thrombotic thrombocytopenic purpura. british j of hematology 2000 history in 1924, dr.eli...
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Thrombotic Thrombocytopenic Purpura
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.
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.
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.
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
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.
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
ULVWF Model
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
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.
Differential Diagnosis
• Disseminated intravascular coagulation.
• Sepsis: cytomegalovirus, rocky mountain spotted fever, meningococcemia.
• Preeclampsia/eclampsia, HELLP.
• Disseminated malignancy.
• Hemolytic-uremic syndrome
• Evans syndrome
• Malignant hypertension.
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.
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.
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
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
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.
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.
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.
British J of Hematology 200
Treatment
• Splenectomy (Crowther et al, 1996)
• Chemotherapy: Cytoxan, Vincristine, Rituxan, CHOP.
• High- dose IV IgG
• Protein A immunoadsorption columns.