a fatal combination of a fatal combination of raraynaud

Clinical Clinical PathophysiologyPathophysiology ConferenceConference

Red, White, Blue and Yellow:Red, White, Blue and Yellow:A Fatal Combination of A Fatal Combination of Raynaud’sRaynaud’s and Jaundiceand Jaundiceyy

Erick Lansigan, MDErick Lansigan, MDg ,g ,Chief Resident Medical Service IChief Resident Medical Service I

Montefiore Medical CenterMontefiore Medical Center

November 3, 2005November 3, 2005

Chief ComplaintChief ComplaintChief ComplaintChief Complaint

25 year25 year old Africanold African American woman withAmerican woman with25 year25 year--old Africanold African--American woman with American woman with a history of Raynaud’s phenomenon a history of Raynaud’s phenomenon complained of shortness of breath nauseacomplained of shortness of breath nauseacomplained of shortness of breath, nausea, complained of shortness of breath, nausea, vomiting and jaundice over the course of vomiting and jaundice over the course of one weekone weekone weekone week

Case HistoryCase HistoryCase HistoryCase HistoryShe had been feeling well untilShe had been feeling well until

––One week prior to admission when she began One week prior to admission when she began experiencing shortness of breath. This experiencing shortness of breath. This progressed over one week and she complained ofprogressed over one week and she complained ofprogressed over one week and she complained of progressed over one week and she complained of dyspnea with minimal exertion. Denied chest dyspnea with minimal exertion. Denied chest pain, diaphoresis or leg swelling.pain, diaphoresis or leg swelling.

––Two days PTA, mother noted her eyes and skin Two days PTA, mother noted her eyes and skin to be yellow. to be yellow.

––The day of admission she went to work and had The day of admission she went to work and had nausea and vomiting associated with dizziness nausea and vomiting associated with dizziness and went to Montefiore ED.and went to Montefiore ED.

Case HistoryCase HistoryCase HistoryCase HistoryPMH: PMH:

R d’ h f 2R d’ h f 2–– Raynaud’s phenomenon for 2 yrs Raynaud’s phenomenon for 2 yrs –– Followed by a rheumatologist for 2 yrs for Followed by a rheumatologist for 2 yrs for

Raynaud’s and abnormal serologiesRaynaud’s and abnormal serologiesy gy g–– No prior surgeriesNo prior surgeries

Meds: Nifedipine QDMeds: Nifedipine QD

Allergies: NKDAAllergies: NKDA

Family History: No family history of connective tissueFamily History: No family history of connective tissueFamily History: No family history of connective tissueFamily History: No family history of connective tissuedisease, cancer, cardiac or liver diseasedisease, cancer, cardiac or liver disease

Social History: Denied tobacco, alcohol or drug use. Social History: Denied tobacco, alcohol or drug use. y , gy , gNot sexually active. Lives with parents. Works atNot sexually active. Lives with parents. Works atLincoln hospital. Denied recent travel.Lincoln hospital. Denied recent travel.

History summaryHistory summaryHistory summaryHistory summary25yo AA female with history of Raynaud’s25yo AA female with history of Raynaud’s–– Dyspnea x 1 weekDyspnea x 1 week–– Jaundice x 2 daysJaundice x 2 days

N / iti 1 dN / iti 1 d–– Nausea/vomiting x 1 dayNausea/vomiting x 1 day

Differential diagnosis? Differential diagnosis? Liver/GILiver/GI:: Hematologic:Hematologic:Liver/GILiver/GI:: Hematologic:Hematologic:––Liver/GILiver/GI: :

Autoimmune hepatitisAutoimmune hepatitisPrimary biliary cirrhosisPrimary biliary cirrhosisAcute hepatitis: viral, toxic, fulminantAcute hepatitis: viral, toxic, fulminant

––Hematologic:Hematologic:Hemolytic anemia Hemolytic anemia

-- Autoimmune, GAutoimmune, G--6PD, sickle cell6PD, sickle cellProthrombotic (APLA) state with Prothrombotic (APLA) state with

––Liver/GILiver/GI: : ––Hematologic:Hematologic:

p , ,p , ,Portal vein thrombosis Portal vein thrombosis -- PE’s and hepatic vein thrombosisPE’s and hepatic vein thrombosis

Severe symptomatic anemiaSevere symptomatic anemia

--RheumatologicRheumatologic::S i h i h l i iS i h i h l i i--RheumatologicRheumatologic::--InfectiousInfectious::--InfectiousInfectious: :

SLE with autoimmune hemolytic anemiaSLE with autoimmune hemolytic anemiaSLE with visceral vasculitis SLE with visceral vasculitis

Pneumonia/Sepsis/DICPneumonia/Sepsis/DICAcute Viral HepatitisAcute Viral HepatitisHIV + opportunistic infections/HepatitisHIV + opportunistic infections/Hepatitis

Physical ExamPhysical ExamPhysical ExamPhysical Exam

ED Triage VitalsED Triage VitalsED Triage VitalsED Triage Vitals–– Temp = 98.1Temp = 98.1°° orallyorally

BP 123/92BP 123/92–– BP 123/92BP 123/92–– Pulse 140Pulse 140

RR 20RR 20–– RR 20RR 20–– Pulse ox = 98% on room airPulse ox = 98% on room air

Physical ExamPhysical ExamPhysical ExamPhysical ExamED exam noted tachycardia and jaundiceED exam noted tachycardia and jaundiceWhile in the ED, patient was noted by nurse and While in the ED, patient was noted by nurse and

mother to have a seizure that lasted one minute: tonicmother to have a seizure that lasted one minute: tonic--l i ll d b k d il i ll d b k d iclonic movements, eyes rolled back, and unresponsive; clonic movements, eyes rolled back, and unresponsive;

Fingerstick was 161 Fingerstick was 161

22 dd f i lf i l22ndnd set of vitalsset of vitals-- Tmax 102.8Tmax 102.8°° rectallyrectally

BP 124/87BP 124/87-- BP 124/87BP 124/87-- Pulse 136Pulse 136-- RR 30RR 30

Pulse ox 98% on room air 100% on NRBPulse ox 98% on room air 100% on NRB-- Pulse ox 98% on room air, 100% on NRBPulse ox 98% on room air, 100% on NRB

Ativan 2mg IV given, Tylenol given, and 2L NS infusedAtivan 2mg IV given, Tylenol given, and 2L NS infused

Physical ExamPhysical ExamPhysical ExamPhysical ExamDetailed Physical ExamDetailed Physical Exam

G l D l th i b t AAO 3G l D l th i b t AAO 3–– General appearance: Drowsy, lethargic but AAO x 3General appearance: Drowsy, lethargic but AAO x 3–– Skin: pale, cool, dry, jaundicedSkin: pale, cool, dry, jaundiced–– HEENT: icteric conjunctiva , PERRL, MMMHEENT: icteric conjunctiva , PERRL, MMMN : cte c co ju ct va , ,N : cte c co ju ct va , ,–– Neck: no lymphadenopathy, no JVDNeck: no lymphadenopathy, no JVD–– Chest: CTA B/LChest: CTA B/L–– Heart: tachycardic, regular rhythm, no murmursHeart: tachycardic, regular rhythm, no murmurs–– Abdomen: soft, mild tenderness, + BS, liver 9cm, Abdomen: soft, mild tenderness, + BS, liver 9cm,

no splenomegalyno splenomegalyp g yp g y–– Extremities: cool extremities (U + L), Extremities: cool extremities (U + L),

“petechiae” lower legs B/L“petechiae” lower legs B/LPulses: noted to be “decreased”Pulses: noted to be “decreased”–– Pulses: noted to be “decreased” Pulses: noted to be “decreased”

History and Physical SummaryHistory and Physical Summary

–– SeizureSeizure––Dyspnea x 1 weekDyspnea x 1 week25yo AA female with history of Raynaud’s25yo AA female with history of Raynaud’s

–– FeverFever–– TachycardiaTachycardia

“ hi ”“ hi ”

––Jaundice x 2 daysJaundice x 2 days

––Nausea/vomiting x 1 dayNausea/vomiting x 1 day–– “Petechiae”“Petechiae”

g yg y

Differential diagnosis?Differential diagnosis?––Liver/GILiver/GI: : ––Hematologic:Hematologic:

––TTP (Thrombotic Thrombocytopenic Purpura)TTP (Thrombotic Thrombocytopenic Purpura)Catastrophic antiCatastrophic anti phospholipid syndromephospholipid syndrome

Autoimmune hepatitisAutoimmune hepatitisPrimary biliary cirrhosisPrimary biliary cirrhosisAcute hepatitis: viral, toxic, fulminantAcute hepatitis: viral, toxic, fulminantPortal ein thrombosisPortal ein thrombosis

Hemolytic anemia Hemolytic anemia -- Autoimmune, GAutoimmune, G--6PD, sickle cell6PD, sickle cell

Prothrombotic (APLA) state with Prothrombotic (APLA) state with -- PE’s and hepatic vein thrombosisPE’s and hepatic vein thrombosis––Catastrophic antiCatastrophic anti--phospholipid syndromephospholipid syndrome

––SLE with vasculitisSLE with vasculitis

i / i i i / i /i / i i i / i /

Portal vein thrombosis Portal vein thrombosis

––InfectiousInfectious: : Pneumonia/Sepsis/DICPneumonia/Sepsis/DIC

-- PE s and hepatic vein thrombosisPE s and hepatic vein thrombosisSevere symptomatic anemiaSevere symptomatic anemia

--Rheumatologic:Rheumatologic:––Pneumonia/Meningitis/Sepsis/DICPneumonia/Meningitis/Sepsis/DICPneumonia/Sepsis/DICPneumonia/Sepsis/DICAcute Viral HepatitisAcute Viral HepatitisHIV + opportunistic infections/HepatitisHIV + opportunistic infections/Hepatitis

SLE with autoimmune hemolytic anemiaSLE with autoimmune hemolytic anemiaSLE with visceral vasculitis SLE with visceral vasculitis

Initial Laboratory DataInitial Laboratory DataInitial Laboratory DataInitial Laboratory DataCBCCBC Chem 7Chem 7 LFTsLFTs

WBCWBC 6.66.6H/H 8.3/26H/H 8.3/26PltPlt 7 07 0

NaNa 134134KK 3.53.5ClCl 100100

TP 7.8TP 7.8Alb 4.3Alb 4.3AST 81AST 81PltsPlts 7.07.0

(normal CBC 2 years prior)(normal CBC 2 years prior)ClCl 100100HCO3 22HCO3 22BUN 15BUN 15

AST 81AST 81ALT 41ALT 41T Bili 6 6T Bili 6 6C BUN 15BUN 15

Cr 0.5Cr 0.5Glu 105Glu 105

T.Bili 6.6T.Bili 6.6D.Bili 0.4D.Bili 0.4

AP 55AP 55

CoagsPT 9.9

Ca 9.4Ca 9.4AP 55AP 55

LDH 1301PTT 26.3

UA: dark yellow clear pH 6 0 SG 1 019 prot >1000UA: dark yellow, clear, pH 6.0, SG 1.019, prot >1000, gluc neg, ketone neg, blood large, LE trace, nitrate neg, small biliRBC 56, WBC 8.2, TP = 256/Cr 106 = ~2.5g/day proteinuria

Peripheral SmearPeripheral Smear

H & P and Lab SummaryH & P and Lab Summary25yo AA female with history of Raynaud’s25yo AA female with history of Raynaud’s

–– SeizureSeizure–– FeverFever–– TachycardiaTachycardia

––Dyspnea x 1 weekDyspnea x 1 week

––Jaundice x 2 daysJaundice x 2 days

/ i i d/ i i d

––ThrombocytopeniaThrombocytopenia

––Hemolytic anemiaHemolytic anemia

S hi i h lS hi i h lyy

–– “Petechiae”“Petechiae”––Nausea/vomiting x 1 dayNausea/vomiting x 1 day ––Schistocytes on peripheral smear Schistocytes on peripheral smear

––Proteinuria and hematuriaProteinuria and hematuria

––TTPTTPDifferential diagnosis?Differential diagnosis?

TTPTTP–– Catastrophic APL syndromeCatastrophic APL syndrome–– SLE with autoimmune hemolytic anemia and vasculitisSLE with autoimmune hemolytic anemia and vasculitis–– Pneumonia/Meningitis/Sepsis/DICPneumonia/Meningitis/Sepsis/DIC

Hematology ConsultHematology ConsultHematology ConsultHematology ConsultHematology was consulted and agreed the Hematology was consulted and agreed the diagnosis was consistent with TTPdiagnosis was consistent with TTPdiagnosis was consistent with TTPdiagnosis was consistent with TTP–– Fever, hemolytic anemia and thrombocytopeniaFever, hemolytic anemia and thrombocytopenia–– Hx autoHx auto--immune diseaseimmune disease–– Recommended:Recommended:

ACTACT»» Admit to ICU, Transfusion services to be made awareAdmit to ICU, Transfusion services to be made aware»» Admit to ICU, Transfusion services to be made awareAdmit to ICU, Transfusion services to be made aware»» Bilateral single or Shiley catheter for initiation of plasma Bilateral single or Shiley catheter for initiation of plasma

exchangeexchange»» Additional blood tests or at least plasma samples frozenAdditional blood tests or at least plasma samples frozenp pp p

-- Coombs (Direct AHG), APLA workCoombs (Direct AHG), APLA work--up, TTP workup, TTP work--upupPRIOR TO:PRIOR TO:»» 22--4 units of FFP in the meantime prior to catheter4 units of FFP in the meantime prior to catheterpp

Thrombotic Thrombocytopenic PurpuraThrombotic Thrombocytopenic Purpura

A A thrombotic, not a bleedingthrombotic, not a bleeding clinical syndromeclinical syndromeDiagnostic criteriaDiagnostic criteria–– Diagnostic criteriaDiagnostic criteria

Acquired (inhibitor) or inherited (deficiency)Acquired (inhibitor) or inherited (deficiency)PathophysiologyPathophysiologyPathophysiologyPathophysiology–– ULvWF ULvWF vWF multimersvWF multimers

vWF cleaving protease vWF cleaving protease ADAMTSADAMTS 1313ADAMTSADAMTS--1313

((aa ddisintegrin isintegrin aand nd mmetalloprotease with etalloprotease with tthrombohrombosspondin typepondin type--1 motifs)1 motifs)

Treatment:Treatment:–– Plasma InfusionPlasma Infusion–– Plasma ExchangePlasma Exchange

Rheumatology ConsultRheumatology ConsultRheumatology ConsultRheumatology Consult

Rheumatology was called to review herRheumatology was called to review herRheumatology was called to review her Rheumatology was called to review her prior rheumatologic history and serologiesprior rheumatologic history and serologiesAccording to her private rheumatologist, the According to her private rheumatologist, the patient had a history of patient had a history of –– Raynaud’s phenomenon for 2Raynaud’s phenomenon for 2--3 years 3 years –– Mild intermittent arthralgiasMild intermittent arthralgias–– Denied morning stiffness, rash, skin changes, Denied morning stiffness, rash, skin changes,

or alopeciaor alopecia–– “Undifferentiated” connective tissue disease“Undifferentiated” connective tissue disease

Rheumatology ConsultRheumatology Consult----LabsLabsRheumatology ConsultRheumatology Consult LabsLabsTwo years agoTwo years agoANA 1:640 speckled, ESR 40ANA 1:640 speckled, ESR 40One year ago (Quest)One year ago (Quest)Anti DNA <30….(negative)Anti DNA <30….(negative)Anti Smith >6……(positive)Anti Smith >6……(positive)

One year ago (Monte)One year ago (Monte)2.5 …….(negative)2.5 …….(negative)>100 …..(positive)>100 …..(positive)

This admissionThis admissionAnti DNA 1.8 …(negative)Anti DNA 1.8 …(negative)

(p )(p )Anti RNP >6……..(positive)Anti RNP >6……..(positive)RF 205……………(positive)RF 205……………(positive)CRP 0 5 (normal)CRP 0 5 (normal)

(p )(p )>100 …..(positive)>100 …..(positive)

CRP 0.5 …………(normal)CRP 0.5 …………(normal)C3 152 …………..(normal)C3 152 …………..(normal)C4 40 …………..(normal)C4 40 …………..(normal)

…………………….…………………….…………………….…………………….

C3 91 ……………(normal)C3 91 ……………(normal)C4 22 ……………(normal)C4 22 ……………(normal)

Anti Ro …………(negative)Anti Ro …………(negative)Anti La Anti La …………(negative)…………(negative)B2 glycoprotein <20 ..(negative)B2 glycoprotein <20 ..(negative)

…………………….…………………….…………………….…………………….………………………………………………

Anti Ro 0.6 ……...(negative)Anti Ro 0.6 ……...(negative)Anti La 0.7 …….. (negative)Anti La 0.7 …….. (negative)B2 glycoprotein 5.7 B2 glycoprotein 5.7 (negative)(negative)

Anti CL IgM, IgG <6 ..(negative)Anti CL IgM, IgG <6 ..(negative)Anti SCL ………...(negative)Anti SCL ………...(negative)

……………………………………………… Anti CL IgM, IgGAnti CL IgM, IgG (negative)(negative)

Connective Tissue DiseaseConnective Tissue DiseaseConnective Tissue DiseaseConnective Tissue Disease

Unclassified CTDUnclassified CTDUnclassified CTDUnclassified CTD–– Does not differentiate or belong to any Does not differentiate or belong to any

particular patternparticular patternparticular patternparticular patternAtypical CTDAtypical CTD

E l t d t ili b t i l tE l t d t ili b t i l t–– E.g. related to silicone breast implantsE.g. related to silicone breast implantsOverlap SyndromeOverlap SyndromeMCTDMCTDDefined CTDDefined CTDe ed Ce ed C


Defined CTDDefined CTD–– Rheumatoid arthritisRheumatoid arthritisRheumatoid arthritisRheumatoid arthritis–– Systemic lupus erythematosusSystemic lupus erythematosus–– Sjögren’s syndromeSjögren’s syndromeSjögren s syndromeSjögren s syndrome–– SclerodermaScleroderma

Polymyositis/DermatomyositisPolymyositis/Dermatomyositis–– Polymyositis/DermatomyositisPolymyositis/Dermatomyositis


Classification relies on:Classification relies on:WellWell defined patterns of diseasedefined patterns of disease–– WellWell--defined patterns of disease defined patterns of disease presentationpresentationAutoantibody profilesAutoantibody profiles–– Autoantibody profilesAutoantibody profiles

–– No definite diagnostic criteriaNo definite diagnostic criteria

U diff ti t d C ti Ti DiU diff ti t d C ti Ti DiUndifferentiated Connective Tissue DiseaseUndifferentiated Connective Tissue Disease

Predictors of evolution to SLE in UCTD at 5Predictors of evolution to SLE in UCTD at 5Predictors of evolution to SLE in UCTD at 5 Predictors of evolution to SLE in UCTD at 5 years*years*–– African American ancestryAfrican American ancestryyy–– AlopeciaAlopecia–– Serositis Serositis ------------------------------------ (4.1)(4.1)–– Discoid lupusDiscoid lupus ---------------------------- (15.8)(15.8)–– Positive Coombs testPositive Coombs test

P i i ANAP i i ANA (4 8)(4 8)–– Positive ANA Positive ANA ---------------------------- (4.8)(4.8)–– Positive antiPositive anti--Smith antibodies Smith antibodies ------ (28.2)(28.2)

Positive antiPositive anti dsDNA andtibodiesdsDNA andtibodies–– Positive antiPositive anti--dsDNA andtibodiesdsDNA andtibodies

J Rheumatol 1996;23:469J Rheumatol 1996;23:469--7575( ) Relative risk( ) Relative risk* Cox multivariate regression analysis of 118 patients* Cox multivariate regression analysis of 118 patients


Autoantibodies in descending frequencyAutoantibodies in descending frequencyAutoantibodies in descending frequencyAutoantibodies in descending frequency–– ANAANA 55 55 –– 98%98%

A tiA ti R /SSAR /SSA 88 64%64%–– AntiAnti--Ro/SSARo/SSA 8 8 –– 64%64%–– AntiAnti--dsDNAdsDNA 4 4 –– 21%21%

A iA i L /SSBL /SSB 5%5%–– AntiAnti--La/SSBLa/SSB ~5%~5%–– AntiAnti--SmSm ~1%~1%

Clin Exp Rheumatol 2004;22:S14Clin Exp Rheumatol 2004;22:S14--S18S18


Predictors of evolution using autoantibodies atPredictors of evolution using autoantibodies atPredictors of evolution using autoantibodies at Predictors of evolution using autoantibodies at 10 years*10 years*AntibodyAntibody DiseaseDisease Predictive valuePredictive valueAntibodyAntibody DiseaseDisease Predictive valuePredictive value–– JoJo--11 Poly/DermatomyositisPoly/Dermatomyositis (ND)(ND)

S lS l 7070 S l dS l d (ND)(ND)–– SclScl--7070 SclerodermaScleroderma (ND)(ND)–– SmSm SLESLE (89) (89)

dd ( )( )–– dsDNAdsDNA SLESLE (64) (64)

ND ND –– no datano dataArth & Rheumat 1999;42:S320Arth & Rheumat 1999;42:S320*186 patients:*186 patients:

17.2% evolved to definite CTD17.2% evolved to definite CTD


Predictors of evolution using antiPredictors of evolution using anti Ro/SSARo/SSAPredictors of evolution using antiPredictors of evolution using anti--Ro/SSA Ro/SSA over 5 years in 148 patientsover 5 years in 148 patients

WellWell defineddefined (24 3%)(24 3%)–– WellWell--defineddefined (24.3%)(24.3%)»» 50% 50% -- Sjögren’sSjögren’s»» 30 5%30 5% -- SLESLE»» 30.5% 30.5% -- SLESLE»» RA (2*), SSc (2), PM/SSc (1), MCTD (1), RA (2*), SSc (2), PM/SSc (1), MCTD (1),

Wegener’s granulomatosis (1)Wegener’s granulomatosis (1)

–– Stable Stable (76%)(76%)

* I di id l ti t* I di id l ti tClin Exp Rheumatol 2001;19:403Clin Exp Rheumatol 2001;19:403--99

* Individual patients* Individual patients


Autoantibody profiles can evolve andAutoantibody profiles can evolve andAutoantibody profiles can evolve and Autoantibody profiles can evolve and accumulate over timeaccumulate over timeI di id l t tib di t t t llI di id l t tib di t t t llIndividual autoantibodies are not totally Individual autoantibodies are not totally predictivepredictive–– SLE seems to be preceded by evolution from SLE seems to be preceded by evolution from

antianti--Ro through ANA or Sm and then dsDNARo through ANA or Sm and then dsDNA

NEJM 2003;349;1526NEJM 2003;349;1526--3333

Mi d C ti Ti DiMi d C ti Ti DiMixed Connective Tissue DiseaseMixed Connective Tissue Disease

SLESLESclerodermaSclerodermaMyositisMyositisyyU1U1--snRNP antibodiessnRNP antibodies

Am J Med 1972;52:148Am J Med 1972;52:148--159159

Mixed Connective Tissue DiseaseMixed Connective Tissue Disease

Sharp (1972) criteria Sharp (1972) criteria Definite diagnosis requires 4 major criteria with positive antiDefinite diagnosis requires 4 major criteria with positive anti--U1 RNP greater than 1:4000 U1 RNP greater than 1:4000

d ti tid ti ti S Ab U1 RNP i th ifi RNP t i i t d ith thiS Ab U1 RNP i th ifi RNP t i i t d ith thiand a negative antiand a negative anti--Sm Ab. U1 RNP is the specific RNP protein associated with this Sm Ab. U1 RNP is the specific RNP protein associated with this syndrome. syndrome. Probable diagnosis requires either 3 major criteria or 2 major criteria (which must come from Probable diagnosis requires either 3 major criteria or 2 major criteria (which must come from the first 3 major criteria listed) and 2 minor criteria plus an antithe first 3 major criteria listed) and 2 minor criteria plus an anti--U1 RNP greater than 1:1000. U1 RNP greater than 1:1000. P ibl di i i 3 j it i ith t l i id f di if tiP ibl di i i 3 j it i ith t l i id f di if tiPossible diagnosis requires 3 major criteria without serologic evidence of disease or, if antiPossible diagnosis requires 3 major criteria without serologic evidence of disease or, if anti--U1 RNP is greater than 1:100, 2 major criteria or 1 major and 3 minor criteria. U1 RNP is greater than 1:100, 2 major criteria or 1 major and 3 minor criteria.

–– Major criteria are severe myositis, pulmonary involvement (diffusing capacity of lung Major criteria are severe myositis, pulmonary involvement (diffusing capacity of lung f b id 70% f l l h t i lif ti lf b id 70% f l l h t i lif ti lfor carbon monoxide 70% of normal pulmonary hypertension proliferating vascular for carbon monoxide 70% of normal pulmonary hypertension proliferating vascular lesions on lung biopsy), Raynaud phenomenon or esophageal hypomotility, swollen lesions on lung biopsy), Raynaud phenomenon or esophageal hypomotility, swollen hands observed or sclerodactyly, and highest observed antihands observed or sclerodactyly, and highest observed anti--U1 RNP (>1:10,000) with U1 RNP (>1:10,000) with negative antinegative anti--Sm Ab. Sm Ab.

–– Minor criteria are alopecia, leukopenia (4000 WBC/cc), anemia (<10 g/dL for females, Minor criteria are alopecia, leukopenia (4000 WBC/cc), anemia (<10 g/dL for females, <12 g/dL for males), pleuritis, pericarditis, arthritis, trigeminal neuralgia, malar rash, <12 g/dL for males), pleuritis, pericarditis, arthritis, trigeminal neuralgia, malar rash, thrombocytopenia (<100,000/cc), mild myositis, and history of swollen hands.thrombocytopenia (<100,000/cc), mild myositis, and history of swollen hands.

Mixed Connective Tissue Disease:Mixed Connective Tissue Disease:Mixed Connective Tissue Disease:Mixed Connective Tissue Disease:Long term outcome over 15 yearsLong term outcome over 15 years

62% had favorable outcome62% had favorable outcome38% had active disease or death38% had active disease or death11 of 47 patients died (22%)11 of 47 patients died (22%)p ( )p ( )–– Cause of death mostly pulmonary Cause of death mostly pulmonary

hypertensionhypertensionypyp

Am J Med 1972;52:148Am J Med 1972;52:148--159159

DiagnosisDiagnosis

UCTDUCTDUCTDUCTD

TTP and UCTD/MCTDTTP and UCTD/MCTDTTP and UCTD/MCTDTTP and UCTD/MCTD

Cl i TTP 3 7 * 1 illiCl i TTP 3 7 * 1 illiClassic TTP: ~3.7 cases* per 1 million Classic TTP: ~3.7 cases* per 1 million residentsresidentsNo association with UCTDNo association with UCTDFew reported cases of MCTD and TTPFew reported cases of MCTD and TTPpp–– 7 in literature7 in literature

*Am J Hematol 1995; 50:84*Am J Hematol 1995; 50:84--9090

Using Clinical Looking GlassUsing Clinical Looking Glass

TTP (ICD9) DemographicsTTP (ICD9) DemographicsMontefiore Montefiore 20002000--2005*2005*

ICD9ICD9

20032003Montefiore*Montefiore*

D hiD hi

Oklahoma Oklahoma RegistryRegistry

19961996--20042004ICD9ICD9 DemographicDemographic 19961996--20042004

Age avg, rangeAge avg, range 41 (941 (9--86)86) 47.1 (2147.1 (21--70)70) 48 48

FemaleFemale 75%75% 64.1%64.1% 67%67%MaleMale 25%25% 35.9%35.9% 33%33%

BlackBlack 61%61% 33.2%33.2% 19.4%19.4%HispanicHispanic 33%33% 38.0%38.0%WhiteWhite 6%6% 15.0%15.0%AsianAsian 1.0%1.0%Other/UnknownOther/Unknown 12 6%12 6% 80 6%80 6%Other/UnknownOther/Unknown 12.6%12.6% 80.6%80.6%

n=36n=36 n=24131n=24131 n=206n=206*CLG data (Cohen, Lansigan, Weiss)

TTP (ICD9) Cases 2000TTP (ICD9) Cases 2000--2005 2005 fifiat Montefioreat Montefiore

DISEASE ASSOCIATIONSDISEASE ASSOCIATIONS

ANAANA14%

HIV%

UNKNOWN50%

36%

*CLG data (Cohen, Lansigan, Weiss)

TTP Lab Data by ICD9TTP Lab Data by ICD9yy

6770

% of patients% of patients

47 5056

4450

60

PLT<1044

230

40

50 PLT<10LDH>1000BILI>2

2520

30 HGB<7Cr>2AST>200

0

10

Labdatawithin5yearperiodLab data within 5 year period

*CLG data (Cohen, Lansigan, Weiss)

TTP (ICD9) Mortality at Montefiore*TTP (ICD9) Mortality at Montefiore*

*CLG data (Cohen, Lansigan, Weiss)*CLG data (Cohen, Lansigan, Weiss)

ICU Course: Day 1 thru 3ICU Course: Day 1 thru 3

25yo woman with Raynaud’s, UCTD, TTP25yo woman with Raynaud’s, UCTD, TTP

FeverFeverIntubation for “airway protection”Intubation for “airway protection”Intubation for airway protectionIntubation for airway protectionHypotension, briefly on pressorsHypotension, briefly on pressorsPulmonary edemaPulmonary edemaPulmonary edemaPulmonary edemaAcute ↓ Hb to 6.1Acute ↓ Hb to 6.1

C 3C 3↑ WBC to 37↑ WBC to 37↑ transaminases and bilirubin↑ transaminases and bilirubinMetabolic acidosisMetabolic acidosis

ICU Course: Day 1 thru 3ICU Course: Day 1 thru 3ICU Course: Day 1 thru 3ICU Course: Day 1 thru 3

Plasma exchange was begun 12hrs into thePlasma exchange was begun 12hrs into thePlasma exchange was begun 12hrs into the Plasma exchange was begun 12hrs into the admission and continued dailyadmission and continued dailyS t ith PRBCS t ith PRBCSupport with PRBCsSupport with PRBCsVanco and Zosyn started for presumed Vanco and Zosyn started for presumed sepsissepsisLasix was started for pulmonary edemaLasix was started for pulmonary edemap yp y

Labs Day 1 thru 3Labs Day 1 thru 3Time 0hrs 6hrs 14hrs 30hrs 42hrs 54hrs 64hrs

Interventions Admission FFPs TPE x 1 TPE x 2 CACWBC 6.6 6.2 17.9 H 18.4 H 36.7 H 23.0 H 42.3 HHEMOGLOBIN 83 L 61 L 106 L 88 L 116 L 88 L 83 LHEMOGLOBIN 8.3 L 6.1 L 10.6 L 8.8 L 11.6 L 8.8 L 8.3 LHEMATOCRIT 26.0 L 18.7 L 30.9 L 26.0 L 34.7 L 26.0 L 23.8 LPLATELET 7.0 * 6.0 * 19.0 * 10.0 * 15.0 * 11.0 L 14.0 LLDH 1301 H 2200 H 2620 HLDH 1301 H 2200 H 2620 H

UREA NITROGEN 15 17 21 H 25 H 25 H 31 H 36 HCREATININE 0.8 0.8 0.8 0.9 1.0 1.0 1.6 HAST 81 H 65 H 713 H 526 H 663 HALT 46 H 35 390 H 342 H 439 H ALKALINE PHOS 55 53 51 57 54BILIRUBINTOTAL 66 H 48 H 114 H 126 H 129 HBILIRUBIN TOTAL 6.6 H 4.8 H 11.4 H 12.6 H 12.9 HBILIRUBIN DIRECT 0.4 H 1.4 H 4.5 H 4.8 H 5.8 H

pH 7.20 L 7.448 7.133 LpH 7.20 L 7.448 7.133 LPCO2 29.0 L 21.6 L 16.4 LPO2 131.0 H 151.0 H 138.0 HLACTIC ACID: 6.6 * 2.6 H 13.8 H

ICU: Day 2 and 3ICU: Day 2 and 3---- LabsLabsICU: Day 2 and 3ICU: Day 2 and 3 LabsLabsHaptoglobin Haptoglobin 8 L8 LCoombs (DAT)Coombs (DAT) negativenegativeCoombs (DAT)Coombs (DAT) negativenegativeAPLA workupAPLA workup negativenegativeFibrinogen Fibrinogen 331 331 ggDD--Dimer Dimer 3.0 H3.0 HUrine toxicology Urine toxicology negativenegativeH titi B&CH titi B&C titiHepatitis B&C Hepatitis B&C negativenegativeRespiratory culture: Many staph aureus, few Respiratory culture: Many staph aureus, few streptococcus pneumoniaestreptococcus pneumoniaestreptococcus pneumoniaestreptococcus pneumoniaeBlood and urine cultures: no growth to dateBlood and urine cultures: no growth to date

ICU: Day 2 and 3ICU: Day 2 and 3 –– Labs and TestsLabs and Tests#1#1 #2#2 #3#3

CPKCPK 520 540520 540

ICU: Day 2 and 3 ICU: Day 2 and 3 Labs and TestsLabs and Tests

CPK CPK 520 540520 540CKCK--MB% MB% 1.31.3 0.90.9TropTrop--TT 0.150.15 0.18 0.120.18 0.12TropTrop TT 0.150.15 0.18 0.120.18 0.12

EKG: sinus tach 144, low voltage compared to EKG: sinus tach 144, low voltage compared to initial EKG initial EKG ECHO: diffuse hypokinesis, small pericardial ECHO: diffuse hypokinesis, small pericardial effusion EF = 30%effusion EF = 30%effusion, EF = 30%effusion, EF = 30%–– Started lowStarted low--dose dobutamine 2.5mcg/kg/mindose dobutamine 2.5mcg/kg/min–– Continued Lasix for diuresisContinued Lasix for diuresis

Chest X-ray: Admission

Chest X-ray: 12 hrs

Chest X-Ray: Day 3

CACCACCACCACOn Day 3, during the 3On Day 3, during the 3rdrd round of plasma round of plasma

h h i i dih h i i diexchange, the patient went into cardiac exchange, the patient went into cardiac arrest arrest B d id ECHO h d ll i di lB d id ECHO h d ll i di lBedside ECHO showed a small pericardial Bedside ECHO showed a small pericardial effusion “not sizeable enough to tap”effusion “not sizeable enough to tap”Sh d d d ft 40 i tSh d d d ft 40 i tShe was pronounced dead after 40 minutes She was pronounced dead after 40 minutes of ACLSof ACLS

ADAMTSADAMTS--13 activity assay: < 0.1u/ml 13 activity assay: < 0.1u/ml (reference range > 0 56)(reference range > 0 56)(reference range > 0.56)(reference range > 0.56)

HeartHeart

Anti-human vWF

Phosphotungstic acid hematoxylin (PTAH)

HeartHeart

Hyaline thrombi rich in platelets and Will b d f t ith i i l fib ivon Willebrand factor with minimal fibrin

deposits

Petechial hemorrhage

Acute ischemic myocardial injury

LungLung

Lung, Right Lower Lobe : Diffuse hemorrhage

LungLung

PlateletPlatelet--rich microthrombi rich microthrombi Bilateral acute inflammation and diffuse Bilateral acute inflammation and diffuse hemorrhagehemorrhage

No evidence of vasculitisNo evidence of vasculitis

KidneyKidney

Anti-human vWF

KidneyKidneyKidneyKidney

Mi th bi i th l l ill iMi th bi i th l l ill iMicrothrombi in the glomerular capillariesMicrothrombi in the glomerular capillariesand arteriolesand arterioles

No evidence of lupus nephritisNo evidence of lupus nephritis

LiverLiver

Anti-human vWF

LiverLiverLiverLiver

MicrothrombiMicrothrombiMicrothrombi Microthrombi Focal necrosisFocal necrosis

Centrilobular congestionCentrilobular congestion

Pancreas: numerous microthrombi (αh-vWF )

Adrenal gland:numerous microthrombi (ah-vWF )

Brain and spinal cordp

Brain and spinal cordBrain and spinal cord

Hyaline thrombi in the gray matter of theHyaline thrombi in the gray matter of the brainstem, hippocampus, neocortex and the cerebellum ce ebe u

Anoxic changes seen within the CNS were consistent with capillary thrombi and with clinical events which included a low cardiac output (EF 30%) seizures acute myocardial infarction(EF 30%), seizures, acute myocardial infarction and repeated episodes of hypotension.

Microvascular platelet and von Willebrand factor-rich thrombi devoid of fibrin are found in the brain heart kidney pancreas adrenalthe brain, heart, kidney, pancreas, adrenal glands, spleen and other organs.

Diffuse multiorgan petechial hemorrhages and ischemia.

Acute Ischemic Myocardial Injury L bil t l t i fl ti diffLung, bilateral, acute inflammation, diffuse hemorrhage

Differential Diagnosis:

Thrombotic Thrombocytopenic Purpura (TTP)y p p ( )

Hemolytic Uremic Syndrome (HUS)

Disseminated intravascular coagulation (DIC)

Systemic Lupus Erythematosus (SLE)

Thrombotic Thrombocytopenic

P (TTP)Purpura (TTP)

Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome Are Distinct Pathologic Entities, A Review of 56 Autopsy CasesGregory A. Hosler, MD, PhD; Ana M. Cusumano, MD; Grover M. Hutchins, MDFrom the Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MdArchives of Pathology and Laboratory Medicine: 2003 Vol. 127, No. 7,

AcknowledgmentsAcknowledgmentsAcknowledgmentsAcknowledgments

Henny Billett MDHenny Billett MD HematologyHematologyHenny Billett, MDHenny Billett, MD HematologyHematologyClement Tagoe, MD, PhD Clement Tagoe, MD, PhD RheumatologyRheumatologyLjiljana Vasovic MDLjiljana Vasovic MD PathologyPathologyLjiljana Vasovic, MD Ljiljana Vasovic, MD PathologyPathologyKaren Weidenheim, MD Karen Weidenheim, MD NeuropathologyNeuropathologyHH M T i MDM T i MD H lH lHanHan--Mou Tsai, MDMou Tsai, MD HematologyHematologySpecial Thanks:Special Thanks:–– Jeff Weiss, MDJeff Weiss, MD–– Jules Cohen, MDJules Cohen, MD

a fatal combination of a fatal combination of raraynaud

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