1. BCSLS Hematology Telehealth Broadcast
Case 2
June 16, 2005
Kin Cheng

2. CASE 2 60 yr old oriental male One week prior to admission:
headache, vomiting, dizziness
In Emergency:
Uncooperative
Combative with staff
“Code White” was called

3. Lab Findings WBC: 9.0 G/L RBC: 2.3 T/L Hgb: 71 g/L MCV: 91 fL
Platelets: Less than 10 G/L with giant platelet forms

4. Lab Results INR: 1.0 aPTT: 30.0 sec Direct Coombs: Negative
Total bilirubin: 46 mmol/L
Haptoglobin: <0.1g/L
Liver enzymes: Normal

7. Thrombotic Thromboctopenic Purpura (TTP)
First described in 1926: in a 16 yr female:
Petechiae, pallor
Paralysis, coma
Death
Microvascular hyaline thrombi in terminal arterioles and capillaries

8. TTP HISTORY 1966: Pentad of TTP symptoms established Fever MAHA
Thrombocytopenia
Neurologic symptoms
Renal dysfunction

9. TTP History 1982: Research on large vWf multimers
4 TTP patients with large multimers
Ability to agglutinate platelets
1991: Plasma exchange: decreased mortality rate by 25%
1996: discovered vWf multimers cleaving protein
2004: Role of ADAMTS-13 protein

10. vWf Multimers Made in megakaryocytes and endothelial cells
Stored in platelet alpha granules and Weibel-Palade bodies of endothelial cells
Ultralarge molecule cleaved to smaller subunits by protease ADAMTS-13
ULVWF : super adhersive to platelets

11. ADAMTS-13 and ULVWF ULVWF Multimers Endothelial Cell
Cleaved vWF Multimers
ADAMTS-13
ULVWF Multimers
Endothelial Cell
Weibel-Palade Body

12. TTP and ULVWF ULVWF Multimers Endothelial Cell ADAMTS-13
Agglutinated platelets
Endothelial Cell
Weibel-Palade Body

13. Factors influencing platelet thrombi formation in TTP
Absence or decreased level of ADAMTS-13 results in formation of ULVWF
Level of ADAMTS-13: <5 % of normal
Role of anchoring protein, P-selectin
Increased fluid shear environment

14. ADAMTS-13
“A Disintegrin-like And Metalloprotease with ThromboSpondin type 1 motif.”
Normal adults: 50 – 178%
<5% of activity found in acquired TTP patients
Genetic: 9q34
Antibody to ADAMTS-13

15. Clinical Picture of TTP
Frequency: 3.7 per million
Median age: 35 (neonate to 90 yrs)
Microvascular thrombi: MAHA
Pentad of symptom:
Fever, neurologic symptoms, renal failure, thrombocytopenia, anemia with schistocytes
Normal coagulation
Increased LDH

16. Acute Idiopathic TTP Acquired Autoantibody to ADAMTS-13 found
Clinical relapse not uncommon
ULVWF multimers present

17. Differential Diagnosis of TTP
Childhood HUS
Pregnancy-associated microangiopathy
Transplant-associated thrombocytopenia pupura
Drug-induced purpura
HELLP
Malignancies
Autoimmune diseases, SLE, APLS

18. HUS vs TTP Patients: 4-5 years old Causative agent: E. coli 0157:H7
Bloody diarrhea
Shiga-toxin binds to glycolipid surface of endothelial cells, influenced by cytokines
Toxin binding induces platelet clumping
Acute renal failure

19. Pregnancy & TTP Risk in near term and post-partum
Accounts for 10% of all TTP in one study
Decreased ADAMTS-13 activity and increased plasma vWF in 2nd / 3rd trimesters
Difficult to distinguish TTP / HELLP syndrome

20. TTP and drugs Quinine Penicillin
Anti-platelet agents: ticlopidine, clopidogrel

21. Diagnosis
TTP
HUS
HELLP
DIC
CNS symptoms /signs
+++
+/-
Renal impairment +
Fever
-/+ -
Liver impairment
Hypertension
Hemolysis ++
Thrombocytopenia
Coagulopathy

22. Treatment Plasma exchange Hemodialysis if kidney fails
Remove antibody
Restores ADAMTS-13
Improves mortality rate to 10 – 20%
Daily for 1-2 weeks
Hemodialysis if kidney fails
Plasma infusion if exchange not available
Corticosteriod for non-responders

23. Remission Some patients have relapsed episodes Some good responders
Reflects diversity of TTP

24. Summary Lab diagnosis of TTP: Treatment: Urgent: plasma exchange
Thrombocytopenia
Microangiopathic anemia:
Schistocytes
Increased LDH: Due to tissue necrosis
Rule out other causes of MAHA
Treatment: Urgent: plasma exchange