Description

• An acute syndrome of microangiopathic hemolytic anemia (MAHA) and consumptive thrombocytopenia with deposition of hyaline thrombi in terminal arterioles and capillaries leads to ischemic multiorgan damage.
• Thrombotic thrombocytopenic purpura (TTP) is characterized by MAHA (schistocytes on peripheral smear) and thrombocytopenia (generally <30,000), with or without the following signs and symptoms:
  • Neurologic symptoms, renal dysfunction, fever
  • Most patients do not show the historic pentad of MAHA, thrombocytopenia, renal dysfunction, neurologic abnormalities, and fever because treatment is initiated before the pentad can develop.

Epidemiology

Incidence

• First episode mostly in adulthood (~90%) with a median age of 41 years and 10% in childhood to adolescence (1)[C]
• Predominant sex: female > male (2:1); higher relapse in females (1)[C]
• Incidence ratio of blacks to whites is 7:1.
• Other features with increased risk: high body mass index and pregnancy
• Annual incidence of ~3 new cases per million people

Prevalence
Annual prevalence of ~10 cases per million people

Etiology and Pathophysiology

• In TTP, the aggregating agent responsible for platelet thrombi is unusually large von Willebrand factor (UL vWF) multimers, which are far larger than those found in normal plasma.
• A metalloprotease, ADAMTS13, which normally enzymatically cleaves UL vWF multimers to prevent clumping within vessels, is deficient, defective, or absent, allowing UL vWF to react with platelets. This leads to endothelial cell damage and disseminated thrombi characteristic of TTP.
• Arterioles often affected: brain, kidney, pancreas, heart, adrenal glands; lungs and liver are relatively spared.
• In familial TTP, patients have an inherited deficiency of ADAMTS13.
• In acquired idiopathic TTP, autoantibodies are directed against the metalloprotease ADAMTS13 (1)[C].
• Endothelial injury, either directly from a drug/toxin or indirectly via platelet/neutrophil activation, has been proposed as a cause of secondary TTP especially in those without ADAMTS13 deficiency.

Genetics

• TTP is most often an acquired disorder. A congenital form of inherited TTP (Upshaw-Schulman syndrome) is due to a mutation at the ADAMTS13 gene locus on chromosome 9q34. This has an autosomal-recessive pattern of inheritance.
• USS typically presents in infancy and is rarely diagnosed after 10 years of age. It does not have the female predominance seen in idiopathic TTP, more often has notable renal impairment, and there is some heterogeneity among siblings.

Risk Factors

• Pregnancy, oral contraceptives, AIDS and early HIV infection, bacterial infection/sepsis, acute pancreatitis
• Autoimmune disease: antiphospholipid antibody syndrome, systemic lupus erythematosus, scleroderma
• Cancer, hematopoietic stem cell transplantation, and solid organ transplant
• Drugs of abuse: MDMA, cocaine, oxymorphone ER
• Drug toxicity
  • Antimicrobials: trimethoprim, ciprofloxacin, famciclovir
  • Chemotherapy: mitomycin C and gemcitabine, pentostatin and vincristine, bleomycin and cisplatin, oxaliplatin, bevacizumab and sunitinib, adalimumab, bortezomib, carfilzomib, and ixazomib
  • Calcineurin inhibitors: tacrolimus and cyclosporine
  • Immune mediated: quinine and quinidine, ticlopidine and clopidogrel

Commonly Associated Conditions

• TTP/hemolytic uremic syndrome (HUS)/atypical HUS have similar presentations with MAHA and thrombocytopenia and multiorgan involvement.
• TTP generally presents with minimal renal involvement and may have neurologic abnormalities, whereas the opposite is more characteristic of HUS/atypical HUS. Creatinine of >2 to 3 is not suggestive of TTP.
• However, patients with HUS and TTP may have both prominent renal and neurologic manifestations, often making the diagnosis unclear—hence the historical hybrid name “TTP-HUS.”
• ADAMTS13 levels are diminished (generally <10%) in adults with familial or acquired idiopathic TTP but are normal in children diagnosed with HUS.