Hemophilia and ITP

Definition of HemophiliaDefinition of Hemophilia

Deficiency characterized by interruption Deficiency characterized by interruption of clot formationof clot formation

Hemophilia A (Classic)Hemophilia A (Classic)

– decreased factor VIIIdecreased factor VIII Hemophilia B (Christmas Disease)Hemophilia B (Christmas Disease)

– decreased factor IXdecreased factor IX

Coagulation CascadeCoagulation Cascade

Casella JF, Casella JF, Oski’s Pediatrics: Principles and Practices, 3rd Ed., 1999Oski’s Pediatrics: Principles and Practices, 3rd Ed., 1999

Coagulant-Anticoagulant SchemeCoagulant-Anticoagulant Scheme

Casella JF, Casella JF, Oski’s Pediatrics: Principles and Practices, 3rd Ed., 1999Oski’s Pediatrics: Principles and Practices, 3rd Ed., 1999

Incidence of HemophiliaIncidence of Hemophilia

Sex-linked inheritance patternSex-linked inheritance pattern 1 in 5000 live male births in U.S.1 in 5000 live male births in U.S. 4:1 ratio Hemophilia A to 4:1 ratio Hemophilia A to

Hemophilia BHemophilia B Many (~ 1/3) cases are new Many (~ 1/3) cases are new

mutationsmutations

Hemophilia - Classification Hemophilia - Classification

Mild Mild 5-30%5-30% ActivityActivity

ModerateModerate 2-5%2-5% ActivityActivity

SevereSevere < 1%< 1% ActivityActivity

Hemophilia - ClassificationHemophilia - Classification

SymptomsSymptoms

MildMild - - Hemorrhage usually only after severe trauma or surgeryHemorrhage usually only after severe trauma or surgery

ModerateModerate - - Hemorrhage more frequent after moderate traumaHemorrhage more frequent after moderate trauma

SevereSevere - - Hemorrhage frequently after minor or unrecognized Hemorrhage frequently after minor or unrecognized

traumatrauma

Complications of HemophiliaComplications of Hemophilia

Joint diseaseJoint disease

Deep soft tissue bleedingDeep soft tissue bleeding

Neurovascular compromiseNeurovascular compromise

Complications of HemophiliaComplications of Hemophilia

InfectionsInfections

Inhibitor formationInhibitor formation

PsychosocialPsychosocial

FinancialFinancial

Philosophy of CarePhilosophy of Care

Normalization of life style and Normalization of life style and prevention of disabilityprevention of disability

Rx still “on-demand” in most cases, but Rx still “on-demand” in most cases, but prophylactic treatment should be prophylactic treatment should be consideredconsidered

Home therapy whenever possibleHome therapy whenever possible

Evaluation of the patient - GeneralEvaluation of the patient - General

Personal History Personal History Family HistoryFamily History MedicationsMedications Physical examPhysical exam Consider circumstances of the bleedConsider circumstances of the bleed Presence of pain usually enough to initiate therapyPresence of pain usually enough to initiate therapy Avoid I.M. injections, NSAIDs contraindicatedAvoid I.M. injections, NSAIDs contraindicated

Joint Bleeds - GeneralJoint Bleeds - General

Most common complicationMost common complication Often spontaneousOften spontaneous Target jointsTarget joints Early treatment desirableEarly treatment desirable Predictable progression once Predictable progression once

anatomical abnormality occursanatomical abnormality occurs

Joint Bleeds - Evaluation Joint Bleeds - Evaluation

Consider circumstances of bleed Consider circumstances of bleed (spontaneous vs traumatic)(spontaneous vs traumatic)

Presence of pain usually enough to Presence of pain usually enough to initiate therapyinitiate therapy

Physical examPhysical exam X-rays of limited valueX-rays of limited value

Joint Bleed - TreatmentJoint Bleed - Treatment

Factor replacement (40-60%)Factor replacement (40-60%) Immobilization and cold packs may help initiallyImmobilization and cold packs may help initially Mobilization as soon as feasibleMobilization as soon as feasible Physical therapy if indicated (restore normal Physical therapy if indicated (restore normal

forces to joint)forces to joint) Prophylaxis in resistant casesProphylaxis in resistant cases Should see response in 6-12 hrs in average bleedShould see response in 6-12 hrs in average bleed

HematomasHematomas

More common in infantsMore common in infants Treatment dictated by site and extentTreatment dictated by site and extent Treat closed spaces aggressively (e.g. throat, Treat closed spaces aggressively (e.g. throat,

hand, wrist, nerve compressions) hand, wrist, nerve compressions) Blood counts often best indicator of extentBlood counts often best indicator of extent

HematuriaHematuria

Treatment controversialTreatment controversial Often resolves spontaneouslyOften resolves spontaneously Treatment may be indicated in some Treatment may be indicated in some

cases (steroids, factor replacement)cases (steroids, factor replacement) Therapeutic misadventures have Therapeutic misadventures have

occurred (Amicar)occurred (Amicar)

GI BleedingGI Bleeding

Can be due to bleeding into the wall Can be due to bleeding into the wall of the intestinesof the intestines

Requires immediate evaluation Requires immediate evaluation Often due to the common sources of Often due to the common sources of

bleedingbleeding

LacerationsLacerations

PressurePressure Factor replacement, especially with Factor replacement, especially with

suturessutures Epsilon amino caproic acid (Amicar) or Epsilon amino caproic acid (Amicar) or

tranexamic acid may be helpful with tranexamic acid may be helpful with mouth bleedsmouth bleeds

Tooth ExtractionTooth Extraction

Treat before (50% or greater, Treat before (50% or greater, depending on extent of procedure)depending on extent of procedure)

Consider DDAVP for mild Consider DDAVP for mild hemophiliachemophiliac

Epsilon amino caproic acid Epsilon amino caproic acid (Amicar) or tranexamic acid after(Amicar) or tranexamic acid after

CNS Bleeds (Head trauma)CNS Bleeds (Head trauma)

Most common cause of fatal bleedingMost common cause of fatal bleeding May occur in delayed fashionMay occur in delayed fashion Treat even minor head trauma in generalTreat even minor head trauma in general 100% replacement, 100% replacement, beforebefore diagnostic procedures diagnostic procedures CT or MRI may be helpfulCT or MRI may be helpful When in doubt, or if any sign of objective head When in doubt, or if any sign of objective head

trauma (abrasion or external hematoma), trauma (abrasion or external hematoma), treattreat

Life-threatening and Critical BleedsLife-threatening and Critical Bleeds

Central Nervous SystemCentral Nervous System Neck and OropharynxNeck and Oropharynx Major fracturesMajor fractures Multiple traumasMultiple traumas Deep lacerationsDeep lacerations Compartment bleedsCompartment bleeds Gastrointestinal bleedsGastrointestinal bleeds

InfectionsInfections

HIVHIV Hepatitis (A, B and C)Hepatitis (A, B and C) Septic ArthritisSeptic Arthritis

General Approach to TreatmentGeneral Approach to Treatment

Prophylactic treatmentProphylactic treatment Get a clot (provide replacement as needed) Get a clot (provide replacement as needed) Suppress fibrinolysisSuppress fibrinolysis Use adjunctive measures maximallyUse adjunctive measures maximally

– Local pressure, closure of woundsLocal pressure, closure of wounds

– Gelfoam (gelatin sponge), topical thrombin or fibrin glue, Gelfoam (gelatin sponge), topical thrombin or fibrin glue, oxidized cellulose (Oxycel, Surgicel) , other local stimulants to oxidized cellulose (Oxycel, Surgicel) , other local stimulants to coagulationcoagulation

– DDAVPDDAVP

TreatmentTreatment

HemophiliaHemophilia Mild Mild DDAVPDDAVP

Epsilon aminocaproic acidEpsilon aminocaproic acid

Moderate or Moderate or Factor replacement Factor replacement

Severe Epsilon aminocaproic acidSevere Epsilon aminocaproic acid

Factor Replacement - GeneralFactor Replacement - General

Previously untreated patients - use Previously untreated patients - use recombinant factor when possiblerecombinant factor when possible

Surgery - any significant surgery Surgery - any significant surgery usually requires factor replacement - usually requires factor replacement - keep levels > 50%, need to monitorkeep levels > 50%, need to monitor

Consider constant infusionConsider constant infusion Remember carriers can bleedRemember carriers can bleed

Factor Replacement - DosingFactor Replacement - Dosing

Factor VIII (intermediate purity, Factor VIII (intermediate purity,

monoclonal, recombinant)monoclonal, recombinant)

1Unit/kg produces 2% increase in VIII 1Unit/kg produces 2% increase in VIII

activity (1-1.5 % increase with IX)activity (1-1.5 % increase with IX)

Use to next full vialUse to next full vial

Factor ReplacementFactor Replacement

Factor VIIIFactor VIII

pharmacokinetics:pharmacokinetics:

- first infusion of shorter duration (4-8 hrs),- first infusion of shorter duration (4-8 hrs),

- second longer, usually 8-12 hrs- second longer, usually 8-12 hrs Factor IXFactor IX

pharmacokinetics:pharmacokinetics: - first infusion of shorter duration (2-6 hrs),- first infusion of shorter duration (2-6 hrs),

- second longer, usually 18-24 hrs- second longer, usually 18-24 hrs

Factor IXFactor IX

None in cryoNone in cryo FFPFFP Vitamin K dependent concentratesVitamin K dependent concentrates Purified factor IXPurified factor IX Recombinant factor IXRecombinant factor IX Can also use continuous infusionCan also use continuous infusion

Suggested Replacement LevelsSuggested Replacement Levels

levellevel durationduration

CNS CNS 100% 10-14 days100% 10-14 daysExtensive soft tissue Extensive soft tissue 70%70%JointJoint 40-60%40-60% 1-4 days 1-4 daysSurgerySurgery >50%>50% 2-7 days 2-7 days

>20-30%>20-30% 3-7 days 3-7 daysMinor soft tissueMinor soft tissue 20-30%20-30% 1-2 days 1-2 days

DDAVPDDAVP

Only if efficacy established for that Only if efficacy established for that

patient, (mild bleeds)patient, (mild bleeds)

Watch fluids (hyponatremia)Watch fluids (hyponatremia)

Chest pain can occur (vasospasm)Chest pain can occur (vasospasm)

Repeated use leads to decreased Repeated use leads to decreased

effectiveness (tachyphylaxis)effectiveness (tachyphylaxis)

DDAVP for Dental Procedures in Mild HemophiliaDDAVP for Dental Procedures in Mild Hemophilia

InhibitorsInhibitors

Three varieties (low titer 1-5 bethesda Three varieties (low titer 1-5 bethesda units, intermediate 5-10, high >10)units, intermediate 5-10, high >10)

10-15% of patients10-15% of patients Recurrence the rule with high titer Recurrence the rule with high titer

patient, with higher and higher levelspatient, with higher and higher levels Poor response to treatment often the Poor response to treatment often the

first signfirst sign

Treatment of InhibitorsTreatment of Inhibitors

Activated factor IXActivated factor IX FEIBAFEIBA VIIaVIIa Porcine factor VIIIPorcine factor VIII High doses of VIIIHigh doses of VIII ImmunosuppressionImmunosuppression

Factor VIIa for Surgical ProceduresFactor VIIa for Surgical Procedures

PreventivePreventive

Padded cribsPadded cribs Avoid platelet antagonists (e.g., aspirin)Avoid platelet antagonists (e.g., aspirin) No contact sportsNo contact sports HelmetsHelmets Immunization (Hepatitis A and B)Immunization (Hepatitis A and B) Choice of lifestyleChoice of lifestyle

EmergenciesEmergencies

Have a medical alert braceletHave a medical alert bracelet

Know emergency resourcesKnow emergency resources

Treat if in doubtTreat if in doubt

What does the HTC do?What does the HTC do?

EvaluationEvaluation Laboratory ServicesLaboratory Services Treatment PlanTreatment Plan CoordinationCoordination CounselingCounseling EducationEducation ReferralReferral

Advantages of Comprehensive CareAdvantages of Comprehensive Care

One-stop ShoppingOne-stop Shopping Coordinated CareCoordinated Care Decreased ExpenseDecreased Expense Patient OrientedPatient Oriented AdvocacyAdvocacy Decreased MortalityDecreased Mortality

Conclusions and Final ThoughtsConclusions and Final Thoughts

Comprehensive care is a proven method for the Comprehensive care is a proven method for the care of hemophilia that reduces morbidity and care of hemophilia that reduces morbidity and mortality (Soucie et al., 2000)mortality (Soucie et al., 2000)

Treatment of hemophiliacs requires a Treatment of hemophiliacs requires a multidisciplinary approach – Pharmacy plays a multidisciplinary approach – Pharmacy plays a major role in quality of life for hemophiliacsmajor role in quality of life for hemophiliacs

Further research into cost-effective management Further research into cost-effective management of problems in hemophiliacs is warrantedof problems in hemophiliacs is warranted

Who Supports Comprehensive CareWho Supports Comprehensive Care

Federal Government (MCHB and CDC)Federal Government (MCHB and CDC) State of Maryland (DHMH)State of Maryland (DHMH) HFMHFM

ITPITP

James F. Casella, M.D.James F. Casella, M.D. Chief, Pediatric HematologyChief, Pediatric Hematology The Johns Hopkins University School of The Johns Hopkins University School of

MedicineMedicine

Idiopathic (Immune) Thrombocytopenic PurpuraIdiopathic (Immune) Thrombocytopenic Purpura

Sometimes referred to as Sometimes referred to as immuneimmune or or autoimmuneautoimmune thrombocytopenic purpura thrombocytopenic purpura (ITP or ATP)(ITP or ATP)

Most commonly encountered acquired Most commonly encountered acquired quantitative platelet disorder of childhoodquantitative platelet disorder of childhood– Overall incidence of ITP is 1:10,000/yrOverall incidence of ITP is 1:10,000/yr

~ ½ of cases in children~ ½ of cases in children

Etiology and PathogenesisEtiology and Pathogenesis

Evidence for an immunologic basisEvidence for an immunologic basis

– Rapid destruction of autologous or heterologous Rapid destruction of autologous or heterologous plateletsplatelets

– Passive transmission by serumPassive transmission by serum

– Increased PAIgG (Platelet-associated IgG) Increased PAIgG (Platelet-associated IgG)

– Demonstration of specific antiplatelet antibodiesDemonstration of specific antiplatelet antibodies

– Transplacental transfer of Transplacental transfer of ““passivepassive”” disease disease

Etiology and PathogenesisEtiology and Pathogenesis

Destruction of platelets in ITPDestruction of platelets in ITP

– Spleen the major site of destructionSpleen the major site of destruction – Less important contribution from the Less important contribution from the

reticuloendothelial system of the liver, bone reticuloendothelial system of the liver, bone marrow, and lungs.marrow, and lungs.

Acute ITPAcute ITP

Often preceded by a viral illnessOften preceded by a viral illness

Viral antigens may trigger antibodies that Viral antigens may trigger antibodies that cross-react with the platelet membrane cross-react with the platelet membrane (e.g. varicella)(e.g. varicella)

Chronic ITPChronic ITP

Often occurs in the setting of other known Often occurs in the setting of other known autoimmune illnessesautoimmune illnesses

Specific anti-glycoprotein IIb/IIIa Specific anti-glycoprotein IIb/IIIa antibodies often demonstratedantibodies often demonstrated

Acute and Chronic ITPAcute and Chronic ITP

Not all platelet-associated IgG (PAIgG) in ITP Not all platelet-associated IgG (PAIgG) in ITP is directed against specific platelet antigensis directed against specific platelet antigens

Other serum proteins (eg albumin) associated Other serum proteins (eg albumin) associated with platelet membranes in increased amountswith platelet membranes in increased amounts

Decreased production of platelets in otherwise Decreased production of platelets in otherwise classic cases of ITP classic cases of ITP

– ? decreased production and increased destruction ? decreased production and increased destruction in some casesin some cases

ITP - Clinical FeaturesITP - Clinical Features

Acute and chronic ITPAcute and chronic ITP

Purpura and mucosal bleeding most prominent symptomsPurpura and mucosal bleeding most prominent symptoms

Children generally appear well, except for purpuraChildren generally appear well, except for purpura

Large submucous hemorrhages in the mouth associated with Large submucous hemorrhages in the mouth associated with increased risk of bleedingincreased risk of bleeding

Hepatomegaly, splenomegaly and lymphadenopathy notably Hepatomegaly, splenomegaly and lymphadenopathy notably absent absent

GI and renal hemorrhage may occurGI and renal hemorrhage may occur

* Central nervous system bleeding the most feared complication* Central nervous system bleeding the most feared complication

Laboratory Diagnosis of ITPLaboratory Diagnosis of ITP

Platelet counts vary from normal to undetectable,Platelet counts vary from normal to undetectable,– (tend to be lower in acute ITP than in chronic ITP)(tend to be lower in acute ITP than in chronic ITP)

Remainder of the CBC should be normalRemainder of the CBC should be normal– (Anemia secondary to bleeding may be seen)(Anemia secondary to bleeding may be seen)

Careful review of the peripheral blood smear Careful review of the peripheral blood smear should be performedshould be performed

Eosinophilia and atypical lymphocytosis may be Eosinophilia and atypical lymphocytosis may be seenseen

Laboratory Diagnosis of ITP Laboratory Diagnosis of ITP

Need to rule out other abnormalities, Need to rule out other abnormalities, including:including:– immature white blood cells immature white blood cells – red cell morphology consistent with red cell morphology consistent with

microangiopathic hemolysismicroangiopathic hemolysis

(Thrombotic Thrombocytopenic Purpura)(Thrombotic Thrombocytopenic Purpura)– spherocytes spherocytes

(Evan(Evan’’s syndrome)s syndrome)


PAIgG on the platelet surface (ie, direct test) PAIgG on the platelet surface (ie, direct test) usually positiveusually positive

Patient's serum may or may not increase the Patient's serum may or may not increase the amount of IgG on the surface of control platelets amount of IgG on the surface of control platelets (i.e., indirect test)(i.e., indirect test)

PT and aPTT should be normalPT and aPTT should be normal Bone marrow aspirates show increased Bone marrow aspirates show increased

megakaryocytesmegakaryocytes There is no definitive test for ITPThere is no definitive test for ITP


ITP is a diagnosis of exclusionITP is a diagnosis of exclusion

When Should You do a Bone Marrow?When Should You do a Bone Marrow?

When there are signs and symptoms of When there are signs and symptoms of possible bone marrow diseasepossible bone marrow disease– Abnormally low or high white blood cell countAbnormally low or high white blood cell count– Immature forms on peripheral smearImmature forms on peripheral smear– Unexplained or severe anemiaUnexplained or severe anemia– MacrocytosisMacrocytosis– Organomegaly or lymphadenopathyOrganomegaly or lymphadenopathy– NotNot when the thrombocytopenia is isolated when the thrombocytopenia is isolated

Isolated ThrombocytopeniaIsolated Thrombocytopenia

What is the risk of leukemia?What is the risk of leukemia?

Isolated thrombocytopenia in ALLIsolated thrombocytopenia in ALL

First author and year Number of patients studied of publication With isolated With leukemia

thrombocytopenia

McIntosh (1985) 0 218

Dubansky (1988) 0 2339

Jones (1985) 41 0

Halperin (1988) 127 0 Calpin (1998) 332 0

ITP - Clinical Course and prognosisITP - Clinical Course and prognosis

Frequently benign in young childrenFrequently benign in young children

Excellent prognosis:Excellent prognosis:– >50% of untreated children recover within four weeks>50% of untreated children recover within four weeks

– >80% spontaneously recover within six months>80% spontaneously recover within six months

Resolution of the thrombocytopenia occurs in a variety Resolution of the thrombocytopenia occurs in a variety of patternsof patterns

Improvement of symptoms often precedes a detectable Improvement of symptoms often precedes a detectable rise in the platelet count.rise in the platelet count.

ITP - Clinical Course and prognosisITP - Clinical Course and prognosis

Generally not considered chronic unless Generally not considered chronic unless

symptoms > than 6 monthssymptoms > than 6 months

Relapses common in chronic ITPRelapses common in chronic ITP

Acute ITP tends not to recur, but relapses Acute ITP tends not to recur, but relapses

reported (~3%) reported (~3%)

Treatment of ITPTreatment of ITP

BackgroundBackground– Incidence of serious complications of ITP is Incidence of serious complications of ITP is

very lowvery low– Mortality and morbidity most often associated Mortality and morbidity most often associated

with intracranial hemorrhagewith intracranial hemorrhage– Given the low incidence of intracranial Given the low incidence of intracranial

hemorrhage, no prospective, randomized trials hemorrhage, no prospective, randomized trials to truly estimate the likelihood of prevention to truly estimate the likelihood of prevention

Rx of ITP - General PrinciplesRx of ITP - General Principles

Goal of Rx: reduce the likelihood of bleeding during periods of Goal of Rx: reduce the likelihood of bleeding during periods of maximal riskmaximal risk

Waiting period usually warranted before treating in mild cases Waiting period usually warranted before treating in mild cases (platelet count >20,000/mm3, no bleeding other than purpura)(platelet count >20,000/mm3, no bleeding other than purpura)

Platelet counts < 20,000/mm3 or extensive mucosal bullae suggest a Platelet counts < 20,000/mm3 or extensive mucosal bullae suggest a higher risk for internal hemorrhage and Rx should be consideredhigher risk for internal hemorrhage and Rx should be considered

If serious complications are present or suspected, or if a protective If serious complications are present or suspected, or if a protective environment cannot be guaranteed, Rx should be initiatedenvironment cannot be guaranteed, Rx should be initiated

ITP - Treatment OptionsITP - Treatment Options

CorticosteroidsCorticosteroids

– Historically, the most commonly used therapyHistorically, the most commonly used therapy

– Effectiveness still debated; the following Effectiveness still debated; the following statements are generally considered to be true:statements are generally considered to be true: Steroids at least transiently increase the platelet count in Steroids at least transiently increase the platelet count in

most patientsmost patients

Even if the platelet count is not increased, a lessening of Even if the platelet count is not increased, a lessening of bleeding symptoms may occurbleeding symptoms may occur

Steroids do not change the natural history of the disease Steroids do not change the natural history of the disease

Prednisone for ITPPrednisone for ITP

Usually administered at an initial Usually administered at an initial

dosage of 2 mg/kg/day orallydosage of 2 mg/kg/day orally

Higher or intravenous dosages up to 30 Higher or intravenous dosages up to 30

mg/kg/day of prednisolone for very mg/kg/day of prednisolone for very

short periods may be more effective. short periods may be more effective.

Important not to taper aggressivelyImportant not to taper aggressively

Intravenous Intravenous --globulinglobulin (IVIgG)(IVIgG)

Useful modality in the treatment of ITPUseful modality in the treatment of ITP

Mechanism of action not entirely clearMechanism of action not entirely clear

– Best evidence suggests reticuloendothelial blockadeBest evidence suggests reticuloendothelial blockade

» Reduces splenic clearance of sensitized RBCsReduces splenic clearance of sensitized RBCs

– Upregulation of inhibitory Fc Receptors (Animal models)Upregulation of inhibitory Fc Receptors (Animal models)

– Anti-idiotypic or anti-Fc receptor antibodies Anti-idiotypic or anti-Fc receptor antibodies

– Modulation of T- or B-cell function postulatedModulation of T- or B-cell function postulated

– Clearance of infection or antigenemia may play a role Clearance of infection or antigenemia may play a role

Intravenous Intravenous --globulinglobulin (IVIgG)(IVIgG)

Treatment varies from 0.5-2 g/kg over 1 to 5 days (Most Treatment varies from 0.5-2 g/kg over 1 to 5 days (Most commonly used dose is 1 g/kg, single administration)commonly used dose is 1 g/kg, single administration)

Responses usually rapid and transitory - should not be Responses usually rapid and transitory - should not be expected in all patientsexpected in all patients

Up to 34% of patients may experience transient Up to 34% of patients may experience transient complications (severe headache, nausea, aseptic meningitis) complications (severe headache, nausea, aseptic meningitis)

Some risk of transmission of infection; appears to be quite Some risk of transmission of infection; appears to be quite safesafe

Extremely expensiveExtremely expensive

Anti-D ImmunoglobulinAnti-D Immunoglobulin

Relatively new, but useful therapy for ITPRelatively new, but useful therapy for ITP Mechanism of action incompletely understoodMechanism of action incompletely understood

– Hypothesis: antibody-coated red cells compete Hypothesis: antibody-coated red cells compete with antibody-coated platelets for destruction in with antibody-coated platelets for destruction in the RE-systemthe RE-system

No response in Rh-negative individualsNo response in Rh-negative individuals Splenectomized individuals may respond Splenectomized individuals may respond

suboptimally, but responses seensuboptimally, but responses seen

Anti-D immunoglobulin Anti-D immunoglobulin

Dose varies from 25Dose varies from 25g/kg/dose on two g/kg/dose on two consecutive days to 50-100 consecutive days to 50-100 g/kg x 1g/kg x 1

Can be infused within 1/2 hourCan be infused within 1/2 hour I.M. use also been reportedI.M. use also been reported Response rates similar to that of IVIgGResponse rates similar to that of IVIgG

– (Slightly longer delay in response reported; may be dose (Slightly longer delay in response reported; may be dose related)related)

Major toxicity a predictable fall in Hgb (mean Major toxicity a predictable fall in Hgb (mean decrease 1.3 g/dl)decrease 1.3 g/dl)

Advantages of Anti-D vs IVIgGAdvantages of Anti-D vs IVIgG

Ease of useEase of use

Outstanding safety record of anti-D for other Outstanding safety record of anti-D for other indicationsindications

Significantly lower protein load and expenseSignificantly lower protein load and expense

Smaller donor pool Smaller donor pool

Mechanisms of IVIgG and Anti-DMechanisms of IVIgG and Anti-D

ITP - Blanchette et al. 1993ITP - Blanchette et al. 1993

53 children (7 mos - 11.3 yrs)53 children (7 mos - 11.3 yrs) IVIgG (1g/kg/day x 2), p.o. prednisone IVIgG (1g/kg/day x 2), p.o. prednisone

(4 mg/kg/day), or no treatment (control)(4 mg/kg/day), or no treatment (control) IVIgG > prednisone > control for plts > 20,000IVIgG > prednisone > control for plts > 20,000

(1 day vs 2days vs 4 days)(1 day vs 2days vs 4 days) IVIgG > prednisone > control for plts > 50,000IVIgG > prednisone > control for plts > 50,000

(2 day vs 4 days vs 16 days)(2 day vs 4 days vs 16 days)

No differences in chronic ITP or side effectsNo differences in chronic ITP or side effects

Blanchette et al. 1993Blanchette et al. 1993


ITP - Blanchette et al. 1994ITP - Blanchette et al. 1994

146 children (6 mos - 18 yrs)146 children (6 mos - 18 yrs) IVIgG (1g/kg/day x 2 IVIgG (1g/kg/day x 2 oror 0.8 g/kg x 1), p.o. prednisone 0.8 g/kg x 1), p.o. prednisone

(4 mg/kg/day), or I.V. Anti-D (Winrho) (25 u/kg/day (4 mg/kg/day), or I.V. Anti-D (Winrho) (25 u/kg/day x 2) x 2)

IVIgG > prednisone > anti-D for plts > 20,000IVIgG > prednisone > anti-D for plts > 20,000 IVIgG > prednisone > anti-D for plts > 50,000IVIgG > prednisone > anti-D for plts > 50,000 0.8 g/kg IVIgG best overall0.8 g/kg IVIgG best overall

No differences in chronic ITP or side effectsNo differences in chronic ITP or side effects



Platelet transfusions Platelet transfusions

Generally avoided because of the Generally avoided because of the shortened survival of transfused plateletsshortened survival of transfused platelets

May be effective in immediately reducing May be effective in immediately reducing serious bleedingserious bleeding

SplenectomySplenectomy

Effective in resolving thrombocytopenia Effective in resolving thrombocytopenia in approximately two thirds of patientsin approximately two thirds of patients

Generally used only in emergencies or in Generally used only in emergencies or in extremely resistant casesextremely resistant cases

Other therapeutic approaches for ITPOther therapeutic approaches for ITP

Vinca-loaded platelets or vincristine infusionsVinca-loaded platelets or vincristine infusions Other immunosuppressive agents,Other immunosuppressive agents,

– azathioprineazathioprine

– cyclosporinecyclosporine

– cyclophosphamidecyclophosphamide Miscellaneous agentsMiscellaneous agents

– interferoninterferon

– ascorbic acidascorbic acid

– danazoldanazol

– protein A adsorption columnsprotein A adsorption columns

Who needs therapy?Who needs therapy?

Platelet count less than ? 5,000/mm3, Platelet count less than ? 5,000/mm3, ?10,000/mm3, ?20,000/mm3 ?10,000/mm3, ?20,000/mm3

Active mucosal bleedingActive mucosal bleeding Suspected internal bleedingSuspected internal bleeding Prolonged thrombocytopeniaProlonged thrombocytopenia

SurveysSurveys

1986 - 3 y.o. with platelets of 10,000/mm3 1986 - 3 y.o. with platelets of 10,000/mm3 and epistaxisand epistaxis

• ~50% of respondents suggested treatment~50% of respondents suggested treatment

1997 - 720 members of ASPHO1997 - 720 members of ASPHO• 490 respondents490 respondents

• 370 questionnaires analyzed370 questionnaires analyzed

Survey by Buchanan, et al., 1998Survey by Buchanan, et al., 1998

Scenario:Scenario: A) 5 y.o. with platelets of 3,000/mm3 , A) 5 y.o. with platelets of 3,000/mm3 ,

purpura onlypurpura only B) 5 y.o. with platelets of 3,000/mm3 , B) 5 y.o. with platelets of 3,000/mm3 ,

more severe bleedingmore severe bleeding– (epistaxis, mucosal bullae, Hgb of 9.7 (epistaxis, mucosal bullae, Hgb of 9.7

gm/dL)gm/dL)


Results:Results:Treatment Treatment A A B B

No treatmentNo treatment 16%16% 1% 1%

SteroidsSteroids 19%19% 11% 11%

IVIgGIVIgG 45%45% 60% 60%

Anti-DAnti-D 10%10% 5% 5%

Steroids & IVIgG Steroids & IVIgG 2% 15% 2% 15%


Results:Results:

HospitalizationHospitalization AA BB

AlwaysAlways 18%18% 61%61%

UsuallyUsually 23%23% 24%24%

SometimesSometimes 29%29% 12%12%

Never Never 30%30% 3% 3%

Bone marrowBone marrow

With steroidsWith steroids 77%77%

No steroidsNo steroids 9% 9%

Differential DiagnosisDifferential Diagnosis

ImmuneImmune

– Drug-Induced Immune ThrombocytopeniaDrug-Induced Immune Thrombocytopenia

– Posttransfusion PurpuraPosttransfusion Purpura

– Alloimmune ThrombocytopeniaAlloimmune Thrombocytopenia

Differential DiagnosisDifferential Diagnosis

NonimmuneNonimmune– Infectious ThrombocytopeniaInfectious Thrombocytopenia

– Inherited ThrombocytopeniasInherited Thrombocytopenias

– Microangiopathic Causes of ThrombocytopeniaMicroangiopathic Causes of Thrombocytopenia

– Nonimmune Drug-InducedNonimmune Drug-Induced

– MiscellaneousMiscellaneous

Sequestration, Infiltration, Rheumatologic, Cyanotic CHD Sequestration, Infiltration, Rheumatologic, Cyanotic CHD disease, Chromosomal defects, Metabolic illnesses, Severe liver disease, Chromosomal defects, Metabolic illnesses, Severe liver disease, hypothermia, anoxia, or iron deficiency, Folate or B12 disease, hypothermia, anoxia, or iron deficiency, Folate or B12 deficiency, Large vessel catheters, Cardiopulmonary bypass, deficiency, Large vessel catheters, Cardiopulmonary bypass, Cardiac prostheses, Rejection phenomenon, Severe allergic Cardiac prostheses, Rejection phenomenon, Severe allergic reactions, Myeloproliferative and myelodysplastic disorders, reactions, Myeloproliferative and myelodysplastic disorders, Aplastic anemiaAplastic anemia

Nonimmune Causes of ThrombocytopeniaNonimmune Causes of Thrombocytopenia

Inherited ThrombocytopeniasInherited ThrombocytopeniasTAR TAR

Amegakaryocytic thrombocytopeniaAmegakaryocytic thrombocytopenia

Wiskott-AldrichWiskott-Aldrich

Bernard-SoulierBernard-Soulier

May-Hegglin anomalyMay-Hegglin anomaly

Ebstein anomalyEbstein anomaly

Hermansky-Pudlak syndromeHermansky-Pudlak syndrome

Autosomal dominant, recessive and sex-linked recessiveAutosomal dominant, recessive and sex-linked recessive

thrombocytopenia thrombocytopenia

Research at JHHResearch at JHH

Lehmann, Casella, BuchananLehmann, Casella, Buchanan– Decision analytic approach to treatment of ITP – NIH Decision analytic approach to treatment of ITP – NIH

TMH networkTMH network» Study of the decision to treatStudy of the decision to treat

» Analysis of center to center variationAnalysis of center to center variation

» Assessment of provider and patient preferences and Assessment of provider and patient preferences and perception of riskperception of risk

Summary - ITPSummary - ITP

Common disorderCommon disorder Acute and chronic formsAcute and chronic forms Low overall morbidity and mortalityLow overall morbidity and mortality Dx of exclusionDx of exclusion Routine bone marrows unnecessaryRoutine bone marrows unnecessary Newer treatment modalities have helped Newer treatment modalities have helped

simplify Rxsimplify Rx

Drug-Induced Immune ThrombocytopeniaDrug-Induced Immune Thrombocytopenia

CharacteristicsCharacteristics– onset of thrombocytopenia tends to be abrupt onset of thrombocytopenia tends to be abrupt

(within hrs of ingestion or administration of the drug)(within hrs of ingestion or administration of the drug)

– ceases with clearance of the drugceases with clearance of the drug– tends to recur with repeated administration of tends to recur with repeated administration of

the drugthe drug– rechallenge very dangerousrechallenge very dangerous– in vitro testing availablein vitro testing available

Drug-Induced Immune ThrombocytopeniaDrug-Induced Immune Thrombocytopenia

MechanismsMechanisms– Specific platelet antigen---drug (ie, hapten) Specific platelet antigen---drug (ie, hapten)

complexcomplex– Absorption of antigen-antibody complexes Absorption of antigen-antibody complexes

onto the platelet surfaceonto the platelet surface (ie, “innocent bystander” phenomenon)(ie, “innocent bystander” phenomenon)

– True autoantibodies True autoantibodies

Drugs Convincingly Associated with Immune Drugs Convincingly Associated with Immune ThrombocytopeniaThrombocytopenia

penicillins penicillins digoxin digoxin

quinine quinine quinidinequinidine

cimetidine cimetidine stibophenstibophen

benzodiazepine benzodiazepine novobiocin novobiocin

heparin heparin trimethoprim-sulfamethoxasoletrimethoprim-sulfamethoxasole

allylisopropylacetylurea (Sedormid)allylisopropylacetylurea (Sedormid)

* Many other agents have the potential for causing immune-mediated * Many other agents have the potential for causing immune-mediated thrombocytopeniathrombocytopenia


Non-immune drug-induced Non-immune drug-induced valproic acidvalproic acidchloramphenicolchloramphenicolthiazide diureticsthiazide diureticsalcoholalcoholchemotherapeutic agentschemotherapeutic agentsanti-convulsantsanti-convulsantsantibioticsantibioticsionizing radiationionizing radiation

Posttransfusion PurpuraPosttransfusion Purpura

Infrequent problem, usually adults - severe Infrequent problem, usually adults - severe thrombocytopenia after erythrocyte transfusionsthrombocytopenia after erythrocyte transfusions

Thrombocytopenia typically abrupt, ~1 week after Thrombocytopenia typically abrupt, ~1 week after transfusiontransfusion

Affected patients typically HPA(1b,1b) (ie, PlA1 negative) Affected patients typically HPA(1b,1b) (ie, PlA1 negative) women with Hx of 1 or more pregnancies, transfused with women with Hx of 1 or more pregnancies, transfused with blood from a HPA(1a,1a) or HPA(1a,1b) (ie, PlA1 blood from a HPA(1a,1a) or HPA(1a,1b) (ie, PlA1 positive) donorpositive) donor

Possibly secondary to passive absorption of soluble HPA Possibly secondary to passive absorption of soluble HPA 1a antigen from the donor's plasma to recipient's platelets, 1a antigen from the donor's plasma to recipient's platelets, but pathophysiology may be more complexbut pathophysiology may be more complex


Infectious ThrombocytopeniaInfectious Thrombocytopeniaviral infections (active infection or postinfectious)viral infections (active infection or postinfectious)

varicella, Epstein-Barr virus, cytomegalovirus, other varicella, Epstein-Barr virus, cytomegalovirus, other herpesviruses, infuenza, scarlatina, measles, mumps, herpesviruses, infuenza, scarlatina, measles, mumps, rubella and HIVrubella and HIV

Other infectious agentsOther infectious agentstoxoplasmosis, erlichiosis, RMSF, hepatitis, malaria, toxoplasmosis, erlichiosis, RMSF, hepatitis, malaria,

syphilis, tuberculosis, overwhelming bacterial or syphilis, tuberculosis, overwhelming bacterial or rickettsial sepsisrickettsial sepsis


MicroangiopathicMicroangiopathicHUSHUS

TTPTTP

DIC DIC

HemangiomasHemangiomas


Miscellaneous ThrombocytopeniasMiscellaneous ThrombocytopeniasSequestration (eg, hypersplenism or sickle cell disease)Sequestration (eg, hypersplenism or sickle cell disease)

Infiltrative (eg, Gaucher's disease)Infiltrative (eg, Gaucher's disease)

Rheumatologic (eg, Felty's syndrome)Rheumatologic (eg, Felty's syndrome)

Cyanotic congenital heart disease with polycythemiaCyanotic congenital heart disease with polycythemia

Chromosomal DefectsChromosomal Defects

Severe liver diseaseSevere liver disease

Severe hypothermia or anoxia Severe hypothermia or anoxia

Severe iron deficiencySevere iron deficiency

Folate or vitamin B12 deficiencyFolate or vitamin B12 deficiency


Miscellaneous ThrombocytopeniasMiscellaneous Thrombocytopenias (Con’t) (Con’t)

Placement of large vessel cathetersPlacement of large vessel catheters

Cardiopulmonary bypassCardiopulmonary bypass

Cardiac prosthesesCardiac prostheses

Rejection phenomenonRejection phenomenon

Severe allergic reactionsSevere allergic reactions

Metabolic abnormalities (e.g. aminoacidopathies)Metabolic abnormalities (e.g. aminoacidopathies)

Myeloproliferative and myelodysplastic disordersMyeloproliferative and myelodysplastic disorders

Aplastic anemiaAplastic anemia

Infections Associated with Viral IllnessesInfections Associated with Viral Illnesses

RubellaRubella VaricellaVaricella

MeaslesMeasles MumpsMumps

RMSFRMSF CMVCMV

EBVEBV Other herpesvirusesOther herpesviruses

HepatitisHepatitis InfluenzaInfluenza

TuberculosisTuberculosis ScarlatinaScarlatina

ErlichiosisErlichiosis HIVHIV

ToxoplasmosisToxoplasmosis MalariaMalaria

SyphilisSyphilis Overwhelming bacterial or rickettsial Overwhelming bacterial or rickettsial sepsissepsis

Documents

Hemophilia and ITP