1. Thrombotic Thrombocytopenic Purpura

2. British J of Hematology 2000 History In 1924, Dr.Eli Moschcowitz described a 16- year old girl with abrupt onset of petechiae, pallor, followed by paralysis, coma, and death. Autopsy showed ‘hyaline’ thrombi occluding terminal arterioles and capillaries.

3. Rock GA, Br J Hematology 2000 Definition Syndrome of Coomb’s negative microangiopathic hemolysis and thrombocytopenia in the absence of an alternative explanation for these manifestations. Presence of Fever, Neurological and renal abnormalities : classic Pentad.

4. Shumak KH, Ann Intern Med 1995 Clinical Presentation Approximately 1000 new cases occur each year Common in middle aged group,median age-40 Female:male (2:1). Acute onset and fulminant course Mortality rate >90% in pre-pheresis era. Relapse rates, 10-40% ranging from months to years have been reported.

5. Clinical Features Renal abnormalities –Proteinuria/hematuria > oliguria/ARF Neurological abnormalities –Mental status changes> focal abnormalities. Profound weakness related to anemia. Abdominal pain,nausea, vomiting & diarrhea Fever without chills. Primary/idiopathic TTP vs. secondary

6. George, Blood Aug 2000 Secondary TTP Drug-induced –Acute immune mediated: Ticlopidine & plavix. –Dose-related: mitomycin, tacrolimus, pencillin, cyclosporine, cisplatin, bleomycin, OCP –Quinine: HUS like illness. Pregnancy and post-partum. Allogenic bone marrow transplant. Autoimmune disorders (SLE,scleroderma) HIV infection.

7. Pathogenesis Deficiency of VWF-cleaving protease –Termed ADAMTS13 ( “a disintegrin-like and metalloprotease with thrombospondin type I repeats –Corresponding gene : chromosome 9q34. –Familial recurrent TTP: constitutional deficiency –Acquired/Idiopathic : transient auto-antibodies –HUS : normal levels of enzyme

9. ULVWF Model

11. George,Blood Aug 2000 Diagnosis Primary diagnostic criteria –Thrombocytopenia ( often below <20,000) –Microangiopathic hemolytic anemia Negative Coomb’s test. Fragmented red cells (schistocytes) on peripheral smear LDH elevation is the hallmark of RBC destruction and tissue injury related to ischemia. Presence of above criteria is sufficient to establish presumptive diagnosis & begin PE

16. Diagnosis At present there are no confirmatory test. Other features in pentad support the diagnosis. Tests for ADAMTS13 deficiency or inhibitors are not readily available and lack standardization.

17. Differential Diagnosis Disseminated intravascular coagulation. Sepsis: cytomegalovirus, rocky mountain spotted fever, meningococcemia. Preeclampsia/eclampsia, HELLP. Disseminated malignancy. Hemolytic-uremic syndrome Evans syndrome Malignant hypertension.

18. Treatment Plasma exchange: –Untreated TTP has 80-90% mortality. –Removes ULvWF multimers, autoantibody and replaces metalloproteinase. –Randomized controlled trial (Rock et al, 1991) –FFP as the replacement fluid is most widely used and cost effective.

19. Treatment Cryosupernatant plasma (Rock et al 2000) –Theoretically superior to FFP in refractory disease –Removal of cryoprecipitate from donor plasma results in removal of vWF ( only 18%), with no change in metalloproteinase concentration. Solvent-detergent plasma (Moake et al 1998) –Lacks high molecular weight forms of VWF –Inactivates lipid-enveloped viruses. –Drawback: parvovirus & hep A not inactivated.

20. Response To Treatment MS changes improve dramatically. Thrombocytopenia require several days. Parameters of hemolysis improve promptly, yet anemia may continue to worsen. Recovery from renal failure is unpredictable and often slow. Prolonged courses of PE, with frequent exacerbations is characteristic of idiopathic TTP

21. American Society of Hematology 2002 Complications of Plasma Exchange Central venous catheter-related Insertion procedure 4% Sepsis 15% Thrombosis 10% Plasma-related Allergic 4% Infection 0 Instrument-related Unintentional plateletpheresis

22. Duration of treatment. No studies precisely determine optimal schedule AABB extracorporeal therapy committee: daily PE until plt ct > 150k for 2-3 days. American Society for Apheresis: daily PE until Plt > 100k, complete normalization of LDH. Tapering schedule to 3 times per week after sustained response is highly recommended.

23. Conn's current therapy ;2004 Treatment Avoid prophylactic platelet transfusion (Gordon et al, 1987; Harkness et al 1981) –Unless life-threatening bleeding is present. –Provide additional substrate for thrombus formation. –MI and strokes have reportedly occurred after transfusion.

24. British J of Hemat 2000 Adjuvant Therapy Antiplatelet agents: –Aspirin (325mg), dipyrimadole ( 400mg) –Ticlopidine maintenance for 1 year. Corticosteroids –Presence of auto antibodies to ADAMTS13 supports the autoimmune disease. –Reserved for patients refractory to PE.

25. British J of Hematology 200 Treatment Splenectomy (Crowther et al, 1996) Chemotherapy: Cytoxan, Vincristine, Rituxan, CHOP. High- dose IV IgG Protein A immunoadsorption columns.