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Thrombotic Thrombocytopenic Purpura. 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. Definition.

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history
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.

British J of Hematology 2000

definition
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.

Rock GA, Br J Hematology 2000

clinical presentation
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.

Shumak KH, Ann Intern Med 1995

clinical features
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
secondary ttp
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.

George, Blood Aug 2000

pathogenesis
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
diagnosis
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

George,Blood Aug 2000

diagnosis1
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
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
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.
treatment1
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
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
complications of plasma exchange
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

American Society of Hematology 2002

duration of treatment
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.
treatment2
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.

Conn's current therapy ;2004

adjuvant therapy
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 Hemat 2000

treatment3
Treatment
  • Splenectomy (Crowther et al, 1996)
  • Chemotherapy: Cytoxan, Vincristine, Rituxan, CHOP.
  • High- dose IV IgG
  • Protein A immunoadsorption columns.

British J of Hematology 200