Thrombotic Thrombocytopenic Purpura
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- An acute syndrome of microangiopathic hemolytic anemia (MAHA) and consumptive thrombocytopenia with deposition of hyaline thrombi in terminal arterioles and capillaries leading to ischemic multiorgan damage
- Thrombotic thrombocytopenic purpura (TTP) is characterized by MAHA (schistocytes on peripheral smear) and thrombocytopenia (generally <30K), with or without the following signs and symptoms (1):
- Neurologic symptoms
- Renal dysfunction
- 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.
- Predominant age: 18 to 49 years
- Predominant sex: female > male (3:1)
- Incidence ratio in blacks to whites is 7:1.
- The age–sex–race standardized incidence of clinically suspected TTP is 8 million/year and 2 million/year in those with ADAMTS13 levels <10% (2).
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 metalloproteinase, 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 the endothelial cell damage and disseminated thrombi characteristic of TTP.
- Arterioles most often affected are in the brain, kidney, pancreas, heart, and adrenal glands. Lungs and liver are relatively spared.
- In familial TTP, patients have an inherited deficiency of ADAMTS13 (1).
- In acquired idiopathic TTP, autoantibodies are directed against the metalloproteinase ADAMTS13 (1,3).
- 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.
- Drug induced (see “Risk Factors”)
- Hematopoietic cell transplantation
- TTP is most often an acquired disorder. A congenital form of inherited TTP (Upshaw-Schulman syndrome) is due to a mutation at the ADAMTS13 metalloproteinase gene locus on chromosome 9q34. This rare form of TTP has an autosomal-recessive pattern of inheritance.
- SUS 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 although parents who are carriers of a single heterozygous ADAMTS13 mutation are typically asymptomatic
- Pregnancy and oral contraceptives
- AIDS and early symptomatic HIV infection
- Bacterial infection/sepsis
- Autoimmune disease
- Antiphospholipid antibody syndrome
- Systemic lupus erythematosus
- Hematopoietic stem cell transplantation
- Solid organ transplant
- Drug toxicity
- Cancer chemotherapy
- Mitomycin C and gemcitabine
- Bleomycin and cisplatin
- Calcineurin inhibitors
- Tacrolimus and cyclosporine
- Immune mediated
- Quinine and quinidine
- Ticlopidine and clopidogrel
- Cancer chemotherapy
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 >2.3 is suggestive against 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 following infection with Escherichia coli (particularly type O157:H7), so-called Shiga toxin-HUS, and in “atypical HUS,” is also called complement-mediated thrombotic microangiopathy reflecting the pathophysiology which is related to complement dysregulation.