BCSLSHematology Telehealth

BroadcastCase 2

June 16, 2005Kin 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

Weibel-Palade Body

ULVWF Multimers

ADAMTS-13

Endothelial Cell

Cleaved vWF Multimers

TTP and ULVWF

Weibel-Palade Body

ULVWF Multimers

ADAMTS-13

Endothelial Cell

Agglutinated platelets

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– 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:– Thrombocytopenia– Microangiopathic anemia:

• Schistocytes– Increased LDH: Due to tissue necrosis– Rule out other causes of MAHA

• Treatment: Urgent: plasma exchange