Immune thrombocytopenia - anti-HLA antibodies pregnancy induced
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Transcript of Immune thrombocytopenia - anti-HLA antibodies pregnancy induced
The Christ HospitalThe Christ HospitalApril 2012April 2012
Diana Girnita MD, PhDDiana Girnita MD, PhD
Internal Medicine Internal Medicine Grand RoundsGrand Rounds
Case PresentationCase Presentation
Chief complainsChief complains
72 yo Caucasian F72 yo Caucasian F
ConfusionConfusion
Back pain in the lumbar areaBack pain in the lumbar area
Easy bruisingEasy bruising
Multiple ecchymoses Multiple ecchymoses
What would you like to know?What would you like to know?
HPIHPIMay 2011: fell on the floor and hit her right hip; May 2011: fell on the floor and hit her right hip; has seen a chiropractor has seen a chiropractor For 1 month tried a herbal product, called For 1 month tried a herbal product, called “Willow Bark” (aspirin substitute), did not help“Willow Bark” (aspirin substitute), did not helpOccasionally Ibuprofen 1-2 tablets/ day PRN for Occasionally Ibuprofen 1-2 tablets/ day PRN for many years many years
Two months after fallTwo months after fall– easy bruising with minimal aggressionseasy bruising with minimal aggressions– fatiguedfatigued– weight loss (6-8 Lbs) weight loss (6-8 Lbs)
July 2011: in the ED due to confusion, severe July 2011: in the ED due to confusion, severe back pain rated as 8/10, irradiated in the groin back pain rated as 8/10, irradiated in the groin area, hips and LEsarea, hips and LEs
ROSROSGeneral/ constitutional: General/ constitutional: weight loss 8lbs, + fatigueweight loss 8lbs, + fatigue, no f/c/s, no f/c/s
Skin: Skin: + petechiae, purpura on UEs &LEs and and + petechiae, purpura on UEs &LEs and and ecchymoses lumbar and sacral areasecchymoses lumbar and sacral areas
HEENT:HEENT: no recent changes in vision/ ear pain, occasionalno recent changes in vision/ ear pain, occasional epistaxis epistaxis with ibuprofen intakewith ibuprofen intakeCardiovascular: no palpitations, chest pain, orthopnea, Cardiovascular: no palpitations, chest pain, orthopnea, Respiratory: no dyspnea, cough, hemoptysisRespiratory: no dyspnea, cough, hemoptysisGastrointestinal: no N/V/C/D, melena, hemetemesis Gastrointestinal: no N/V/C/D, melena, hemetemesis GenitourinaryGenitourinary: : no dysuria, changes in urine color, odor or no dysuria, changes in urine color, odor or flow flow Musculoskeletal: no muscle weaknessMusculoskeletal: no muscle weaknessNeurologic: no focal neurologic changesNeurologic: no focal neurologic changes
PMHPMH: none, have not seen a doctor in 20 years: none, have not seen a doctor in 20 years
HOME MEDSHOME MEDS: MULTIVITAMIN po: MULTIVITAMIN po
ALLERGIESALLERGIES: Codeine (Nausea,Vomiting ): Codeine (Nausea,Vomiting )
SURGICAL HX: SURGICAL HX: nonenone
FHXFHX::Cancer, diabetes -MotherCancer, diabetes -MotherCancer, HTN -Father Cancer, HTN -Father
SOCIAL HXSOCIAL HX: Married, G3P3, non-smoker, : Married, G3P3, non-smoker, occasionally alcoholoccasionally alcohol
Physical examinationPhysical examination
VS: temp 97.9/ HR 57/ RR18/VS: temp 97.9/ HR 57/ RR18/BP 168/78BP 168/78/ weight / weight 231lbs231lbs
General:General: obese, well developed, NAD obese, well developed, NADHEENT: HEENT: PERRLA, EOMI, throat non-edematous/ PERRLA, EOMI, throat non-edematous/ erythematous, normal mucoses , erythematous, normal mucoses , no epistaxisno epistaxis
Neck:Neck: normal ROM, nontender, trachea midline, normal ROM, nontender, trachea midline, LN LN nonpalpablenonpalpable/ nontender, no JVD, no carotid bruit / nontender, no JVD, no carotid bruit
CV:CV: RRR, normal S1, S2, no m/r/g RRR, normal S1, S2, no m/r/gResp:Resp: CTA bilaterally without r/r/w CTA bilaterally without r/r/w
Abd:Abd: soft, ND/NT, + BS, soft, ND/NT, + BS, no HSMno HSMExt:Ext: 2+ pulses, without clubbing, cyanosis, or edema 2+ pulses, without clubbing, cyanosis, or edema
Physical examinationPhysical examination
Skin:Skin: warm, dry, warm, dry, – multiple petechiae on her UE &LEmultiple petechiae on her UE &LE– purpurapurpura– ecchymoses more on the UEs, few on LEs, a ecchymoses more on the UEs, few on LEs, a
large ecchymose on the R lumbar arealarge ecchymose on the R lumbar area
Neuro: Neuro: AOx 2 (person, time), CN II-XII AOx 2 (person, time), CN II-XII grossly intact, motor and sensory function grossly intact, motor and sensory function intact with no focal deficitsintact with no focal deficits
What would you like for work up?What would you like for work up?
LabsLabsCBCCBCBMPBMPPT, INR, aPTT, bleeding timePT, INR, aPTT, bleeding timeTSHTSHLiver profileLiver profile
Results- admission at OSHResults- admission at OSH
CBC:CBC:– Hb=10.4; Ht=31.5, MCV 89Hb=10.4; Ht=31.5, MCV 89– WBC =6000/mm3WBC =6000/mm3– Platelets =2000/mm3Platelets =2000/mm3
INR =1.03INR =1.03
TSH -1.54 (WNL)TSH -1.54 (WNL)
ESR =30/1hESR =30/1h
BMP BMP 138
3.8
103
23
0.8
11
Differential Differential diagnosisdiagnosis
CLL / lymphomaCLL / lymphoma
MDSMDS
ITPITP
Collagen disease (APLS, SLE)Collagen disease (APLS, SLE)
TTP, DIC/sepsisTTP, DIC/sepsis
Drugs (NSAIDs, Willow bark/ASA)Drugs (NSAIDs, Willow bark/ASA)
Splenic sequestration/ hypersplenismSplenic sequestration/ hypersplenism
Pseudothrombocytopenia-unikelyPseudothrombocytopenia-unikely
Dilutional s/p massive transfusionDilutional s/p massive transfusion
ImagingImaging
CT head
MRI head
CXR
CT chest/ abdomen/pelvis
Xray of lumbar spine
PET scan
US abdomen – spleen
CT head w/out contrastCT head w/out contrast
Hyperdense intracranial masses compatible with metastatic disease/ possible that these are hyperdense due to blood
MRI headMRI head
MRI impressionMRI impression
Intracranial lesions do not demonstrate Intracranial lesions do not demonstrate significant contrast enhancement as significant contrast enhancement as expected for metastatic diseaseexpected for metastatic disease
Have characteristics compatible with Have characteristics compatible with acute/early subacute blood lossacute/early subacute blood loss
Multifocal intraparenchymal brain Multifocal intraparenchymal brain hemorrhagehemorrhage
CXRCXR
CT chest, abdomen, pelvisCT chest, abdomen, pelvis
CT chest, abdomen, pelvis CT chest, abdomen, pelvis impressionimpression
No mass or adenopathy in the chest, No mass or adenopathy in the chest, abdomen, pelvisabdomen, pelvis
Bilateral pulmonary ground glass infiltratesBilateral pulmonary ground glass infiltrates
Likely alveolar hemorrhageLikely alveolar hemorrhage
US spleen -normalUS spleen -normal
X-ray lumbar spineX-ray lumbar spine
No fracture, Mild scoliosisNo fracture, Mild scoliosis
Degenerative disc disease:L2-L3, L4-L5Degenerative disc disease:L2-L3, L4-L5
PET scanPET scan
nonoevidence evidence of skeletal of skeletal metastatic metastatic
diseasedisease
What do we know so far?What do we know so far?
Critical platelets counts Critical platelets counts
Multiorgan hemorrhagesMultiorgan hemorrhages
OSH treatmentOSH treatment
8U of platelets8U of platelets
Decadron iv 4mg Q6HDecadron iv 4mg Q6H
One dose of IVIG =1mg/kg (1000mg)One dose of IVIG =1mg/kg (1000mg)
Platelets remained in the 2-3000/mm3Platelets remained in the 2-3000/mm3
Patient was transferred to TCHPatient was transferred to TCH
TCH work-upTCH work-up
CBC: CBC: –WBC=6000/mm3, WBC=6000/mm3, –H/H = 8.2/24.8,MCV =91 H/H = 8.2/24.8,MCV =91 –Platelets =3000/mm3Platelets =3000/mm3
BMP -normalBMP -normal
Anemia work-upAnemia work-upRetic count -110976 (H)Retic count -110976 (H)
LDH -269 (H)LDH -269 (H)
Haptoglobin 64 (N)Haptoglobin 64 (N)
COOMBS test and RH positiveCOOMBS test and RH positive
Iron studies: normalIron studies: normal
Vit B12/folate were normalVit B12/folate were normal
Peripheral smear: no schystocytesPeripheral smear: no schystocytes
TCH work-upTCH work-up
Liver tests were normalLiver tests were normal
TSH -0.23 (L)TSH -0.23 (L)
Fecal occult test -NEGATIVEFecal occult test -NEGATIVE
TCH work-upTCH work-upFibrinogen – 307 (range 175-425)Fibrinogen – 307 (range 175-425)
INR -1.3 (0.9-1.1)INR -1.3 (0.9-1.1)
PT – 16.1 (11.9-14.8)PT – 16.1 (11.9-14.8)
aPTT -23.5 (23.6-33.5)aPTT -23.5 (23.6-33.5)
Serum protein electrophoresisSerum protein electrophoresis– Alpha1,2; beta normalAlpha1,2; beta normal– Gamma globulin 3.9 (H)Gamma globulin 3.9 (H)– Globulin 4 (H)Globulin 4 (H)– Albumin (3.2) Albumin (3.2)
Kappa/lambda ratio –normalKappa/lambda ratio –normal
– Kappa-12.5 (3.3-14)Kappa-12.5 (3.3-14)
– Lambda -14.10 (5.7-26.3)Lambda -14.10 (5.7-26.3)
– Ratio – 0.89 (0.26-1.65)Ratio – 0.89 (0.26-1.65)
Parvovirus B 19 IgG positive, no IgMParvovirus B 19 IgG positive, no IgM
Consult to hematology Consult to hematology
Bone Marrow biopsyBone Marrow biopsy
Cellularity is 85%. Cellularity is 85%.
Hyperplasia of the erythroid, as well as the Hyperplasia of the erythroid, as well as the megakaryocyte series with normal megakaryocyte series with normal morphologic features.morphologic features.
Dysplasia is not evident.Dysplasia is not evident.
Findings most compatible with peripheral Findings most compatible with peripheral platelet destruction.platelet destruction.
Bone marrow biopsyBone marrow biopsy
Special STAINS:Special STAINS:
Storage iron decreased.Storage iron decreased.
Reticulin stain shows no increase in Reticulin stain shows no increase in reticulin fibrosisreticulin fibrosisPAS stain highlights the megakaryocyte PAS stain highlights the megakaryocyte population population
ITP diagnosis and therapyITP diagnosis and therapy
IVIG
WinRho
Rituximab 1st Rituximab 2nd
Splenectomy
Methyprednisolone, f/b PDN taper
1st 2nd
Question Question
Why was this patient refractory to Why was this patient refractory to platelet transfusions therapy ?platelet transfusions therapy ?
PlateletsPlatelets
Glycoproteins (GP)Glycoproteins (GP)
GP Ib/IX =receptor for GP Ib/IX =receptor for VWFVWF
GP IIb/IIIa = receptor for GP IIb/IIIa = receptor for fibrinogenfibrinogen
GP Ia/IIa = collagen GP Ia/IIa = collagen receptor.receptor.
HLA class I: A, BHLA class I: A, B
The cell surface is a jungle!!
Gebel and Bray, Transplantation 2004
0
100
200
300
400
500
600
A B C DRB1
1990
1997
2001
2002
2004 N > 2400
HLA -A and B are important in HLA -A and B are important in platelet transfusionplatelet transfusion
Refractoriness to platelet Refractoriness to platelet transfusiontransfusion
ELISA-positive for:ELISA-positive for:
platelet-specific antibodies (1a, 1b, 3a, 3b, platelet-specific antibodies (1a, 1b, 3a, 3b, 4a, 5a, 5b) and4a, 5a, 5b) and
HLA-specific antibodiesHLA-specific antibodies
Broad IgG reactivity towards HLA Broad IgG reactivity towards HLA antigens determined by Luminex antigens determined by Luminex
single-antigen beadssingle-antigen beads
Calculated PRA = 82%
SELF HLA -NEGATIVE
The high (82%) allo-reactivity was The high (82%) allo-reactivity was explained by only two specificities: explained by only two specificities: anti-HLA A3 (private epitope) and anti-HLA A3 (private epitope) and
anti-HLA w4 (public epitope) anti-HLA w4 (public epitope)
A3
W4 epitope
The w4 epitope (78-82 RENLR) is known as The w4 epitope (78-82 RENLR) is known as a very immunogenic public epitopea very immunogenic public epitope
Magenta – Heavy Chain (Alpha chain)Blue – Light chain (Beta-2 microglobulin)Brown – PeptideYellow – Bw4 epitope
Patient had no previous transplants Patient had no previous transplants and/or transfusions;and/or transfusions;Three pregnancies;Three pregnancies;
Patient and husband HLA typing Patient and husband HLA typing
Husband’s mismatched HLA class I:A3
B57 (bearing the Bw4 epitope)
Antibodies towards HLA class II Antibodies towards HLA class II were also explained by pregnancy were also explained by pregnancy
sensitizationsensitization
Husband’s mismatched HLA: DR7, DR17, DQ2, DQ9
The IgG subtype analysis demonstrated The IgG subtype analysis demonstrated IgG1, which is a strong complement binderIgG1, which is a strong complement binder
IMMUNE IMMUNE TROMBOCYTOPENIA TROMBOCYTOPENIA
(ITP)(ITP)
Immune thrombocytopenia vs ITPImmune thrombocytopenia vs ITP
can no longer be considered idiopathiccan no longer be considered idiopathic
DefinitionDefinition
– Platelet count < 100 x 10Platelet count < 100 x 1099/L/L– No other cause of thrombocytopenia No other cause of thrombocytopenia – No No clinically evident clinically evident secondary form secondary form
Rodeghiero F, et al. Blood. 2009;113:2386-2393
Timing in ITPTiming in ITP
Newly Newly diagnosed < 3 modiagnosed < 3 mo
Persistent ITPPersistent ITP – 3 -12 mo and patients not – 3 -12 mo and patients not reaching/maintaining remission off therapyreaching/maintaining remission off therapy
Chronic ITP: > Chronic ITP: > 12 mo12 mo
Primary ITP – mechanismsPrimary ITP – mechanisms–molecular mimicrymolecular mimicry–epitope spreadepitope spread
Primary vs Secondary ITPPrimary vs Secondary ITP
Molecular mimicryMolecular mimicry
HIV HCV H. pylori
ITP Post-infection:ITP Post-infection:Molecular Mimicry GPIIIa (aa 49-66)Molecular Mimicry GPIIIa (aa 49-66)
Nardi MA, et al. Proc Natl Acad Sci U S A. 1997;94:7589-7594. 2. Zhang W, et al. Blood. 2009;113:4086-4093. 3. Takahashi T, et al. Br J Haematol. 2004;124:91-96.
EPITOPE SPREADEPITOPE SPREAD
Cines DB,Cines DB,
NEJM 2002;NEJM 2002;
346:995-1008346:995-1008
Alloantibodies determineAlloantibodies determine
–reduced platelet survival reduced platelet survival
– impaired platelet production impaired platelet production (megakaryocytes)(megakaryocytes)
Prevalence of Prevalence of SecondarySecondary ITP ITP
SLE 5%
APS 2%
CVID 1%
CLL 2%
Evan’s 2%
ALPS, post-tx 1%HIV 1%
Hep C 2%
H. pylori 1%Postvaccine 1%
Misc systemic infection 2%
Primary80%
Cines DB, et al. Blood. 2009;113:6511-6521.
Initial Evaluation for ITP 2010Initial Evaluation for ITP 2010
ASH: CBC, blood smear, BM (age > 60 ASH: CBC, blood smear, BM (age > 60 yrs), r/o other causesyrs), r/o other causes
Infection: HIV, HCV, HBV, H. pylori, PPDInfection: HIV, HCV, HBV, H. pylori, PPD
Autoimmune: ANA, APLA, ATA/TSHAutoimmune: ANA, APLA, ATA/TSH
Secondary: DAT, reticulocytes, LFTs, CT Secondary: DAT, reticulocytes, LFTs, CT scan/echo scan/echo
Bone marrow: reticulin at baseline?Bone marrow: reticulin at baseline?
Provan D, et al. Blood. 2010 115: 168-186
BM> 60 yrs BM> 60 yrs to exclude MDS/ CLLto exclude MDS/ CLL
Quantitative IG before patients receive IVIG (CVID Quantitative IG before patients receive IVIG (CVID or IgA deficiency)or IgA deficiency)
Direct antiglobulin testDirect antiglobulin test - - 22% pt have DAT+ 22% pt have DAT+
Blood group Rh(D) typingBlood group Rh(D) typing :: if treatment with anti- if treatment with anti-RhD immunoglobulin is being consideredRhD immunoglobulin is being considered
1. Provan D, et al. Blood. 2010. 2. Cines DB, et al. Blood. 2009;113:6511-6521.
Additional TestsAdditional TestsThyroglobulin antibodies and/or TSHThyroglobulin antibodies and/or TSH -8% to 14% ITP -8% to 14% ITP can develop hyperthyroidism; the presence of can develop hyperthyroidism; the presence of hyper/hypothyroidism result in resistance to therapyhyper/hypothyroidism result in resistance to therapy
ANA ANA is predictive of chronicity in childhood ITPis predictive of chronicity in childhood ITP
H/o fetal loss/ thrombosis- H/o fetal loss/ thrombosis- antiphospholipid antibodiesantiphospholipid antibodies 15% have ITP15% have ITP
1. Provan D, et al. Blood. 2009;[Epub ahead of print]. 2. Liebman H. Semin Hematol. 2007;44(4 suppl 5): S24-S34. 3. Altintas A, et al. J Thromb Thrombolysis. 2007;24:163-168.
Treatment in ITPTreatment in ITP
Timeline: introduction of modern Timeline: introduction of modern day ITP drug treatmentday ITP drug treatment
Splenectomy
Corticosteroids
IVIg
Anti-D
Rituximab
TPO mimetics
1900 1920 1960 20001940 1980
ITPITPWho and When to TreatWho and When to Treat
Only platelet # < 20-30 x 10Only platelet # < 20-30 x 1099/L or /L or symptomaticsymptomatic
Bleeding risk > 60 yrsBleeding risk > 60 yrs
Post-splenectomy Post-splenectomy
Bleeding and infection contribute equally Bleeding and infection contribute equally to mortalityto mortality
Provan D, et al. Blood. 2010 115: 168-186
Relevant factors: Relevant factors:
– extent of bleedingextent of bleeding– comorbidities predisposing to bleedingcomorbidities predisposing to bleeding– complications of specific therapiescomplications of specific therapies– activity and lifestyleactivity and lifestyle– potential interventions that may cause potential interventions that may cause
bleedingbleeding– patient expectations, anxietypatient expectations, anxiety
CorticosteroidsCorticosteroids
IVIg and Anti-D (Winrho)IVIg and Anti-D (Winrho)
Rituximab (anti CD20 mAb)Rituximab (anti CD20 mAb)
Splenectomy –removes B and plasma Splenectomy –removes B and plasma cellscells
Anti-plasma cell drugs (proteasome Anti-plasma cell drugs (proteasome inhibitors)inhibitors)
TPO mimmeticsTPO mimmetics
ITPITPHow to TreatHow to Treat
Rajan Lakhia, MDSuzanne Partridge, MDHoxworth Blood Center
Treatment Strategy
Response Rate
Time to Response
Response Duration
Cortico-steroids
Prednisone 70-80% Several days to weeks
Uncertain
Me-Pred ≤ 95% Few days 23% have > 50x109/L at 39 months
Immune Globulin
IVIg ≥ 80% 1-2 days 3-4 weeks, months in some
Anti-D: 50-80% (dose dependent)
1-5 days (dose dependent)
Typically 3–4 weeks, months in some
Provan D, et al. Blood. 2009;[
Frontline Therapies -Adult ITPFrontline Therapies -Adult ITP
IV Immune globulin (IVIg)IV Immune globulin (IVIg)
Mechanism of actionMechanism of action– Effects on humoral and cellular immune functionEffects on humoral and cellular immune function11 – Impairs of clearance of opsonized plateletsImpairs of clearance of opsonized platelets11
Effect mediated through FcγRIIb receptor (murine Effect mediated through FcγRIIb receptor (murine model)model)22
– Increases clearance of antiplatelet antibodies via Increases clearance of antiplatelet antibodies via saturation of the FcRn (rodent model)saturation of the FcRn (rodent model)33
1. Sandler and Tutuncuoglu. Expert Opin Pharmacother. 2004;5:2515-2527. 2. Samuelsson et al. Science. 2001;291:484-486. 3. Hansen and Balthasar. Blood. 2002;100:2087-2093. 4. George J, et al. Blood. 1996;88:3-40.
Rituximab Rituximab
Anti-CD20 monoclonal antibodyAnti-CD20 monoclonal antibody
Hypothesis: B-cell depletion: ? Hypothesis: B-cell depletion: ? ↓ antiplatelet ↓ antiplatelet antibodiesantibodies
No RCT studies availableNo RCT studies available
Effective dose not known, not FDA-approved Effective dose not known, not FDA-approved
Before splenectomy, when the surgical Before splenectomy, when the surgical option is not well accepted/ high risk of option is not well accepted/ high risk of complicationscomplications
SplenectomySplenectomy
Mechanism of actionMechanism of action– Removes a primary site of platelet destruction Removes a primary site of platelet destruction
by macrophagesby macrophages– Possible site of autoantibody productionPossible site of autoantibody production
Sandler SG, et al. Expert Opin Pharmacother. 2004;5:2515-2527.
Splenectomy: complete response Splenectomy: complete response vs timevs time
47 case series, adults only, f/u median: 29 mos (range: 1-153)
Kojouri K, et al. Blood. 2004;104:2623-2634.
0
20
40
60
80
100
0 40 160
Follow-up (Mos)
% C
ompl
ete
Rem
issi
on
20 8060 100 140120
r = -0.1031, P = .490
Kosugi S, et al. Br J Haematol. 1996;93:704-706. Copyright © 1996. Reproduced with permission of John Wiley & Sons, Inc.
Patient Group
Anaplastic anemia(n = 12)
Now vs thenNow vs then
30
ITP(n = 43)
Normal(n = 21)
TP
O (
fem
tom
oles
/mL)
25
15
20
10
5
0
Plasma TPO Levels in ITP
1) healthy: platelet # is high and serum thrombopoietin is low2) ITP: both the platelet # and serum thrombopoietin levels are low3)AA: platelet # low, but serum thrombopoietin levels are high
% C
ontr
ol
Meg
akar
yocy
tes
Suppression of Megakaryocyte Suppression of Megakaryocyte Production by ITP PlasmaProduction by ITP Plasma
100
75
50
25
0ITP-1 ITP-2 ITP-3 ITP-4 ITP-5 ITP-6 ITP-7 ITP-8 ITP-9 ITP-10 ITP-11 ITP-12
McMillan R, et al. Blood. 2004;103:1364-1369.