BCSLS Hematology Telehealth Broadcast Case 2 June 16, 2005 Kin Cheng higbc@yahoo.ca

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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