ThromboticThromboticThrombotic Thrombotic Thrombocytopenic Thrombocytopenic PurpuraPurpura

BehzadBehzad PoopakPoopak, DCLS PhD., DCLS PhD.Tehran medical Branch Tehran medical Branch –– Islamic Azad universityIslamic Azad university

bpoopak@yahoo.combpoopak@yahoo.com

Case SummaryCase SummaryCase SummaryCase Summary

MsMs XX aa 3535 yearyear oldold womanwomanMsMs.. X,X, aa 3535--yearyear--oldold womanwomanComplainedComplained ofof weakness,weakness, lowlow gradegrade fever,fever, periodsperiods ofofforgetfulnessforgetfulness andand memorymemory lossloss forfor lastlast weekweek oror sosoforgetfulness,forgetfulness, andand memorymemory lossloss forfor lastlast weekweek oror soso..DeniedDenied anyany viral/bacterialviral/bacterial illnessillness priorprior toto onsetonset ofofsymptomssymptoms..symptomssymptoms..++ OralOral contraceptives,contraceptives, butbut nono otherother drugsdrugs..LargeLarge numbernumber ofof bruisesbruises onon herher extremitiesextremitiesLargeLarge numbernumber ofof bruisesbruises onon herher extremitiesextremities..AsAs herher conditioncondition worsen,worsen, sheshe beganbegan toto bebe afflictedafflictedwithwith frequentfrequent seizures,seizures, headaches,headaches, andand dizzinessdizziness..withwith frequentfrequent seizures,seizures, headaches,headaches, andand dizzinessdizziness..

Key Information Pointing to DiagnosisKey Information Pointing to Diagnosis

Table 1: Laboratory Results

Test Result Normal Range

H l bi 6 0 /dL 12 3 15 3 /dL

SymptomsSymptomsLow grade feverLow grade fever

Hemoglobin 6.0 g/dL 12.3-15.3 g/dL

Hematocrit 0.18 L/L 0.38-0.46 L/L

White Blood Cells 8.9 x 109/L 4.1-10.9x109/L

Periods of forgetfulness and Periods of forgetfulness and memory lossmemory loss

Seizures, headaches, and dizzinessSeizures, headaches, and dizzinessPlatelet 31 x109/L 150-450x109/L

Reticulocyte 2.5%

Bruises on extremitiesBruises on extremities

Sinificant Laboratory FindingsSinificant Laboratory FindingsSinificant Laboratory FindingsSinificant Laboratory FindingsPeripheral Smear:Peripheral Smear:

––Schistocytes and Schistocytes and polychromasiapolychromasia

Table 2: Results of urinalysispolychromasiapolychromasia Protein 2+

Blood +

* Renal insufficiencies

Diagnosis: MAHADiagnosis: MAHASignificant lab results confirmed Significant lab results confirmed the presence of the presence of hematuriahematuria, , decreased hemoglobin anddecreased hemoglobin anddecreased hemoglobin, and decreased hemoglobin, and thrombocytopenia, but most thrombocytopenia, but most importantly, the presence of importantly, the presence of SchistocytesSchistocytes All of theseAll of theseSchistocytesSchistocytes. . All of these All of these findings are consistent with a findings are consistent with a hemolytic episode associated hemolytic episode associated

ithithwith:with:–– MicriangyophaticMicriangyophatic

Hemolytic Anemia Hemolytic Anemia (MAHA)(MAHA)..

EpidemiologyEpidemiologyEpidemiologyEpidemiology

Suspected TTPSuspected TTP--HUSHUS-- 1111cases/million/yrcases/million/yrSuspected TTPSuspected TTP HUSHUS 1111cases/million/yrcases/million/yrIdiopathic TTPIdiopathic TTP--HUSHUS-- 44..5 5 cases/million/yrcases/million/yrS ADAMTSS ADAMTS1313 d fi id fi i 11 77Severe ADAMTSSevere ADAMTS13 13 deficiencydeficiency-- 11..7 7 cases/million/yrcases/million/yrIncidence rates were greater for women Incidence rates were greater for women and Africanand African--AmericansAmericansPrior to plasma exchange, mortality rate Prior to plasma exchange, mortality rate was as high as was as high as 9090%%, now less than , now less than 2020%%gg ,,

Classic Symptoms of Classic Symptoms of SSTTPTTP--HUSHUS

MicroangiopathicMicroangiopathic hemolytic anemia (MAHA)hemolytic anemia (MAHA)MicroangiopathicMicroangiopathic hemolytic anemia (MAHA)hemolytic anemia (MAHA)ThrombocytopeniaThrombocytopeniaAcute renal insufficiency (more common in HUS)Acute renal insufficiency (more common in HUS)Acute renal insufficiency (more common in HUS)Acute renal insufficiency (more common in HUS)Neurologic abnormalities (more common in TTP)Neurologic abnormalities (more common in TTP)FeverFeverFeverFever

** Only thrombocytopenia and MAHA withoutOnly thrombocytopenia and MAHA without** Only thrombocytopenia and MAHA without Only thrombocytopenia and MAHA without another apparent etiology are required to initiate another apparent etiology are required to initiate plasma exchange for presumed TTPplasma exchange for presumed TTP--HUSHUSplasma exchange for presumed TTPplasma exchange for presumed TTP HUS.HUS.

TerminologyTerminologyTerminologyTerminology

TTP and HUS (hemolytic uremic syndrome) areTTP and HUS (hemolytic uremic syndrome) areTTP and HUS (hemolytic uremic syndrome) are TTP and HUS (hemolytic uremic syndrome) are both acute syndromes with abnormalities in both acute syndromes with abnormalities in multiple organ systems multiple organ systems Although Although some studies appear to distinguish some studies appear to distinguish these two entities the presenting features are these two entities the presenting features are essentially the same in most adult patients. essentially the same in most adult patients. FurthermoreFurthermore, , the pathologic changes are the the pathologic changes are the

d h ld h lsame and so is the initial treatment.same and so is the initial treatment.

Definitions and DiagnosisDefinitions and DiagnosisDefinitions and DiagnosisDefinitions and Diagnosis

The Classic Pentad of TTPThe Classic Pentad of TTPThe Classic Pentad of TTPThe Classic Pentad of TTP–– MicroangiopathicMicroangiopathic hemolytic anemiahemolytic anemia–– ThrombocytopeniaThrombocytopeniay py p–– Renal insufficiency or abnormalitiesRenal insufficiency or abnormalities–– Neurologic abnormalities that can be fluctuatingNeurologic abnormalities that can be fluctuating–– FeverFever

Most common symptoms at presentation are Most common symptoms at presentation are ifi d i l d bd i l iifi d i l d bd i l inonspecific and include abdominal pain, nausea, nonspecific and include abdominal pain, nausea,

vomiting and weakness.vomiting and weakness.

TTPTTP HUSHUSTTP TTP HUSHUSNUMBER OF SUBJECTSNUMBER OF SUBJECTS 6666 4545JJ 6666 4545Hemolytic AnemiaHemolytic Anemia 100100 100100ThrombocytopeniaThrombocytopenia 9494 6060ThrombocytopeniaThrombocytopenia 9494 6060Neurologic changesNeurologic changes 9090 1515Acute Renal FailureAcute Renal Failure 22 9898FeverFever 5050 2121

Reminder: Both are clinical diagnoses!Reminder: Both are clinical diagnoses!

Adapted from Adapted from VeyradierVeyradier, A, et al. Blood , A, et al. Blood 20012001; ; 9898::17651765..

Major Causes of TTPMajor Causes of TTP--HUSHUSMajor Causes of TTPMajor Causes of TTP HUSHUSIdiopathic: Idiopathic: 3737%% Infection: Infection: 99%%DrugDrug--Associated: Associated: 1313%%–– CyclosporineCyclosporine–– TacrolimusTacrolimus

–– HIVHIV–– Streptococcus Streptococcus pneumoniaepneumoniae

Pregnancy/Postpartum: Pregnancy/Postpartum: 77%%–– MitomycinMitomycin CC

–– BleomycinBleomycin and and cisplatincisplatin–– GemcitabineGemcitabine

Q i iQ i i

77%%Bloody Diarrhea Bloody Diarrhea ProdromeProdrome: : 66%%

–– QuinineQuinine–– TiclopidineTiclopidine and and clopidogrelclopidogrel

Autoimmune Disease: Autoimmune Disease: 1313%%

–– Shiga toxin production (ex: Shiga toxin production (ex: E. coli E. coli 01570157:H:H77))

–– ShigellaShigella dysenteriaedysenteriae type type 11–– VerocytotoxinVerocytotoxin productionproduction1313%%

–– SclerodermaScleroderma–– SLESLE–– APLAAPLA

–– VerocytotoxinVerocytotoxin production production by by CitrobacterCitrobacter freundiifreundii

Hematopoietic cell Hematopoietic cell transplantation: transplantation: 44%%–– APLAAPLA pp

Differential DiagnosisDifferential DiagnosisDifferential DiagnosisDifferential Diagnosis

VasculitisVasculitisVasculitisVasculitisMalignant HypertensionMalignant HypertensionDICDICDICDICAntiphosphospholipid SyndromeAntiphosphospholipid Syndrome

TTP: Current DiagnosticTTP: Current DiagnosticTTP: Current Diagnostic TTP: Current Diagnostic CriteriaCriteria

ThrombocytopeniaThrombocytopeniaMicroangiopathic Microangiopathic hemolytic anemiahemolytic anemiahemolytic anemia hemolytic anemia No alternative explanationNo alternative explanation

Definitions ContinuedDefinitions ContinuedDefinitions Continued…Definitions Continued…MAHAMAHA--nonimmunenonimmune hemolysishemolysis ((negative negative DATDAT) ) with with

i t d ll f t ti (i t d ll f t ti ( hi t thi t t ))prominent red cell fragmentation (prominent red cell fragmentation (schistocytesschistocytes) on ) on peripheral blood smear. Will exhibit increased LDH and peripheral blood smear. Will exhibit increased LDH and indirect indirect bilibili..S hi t tS hi t t i th i t li i l ttii th i t li i l ttiSchistocytesSchistocytes--in the appropriate clinical setting in the appropriate clinical setting schistocyteschistocyte count>count>11% was strongly suggestive of TTP% was strongly suggestive of TTP--HUS, HUS, ieie 2 2 or more or more schistosschistos in microscopic field at in microscopic field at 100100x x magnificationmagnificationmagnification.magnification.ThromoboctyopeniaThromoboctyopenia-- mean in a series was mean in a series was 2525,,300 300 prior to treatment.prior to treatment.Renal diseaseRenal disease due to renal thromboticdue to renal thromboticRenal diseaseRenal disease-- due to renal thrombotic due to renal thrombotic microangiopathymicroangiopathy, which is usually associated with a UA , which is usually associated with a UA that is often near normal with only mild that is often near normal with only mild proteinuriaproteinuria(between(between 11--22 g/day) and few cells or castsg/day) and few cells or casts(between (between 11 2 2 g/day) and few cells or castsg/day) and few cells or casts

Definitions ContinuedDefinitions ContinuedDefinitions Continued…Definitions Continued…Neurologic symptoms Neurologic symptoms -- most are subtle, such most are subtle, such g y pg y p ,,as transient confusion or severe headache. as transient confusion or severe headache. Focal, objective abnormalities are less common, Focal, objective abnormalities are less common, but grand mall seizures and coma can occur.but grand mall seizures and coma can occur.but grand mall seizures and coma can occur.but grand mall seizures and coma can occur.FeverFever-- less frequent finding, but the presence less frequent finding, but the presence of chills and high spiking fever should suggest of chills and high spiking fever should suggest dxdx of sepsis or DICof sepsis or DICdxdx of sepsis or DIC.of sepsis or DIC.Cardiac involvementCardiac involvement-- incidence is difficult to incidence is difficult to determine, but diffuse platelet thrombi and determine, but diffuse platelet thrombi and

d h h dd h h dassociated hemorrhage in cardiac tissues can associated hemorrhage in cardiac tissues can lead to lead to arrythmiasarrythmias, MIs, sudden death, shock, or , MIs, sudden death, shock, or heart failure.heart failure.

Labs to Look ForLabs to Look ForLabs to Look ForLabs to Look For

Schistocytes on peripheral smearSchistocytes on peripheral smearSchistocytes on peripheral smearSchistocytes on peripheral smearElevated LDHElevated LDHD d H t l biD d H t l biDecreased HaptoglobinDecreased HaptoglobinIncreased CreatinineIncreased CreatinineThrombocytopenia (more pronounced in Thrombocytopenia (more pronounced in TTP than HUS)TTP than HUS)))

Renal DiseaseRenal Disease*Intravascular Hemolysis is also associated with the presence of

Burr CellsBurr Cells Liver DiseaseLiver Disease

BurnsBurns

the presence of Schistocytes

Morphology :Fragmented Morphology :Fragmented Possible

PathologyPossible

Pathology

Prosthetic Heart ValveProsthetic

Heart Valve

MicroangiopathicMicroangiopathic

Disseminated Intravascular Coagulation

Disseminated Intravascular Coagulation

ThromboticThromboticgCells gCells

PathologyPathology SchistocyteSchistocyte Microangiopathic Hemolytic AnemiaMicroangiopathic Hemolytic Anemia

Thrombotic Thrombocytope

nic Purpura

Thrombotic Thrombocytope

nic Purpura

Hemolytic Uremic Syndrome

Hemolytic Uremic Syndrome

Clostridial InfectionsClostridial Infections

SyndromeSyndrome

Helmet CellsHelmet Cells

G6PD Deficiency

G6PD Deficiency

Pulmonary Pulmonary EmboliEmboli

Microangiopathic Hemolytic Anemia (MAHA)

SCHISTOCYTES!SCHISTOCYTES!SCHISTOCYTES!SCHISTOCYTES!

SchistocytesSchistocytes--TTPTTP

HUSHUS--DiagnosisDiagnosis• Diarrhoea (often bloody)• Haematological – microangiopathic haemolytic

anaemia‐ thrombocytopenia

Fragmented red cellsFragmented red cells

Absence of platelets

ADAMTSADAMTS13 13 ( h b O d )( h b O d )(Another Lab to Order)(Another Lab to Order)

AA DDisintegrinisintegrin--likelike AAndnd MMetalloproteaseetalloprotease withwithAA DDisintegrinisintegrin like like AAnd nd MMetalloproteaseetalloprotease with with TThrombohromboSSpondinpondin type type 1 1 repeatsrepeatsMapped the gene for theMapped the gene for the metalloproteasemetalloprotease totoMapped the gene for the Mapped the gene for the metalloproteasemetalloprotease to to chromosome chromosome 99qq3434 with linkage analysiswith linkage analysisProtease that cleaves Protease that cleaves ULVWfULVWf (Unusually Large (Unusually Large ( y g( y gVon Von WillebrandWillebrand factor) in the circulationfactor) in the circulationDecreased activity or inhibitor present in TTP, Decreased activity or inhibitor present in TTP, but not but not HUSHUSIdentified Identified 12 12 mutations in patients with mutations in patients with hereditary TTP clinical picturehereditary TTP clinical picture

VWF Cleaving Protease (ADAMTS13)g ( )

Metalloprotease Thrombospondin 1

CUBCUBS MMP CysCysDD SpacerSpacer11 22 33 44 55 66 77 88 CUBCUB

Disintegrin

A Disintegrin-like And Metalloproteasewith ThromboSpondin 1 repeatswith ThromboSpondin-1 repeats

(#13 among 19 total)(#13 among 19 total)

ADAMTSADAMTS1313ADAMTSADAMTS1313

30 30 pts diagnosed with TTP:pts diagnosed with TTP:3030 p s d ag os dp s d ag os d–– 6 6 pts. with familial TTP lacked all ADAMTSpts. with familial TTP lacked all ADAMTS13 13

activityactivity2424 t ith f ili l TTPt ith f ili l TTP–– 24 24 pts. with nonfamilial TTPpts. with nonfamilial TTP

20 20 had severe deficiency (<had severe deficiency (<55% of normal activity)% of normal activity)4 4 had moderate deficiency (had moderate deficiency (55--2525% of nml activity)% of nml activity)y (y ( y)y)

23 23 pts diagnosed with HUS:pts diagnosed with HUS:–– 21 21 pts. with normal activitypts. with normal activity

Furlan, M, et al.Furlan, M, et al. Von Willebrand factorVon Willebrand factor--cleaving protease in thrombotic cleaving protease in thrombotic thrombocytopenic purpura and the hemolyticthrombocytopenic purpura and the hemolytic--uremic syndrome. NEJM uremic syndrome. NEJM 19981998;; 339339::1578157819981998; ; 339339::15781578..

PathogenesisPathogenesisPathogenesisPathogenesisVWF is synthesized in endothelial cells and assembled in VWF is synthesized in endothelial cells and assembled in yylarge large multimersmultimers that are present in normal plasma. The that are present in normal plasma. The large large multimersmultimers, , ieie unusually large von unusually large von willebrandwillebrand factor factor (ULVWF) (ULVWF) are rapidly degraded in the circulation into are rapidly degraded in the circulation into ( )( ) p y gp y gnormal size range of VWF normal size range of VWF multimersmultimers by ADAMTSby ADAMTS1313..

ADAMTSADAMTS1313 deficiency could lead to accumulation ofdeficiency could lead to accumulation ofADAMTSADAMTS13 13 deficiency could lead to accumulation of deficiency could lead to accumulation of ULVWF ULVWF multimersmultimers, platelet aggregation, and platelet , platelet aggregation, and platelet clumping. ULVWF clumping. ULVWF multimersmultimers accumulate in patients with accumulate in patients with TTP being found in platelet thrombi and serum TheTTP being found in platelet thrombi and serum TheTTP being found in platelet thrombi and serum. The TTP being found in platelet thrombi and serum. The ULVWF can attach to activated platelets thereby ULVWF can attach to activated platelets thereby promoting aggregationpromoting aggregation..

Figure 1. Pathogenesis of idiopathic thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 deficiency

S dl J E H t l 2006 2006 415 420

Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.

Sadler, J. E. Hematology 2006;2006:415-420

Von Willebrand Factor Cleaving Protease, vWF, and Platelets Under Normal Conditions

vWF-cleaving protease (ADAMTS13)

b dTyr-Met AA bond in vWFReceptor for GP Ib on the platelets

Platelet

vWF and Platelets When Von Willebrand Factor Cleaving Protease is Absent or Deficient

vWF and Platelets When Von Willebrand Factor Cleaving Protease is Absent or Deficient, Cont.

VWF, ADAMTS13 and Platelet Adhesion

With ADAMTS13 Without ADAMTS13

Normal VWF MultimersNormal Hemostasis

Ultralarge VWF MultimersMicrovascular Thrombosis

(TTP)

TTPTTP

TTP can be categorized into TTP can be categorized into 2 2 major formsmajor forms: : –– Hereditary:Hereditary: Often seen inOften seen in childrenchildren and causedand causedHereditary:Hereditary: Often seen in Often seen in childrenchildren, , and caused and caused

by mutations of ADAMTSby mutations of ADAMTS13 13 genegene–– Acquired:Acquired: Mainly seen in adults, may beMainly seen in adults, may beAcquired: Acquired: Mainly seen in adults, may be Mainly seen in adults, may be

idiopathic or idiopathic or nonidiopathicnonidiopathic..Idiopathic: Idiopathic: results from results from autoantibodiesautoantibodies that inhibit that inhibit ADAMTSADAMTS13 13 functionfunctionNonidopathicNonidopathic: : TTP is secondary to other conditions TTP is secondary to other conditions such assuch as hematopoeitichematopoeitic stem cell transplantation certainstem cell transplantation certainsuch as such as hematopoeitichematopoeitic stem cell transplantation, certain stem cell transplantation, certain drugs, infections, other autoimmune diseases, cancers, drugs, infections, other autoimmune diseases, cancers, and so on.and so on.

ADAMTS13 – Clinical Correlations

ADAMTS13 deficiency (<5%) predicts:y ( ) p• Idiopathic TTP• Complete response to plasma exchange

S i l• Survival

ADAMTS13 inhibitor predicts:ADAMTS13 inhibitor predicts:• Prolonged time to complete response• DeathDeath• Relapse

Reviewed in Coppo et al, Br J Haematol 2005; 132: 66-74

The Oklahoma TTPThe Oklahoma TTP--HUS HUS RegistryRegistry

d i di l b fd i di l b fADAMTSADAMTS13 13 measured immediately beforemeasured immediately beforebeginning the first plasma exchange, beginning the first plasma exchange, NovemberNovember 1313 19951995 DecemberDecember 3131 20082008November November 1313,, 1995 1995 –– December December 3131, , 20082008

282282 patients withpatients with 11stst episode of TTPepisode of TTP282 282 patients with patients with 11stst episode of TTPepisode of TTPADAMTSADAMTS13 13 measured in measured in 261 261 ((9393%)%)Measurements (Measurements (immunoblotimmunoblot FRETS)FRETS)Measurements (Measurements (immunoblotimmunoblot, FRETS), FRETS)

The Oklahoma TTPThe Oklahoma TTP--HUS RegistryHUS RegistryADAMTSADAMTS13 13 Activity <Activity <1010%%

____________________________________________________________________________________________________________________________________Stem cell transplantStem cell transplant 11//10 10 ((1010%)%)

// // (( ))Pregnant/postpartum Pregnant/postpartum 33//15 15 ((2121%)%)DrugDrug--associated associated 00//35 35 ((00%) %) Bloody diarrheaBloody diarrhea 22//2222 ((1010%)%)Bloody diarrheaBloody diarrhea 22//22 22 ((1010%)%)Additional/alternative diagnosis Additional/alternative diagnosis •• autoimmune diseasesautoimmune diseases 33//31 31 ((1010%)%)•• sepsissepsis 44//2222 ((1818%)%)•• sepsissepsis 44//22 22 ((1818%)%)•• malignancymalignancy 11//10 10 ((1010%)%)•• other disordersother disorders 00//18 18 ((00%) %) di hidi hi 66//9898 (( %)%)Idiopathic Idiopathic 4646//98 98 ((4747%)%)

The Oklahoma TTPThe Oklahoma TTP--HUS RegistryHUS Registryg yg y60 60 Consecutive Patients with Severe Consecutive Patients with Severe

ADAMTSADAMTS1313 Deficiency (<Deficiency (<1010%% activity)activity)ADAMTSADAMTS13 13 Deficiency (<Deficiency (<1010% % activity)activity)

AgeAge 41 41 years (years (99--7171))SexSex 4949 ((8282%)%) femalefemaleSexSex 49 49 ((8282%) %) femalefemaleRaceRace 21 21 ((3535%) %) blackblack

The Oklahoma TTPThe Oklahoma TTP--HUS RegistryHUS RegistryADAMTSADAMTS13 13 Deficiency (<Deficiency (<1010% % activity)activity)

Neurologic abnormalitiesNeurologic abnormalitiesNeurologic abnormalitiesNeurologic abnormalitiesseveresevere 30 30 ((5050%)%)mildmild 13 13 ((2222%)%)nonenone 17 17 ((2828%)%)(( ))

Renal functionRenal functionacute renal failureacute renal failure 6 6 ((1010%)%)(( ))renal insufficiencyrenal insufficiency 27 27 ((4545%)%)normalnormal 27 27 ((5555%)%)

FeverFever 13 13 ((2222%)%)

Complete PentadComplete Pentad 5 5 ((88%)%)

ADAMTSADAMTS1313ADAMTSADAMTS1313

An An inhibitory autoantibody inhibitory autoantibody to ADAMTSto ADAMTS13 13 has has b to y autoa t bodyb to y autoa t body to Sto S 33 asasbeen found at been found at varying titers varying titers among among high high percentage of patients with idiopathic TTP percentage of patients with idiopathic TTP who who have severe ADAMTShave severe ADAMTS1313 deficiency and thedeficiency and thehave severe ADAMTShave severe ADAMTS13 13 deficiency, and the deficiency, and the inhibitory inhibitory IgGIgG is directed at various elements of is directed at various elements of the protease.the protease.ppIt has been suggested that levels of ADAMTSIt has been suggested that levels of ADAMTS13 13 less than less than 55% with or without an inhibitor % with or without an inhibitor

tib d b t f l t itib d b t f l t iantibody may be part of a larger autoimmune antibody may be part of a larger autoimmune response. response. NonNon--inhibitory antibodies to inhibitory antibodies to ADAMTSADAMTS1313 have also been demonstrated.have also been demonstrated.ADAMTSADAMTS13 13 have also been demonstrated.have also been demonstrated.

ADAMTSADAMTS1313 and prognosisand prognosisADAMTSADAMTS13 13 and prognosisand prognosisSo usually, in acute idiopathic TTP, there is a severe So usually, in acute idiopathic TTP, there is a severe y, p ,y, p ,deficiency in ADAMTSdeficiency in ADAMTS13 13 activity (undetectable or <activity (undetectable or <55%), %), although although senstivitysenstivity/specificity remains controversial. /specificity remains controversial. Severe deficiency is less common in secondary TTP.Severe deficiency is less common in secondary TTP.y yy yFor most patients, a complete response to plasma For most patients, a complete response to plasma exchange is accompanied by normalization of ADAMTSexchange is accompanied by normalization of ADAMTS13 13 activity and disappearance of inhibitors if presentactivity and disappearance of inhibitors if presentactivity and disappearance of inhibitors, if present.activity and disappearance of inhibitors, if present.Persistently undetectable ADAMTSPersistently undetectable ADAMTS13 13 in plasma in plasma during remission was found to be during remission was found to be highly highly predictive of recurrence,predictive of recurrence, and also the and also the higher the higher the antibody titersantibody titers, clinical manifestations were more , clinical manifestations were more severe and responses to plasma exchange weresevere and responses to plasma exchange weresevere and responses to plasma exchange were severe and responses to plasma exchange were delayeddelayed

TreatmentTreatmentTreatmentTreatmentPlasma ExchangePlasma ExchangeCorticosteroidsCorticosteroidsRITUXIMABRITUXIMAB

H i d l l tib d i tH i d l l tib d i t CDCD2020–– Humanized monoclonal antibody against Humanized monoclonal antibody against CDCD2020, , which is expressed on B cells, and it rapidly clears B which is expressed on B cells, and it rapidly clears B cells from circulation, preventing replenishment of cells from circulation, preventing replenishment of pathological plasma cellspathological plasma cellspathological plasma cells.pathological plasma cells.

–– Remission associated with disappearance of Remission associated with disappearance of ADAMTSADAMTS13 13 inhibitors and normalization of activity inhibitors and normalization of activity levelslevelslevelslevels

–– Should be considered in TTP patients who fail to Should be considered in TTP patients who fail to respond to daily PE and corticosteroids after respond to daily PE and corticosteroids after 77--14 14 daysdaysdaysdays

Conclusions: EvaluationConclusions: EvaluationConclusions: EvaluationConclusions: Evaluation

Forget the “Classic Pentad” of Forget the “Classic Pentad” of clinical features of TTPclinical features of TTPclinical features of TTPclinical features of TTP

ADAMTSADAMTS13 13 measurements:measurements:––Limited diagnostic valueLimited diagnostic value––Important prognostic valueImportant prognostic valuep p gp p g

Conclusions: ManagementConclusions: ManagementConclusions: ManagementConclusions: Management

Plasma exchange remains essential Plasma exchange remains essential treatment, but it has risks of death treatment, but it has risks of death ,,and major complicationsand major complications

A i t f l t l tA i t f l t l tAppropriate use of platelet Appropriate use of platelet transfusions is appropriatetransfusions is appropriate

Conclusions: LongConclusions: Long--Term Term O tO tOutcomes Outcomes

Relapse occurs in almost half of patients Relapse occurs in almost half of patients with ADAMTSwith ADAMTS13 13 <<1010%%

Risk of future pregnancies is smallRisk of future pregnancies is small

Risk of additional autoimmune disorders Risk of additional autoimmune disorders may be increasedmay be increased

Neurocognitive abnormalities are Neurocognitive abnormalities are commoncommoncommoncommon

ReferencesReferencesReferencesReferencesNEJM NEJM 20062006; ; 354354::19271927--35 35 George, James MDGeorge, James MD--Thrombotic Thrombocytopenic Purpura.Thrombotic Thrombocytopenic Purpura.Uptodate Diagnosis Causes and Treatment of TTPUptodate Diagnosis Causes and Treatment of TTP HUSHUSUptodate. Diagnosis, Causes, and Treatment of TTPUptodate. Diagnosis, Causes, and Treatment of TTP--HUSHUSHematology Hematology 20042004::407407--423423.Recent Advances in Thrombotic Thrombocyotopenic .Recent Advances in Thrombotic Thrombocyotopenic Purpura, Sadler Et alPurpura, Sadler Et alHematology Hematology 20072007. TTP and ADAMTS. TTP and ADAMTS1313: When is testing appropriate? Mannucci et al: When is testing appropriate? Mannucci et alHematologyHematology 20062006 Thrombocytopenic Purpura:A moving Target SadlerThrombocytopenic Purpura:A moving Target SadlerHematology Hematology 20062006.Thrombocytopenic Purpura:A moving Target. Sadler.Thrombocytopenic Purpura:A moving Target. SadlerHoffman:Hematology: Basic Principles and Practice fourth edition. Chapters Hoffman:Hematology: Basic Principles and Practice fourth edition. Chapters 42 42 and and 132132Swiss Med Wkly Swiss Med Wkly 20072007;;137137::518518--524524. Rituximab for acute plasma refractory thrombotic . Rituximab for acute plasma refractory thrombotic thrombocyotopenic purpura.thrombocyotopenic purpura.Eur J Haematology Eur J Haematology 20052005;;7575::436436--440440. Acquired TTP as presenting symptom of SLE. . Acquired TTP as presenting symptom of SLE. Successful treatment with plasma exchange and immunosuppressionSuccessful treatment with plasma exchange and immunosuppression--report of report of 2 2 casescasesBlood cells, Molecules and Diseases (Blood cells, Molecules and Diseases (20022002) ) 2828((33) May/June:) May/June:385385--391391. Ritux Therapy . Ritux Therapy for Refractory TTPfor Refractory TTPfor Refractory TTPfor Refractory TTPThrombotic Thrombocytopenic Purpura and Systemic Lupus Erythematous:Distinct Thrombotic Thrombocytopenic Purpura and Systemic Lupus Erythematous:Distinct entities or overlapping syndromes. Internet Journal of Internal Medicine; Cheungentities or overlapping syndromes. Internet Journal of Internal Medicine; Cheung