Anemia Hemolitik

HEMOLYTIC ANEMIA:OVERVIEWSri MulatsihHematology-oncology, Pediatric Department, Sardjito Hospital, Faculty of Medicine, Gadjah Mada University2004

OVERVIEW

Normal RBC life span is 110-120 days

OVERVIEW

With age:Decreased membrane lipid componentSpherocytic shapeLess pliable and deformableTrapped and removed by the RE system

CLINICAL PRESENTATIONPatients may present with a variety of symptoms due to anemia

Related to tissue hypoxiaFatigue, weakness, lightheadedness, CP, SOB

Related to cardiovascular compensationTachycardia, palpitations

Related to underlying etiology

CLINICAL PRESENTATION

JAUNDICE

SCLERAL ICTERUS

SPLENOMEGALY

LABORATORY EVALUATIONInitialCBCP with MCVReview peripheral blood smearReticuloctye count (retic. count)LDHBillirubin-direct and indirectConsider haptoglobin, urinalysis

LABORATORY EVALUATIONAdditional / Directed studiesCoombs testUnderlying disordersOsmotic fragility testHgb electrophoresisG-6PD assaysEnzyme assaysBone marrow aspirate / biopsyReversed M:E ratio

DEFINITIONHemolysisAny situation resulting in accelerated destruction of RBCs (lifespan < 120 days)

Anemia may or may not be present

Site of Hemolysis

Extravascularvs.Intravascular

EXTRAVASCULARHEMOLYSIS90% OF CASES

Inappropriate removal of RBCs by the RE system

Exaggeration of the normal removal of RBCs

EXTRAVASCULARHEMOLYSIS

INTRAVASCULARHEMOLYSIS10% of all cases

Red cells are disrupted in the general circulation

Free hemoglobin is released into the plasma

INTRAVASCULARHEMOLYSIS

INTRAVASCULARHEMOLYSISBy products of intravascular hemolysis include:

HemoglobinemiaHemoglobinuriaHemosiderinuriaLow haptoglobin

HEMOLYSIS

Most hemolytic anemias have an element of both extravascular and intravascular destructionEx. sickle cell anemia

MECHANISM OF HEMOLYSIS

INTRINSICVS.EXTRINSIC

INTRINSICReason for hemolysis is intrinsic to the RBC itself:

membrane disordersmetabolic disordershemoglobin variants

Membrane Disorders:Hereditary SpherocytosisMost common cause of hereditary hemolytic anemia in Caucasians

1/5000 incidenceHeterogeneous molecular basisMost commonly AD inheritanceDeficiency of membrane proteinsSpectrin, ankyrin, band 3

Membrane Disorders:Hereditary Spherocytosis


Often the hemolysis is well compensated

Very diverse clinical presentation

History of gallstones is common

Splenectomy often very effective

Hereditary Spherocytosis Common

Diverse clinical presentationSometimes diagnosed in adulthood

Diverse molecular defects

Spherocytes, osmotic fragility test

Paroxysmal Nocturnal Hemoglobinuria (PNH)Acquired stem cell disorder:

Anemia, leukopenia, thrombocytopeniaHypocellular bone marrowIntravascular hemolysisRisk for thrombosis

PNHDefect leads to the lack of a phosphatidylinositol-glycan (PIG) anchor protein

Lack of multiple related surface proteins which depend on the missing anchoring protein

Make rbc more prone to lysis by complementChronic intravascular hemolysis

PNHPreviously diagnosed by:Hams testSucrose hemolysis test

Now use flow cytometry to detect cells missing various cell surface antigens /proteinsCD-59

INTRNSICReason for hemolysis is intrinsic to the RBC itself:


INTRINSICMature RBC requires glucose metabolism for energy requirements (ATP):Maintenance of protein integrity, cell deformability, shapePreservation of heme iron in ferrous formModulation of oxygen affinity of hemoglobin

Main playersGlycolytic pathway-90% of RBC ATPHMP shunt- generates reduced glutathioneNucleotide salvage pathways

Metabolic DisordersDue to defects in:

Glycolytic pathwayPyruvate kinase deficiency most commonPurine metabolismPyrimidine metabolismHexose-monophosphate shunt

Metabolic Disorders: G-6PD DeficiencyHMP shunt functions to maintain glutathione in a reduced stateGeneration of NADPH

Essential co-factor for detoxifying H2O2Essential for ability of RBC to withstand oxidant stressFailure leads to oxidation and damage to hemoglobin, enzymes, and membrane

Metabolic Disorders: G-6PD DeficiencyG-6PD catalyzes the first step in the HMP shunt

X-linked recessive inheritance

Most common metabolic disorder of RBCsEsp. in African American males (10-15%)

Metabolic Disorders: G-6PD DeficiencyHallmark is acute hemolysis following exposure to a variety of oxidant drugs or stressorsAntimalarial- AcidosisSulfonamides- InfectionNitrofurantoin- Fava beanVitamin K

Metabolic Disorders: G-6PD DeficiencySuspect when bite cells seen on peripheral smear in the presence of acute hemolytic anemia

Heinz body staining is often positive

More definitive tests available

Dont send during acute crisis

Hemoglobin variantsNumerous inherited abnormalities in the hemoglobin molecule or synthesis make theRBC prone to premature hemolysis

Sickle cell syndromesThallassemiasUnstable hemoglobins

EXTRINSICReason for hemolysis has nothing to do with intrinsic properties of RBC itself

Immune mediated

Red cell fragmentation

Infection

EXTRINSIC:IMMUNE MEDIATEDShortened RBC survival due to antibody or complement coating the red cell surface

AutoimmuneWarmCold agglutinin disease

DrugsMultiple mechanisms

AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)Typically either IgG or IgM / complement coat the RBC surface:

Recognized as abnormal by RE system

Leads to hemolysis (IgG)

Agglutination (IgM / C3)

AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

Spherocytes (IgG) or agglutination (IgM) typically noted on the peripheral blood smear

AIHAWarm autoimmune hemolytic anemiaRBCs coated with IgG Reactive at room/warm temperaturesAcute and severeYounger age groupFix complement poorlySpleen is primary site of destructionSpherocytes seen on blood smearIdiopathic, collagen vascular, lymphoproliferative disorders

WARM AIHA :BANYAK SFEROSIT

AIHAWarm autoantibody hemolytic anemiaTreatment is primarily steroids Splenectomy is often second line

Other immunosuppressants are second/third line

AIHACold agglutinin diseaseRBCs coated with IgM which fixes complementReactive at cold temperaturesOlder age groupIntravascular site of destructionAgglutination noted on blood smear unless warmedPost infectious, lymphoma, idiopathic

Agglutination

AIHACold agglutinin diseaseTreatment includes avoidance of cold

Usually need to try catatonic therapy if persistent

Plasmapheresis in refractory cases

AIHACoombs testCritical in the evaluation of AIHA

Anti-globulin reagent prepared by injecting human globulin into animals-antibody isolated

IgGC3

Mixed with patient rbc or serum and test for clotting in the test tube

Yang di tes :Eritrosit penderita

Coombs ResultsExamplesDAT: warm antibodyIgG3+ (strong)C3negative or weak

DAT cold agglutininIgGnegative /weakC33+

ExtrinsicReason for hemolysis has nothing to do with the RBC itselfImmune mediated


Infection

RBC FragmentationMicroangiopathic Anemias

Schistocytes and microspherocytes noted on the blood smear

High shear stress leads to intravascular hemolysisMicrovascular diseaseDIC, TTP etc.Heart valveTrauma / implanted devices

RBC FragmentationMicrovascular disease

DIC-microvascular thrombosis due to activation and consumption of platelets, clotting factors

RBCs hemolyzed as they flow through the micro-environment of the damaged vasculature

Almost always secondary to underlying catastrophe

Present with bleeding or clotting

Treat underlying disease with blood product or anticoagulant support

RBC FragmentationMicrovascular disease

Thrombotic Thrombocytopenic Purpura (TTP)Microangiopathic hemolytic anemiaThrombocytopeniaMental status changesRenal failureFevers

Treatment is plasma exchange procedures

ExtrinsicReason for hemolysis has nothing to do with the RBC itselfImmune mediated


Infection

ExtrinsicInfectionClostridia sepsisParasitesmalariaVirusesBacterial

SUMMARYLocation of defect:

Intrinsicvs.Extrinsic

Membrane Hb Metabolic Immune Infectious Mechanical

SUMMARYLocation of hemolysis:

Extravascularvs.Intravascular

SUMMARYInitial evaluation and labs similar:CBC, MCV, Retic count, review blood smearLDH, billirubin, haptoglobin, UA

Further workup and treatment are specific to the suspected cause of hemolysisEx. DAT, electrophoresis, osmotic fragility test

BM usually not necessary, unless you need to rule out and underlying lymphoprolifera-tive or primary BM disorderReversed or decreased M:E ratio

CaseA woman in her thirties has a long history of SLE. She has had many complications of her disease. She now presents with worsening dyspnea, shortness of breath, and chest pain. Cbc shows a hgb of 7.3 gm/dl, hematocrit of 24%, normal wbc and platelets. You suspect AIHA. Which of the following lab data would not support this diagnosis?a. Macrocytosis / elevated MCVb. Elevated indirect billirubinc. Positive Direct Coombs testd. Elevated LDHe. Low reticulocyte count

CaseA previously healthy 34 year-old African American female was treatedwith bactrim (trimethoprin/sulfamethoxazole) for a UTI. She presents 4 days later with extreme fatigue, lethargy and weakness. Lab evaluation reveals a marked hemolytic anemia. You suspect G-6PD deficiency and request to review the peripheral blood smear. Which of the following findings would most support your diagnosis?

a. bite cellsb. schistocytesc. spherocytesd. sickle cellse. target cells

CaseA previously well 34 year old male presents with fever, mental status changes, thrombocytopenia, hemolytic anemia, and renal failure. You suspect TTP, with a microangiopathic intravascular hemolytic anemia as the underlying diagnosis. All of the following could be expected on laboratory evaluation except:a. low serum haptoglobinb. schistocytes on peripheral blood smearc. positive direct Coombs testd. hemoglobinuriae. elevated LDH

CasesA 45 year-old male is referred for evaluation of a hemolytic anemia. He has no obvious underlying infection, malignancy or vasculitis. You suspect he has a AIHA. You order a direct Coombs test and are told it is strongly positive with IgG, but negative with complement at room temperature. This data:a.) supports the diagnosis of cold agglutinin diseaseb.) supports the diagnosis of warm autoimmune hemolytic anemiac.) supports both diagnosisd.) supports neither diagnosis as no underlying disease is identified

Anemia Hemolitik

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