thrombotic thrombocytopenic purpura (TTP)

Introduction

Acute disorder of increased platelet consumption. TTP is a medical emergency.

Etiology

• non familial form of TTP is due to an inhibitor of vWF-cleaving protease
• familial form of TTP is due to deficiency of vWF-cleaving protease (ADAMTS13)
• organ transplantation
• malignancies
• pharmaceuticals:
  • mitomycin C
  • bleomycin
  • gemcitabine
  • cyclosporin A
  • quinine
  • clopidogrel
  • ticlopidine
• radiation
• association with pregnancy & use of oral contraceptives
• immune-mediated drug hypersensitivity
• E. coli 0157 & Shigella more common with hemolytic-uremic syndrome

Epidemiology

• generally affects younger adults
• peak incidence in 3rd decade of life
• 70% of patients are female

Pathology

• thrombocytopenic & microangiopathic hemolytic anemia
• ultra-large von-Willebrand factor multimers may be observed
  • deficiency in ADAMTS13 (vWF-cleaving protease)
  • platelet aggregates & microvascular thrombosis
• endothelial cell injury
• subendothelial cell deposits
• glomerular lesion also seen with:
  • malignant hypertension
  • scleroderma
  • post-partum renal failure
• fever likely from microinfarcts
• thrombocytopenia of thrombotic thrombocytopenia is a comsumptive process whereby thrombocytopenia occurs by platelet activation of the clotting system with resultant depletion of platelets
• antibodies to platelet factor 4 in nearly all patients

Genetics

(familial form)

• autosomal recessive
• defects in ADAMTS13 are associated with congenital thrombotic thrombocytopenic purpura (TTP)

Clinical manifestations

• severe thrombocytopenia
• microangiopathic hemolytic anemia (all patients)
• fluctuating neurologic signs
  • confusion
  • focal neurologic signs
  • headache
  • transient numbness
  • coma
• renal insufficiency, renal failure
  • progressive renal failure is uncommon
• fever (variable)
• severe hypertension
• purpura, petechiae
• pallor
• abdominal pain
  • nausea, vomiting, diarrhea due to intestinal ischemia
• chest pain, cardiac arrhythmia due to myocardial injury
• familial form:
  • neonatal onset
  • response to fresh plasma infusion
  • frequent relapses

Laboratory

• complete blood count (CBC)
  • anemia
  • thrombocytopenia (100%)
• peripheral smear
  • erythrocyte fragments, schistocytes (100%)
  • diminished platelets
• increased reticulocyte count (reticulocytosis)
• serum chemistries
  • serum lactate dehydrogenase (LDH) increased
  • serum urea nitrogen increased
  • serum creatinine increased
  • serum bilirubin: increased unconjugated (indirect) bilirubin
  • serum haptoglobin is diminished
• urinalysis
  • WBC (pyuria)
  • RBC
  • hemoglobin (hematuria) from microthrombi
  • large amounts of albumin (albuminuria)
• prothrombin time (PT) is generally normal
• activated partial thromboplastin time (aPTT) is generally normal
• direct antiglobulin test (Coomb's test) is negative
• plasma fibrinogen is normal
• antinuclear antibody (rule out lupus erythematosus)
• ADAMTS13 in plasma may be useful for prognosis
  • decreased plasma ADAMTS13 activity
  • positive plasma ADAMTS13 inhibitor

Radiology

• neuroimaging (CT of brain)
  • may show ischemic stroke
  • transient microthrombi may lead to reversible findings

Complications

• mortality rate is high (15%)

Differential diagnosis

• immune thrombocytopenic purpura (ITP)
  • normal LDH
  • no erythrocyte fragments on peripheral smear
• severe vasculitis
• hemolytic-uremic syndrome
• HELLP syndrome
• disseminated intravascular coagulation (DIC)
  • prolonged PT & aPTT
  • elevated fibrin-split products (D-dimer)
  • diminished plasma fibrinogen
• Evan's syndrome
  • Coomb' positive hemolytic anemia
    • direct antiglobulin test is positive
• paroxysmal nocturnal hemoglobinuria
  • no microangiopathic hemolytic anemia, no schistocytes

Management

• plasmapheresis
  • do not wait for laboratory confirmation (ADAMTS13 in plasma)
  • continue until patient improves or expires
  • superior to plasma infusion
• other treatments if plasmapheresis not available
  • high-dose gamma globulin
  • plasma exchange with fresh frozen plasma (FFP)
    • 30 mL/kg in the 1st 24 hours
    • then 15 mL/kg/day, until apheresis can be performed
    • plasma exchange removes ADAMTS13 inhibitor & replaces ADAMTS13
    • fluid overload is common, begin diuretic therapy simultaneously
  • prednisone & rituximab suppress autoantibody formation
  • other treatments suggested in the past
    • whole blood exchange transfusion
    • anti-platelet drugs (if FFP is ineffective)
    • vincristine
    • caplacizumab
      • prevents formation of platelet aggregates & microvascular thrombosis by inhibiting von Willebrand factor
      • for lasting remission in acquired TTP, may be necessary to restore normal levels of ADAMTS13, (vWF-cleaving protease)
• glucocorticoids may also be useful because of difficulty distinguishing TTP from vasculitis
• do not order platelet transfusions, may exacerbate microvascular occlusion
• anticoagulation
  • argatroban, danaparoid, fondaparinux, or direct oral anticoagulants
• discontinue offending medications
• splenectomy
• mortality rate is 25%
• best prognostic indicators
  • platelet count return to normal
  • decreasing LDH
  • resolution of neurologic symptoms
• relapse months to years later in 20-30%
  • prior to plasma exchange, patients either died (75%) or recovered without relapse (25%)

More general terms

• thrombotic microangiopathy
• thrombocytopenia
• hypercoagulability

Additional terms

• A disintegrin & metalloproteinase with thrombospondin type 1 motif 13; ADAMTS-13; ADAM-TS 13; ADAM-TS13; von Willebrand factor-cleaving protease; vWF-cleaving protease; vWF-CP (ADAMTS13, C9orf8, UNQ6102/PRO20085)
• HELLP syndrome
• hemolytic uremic syndrome (HUS)

Database

• OMIM: https://mirror.omim.org/entry/274150