A 15-year-old female presented with fever, abdominal pain, and thrombocytopenia. Tests indicated a diagnosis of thrombotic thrombocytopenic purpura (TTP) and systemic lupus erythematosus (SLE) with its associated complications. The patient was treated with plasma exchange and admitted to the ICU due to the severity of her condition.

1. CASE CONFERENCE
Okayama University Hospital
The 26th Generalist Training Seminar
Yuto Matsuoka 2017. 3. 19. Sun

2. 15YEARS OLD FEMALE
WITH FEVER AND
ABDOMINAL PAIN

3. HISTORY
Presenting Complaints
7-days history of fever and
abdominal pain

4. HISTORY
-7 days
-6 days
Admission
Abdominal Pain,mainly epigastric area
Fever and Nausea
Visited the previous hospital.
Blood test and CT was performed.
Referred to Okayama University Hospital
immediately.

5. HISTORY(7 DAYS BEFORE ADMISSION)
Abdominal pain: Acute onset ,mainly epigastric area.
Usual state of good health until 7days PTA;
Abdominal pain developed.

6. HISTORY(6 DAYS BEFORE ADMISSION)
Fever: run a fever up to 38℃, higher in the night
and became better in the morning.
Nausea: Gradual onset without vomiting.
No relation with oral intake.
No headache/ photophobia/retro-orbital pain
No associated neck/chest pain.

7. HISTORY(On ADMISSION)
Pt took acetaminophene repeatedly when she
had a fever.
Blood tests (At the previous hospital)
Hb 6.7,Plt 16000,BUN 27.6,Cre 1.50,AST 43,ALT 35
erythrocyte fragmentation(+)
Erythrocyte fragmentashon: 破砕赤血球

8. ON DIRECT QUESTIONING
Fever
No earache.
No sore throat, no sputum and cough.
No diarrhea.
Constipation (+)
No sick contact.
Vaccinated for flu.

9. ON DIRECT QUESTIONING
Abdominal pain
Acute onset. mainly epigastric area.
Not migratory pain.
Intermittent pain. NRS: 4-5/10
No diarrhea (-)
Constipation (+)
No association with oral intake.
No association with movement.
No sick contact.

10. ON DIRECT QUESTIONING
Anemia
No previous episodes.
No hematochezia and hematuria.
No family history of hemoglobinopathy.
No associated menstruation.
No associated pain.

11. ON DIRECT QUESTIONING
Thrombocytopenia
No previous episodes.
No hemorrhagic episodes before.
No pseudothrombocytopenia.
No family history of hematologic disorders.
No associated menstruation.
No associated pain.

12. REVIEW OF SYSTEMS
No headaches.
No chest pain, cough or dyspnea.
No abdominal fullness, melena or hematochezia.
No history of abdominal surgery.
Menstrual period: regular
No possibility of pregnancy
Other REVIEW OF SYSTEMS questions were
negative(not shown).

13. MEDICAL AND SURGICAL HISTORY
Pneumothorax⇨neonatal period,
conservative treatment.
No abnormality in the perinatal period.
Drugs
No medications or supplements.

14. SOCIAL HISTORY
Social History
No smoking and no ethanol.
No sick contacts.
Birthplace: Okayama prefecture.
Occupation: Student.
Pets: Cat.
Allergies
No allergy.

15. VITAL SIGNS
GCS15/15
Body temperature: 37.7℃
Blood Pressure: 140/80mmHg
Heart rate: 83bpm
Respiratory rate: 18/min
SpO2: 99%(room air)

16. PHYSICAL EXAMINATION
HEENT
Atraumatic and normocephalic
Not in acute distress
No neck stiffness, pallor, jaundice.
No Lymphadenopathy or goiter.
Hyperemic conjunctiva(-)
Anemic conjunctiva(+)
Erythema(+)
Normal oral cavity

18. PHYSICAL EXAMINATION
Cardiovascular
No jugular venous distension.
No heaves or thrills
Apex in normal position
S1→S2→S3(-) S4(-)
No murmur, rubs or gallops
Respiratory
Trachea central, no tug sign.
Percussion resonant throughout.
Auscultation: Normal vesicular breath sounds

19. PHYSICAL EXAMINATION
Abdomen
No abdominal distension, normal bowel
sounds and no tenderness.
Hepatosplenomegaly (-)
Mcburney (-)
Murphy sign (-)
Digital Rectal Exam was not performed.
Extremities
No clubbing or edema.
No joint swelling.

20. PHYSICAL EXAMINATION
Skin
No erythema or swelling.
Musculoskeletal examination
All joints appeared normal. No erythema,
calor or swelling. Full range of motion on
all joints.

21. PHYSICAL EXAMINATION
Cranial Nerves
II: Pupillary reflexes: bilaterally prompt.
3mm/3mm. Normal consensual reflexes.
Normal visual fields.
III/IV/VI- NAD
V – motor and sensory NAD
VII,VIII, IX, X, XI, XII - NAD
Normal cerebellar function

22. PHYSICAL EXAMINATION
Peripheral Nervous Examination
Tone: Normal
Power: 5/5 in all muscle groups throughout
Reflexes: 2+ throughout
Babinski: ⇩/⇩
Coordination: Normal
Sensation: Grossly normal

23. PROBLEM LIST
HISTORY / Physical Exams
#1 Fever
#2 Abdominal pain
#3 Nausea
#4 Mild facial erythema

24. What is your differential
diagnosis and what tests
would you undertake?

25. LABORATORY DATA
Biochemistry
CPK 18 IU/l
T.BIL 1.09 mg/dl
AST 43 IU/l
ALT 35 IU/l
LDH 464 IU/l
γ-GTP 38 IU/l
ALP 229 IU/l
TP 7.1 g/dl
Alb 3.8 g/dl
BUN 27.6 mg/dl
CRE 1.50 mg/dl
UA 5.0 mg/dl
Na 137 mEq/l
K 4.6 mEq/l
Cl 112 mEq/l
Cacorr 8.6 mg/dl
IP 3.9 mg/dl
Fe 13 μg/dL
TIBC 290 μg/dL
Ferritin 33.5 ng/mL
CRP 0.93 mg/dl
Urinalysis
Specific grv 1.017
Protein (+)
Ketones (-)
RBC 30-49 /HPF
WBC 1-4/HPF
CASTS (+)
Bacteria (2+)
Pregnancy (-)
Complete blood count
WBC 5,300
Hb 6.7 g/dl
MCV 65.9 fl
PLT 1.6 10^4/
Neut 62.7 %
Lymph 27.5 %
Ret 2.75 %
Coagulation
PT-INR 1.15
APTT 72.8
Ddimer 8.3 μg/mL
Hp <10 mg/dL

26. BLOOD CELL PROFILE

27. CHEST RADIOGRAPH

28. ELECTROCARDIOGRAM

29. COMPUTED TOMOGRAPHY

30. EXTENDED PROBLEM LIST
HISTORY / Physical Exams
#1 Fever
#2 Abdominal pain
#3 Nausea
#4 Mild facial erythema
Labs/ECG/Xp
#5 Microcytic anemia
#6 Erythrocyte fragmentation
#7 Thrombocytopenia
#8 High serum BUN and Cre
#9 High serum Ddimer
#10 Prolonged APTT
#11 Hematuria
#12 Proteinuria
#13 Casts in urine

31. DDX FOR ANEMIA and
THROMBOCYTEPENIA
 Thrombotic Thrombocytopenic Purpura (TTP)
 Hemolytic Uremic Syndrome (HUS)
 Disseminated Intravascular Coagulation (DIC)
Autoimmune causes
Hematologic cause
Miscellaneous cause
 Evan's Syndrome: Autoimmune Hemolytic Anemia and Thrombocytopenia
(AIHA)
 Paroxysmal Nocturnal Hemoglobinuria (PNH)
 Systematic Lupus Erythematosus (SLE)
 Megaloblastic Anemia Due to Vitamin B12 or Folic Acid Deficiency
 Malignancy, Drugs, Sepsis, HELLP syndrome, Malignant hypertension

32. LABORATORY DATA
RF 11.2
ANA 8.22
Anti-Sm antibodies 15.40
Anti-SS-A / Ro antibody <0.50
Anti-SS-B / La antibody <0.50
Anti-ds DNA IgG antibody 57.40
Anticardiolipin antibody 149.00
CH50 15
IgG 1447.2
IgA 174.7
IgM 116
C3 56.5
C4 3.8
Anti-centromere antibody (-)
Anti-RNP antibody (-)
Anti-scl-70 antibody (-)
Anti-Jo-1 antibody (-)
PR3-ANCA <0.50
MPO-ANCA <0.50
Anti-GBM antibody <1.40
Coombs (-)
FLU (-)
O-157 (-)
Fecal occult blood (-)

33. AUTOANTIBODY
Autoantibody Target antigen Disease Associated
Anti-Sm Core proteins of snRNPs SLE
Anti-SS-A RNPs SLE, Sjögren syndrome
Anti-SS-B RNPs Systemic Scleroderma (SSc)
Anti-ds DNA DNA SLE
Anticardiolipin β2-GPI Antiphospholipid Syndrome (APS)
Anti-RNP snRNP70 SLE, SSc, PM/DM, MCTD
Anti-scl-70 Type I topoisomerase SSc
Anti-Jo-1 Histidine-tRNA ligase PM/DM
PR3-ANCA Neutrophil cytoplasm GPA
MPO-ANCA Neutrophil cytoplasm MPA, EGPA
Anti-GBM GBM Goodpasture’s disease

34. LABORATORY DATA
ADAMTS-13 activity 1.7% (70-120 %)
ADAMTS-13 inhibitor <0.5 BU/mL

35. DIAGNOSIS
# Thrombotic Thrombocytopenic Purpura
and
# SLE
#Antiphospholipid syndrome

36. TTP
5 CLASSIC PENTAD
1. Thrombocytopenia
2. Hemolytic anemia
3. Renal dysfunction
4. Fever
5. Neurologic manifestation
ADAMTS-13 activity 1.7% (70-120 %)
ADAMTS-13 inhibitor <0.5 BU/mL
O-157 (-)
Fecal occult blood (-)

37. Requirement≧4 criteria (at least 1 clinical and a laboratory criteria)
OR biopsy-proven lupus nephritis with posirtive ANA or Anti-DNA
CLINICAL CRITERIA IMMUNOLOGIC CRITERIA
1. Acute Cutenious Lupus
2. Chronic Cutenious Lupus
3. Oral or nasal ulcers
4. Non-Scarring alopecia
5. Arthritis
6. Serositis
7. Renal
8. Neurologic
9. Hemolytic anemia
10.Leukopenia
11.Thrombocytopenia(<100,000/mm3)
1. ANA
2. Anti-DNA
3. Anti-Sm
4. Antiphospholipid Ab
5. Low complement(C3, C4, CH50)
6. Direct Coombs’ test(do not count
in the presence of hemolytic
anemia)
Petris M, et al. Arthritis and Rheumatism Aug 2012
SLE┃2012 SLICC Criteria

38. Platelet transfusion would be contraindicated
since the patient had possiblity to have TTP .
AFTER HOSPITALIZATION
Pt was admitted to the ICU. Plasma exchange(PE)
was performed for the possibility of TTP before
diagnosis.

39. 0
2
4
6
8
10
12
14
16
18
0
2
4
6
8
10
12
60mg/day
ICU Adimission ICU discharge
AFTER HOSPITALIZATION
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29
Day
Hb
(g/dL)
Plt
(10^4/)
RBC 2U
Cre
(mg/dL)
PE PE
Steroid Pulse
1000mg/day
Steroid Pulse
1000mg/day
48mg/day
Diagnosed

40. 1) What is the appropriate approach for
DDx of anemia and thrombocytopenia?
2) Is there any association between TTP
and SLE?
Clinical Questions

41. ANEMIA
and
THROMBOCYTOPENIA

42. DIAGNOSTIC APPROACH┃ANEMIA

43. DIAGNOSTIC APPROACH┃
THROMBOCYTOPENIA
Roberto Stasi Hematology 2012;2012:191-197
Erythrocyte fragmentation

44. DDX FOR ANEMIA and
THROMBOCYTEPENIA
 Thrombotic Thrombocytopenic Purpura (TTP)
 Hemolytic Uremic Syndrome (HUS)
 Disseminated Intravascular Coagulation (DIC)
Autoimmune causes
Hematologic cause
Miscellaneous cause
 Evan's Syndrome: Autoimmune Hemolytic Anemia and Thrombocytopenia
(AIHA)
 Paroxysmal Nocturnal Hemoglobinuria (PNH)
 Systematic Lupus Erythematosus (SLE)
 Megaloblastic Anemia Due to Vitamin B12 or Folic Acid Deficiency
 Malignancy, Drugs, Sepsis, HELLP syndrome, Malignant hypertension

45. ERYTHROCYTE FRAGMENTATION

46. DDX FOR ERYTHROCYTE
FRAGMENTATION
 Thrombotic Thrombocytopenic Purpura (TTP)
 Hemolytic Uremic Syndrome (HUS)
 Disseminated Intravascular Coagulation (DIC)
Autoimmune causes
Hematologic cause
Miscellaneous cause

47. EPIDEMIOLOGY OF TTP
5% Hereditary
95% Acquired
 Suspected TTP-HUS 11 cases/million/yr
 Idiopathic TTP-HUS 4.5 cases/million/yr
 Severe ADAMTS13 deficiency
1.7 cases/million/yr
 Prior to plasma exchange, mortality rate
was as high as 90%, now less than 20%.

48. MECHANISMS OF TTP
Joel L NEJM 2002;347:589-

49. MECHANISMS OF TTP
Joel L NEJM 2002;347:589-
ADAMTS-13 activity 1.7% (70-120 %)
ADAMTS-13 inhibitor <0.5 BU/mL

50. SOME FACTS┃TTP and SLE
 TTP may occur secondary to infections, malignancy, drugs,
pregnancy, and autoimmune diseases such as SLE.
Veyradier A, et al J Thromb Haemost 3:2420–2427.
 Although plasma exchange dramatically improved the prognosis of
TTP with over 80 % of survival rate, the episode will be severe and
lethal (from 34.1 to 62.5 % morality rate) when TTP occurs in patient
s with SLE
Sadler JE, et al Hematology Am Soc Hematol Educ Program: 407–423.
Letchumanan P, et al Rheumatology (Oxford) 48:399–403.
Musio F, et al Semin Arthritis Rheum 28:1–19

51. SOME FACTS┃TTP and SLE
Vasso S, et al. Scand J Rheumatol. 30 : 308-310, 2001.
How TTP associated with SLE occurs and how to
improve its prognosis remain unclear until now.
TTP associated with SLE appears to be caused by not only deficient
ADAMTS 13 activity but endothelial dysfunction and cytokine disorder.
But…

52. INITIAL TREATMENT OF TTP

53. TAKE HOME MESSAGE
When you see anemia and thrombocytopenia,
never forget to check peripheral blood smear.
“Erythrocyte fragmentation!”
TTP may occur secondary to autoimmune
diseases such as SLE.
A patient who has an acquired syndrome that
could be either TTP or HUS should be presumed
to have TTP, and PE should be initiated as soon
as possible.