anemia with reticulocytosisVery severe anemia with reticulocytosis Hypoplastic or aplastic crisesHypoplastic or aplastic crises Poor growthPoor growth CardiomegalyCardiomegaly

G6PD DeficiencyG6PD Deficiency Glucose-6-phosphate dehydrogenase deficiencyGlucose-6-phosphate dehydrogenase deficiency

First enzyme of the pentose phosphate pathwayFirst enzyme of the pentose phosphate pathway Deficiency diminishes the reductive energy of the RBC causing Deficiency diminishes the reductive energy of the RBC causing

hemolysishemolysis Severity depends on the type pf G6PD, and the nature of the Severity depends on the type pf G6PD, and the nature of the

hemolytic agent (oxidant stressor)hemolytic agent (oxidant stressor) Sex linked recessive mode of inheritanceSex linked recessive mode of inheritance Point mutations: sporadic (not specific to any geographic area) or Point mutations: sporadic (not specific to any geographic area) or

polymorphic (malarial selection)polymorphic (malarial selection)

G6PD DeficiencyG6PD Deficiency PathogenesisPathogenesis

Red cell G6PD activity falls rapidly and prematurelyRed cell G6PD activity falls rapidly and prematurely Decreased glucose metabolismDecreased glucose metabolism Diminished NADPH/ NADP and GSH/ GSSG ratiosDiminished NADPH/ NADP and GSH/ GSSG ratios Impaired elimination of oxidantsImpaired elimination of oxidants Oxidation of hemoglobin and sulfhydryl groupsOxidation of hemoglobin and sulfhydryl groups RBC integrity impaired upon exposure to oxidizing agentsRBC integrity impaired upon exposure to oxidizing agents

G6PD DeficiencyG6PD Deficiency Clinical Manifestations:Clinical Manifestations:

Acute self-limiting hemolytic anemia with hemoglobinuriaAcute self-limiting hemolytic anemia with hemoglobinuria Heinz bodies in circulating cellsHeinz bodies in circulating cells Blister cells, fragmented cells and spheorcytesBlister cells, fragmented cells and spheorcytes ReticulocytosisReticulocytosis Hemoglobin normal between episodesHemoglobin normal between episodes

Hemolytic crisis:Hemolytic crisis: Drugs (analgesics, antipyretics, antimalarial agents, sulfonamides, Drugs (analgesics, antipyretics, antimalarial agents, sulfonamides,

nitrofurans, sulfones, miscellaneous)nitrofurans, sulfones, miscellaneous) Fava beansFava beans InfectionsInfections

G6PD DeficiencyG6PD Deficiency TreatmentTreatment

Avoidance of oxidant stressorsAvoidance of oxidant stressors Genetic counsellingGenetic counselling Chronic non-spherocytic hemolytic anemia (NSHA)Chronic non-spherocytic hemolytic anemia (NSHA)

Severe chronic anemia: PRBC if hemoglobin < 9\8-10 g/ dLSevere chronic anemia: PRBC if hemoglobin < 9\8-10 g/ dL IndicationsIndications

Hypersplenism, severe chronic anemia, splenomegaly causing physical Hypersplenism, severe chronic anemia, splenomegaly causing physical impedimentimpediment

PRBC transfusionPRBC transfusion Hemoglobin < 7 g/ dLHemoglobin < 7 g/ dL Persistent hemoglobinuria and hemoglobin < 9 g/ dLPersistent hemoglobinuria and hemoglobin < 9 g/ dL

Hemoglobin DisordersHemoglobin Disorders

Classification of hemoglobin disordersClassification of hemoglobin disorders STRUCTURAL ABNORMALITIESSTRUCTURAL ABNORMALITIES

Hemoglobinopathies/ Qualitative defectsHemoglobinopathies/ Qualitative defects Changes in amino acid sequences of the globin chainsChanges in amino acid sequences of the globin chains Single amino acid substitutionsSingle amino acid substitutions

THALASSEMIA SYNDROMESTHALASSEMIA SYNDROMES Quantitative defectsQuantitative defects

Synthesis of 1 or more globin chains is decreased or totally suppressedSynthesis of 1 or more globin chains is decreased or totally suppressed

HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN (HPFH)(HPFH) Elevated levels of Hemoglobin F continuing throughout adult lifeElevated levels of Hemoglobin F continuing throughout adult life

CHROMOSOME 11 CHROMOSOME 16

Gγ Aγ δ β α ---- α

α2γ2 α2β2α2δ2

Amount in red cells after 1 yr

of age

(HbF) (HbA)(HbA2)

<1% <96%<3%

Hemoglobin Types and Normal Hemoglobin Types and Normal ValuesValues

Normal values:Normal values: Normal hemoglobin findings differ between adults and children. Normal hemoglobin findings differ between adults and children.

ADULTSADULTS CHILDREN CHILDRENHb A1Hb A1 95-98%95-98% Hb FHb FHb A2Hb A2 2-3%2-3% newbornnewborn 50-80%50-80%Hb FHb F 0.8 to 2%0.8 to 2% 6 months6 months 8%8%Hb SHb S 0%0% over 6 mosover 6 mos 1-2%1-2%Hb CHb C 0%0%

*Values expressed as a percentage of total hemoglobin.

Thalassemia SyndromesThalassemia Syndromes

Thalassemia SyndromesThalassemia Syndromes Heterogenous groups of heritable hypochromic anemiasHeterogenous groups of heritable hypochromic anemias Homozygous Beta thalassemia (Cooley Anemia, Homozygous Beta thalassemia (Cooley Anemia,

Thalassemia Major)Thalassemia Major) Severe, progressive hemolytic anemia during the second 6 Severe, progressive hemolytic anemia during the second 6

months of lifemonths of life Regular blood transfusions are necessary to prevent the Regular blood transfusions are necessary to prevent the

profound weakness and cardiac decompensationprofound weakness and cardiac decompensation Without blood transfusion, life expectancy is less than 20 Without blood transfusion, life expectancy is less than 20

years old.years old.


Thalassemia SyndromesThalassemia Syndromes Clinical manifestationsClinical manifestations

Severe pallorSevere pallor Hypertrophy of erythropoietic tissues in both medullary and extramedullary Hypertrophy of erythropoietic tissues in both medullary and extramedullary

locations occur locations occur bones become thin and pathologic fractures occurs bones become thin and pathologic fractures occurs Massive expansion of the bone marrow in the face and skull produces a Massive expansion of the bone marrow in the face and skull produces a

characteristic facies.characteristic facies. Pallor, hemosiderosis (iron deposition in tissues) and jaundice -Pallor, hemosiderosis (iron deposition in tissues) and jaundice -

greenish brown complexiongreenish brown complexion Hepatosplenomegaly due to extramedullary hematopoiesis and Hepatosplenomegaly due to extramedullary hematopoiesis and

hemosiderosishemosiderosis Growth retardationGrowth retardation


Thalassemia SyndromesThalassemia Syndromes Clinical ManifestationsClinical Manifestations

Delayed or absent puberty due to secondary endocrine abnormalitiesDelayed or absent puberty due to secondary endocrine abnormalities DM occurs due to pancreatic hemosiderosisDM occurs due to pancreatic hemosiderosis Cardiac complications: intractable arrythmias, chronic CHF due to Cardiac complications: intractable arrythmias, chronic CHF due to

myocardial hemosiderosis -myocardial hemosiderosis - death death Failure to thrive early in childhoodFailure to thrive early in childhood Skull x-ray: “hair on end appearance”, fractures, osteoporosisSkull x-ray: “hair on end appearance”, fractures, osteoporosis Leg ulcersLeg ulcers Skin bronzingSkin bronzing


DiagnosisDiagnosis History and physical examinationHistory and physical examination Laboratory testsLaboratory tests

CBC platelet countCBC platelet count Reticulocyte countReticulocyte count Red cell indicesRed cell indices Peripheral blood smearPeripheral blood smear Hemoglobin electrophoresisHemoglobin electrophoresis

Blood film in Thalassemia


ComplicationsComplications Due to chronic anemia with no or minimal transfusionsDue to chronic anemia with no or minimal transfusions Due to chronic blood transfusion with hemochromatosisDue to chronic blood transfusion with hemochromatosis Poor compliance with chelationPoor compliance with chelation Endocrine disturbancesEndocrine disturbances Liver cirrhosis and liver failureLiver cirrhosis and liver failure Cardiac failure to myocardial iron overloadCardiac failure to myocardial iron overload Extramedullary hematopoiesisExtramedullary hematopoiesis Marked osteoporosisMarked osteoporosis

Thalassemia SyndromesThalassemia Syndromes ManagementManagement

Hypertransfusion protocol (hemoglobin 10.5-11.0 g/dL)Hypertransfusion protocol (hemoglobin 10.5-11.0 g/dL) SplenectomySplenectomy

Persistent increase in blood transfusion by > 50% for > 6 months, annual PRBC Persistent increase in blood transfusion by > 50% for > 6 months, annual PRBC transfusion > 250 ml/kg/year with uncontrolled iron overload, leukopenia or transfusion > 250 ml/kg/year with uncontrolled iron overload, leukopenia or thrombocytopeniathrombocytopenia

Chelation therapy (ferritin > 1000ng/ ml)Chelation therapy (ferritin > 1000ng/ ml) Desferriioxamine 40 mg/ kg IV or 40-60 mg/ kg/ day SC 4-6 nights/ weekDesferriioxamine 40 mg/ kg IV or 40-60 mg/ kg/ day SC 4-6 nights/ week

Causes of DeathCauses of Death Congestive heart failureCongestive heart failure ArrhhythmiaArrhhythmia Sepsis secondary to OPSISepsis secondary to OPSI Multiple organ failure due to hemochromatosisMultiple organ failure due to hemochromatosis

Thalassemia SyndromesThalassemia Syndromes Beta thalassemia intermediaBeta thalassemia intermedia

Do not require transfusionsDo not require transfusions Hemoglobin 7-10 g/ dlHemoglobin 7-10 g/ dl Marked medullary expansion, hepatosplenomegaly, growth retardation, facial Marked medullary expansion, hepatosplenomegaly, growth retardation, facial

anomalies and hyperbilirubinemia if not adequately transfusedanomalies and hyperbilirubinemia if not adequately transfused Mostly healthy if managed vigorouslyMostly healthy if managed vigorously Treatment:Treatment:

Folic acid 1 mg/ dayFolic acid 1 mg/ day Iron rich diet/ supplements should be avoidedIron rich diet/ supplements should be avoided Chelation therapy (if needed)Chelation therapy (if needed) PRBC transfusions if hemoglobin < 7 g/ dl, aplastic crisis, acute infectionPRBC transfusions if hemoglobin < 7 g/ dl, aplastic crisis, acute infection splenectomysplenectomy


Beta thalassemia minorBeta thalassemia minor AsymptomaticAsymptomatic Discovered on routine blood test: slightly reduced hemoglobin, Discovered on routine blood test: slightly reduced hemoglobin,

basophilic stippling, low MCV, normal RDWbasophilic stippling, low MCV, normal RDW Discovered in family investigationDiscovered in family investigation


Alpha thalassemiaAlpha thalassemia TypesTypes

Silent carrier: deletion of 1 alpha geneSilent carrier: deletion of 1 alpha gene Alpha thalassemia trait: deletion of 2 alpha genesAlpha thalassemia trait: deletion of 2 alpha genes Hemoglobin H disease: deletion of 3 alpha genesHemoglobin H disease: deletion of 3 alpha genes Hydrops fetalis: deletion of all 4 alpha genesHydrops fetalis: deletion of all 4 alpha genes

Hydrops fetalis

Anemia of Bone Marrow FailureAnemia of Bone Marrow Failure Aplastic AnemiaAplastic Anemia

Causes of Acquired Aplastic AnemiaCauses of Acquired Aplastic Anemia Idiopathic: > 70% casesIdiopathic: > 70% cases Secondary Secondary

PregnancyPregnancy MalnutritionMalnutrition PNHPNH Myelodysplastic syndromeMyelodysplastic syndrome Hypoplastic preleukemiaHypoplastic preleukemia Immunologic disorders: GVHD Immunologic disorders: GVHD Infections: hepatitis A, B, C, AIDS, EBV, rubellaInfections: hepatitis A, B, C, AIDS, EBV, rubella IrradiationIrradiation Toxins: benzene, tolueneToxins: benzene, toluene Chemicals: insecticidesChemicals: insecticides DrugsDrugs

Unpredictable, normal doses (defect or damage to pluripotent stem cells): antibiotics, Unpredictable, normal doses (defect or damage to pluripotent stem cells): antibiotics, anticonvulsants, anti-rheumatics, antimalarials, anti-diabeticsanticonvulsants, anti-rheumatics, antimalarials, anti-diabetics

Predictable, does-dependent, rapidly reversible: ^ MP, MTX, chlorampehnicolPredictable, does-dependent, rapidly reversible: ^ MP, MTX, chlorampehnicol

Anemia of Bone Marrow FailureAnemia of Bone Marrow Failure Etiologic classficationEtiologic classfication

Direct toxicity: radiation, chemotherapy, benzneDirect toxicity: radiation, chemotherapy, benzne Immune mediated causes: iatrogenic, hepatitis, pregnancy, idiopathicImmune mediated causes: iatrogenic, hepatitis, pregnancy, idiopathic

White Blood CellsWhite Blood Cells LeukocytosisLeukocytosis

Causes:Causes: Physiologic (newborn: 38,000/ cumm)Physiologic (newborn: 38,000/ cumm) Emotional disordersEmotional disorders Ovulation, labor, pregnancyOvulation, labor, pregnancy Acute infections: bacterial, viral, fungal, protozoal, spirochetalAcute infections: bacterial, viral, fungal, protozoal, spirochetal Metabolic causes: diabetic coma, seizuresMetabolic causes: diabetic coma, seizures Drugs: steroids, epinephrineDrugs: steroids, epinephrine Poisoning: lead, mercuryPoisoning: lead, mercury Acute hemorrhageAcute hemorrhage Malignant neoplasmsMalignant neoplasms Connective tissue diseasesConnective tissue diseases Hematologic diseasesHematologic diseases

White Blood CellsWhite Blood Cells

LeukocytosisLeukocytosis NeutrophiliaNeutrophilia LymphocytosisLymphocytosis MonocytosisMonocytosis BasophiliaBasophilia EosinophiliaEosinophilia

White Blood CellsWhite Blood Cells

Leukemoid ReactionLeukemoid Reaction TWBC> 50,000/ cu mmTWBC> 50,000/ cu mm Shift to the left: presence of young WBC’sShift to the left: presence of young WBC’s With evidence of infectionWith evidence of infection No anemia, thrombocytopenia, blastsNo anemia, thrombocytopenia, blasts Normal BMANormal BMA LAP increasedLAP increased

BASOPHIL

LYMPHOCYTE

NEUTROPHILEOSINOPHIL

MONOCYTE

LymphocytosisLymphocytosis

Physiologic: 4 months-4 years oldPhysiologic: 4 months-4 years old LeukemiaLeukemia

ALLALL InfectionsInfections

ChronicChronic TB, syphilisTB, syphilis

AcuteAcute Moderate lymphocytosis: measles, rubella, mumps, varicellaModerate lymphocytosis: measles, rubella, mumps, varicella Marked lymphocytosis: acute infectious lymphocytosis, infectious Marked lymphocytosis: acute infectious lymphocytosis, infectious

mononucleosis, CMV, pertussismononucleosis, CMV, pertussis

Atypical LymphocytosisAtypical Lymphocytosis Less than 20%Less than 20%

Miscellaneous: hematologic (LCH, ALL, lymphoma) lead intoxication, stressMiscellaneous: hematologic (LCH, ALL, lymphoma) lead intoxication, stress RadiationRadiation InfectionsInfections

Bacterial: TBBacterial: TB Viral: mumps, varicella, rubella, HSV, VZVViral: mumps, varicella, rubella, HSV, VZV Protozoal: toxoplasmosisProtozoal: toxoplasmosis Rickettsial: ricekttsialpoxRickettsial: ricekttsialpox Spirochetal: syphilisSpirochetal: syphilis

More than 20%More than 20% Infectious mononucleosisInfectious mononucleosis Infectious hepatitisInfectious hepatitis Post-transfusion syndromePost-transfusion syndrome CMVCMV Drug hypersensitvity: PAS, phenyotinDrug hypersensitvity: PAS, phenyotin

PlateletsPlatelets Important in the first phase of coagulation – platelet plug formationImportant in the first phase of coagulation – platelet plug formation

Platelet size: 1-4 um (younger platelets are larger)Platelet size: 1-4 um (younger platelets are larger)

Platelet count: 150,000-400,000/ cummPlatelet count: 150,000-400,000/ cumm

Distribution: 1/3 in the spleen + 2/3 in the bloodstreamDistribution: 1/3 in the spleen + 2/3 in the bloodstream

Life span: 7-10 daysLife span: 7-10 days

PLATELETSPLATELETS

PlateletsPlatelets

Clinical manifestations of platelet disordersClinical manifestations of platelet disorders

BLEEDING: skin and mucous membranesBLEEDING: skin and mucous membranes

Petecchia, purpura, ecchymoses, epistaxis, hematuria, Petecchia, purpura, ecchymoses, epistaxis, hematuria, menorrhagia, GI hemorrhage, intracranial hemorrhagemenorrhagia, GI hemorrhage, intracranial hemorrhage

PlateletsPlatelets Platelet diseases based on platelet sizePlatelet diseases based on platelet size

MACROTHROMBOCYTES (HIGH MPV)MACROTHROMBOCYTES (HIGH MPV) ITP or any condition with increased PLT turnoverITP or any condition with increased PLT turnover Bernard Souillier syndromeBernard Souillier syndrome May Hegglin anomalyMay Hegglin anomaly Gray platelet syndromeGray platelet syndrome

NORMAL SIZE (NORMAL MPV)NORMAL SIZE (NORMAL MPV) Hypocellular BMA or Metastasis to the BMAHypocellular BMA or Metastasis to the BMA

MICROTHROMBOCYTES (LOW MPV)MICROTHROMBOCYTES (LOW MPV) WASWAS TAR syndromeTAR syndrome Storage pool disordersStorage pool disorders IDAIDA

PlateletsPlatelets

Laboratory evaluation of platelets and platelet function:Laboratory evaluation of platelets and platelet function: Examination of peripheral blood smearExamination of peripheral blood smear Bleeding timeBleeding time Platelet countPlatelet count Platelet aggregation studies (platelet aggregometry)Platelet aggregation studies (platelet aggregometry)

PlateletsPlatelets

Pathophysiological Classification of Pathophysiological Classification of thrombocytopenic states:thrombocytopenic states:

Increased PLT destruction Increased PLT destruction Disorders of PLT distribution or poolingDisorders of PLT distribution or pooling Decreased PLT production – deficient thrombopoiesisDecreased PLT production – deficient thrombopoiesis PseudothrombocytopeniaPseudothrombocytopenia

ITPITP Most frequent cause of thrombocytopeniaMost frequent cause of thrombocytopenia immune-mediated PLT destruction due to auto-antibodies, immune-mediated PLT destruction due to auto-antibodies,

drug-dependent antibodies or alloantibodiesdrug-dependent antibodies or alloantibodies Syndrome characterized by:Syndrome characterized by:

Thrombocytopenia (PLT < 100,000/ cumm)Thrombocytopenia (PLT < 100,000/ cumm) Shortened platelet survivalShortened platelet survival Presence of antiplatelet antibody in the plasmaPresence of antiplatelet antibody in the plasma Increased megakaryocytes in the bone marrow Increased megakaryocytes in the bone marrow

ITPITP

Types of ITP according to durationTypes of ITP according to duration

ACUTE: < 6 monthsACUTE: < 6 months

RECURRENT: PLT decreases after having returned to RECURRENT: PLT decreases after having returned to normal levelsnormal levels

CHRONIC: > 6 months CHRONIC: > 6 months

ITPITPACUTE ITPACUTE ITP CHRONIC ITPCHRONIC ITP

AgeAge childrenchildren adultsadultsSex distributionSex distribution equalequal > females> femalesSeasonal predilectiionSeasonal predilectiion (+)(+) (-)(-)Preceding infectionPreceding infection (+)(+) (-)(-)Associated autoimmmuneAssociated autoimmmune

conditionsconditions lowlow highhighOnsetOnset acuteacute insidiousinsidiousPLT countPLT count < 20,000< 20,000 40-80, 00040-80, 000Eosinophilia/ lymphocytosisEosinophilia/ lymphocytosis (+)(+) (-)(-)IgAIgA normalnormal lowerlowerDurationDuration 2-6 weeks2-6 weeks months to yearsmonths to yearsPrognosisPrognosis spontaneousspontaneous fluctuating chronic coursefluctuating chronic course

remission (80%)remission (80%)

ITPITP Clinical manifestationsClinical manifestations

Age: 2 – 8 years oldAge: 2 – 8 years old Sex: equalSex: equal Predisposing factors: preceding viral infection occurring 3 weeks Predisposing factors: preceding viral infection occurring 3 weeks

(50-80%)(50-80%) Non-specific URTI, rubella, measles, varicella, pertussis, mumps, Non-specific URTI, rubella, measles, varicella, pertussis, mumps,

CMV, hepatitis A, B, C, EBV, parvovirusCMV, hepatitis A, B, C, EBV, parvovirus Smallpox or live measles vaccinationSmallpox or live measles vaccination

Pathogenesis of ITPPathogenesis of ITP Platelet antibodiesPlatelet antibodies Platelet survivalPlatelet survival

ITPITP

Infantile ITPInfantile ITP- infants less than 2 years old- infants less than 2 years old- higher male/ female ratio- higher male/ female ratio- less frequent occurrence of infection before ITP- less frequent occurrence of infection before ITP- less frequent occurrence of chronic ITP- less frequent occurrence of chronic ITP- poor response to treatment- poor response to treatment- more severe clinical course- more severe clinical course

ITPITP Clinical manifestationsClinical manifestations

Bleeding on the skin: anterior surfaces of the lower extremities Bleeding on the skin: anterior surfaces of the lower extremities and over bony prominencesand over bony prominences

Bleeding in the mucous membranesBleeding in the mucous membranes Bleeding in internal organs: CNS, eyes, middle ear, deep muscles Bleeding in internal organs: CNS, eyes, middle ear, deep muscles

and jointsand joints PALLOR is usually ABSENT unless significant bleeding has taken PALLOR is usually ABSENT unless significant bleeding has taken

place.place. HEPATOSPLENOMEGALY is usually ABSENT. HEPATOSPLENOMEGALY is usually ABSENT. CERVICAL LYMPHADENOPATHY is usually ABSENT.CERVICAL LYMPHADENOPATHY is usually ABSENT.

ITPITP Laboratory findingsLaboratory findings

LOW PLT COUNT (always < 50,000/ cu mm)LOW PLT COUNT (always < 50,000/ cu mm) PERIPHERAL BLOOD SMEAR: low PLTPERIPHERAL BLOOD SMEAR: low PLT BONE MARROW ASPIRATE: increased megakaryocytesBONE MARROW ASPIRATE: increased megakaryocytes COAGULATION PROFILE: PROLONGED bleeding time, normal COAGULATION PROFILE: PROLONGED bleeding time, normal

PT and aPTTPT and aPTT

Related laboratory tests: ANA and anti-dsDNA (connective tissue Related laboratory tests: ANA and anti-dsDNA (connective tissue disorders), Blood typing, Coomb’s test, Liver function tests, EBV disorders), Blood typing, Coomb’s test, Liver function tests, EBV teststests

ITPITP DiagnosisDiagnosis

Clinical examinationClinical examination PLT count and peripheral blood smearsPLT count and peripheral blood smears Bone marrow aspirationBone marrow aspiration Exclusion of secondary causes of thrombocytopeniaExclusion of secondary causes of thrombocytopenia

THROMBOCYTOPENIA: THROMBOCYTOPENIA:

Immune Thrombocytopenic PurpuraImmune Thrombocytopenic Purpura

ITPITP Drugs capable of causing thrombocytopenia through drug-Drugs capable of causing thrombocytopenia through drug-

induced antibody formation:induced antibody formation: Anti-inflammatory drugsAnti-inflammatory drugs AntibioticsAntibiotics Anti-neoplasticsAnti-neoplastics Anti-convulsants, sedatives and anti-depressantsAnti-convulsants, sedatives and anti-depressants Cardiac and antihypertensive drugsCardiac and antihypertensive drugs H2 antagonistsH2 antagonists Cinchona alkaloidsCinchona alkaloids Others: food (beans)Others: food (beans)

ITPITP TreatmentTreatment

No treatment when the PLT count is > 20,000/ cu mmNo treatment when the PLT count is > 20,000/ cu mm Treatment recommended if PLT < 20,000/ cu mm + significant Treatment recommended if PLT < 20,000/ cu mm + significant

mucous membrane bleeding or PLT < 10,000/ cu mm with minor mucous membrane bleeding or PLT < 10,000/ cu mm with minor purpurapurpura SteroidsSteroids High dose IV immunoglobulinHigh dose IV immunoglobulin Anti-D therapyAnti-D therapy RituximabRituximab PlasmapheresisPlasmapheresis PLT transfusionsPLT transfusions SplenectomySplenectomy

ITPITP SplenectomySplenectomy

IndicationsIndications Severe acute ITP with acute life-threatening bleeding unresponsive to Severe acute ITP with acute life-threatening bleeding unresponsive to

medical treatment.medical treatment. Chronic purpura with bleeding symptoms Chronic purpura with bleeding symptoms PLT count persistently < 30,000/ cu mmPLT count persistently < 30,000/ cu mm

OPSI (Overwhelming Post-Splenectomy Infection)OPSI (Overwhelming Post-Splenectomy Infection) Vaccinations against N. meningitidis, H. influenzae b, Strep pneumoniaeVaccinations against N. meningitidis, H. influenzae b, Strep pneumoniae Lifelong daily prophylaxis with Penicillin V 250 mg BIDLifelong daily prophylaxis with Penicillin V 250 mg BID All febrile episodes should be aggressively managedAll febrile episodes should be aggressively managed

ITPITP Treatment of life threatening bleeding:Treatment of life threatening bleeding:

PLT transfusionPLT transfusion IV steroidsIV steroids IV immunoglobulinIV immunoglobulin Emergency splenectomyEmergency splenectomy

ITPITP PrognosisPrognosis

EXCELLENT: 50% recovery within 1 month, 70-80% recovery EXCELLENT: 50% recovery within 1 month, 70-80% recovery within 6 monthswithin 6 months

Spontaneous remission after 1 year is uncommon, although may Spontaneous remission after 1 year is uncommon, although may occur after several yearsoccur after several years

Age > 10, insidious onset, female gender: high risk for chronic ITPAge > 10, insidious onset, female gender: high risk for chronic ITP In Chronic ITP: 50-60% eventually stabilize without treatment and In Chronic ITP: 50-60% eventually stabilize without treatment and

without recourse to splenectomywithout recourse to splenectomy

NEONATAL THROMBOCYTOPENIANEONATAL THROMBOCYTOPENIA Causes of neonatal thrombocytopeniaCauses of neonatal thrombocytopenia

Normal or increased megakaryocytes in the bone marrow Normal or increased megakaryocytes in the bone marrow (megakaryocytic thrombocytopenia)(megakaryocytic thrombocytopenia) Immune (autoimmune, alloimmune)Immune (autoimmune, alloimmune) InfectionInfection DrugsDrugs DICDIC Inherited thrombocytopeniaInherited thrombocytopenia

Decreased or absent megakaryocytes in the bone marrow Decreased or absent megakaryocytes in the bone marrow (amegakaryocytic thrombocytopenia): isolated megakaryocytic (amegakaryocytic thrombocytopenia): isolated megakaryocytic hypoplasia, generalized bone marrow disorders, metabolic hypoplasia, generalized bone marrow disorders, metabolic causescauses

NEONATAL THROMBOCYTOPENIANEONATAL THROMBOCYTOPENIA NITP (neonatal idiopathic or autoimmune purpura)NITP (neonatal idiopathic or autoimmune purpura)

Passive transfer of PLT antibody from the motherPassive transfer of PLT antibody from the mother Mothers have LOW PLT countsMothers have LOW PLT counts Self-limiting but may last for several weeksSelf-limiting but may last for several weeks Transplacental passage of maternal IgG autoantibodies into the fetal circulation Transplacental passage of maternal IgG autoantibodies into the fetal circulation

-- destruction of fetal PLT destruction of fetal PLT True maternal ITP vs. GESTATIONAL THROMBOCYTOPENIA: maternal True maternal ITP vs. GESTATIONAL THROMBOCYTOPENIA: maternal

thrombocytopenia is NOT severe (PLT > 100,000/ cu mm) and infants are NOT thrombocytopenia is NOT severe (PLT > 100,000/ cu mm) and infants are NOT at risk of thrombocytopeniaat risk of thrombocytopenia

Treatment:Treatment: IV immunoglobulinIV immunoglobulin SteroidsSteroids Exchange transfusionExchange transfusion PLT transfusionsPLT transfusions

NEONATAL THROMBOCYTOPENIANEONATAL THROMBOCYTOPENIA

NATP (neonatal alloimmune or isoimmune NATP (neonatal alloimmune or isoimmune thrombocytopenia)thrombocytopenia) Born to mothers with NORMAL PLT countsBorn to mothers with NORMAL PLT counts Immunization due to fetomaternal passage of PLT in which there Immunization due to fetomaternal passage of PLT in which there

is incompatibiltiy of fetal and maternal antigensis incompatibiltiy of fetal and maternal antigens Associated with human PLT antigen (HPA-1a) or Pl A1Associated with human PLT antigen (HPA-1a) or Pl A1 Also causes associated platelet qualitative defects due to Also causes associated platelet qualitative defects due to

impairment of PLT aggregationimpairment of PLT aggregation


Diagnosis of NATPDiagnosis of NATP Congenital thrombocytopeniaCongenital thrombocytopenia Normal maternal PLT count and negative history of maternal ITPNormal maternal PLT count and negative history of maternal ITP No evidence of systemic disease, inefction, malignancy or No evidence of systemic disease, inefction, malignancy or

hemangiomahemangioma Recovery of platelets within 2-3 weeks.Recovery of platelets within 2-3 weeks. Increased megakaryocytes in bone marrow aspirationIncreased megakaryocytes in bone marrow aspiration


TreatmentTreatment PLT transfusion (washed or irradiated)PLT transfusion (washed or irradiated) IV immnoglobulinIV immnoglobulin steroidssteroids

HEMOSTASISHEMOSTASIS

Physiology of hemostasisPhysiology of hemostasis Vascular phase: vasoconstrictionVascular phase: vasoconstriction Platelet phase: platelet plug formation or primary hemostatic Platelet phase: platelet plug formation or primary hemostatic

mechanismmechanism Plasma phase: fibrin thrombus formation (initiation, amplification, Plasma phase: fibrin thrombus formation (initiation, amplification,

propagation)propagation)

CLOTTING CASCADECLOTTING CASCADE

Intrinsic PathwayIntrinsic Pathway Extrinsic PathwayExtrinsic Pathway ContactContactXIIXII XIIaXIIa

XIXI XIaXIa Tissue Factor Tissue Factor

IXIX IXa IXa VIIaVIIa VIIVII VIIIa+PlVIIIa+Pl

XX XaXa Va+PlVa+PlIIII IIa IIa

FibrinogenFibrinogen Fibrin ClotFibrin Clot

FIBRINOLYSISFIBRINOLYSIS MECHANISM for the removal of physiologically deposited MECHANISM for the removal of physiologically deposited

fibrinfibrin Clot lysis is brought about by the action of PLASMIN on Clot lysis is brought about by the action of PLASMIN on

fibrinfibrin PLASMINOGEN (zymogen) is synthesized in the liver.PLASMINOGEN (zymogen) is synthesized in the liver. Alpha 1 antiplasmin is a PLASMIN inhibitor.Alpha 1 antiplasmin is a PLASMIN inhibitor. Tissue plasminogen activator (tPA) is the principal Tissue plasminogen activator (tPA) is the principal

intravascular activator of plasminogen is found in body intravascular activator of plasminogen is found in body tissues and fluids.tissues and fluids.

Urokinas plasminogen activator (uPA) is found in urine.Urokinas plasminogen activator (uPA) is found in urine.

FIBRINOLYSISFIBRINOLYSIS

Plasmin SPLITS fibrin and fibrinogen into FDP’s (fibrin Plasmin SPLITS fibrin and fibrinogen into FDP’s (fibrin degradation products) or FSP’s (fibrin split products)degradation products) or FSP’s (fibrin split products) Fragment XFragment X Fragment YFragment Y Fragment DFragment D Fragment EFragment E

NATURAL INHIBITORS OF NATURAL INHIBITORS OF COAGULATIONCOAGULATION

Antithrombin III (heparin cofactor)Antithrombin III (heparin cofactor)Antiplasmin (alpha 2-plasmin inhibitor)Antiplasmin (alpha 2-plasmin inhibitor)Alpha-2 macroglobulinAlpha-2 macroglobulinAlpha-1 antitrypsinAlpha-1 antitrypsinC1 inhibitorC1 inhibitorTAFI (thrombin activatable inhibitor of fibrinolysis)TAFI (thrombin activatable inhibitor of fibrinolysis)TFPI (tissue factor pathway inhibitor)TFPI (tissue factor pathway inhibitor)Protein CProtein CProtein SProtein SProtein C inhibitorProtein C inhibitor

HEMOSTASIS IN THE NEWBORNHEMOSTASIS IN THE NEWBORN PlateletsPlatelets

Increased PLT adhesion due to increased vWF and HMW vWF multimersIncreased PLT adhesion due to increased vWF and HMW vWF multimers PLT aggregation abnormalitiesPLT aggregation abnormalities PLT activation is increased due to increased TXA2, beta thromboglobulin and PLT activation is increased due to increased TXA2, beta thromboglobulin and

PF 4PF 4

Blood vesselsBlood vessels Increased capillary fragilityIncreased capillary fragility Increased prostacyclin productionIncreased prostacyclin production

Plasma factorsPlasma factors Increased plasma levels of tPA and PAI-1Increased plasma levels of tPA and PAI-1 Decreased activity of anticoagulant factors AT III, PC, PSDecreased activity of anticoagulant factors AT III, PC, PS

TESTS FOR HEMOSTASISTESTS FOR HEMOSTASIS Laboratory evaluation to detect hemostatic disorders:Laboratory evaluation to detect hemostatic disorders:

CBC platelet countCBC platelet count Bleeding timeBleeding time Platelet function analyzerPlatelet function analyzer Bleeding timeBleeding time PTPT aPTTaPTT FibrinogenFibrinogen Thrombin timeThrombin time Mixing studiesMixing studies Clotting factor assaysClotting factor assays vWF antigen : quantitative assay for vWF vWF antigen : quantitative assay for vWF

TESTS FOR HEMOSTASISTESTS FOR HEMOSTASIS

Von Willebrand factor (ristocetin cofactor acitivty): Von Willebrand factor (ristocetin cofactor acitivty): functional/ qualitative assay for vWFfunctional/ qualitative assay for vWF

Platelet aggregation studies: qualitative assessment of PLT Platelet aggregation studies: qualitative assessment of PLT functionfunction

Urea clot lysis assay” screening for FXIII deficiencyUrea clot lysis assay” screening for FXIII deficiency

CONGENITAL COAGULATION FACTOR CONGENITAL COAGULATION FACTOR DISORDERSDISORDERS

Hemophilia Hemophilia Most common severe coagulation disordersMost common severe coagulation disorders Due to deficiency or defect in clotting factors VIII, IX, XIDue to deficiency or defect in clotting factors VIII, IX, XI Sex linked recessive mode of transmissionSex linked recessive mode of transmission Almost exclusively affects malesAlmost exclusively affects males Mothers are carriers Mothers are carriers 30% has a positive family history30% has a positive family history 30% has no family history and may be due to spontaneous 30% has no family history and may be due to spontaneous

genetic mutationgenetic mutation

HEMOPHILIA HEMOPHILIA Type of hemophiliaType of hemophilia

According to the missing clotting factorAccording to the missing clotting factor Hemophilia A: missing clotting factor VIIIHemophilia A: missing clotting factor VIII Hemophilia B: missing clotting factor IXHemophilia B: missing clotting factor IX Hemophilia C: missing clotting factor XIHemophilia C: missing clotting factor XI

According to severityAccording to severity MILD: clotting factor level > 5%MILD: clotting factor level > 5% MODERATE: clotting factor level 1-5%MODERATE: clotting factor level 1-5% SEVERE: clotting factor level < 1%SEVERE: clotting factor level < 1%

According to frequency of bleedingAccording to frequency of bleeding MILD: once a year or even rarely; with traumaMILD: once a year or even rarely; with trauma MODERATE: once every quarter: with or without traumaMODERATE: once every quarter: with or without trauma SEVERE: once a month or even more often: spontaneousSEVERE: once a month or even more often: spontaneous

HEMOPHILIAHEMOPHILIA

Common sites of bleeding for hemophiliacsCommon sites of bleeding for hemophiliacs

Hemarthrosis (joints): HALLMARK of hemophiliaHemarthrosis (joints): HALLMARK of hemophilia Intramuscular hematomaIntramuscular hematoma HematuriaHematuria Mucous membranesMucous membranes

hematoma/bruiseshematoma/bruises post-venipuncturepost-venipuncture

• hemarthrosis

•hemarthrosis

2 yr old Hemophilia A 2 yr old Hemophilia A with inhibitor, with inhibitor, developed developed

scalp hematomascalp hematoma

Pseudotumor in a Pseudotumor in a hemophilia A patienthemophilia A patient


High Risk Bleeding sitesHigh Risk Bleeding sites CNS (intracranial, intraspinal)CNS (intracranial, intraspinal) RetropharyngealRetropharyngeal RetroperitonealRetroperitoneal Hemorrhage causing compartment/ nerve compression syndromeHemorrhage causing compartment/ nerve compression syndrome

Femoral (iliopsoas muscle)Femoral (iliopsoas muscle) Sciatic (buttock)Sciatic (buttock) Tibial (calf muscle)Tibial (calf muscle) Perineal (anterior compartment of the leg)Perineal (anterior compartment of the leg) Median and ulnar nerves (flexor muscles of the forearm)Median and ulnar nerves (flexor muscles of the forearm)

HEMOPHILIAHEMOPHILIA Laboratory testsLaboratory tests

Prolonged aPTTProlonged aPTT Decreased specific clotting factor assaysDecreased specific clotting factor assays Corrected mixing studiesCorrected mixing studies

TreatmentTreatment DDAVP for mild hemophiliacsDDAVP for mild hemophiliacs

Facilitates release of factor VIII and vW factor in the circulationFacilitates release of factor VIII and vW factor in the circulation Clotting factor replacement therapyClotting factor replacement therapy

Blood components: fresh frozen plasma, cryoprecipitate, cryosupernateBlood components: fresh frozen plasma, cryoprecipitate, cryosupernate Plasma derived or recombinant clotting factor concentratesPlasma derived or recombinant clotting factor concentrates


Complications of the diseaseComplications of the disease Crippling joint deformityCrippling joint deformity Psychological incapacityPsychological incapacity

Complications of the treatmentComplications of the treatment Transfusion transmissible viral infectionsTransfusion transmissible viral infections Inhibitor developmentInhibitor development

VON WILLEBRAND DISEASEVON WILLEBRAND DISEASE

Most common hereditary bleeding disorderMost common hereditary bleeding disorder Autosomal dominant mode of transmissionAutosomal dominant mode of transmission Due to deficiency, dysfunction or complete absence of von Due to deficiency, dysfunction or complete absence of von

Willebrand factorWillebrand factor Functions of the vWF:Functions of the vWF:

Mediates adherence of platelets at sites of endothelial damage Mediates adherence of platelets at sites of endothelial damage promoting formation of the platelet plugpromoting formation of the platelet plug

Binds and transport s factor VIII protecting it from degradation by Binds and transport s factor VIII protecting it from degradation by plasma proteasesplasma proteases

VON WILLEBRAND DISEASEVON WILLEBRAND DISEASE Site of synthesis: megkaryocytes and enodthelial cellsSite of synthesis: megkaryocytes and enodthelial cells Site of storage: alpha granules (platelets) and Weibel Palade bodies Site of storage: alpha granules (platelets) and Weibel Palade bodies

(endothelial cells)(endothelial cells) Clinical manifestations: muco-cutaneous bleeding, prolonged oozing Clinical manifestations: muco-cutaneous bleeding, prolonged oozing

from surgery or after traumafrom surgery or after trauma Types of vWDTypes of vWD

Type IType I Type 2AType 2A Type 2BType 2B Type 2NType 2N Type 2MType 2M Type 3Type 3


Type 1 VWDType 1 VWD

Most common form of the disorderMost common form of the disorder Mild to moderate decrease in plasma VWFMild to moderate decrease in plasma VWF Plasma VWF has normal structurePlasma VWF has normal structure Low ristocetin cofactor and VWF antigenLow ristocetin cofactor and VWF antigen DDAVP is effectiveDDAVP is effective


Type 2A VWDType 2A VWD

Decreased PLT dependent VWF function + lack of large HMW Decreased PLT dependent VWF function + lack of large HMW multimers in plasma and plateletsmultimers in plasma and platelets

Localized in the A2 domain of VWFLocalized in the A2 domain of VWF DDAVP is effectiveDDAVP is effective Clotting factor concentrates (intermediate purity) may helpClotting factor concentrates (intermediate purity) may help


Type 2B VWDType 2B VWD

Dominant gain in functional mutations in the A1 domain of VWFDominant gain in functional mutations in the A1 domain of VWF MILD thrombocytopenia present due to spontaneous MILD thrombocytopenia present due to spontaneous

agglutination of plateletsagglutination of platelets Reduced PLT aggregation with ristocetinReduced PLT aggregation with ristocetin DDAVP is CONTRAINDICATED due to transient DDAVP is CONTRAINDICATED due to transient

thrombocytopenia resulting from release and clearance of thrombocytopenia resulting from release and clearance of abnormal VWFabnormal VWF

Clotting factor replacement (intermediate purity) is effectiveClotting factor replacement (intermediate purity) is effective


Type 2N VWDType 2N VWD

Abnormal VWF that DOES NOT bind factor VIII -Abnormal VWF that DOES NOT bind factor VIII - unbound unbound factor VIII is rapidly cleared from the circulation -factor VIII is rapidly cleared from the circulation - low factor VIII low factor VIII

MISDIAGNOSED as hemophiliaMISDIAGNOSED as hemophilia Clotting factor concentrate (intermediate purity) may be effectiveClotting factor concentrate (intermediate purity) may be effective


Type 2M VWDType 2M VWD

Abnormal binding site on VWF for PLT GP Ib --Abnormal binding site on VWF for PLT GP Ib -- reduced reduced ristocetin cofactor activity (functional defect)ristocetin cofactor activity (functional defect)

Multimers of all sizes are presentMultimers of all sizes are present DDAVP is effective for heterozygous variantsDDAVP is effective for heterozygous variants Clotting factor concentrates (intermediate purity) is effective for Clotting factor concentrates (intermediate purity) is effective for

homozygous variantshomozygous variants


Type 3 VWDType 3 VWD

Severe bleeding disorder with major deficits in both primary and Severe bleeding disorder with major deficits in both primary and secondary hemostasissecondary hemostasis

Plasma FVIII and vWF are UNDETECTABLE.Plasma FVIII and vWF are UNDETECTABLE. Plasma derived clotting factor concentrates (intermediate purity) Plasma derived clotting factor concentrates (intermediate purity)

may cause ANAPHYLACTIC reactions so only recombinant may cause ANAPHYLACTIC reactions so only recombinant preparations are usedpreparations are used

Recombinant FVIIa may helpRecombinant FVIIa may help


Platelet type-pseudo VWDPlatelet type-pseudo VWD

Mutation in the PLT GP Ib receptorMutation in the PLT GP Ib receptor Similar to type 2B VWDSimilar to type 2B VWD Excessive binding of VWF to PLT GP Ib receptor -Excessive binding of VWF to PLT GP Ib receptor -

PLT activation and VWF removal from the circulation -PLT activation and VWF removal from the circulation - low plasma VWF - low plasma VWF - increased PLT aggregation increased PLT aggregation

PLT transfusion is the treatment of choicePLT transfusion is the treatment of choice

VON WILLEBRAND DISEASEVON WILLEBRAND DISEASE Acquired VWDAcquired VWD

Low VWF in a person with no lifelong bleeding disorderLow VWF in a person with no lifelong bleeding disorder Associated DisordersAssociated Disorders

MalignanciesMalignancies Autoimmune disordersAutoimmune disorders Myeloprliferative disordersMyeloprliferative disorders Lymphoproliferative disordersLymphoproliferative disorders DrugsDrugs AngiodysplasiaAngiodysplasia

Mechanisms:Mechanisms: Specific autoantibodiesSpecific autoantibodies Adsorption onto malignant cell clonesAdsorption onto malignant cell clones Depletion in conditions of high vascular shear forceDepletion in conditions of high vascular shear force

ACQUIRED HEMOSTATIC DISORDERSACQUIRED HEMOSTATIC DISORDERS

Vitamin K Deficiency Bleeding (VKDB)Vitamin K Deficiency Bleeding (VKDB) Hemorrhagic Disease of the NewbornHemorrhagic Disease of the Newborn At birth, factors 2, 7, 9, 10 are physiologically LOW.At birth, factors 2, 7, 9, 10 are physiologically LOW. Lowest point is on DAY 3 of life.Lowest point is on DAY 3 of life. Due to low body stores of vitamin K plus subsequent Due to low body stores of vitamin K plus subsequent

poor intake of vitamin Kpoor intake of vitamin K Minimum requirement: 25 ug of vitamin KMinimum requirement: 25 ug of vitamin K

VITAMIN K DEFICIENCY BLEEDINGVITAMIN K DEFICIENCY BLEEDING Conditions associated with deficiency of Vitamin K dependent clotting Conditions associated with deficiency of Vitamin K dependent clotting

factors:factors: Normal newborn (normal by 3 months of age), prematurityNormal newborn (normal by 3 months of age), prematurity DietDiet Altered bacterial colonizationAltered bacterial colonization Hepatocellular diseaseHepatocellular disease DrugsDrugs

Clinical manifestations:Clinical manifestations: Bleeding on days 2-4Bleeding on days 2-4 Sites of bleeding: GIT, umbilicus, internal organsSites of bleeding: GIT, umbilicus, internal organs

VITAMIN K DEFICIENCY BLEEDINGVITAMIN K DEFICIENCY BLEEDING

Laboratory findings:Laboratory findings:

RBC morphologyRBC morphology normalnormal aPTTaPTT prolongedprolonged PTPT prolongedprolonged Fibrin split productsFibrin split products normalnormal PlateletsPlatelets normalnormal Clotting factors decreasedClotting factors decreased 2, 7, 9, 102, 7, 9, 10

VITAMIN K DEFICIENCY BLEEDINGVITAMIN K DEFICIENCY BLEEDING

TreatmentTreatment

Vitamin KVitamin K Fresh frozen plasma transfusionFresh frozen plasma transfusion

DICDIC INTRAVASCULAR consumption of PLT and plasma clotting factorsINTRAVASCULAR consumption of PLT and plasma clotting factors Widespread coagulation results in the deposition of fibrin thrombi and Widespread coagulation results in the deposition of fibrin thrombi and

the production of a hemorrhagic statethe production of a hemorrhagic state Accummulation of fibrin in the micorcirculation leads to mechanical Accummulation of fibrin in the micorcirculation leads to mechanical

injury to the RBC -injury to the RBC - RBC fragmentation and microangiopathic RBC fragmentation and microangiopathic hemolytic anemiahemolytic anemia

Phases:Phases: Thrombin causes intravascular coagulation + consumption of PLT, fibrinogen, Thrombin causes intravascular coagulation + consumption of PLT, fibrinogen,

FV, FVIII, FXIIIFV, FVIII, FXIII Plasminogen is converted to plasmin by tPA causing release of FDP or FSP Plasminogen is converted to plasmin by tPA causing release of FDP or FSP

leading to clot lysisleading to clot lysis

DICDIC

Laboratory findingsLaboratory findings Prolonged PT and aPTTProlonged PT and aPTT Decreased fibrinogenDecreased fibrinogen Decreased PLT countDecreased PLT count Increased FDP or FSPIncreased FDP or FSP Presence of fragmented RBCPresence of fragmented RBC Increased PF 4Increased PF 4 Increased fibrinopeptide AIncreased fibrinopeptide A Decreased FV, FVIII, FXIIIDecreased FV, FVIII, FXIII

DICDIC

Disease states associated with DICDisease states associated with DIC Tissue injury (trauma, crush injuries, head injury, burns, Tissue injury (trauma, crush injuries, head injury, burns,

venoms, malignancy, obstetrical accidents, major venoms, malignancy, obstetrical accidents, major surgery)surgery)

Endothelial cell injury and/ or abnormal vascular Endothelial cell injury and/ or abnormal vascular surfaces (infection, immune complexes, malignancy)surfaces (infection, immune complexes, malignancy)

Platelet, leukocyte or RBC injury (incompatible blood Platelet, leukocyte or RBC injury (incompatible blood transfusion, infection, allograft rejection, drug transfusion, infection, allograft rejection, drug hypersensitivty)hypersensitivty)

DICDIC TreatmentTreatment

Remove/ reverse underlying disorderRemove/ reverse underlying disorder IV heparinizationIV heparinization IV direct thrombin inhibitorsIV direct thrombin inhibitors Anti-PLT drugsAnti-PLT drugs Anti-thrombin concentratesAnti-thrombin concentrates Activated Protein C concentrateActivated Protein C concentrate Replacement therapyReplacement therapy

PLT concentratesPLT concentrates CryoprecipitateCryoprecipitate Fresh frozen plasmaFresh frozen plasma

THROMBOSISTHROMBOSIS

Mechanisms of thrombosisMechanisms of thrombosis INHERITED THROMBOPHILIASINHERITED THROMBOPHILIAS

Impaired neutralization of thrombinImpaired neutralization of thrombin Failure to control the generation of thrombinFailure to control the generation of thrombin Malfunction in the system of natural anticoagulants that Malfunction in the system of natural anticoagulants that

maintain the fluidity of bloodmaintain the fluidity of blood Decreased AT III -Decreased AT III - impairment of thrombin neutralization impairment of thrombin neutralization Decreased PC or PS -Decreased PC or PS - diminished control of thrombin generation diminished control of thrombin generation Mutations in FV or FII -Mutations in FV or FII - slows down proteolytic activation of factor slows down proteolytic activation of factor

Va -Va - augmented generation of thrombin augmented generation of thrombin

THROMBOSISTHROMBOSIS Clinical manifestations of hypercoagulable statesClinical manifestations of hypercoagulable states

Family history of thrombosisFamily history of thrombosis Recurrent spontaneous thrombosesRecurrent spontaneous thromboses Thrombosis in unusual sitesThrombosis in unusual sites Resistance to anticoagulant therapyResistance to anticoagulant therapy Coumarin necrosis syndromeCoumarin necrosis syndrome Recurrent spontaneous abortionsRecurrent spontaneous abortions Thrombosis during pregnancy or oral contraceptivesThrombosis during pregnancy or oral contraceptives Migratory superficial thrombophlebitisMigratory superficial thrombophlebitis Antiphospholipid syndrome (APAS)Antiphospholipid syndrome (APAS) Autoimmune disordersAutoimmune disorders MalignancyMalignancy Nephrotic syndromeNephrotic syndrome infectionsinfections

THROMBOSISTHROMBOSIS

Laboratory findingsLaboratory findings Primary hemostasisPrimary hemostasis

ThrombocytosisThrombocytosis PLT aggregationPLT aggregation Increased PLT adhesivenessIncreased PLT adhesiveness Increased beta-thromboglobulin, VWF, PF4Increased beta-thromboglobulin, VWF, PF4 Short PLT life spanShort PLT life span

THROMBOSISTHROMBOSIS Laboratory findingsLaboratory findings

Secondary hemostasisSecondary hemostasis Shortened PT/ aPTTShortened PT/ aPTT Elevated coagulation factors (1,2,5,7,8,9,10,11)Elevated coagulation factors (1,2,5,7,8,9,10,11) Reduced ATIII, PC, PSReduced ATIII, PC, PS Factor V Leiden/ APC resistanceFactor V Leiden/ APC resistance PT gene mutationPT gene mutation Increased alpha-2-antiplasmin, PAI, alpha-2-macroglobulinIncreased alpha-2-antiplasmin, PAI, alpha-2-macroglobulin Increased lipoporoteinIncreased lipoporotein Deficient thrombomodulinDeficient thrombomodulin Increased fibrinopeptide AIncreased fibrinopeptide A Increased FDP or FSPIncreased FDP or FSP Short fibrinogen life spanShort fibrinogen life span DysfibrinogenemiaDysfibrinogenemia HomocysteinuriaHomocysteinuria Lupus anticoagulantsLupus anticoagulants Anticardiolipin antibodiesAnticardiolipin antibodies

VENOUS THROMBOSISVENOUS THROMBOSIS

DEVELOP under conditions of SLOW blood flowDEVELOP under conditions of SLOW blood flow Activation of the coagulation system with or without Activation of the coagulation system with or without

vascular damagevascular damage Venous thrombi: large amounts of fibrin with numerous Venous thrombi: large amounts of fibrin with numerous

RBC, PLT and WBC (red thrombus)RBC, PLT and WBC (red thrombus) Produces significant obstruction to blood flowProduces significant obstruction to blood flow Most serious consequence: DEEP VEIN THROMBOSIS Most serious consequence: DEEP VEIN THROMBOSIS

embolization causing PULMONARY EMBOLISMembolization causing PULMONARY EMBOLISM


Detection of DVTDetection of DVT Clinical assessmentClinical assessment

Signs and symptoms of DVTSigns and symptoms of DVT Presence or absence of an alternative diagnosisPresence or absence of an alternative diagnosis Presence and number of predisposing factors for DVTPresence and number of predisposing factors for DVT

Impedance plethysmographyImpedance plethysmography Venous ultrasoundVenous ultrasound D-dimer assayD-dimer assay VenogramVenogram


Risk factors for PERisk factors for PE Recent surgeryRecent surgery Immobilization (> 3 days bed rest)Immobilization (> 3 days bed rest) Previous DVT or PEPrevious DVT or PE Lower extremity plaster castLower extremity plaster cast Lower extremity paralysisLower extremity paralysis Strong family history of DVT or PEStrong family history of DVT or PE CancerCancer Post-partumPost-partum

ARTERIAL THROMBOSISARTERIAL THROMBOSIS

Develops under conditions of RAPID blood flowDevelops under conditions of RAPID blood flow Results from processes that DAMAGE the vessel Results from processes that DAMAGE the vessel

wallwall Arterial thrombi: tightly coherent PLT that contain Arterial thrombi: tightly coherent PLT that contain

small amounts of fibrin and few RBC (white small amounts of fibrin and few RBC (white thrombus)thrombus)

Most serious consequence of arterial thrombosis: Most serious consequence of arterial thrombosis: VASCULAR OCCLUSIONVASCULAR OCCLUSION


Risk Factors for Arterial ThrombosisRisk Factors for Arterial Thrombosis Cardiac catheterizationCardiac catheterization Cardiac proceduresCardiac procedures Umbilical artery catheterizationUmbilical artery catheterization Renal artery thrombosisRenal artery thrombosis Hepatic artery thrombosisHepatic artery thrombosis Kawasaki diseaseKawasaki disease APASAPAS


Specific Risk factorsSpecific Risk factors HomocysteineHomocysteine Lipoprotein ALipoprotein A FibrinogenFibrinogen FDP (D-dimers)FDP (D-dimers) TPATPA PAI-1PAI-1 CRPCRP


General Risk FactorsGeneral Risk Factors Cigarette smokingCigarette smoking CholesterolCholesterol HypertensionHypertension PregnancyPregnancy DiabetesDiabetes ObesityObesity Physical inactivityPhysical inactivity

THROMBOSIS IN THE NEWBORNTHROMBOSIS IN THE NEWBORN Congenital: multiple-gene disorderCongenital: multiple-gene disorder AcquiredAcquired

Systemic Arterial Thromboembolic DisordersSystemic Arterial Thromboembolic Disorders Arterial ischemic strokeArterial ischemic stroke

Renal Vein thrombosis: most common non-catheter related Renal Vein thrombosis: most common non-catheter related venous thrombotic event in the newbornvenous thrombotic event in the newborn

Central venous catheter related thrombosis: most common cause Central venous catheter related thrombosis: most common cause of acquired thrombosis in the newbornof acquired thrombosis in the newborn Umbilical venous cathetersUmbilical venous catheters Central venous cathetersCentral venous catheters

Systemic venous thromboembolic disordersSystemic venous thromboembolic disorders Sinovenous thrombosisSinovenous thrombosis

TREATMENT OF THROMBOSISTREATMENT OF THROMBOSIS

Anticoagulant therapyAnticoagulant therapy

Thrombolytic therapyThrombolytic therapy

Intracaval filterIntracaval filter

Pulmonary embolectomyPulmonary embolectomy

ANTI-THROMBOTIC AGENTSANTI-THROMBOTIC AGENTS

WarfarinWarfarin Competitively inhibits vitamin K -Competitively inhibits vitamin K - decreased post- decreased post-

translational carboxylation of factors 2,7,9,10translational carboxylation of factors 2,7,9,10 HeparinHeparin

Catalyzes the activity of the natural anticoagulant ATIIICatalyzes the activity of the natural anticoagulant ATIII Protamine sulfate is the ANTIDOTE for heparin Protamine sulfate is the ANTIDOTE for heparin

overdoseoverdose

ANTI-PLATELET AGENTSANTI-PLATELET AGENTS AspirinAspirin

Acetylates cyclooxygenase -Acetylates cyclooxygenase - interferes with the production of interferes with the production of TXA2 -TXA2 - impaires PLT aggregation impaires PLT aggregation

DipyridamoleDipyridamole Increases cyclic AMP Increases cyclic AMP inhibits PLT function inhibits PLT function

IndicationsIndications Cardiac disordersCardiac disorders Cardiovascular eventsCardiovascular events Kawasaki diseaseKawasaki disease

THROMBOLYTIC AGENTSTHROMBOLYTIC AGENTS

Dissolve established thrombus by converting Dissolve established thrombus by converting endogenous plasminogen to plasmin which can endogenous plasminogen to plasmin which can lyse existing thrombuslyse existing thrombus Tissue Plasminogen Activator (tPA)Tissue Plasminogen Activator (tPA) UrokinaseUrokinase StreptokinaseStreptokinase

eac-hema

Documents

mlkg anemia

hemoglobin levels

higher hemoglobin

larger red blood cells

massive blood loss injuries

postnatal blood lossexternal

neonatal periodhemorrhage

bone marrow failure