Table 2.

The thrombotic microangiopathies: epidemiology, pathogenesis, and management

TMAEpidemiologyPathogenesisManagement Recommendations
Complement-mediated aHUSIncidence (UK): 0.42 per million per yr (32)Complement dysregulation caused by:Eculizumab
Hereditary: incomplete penetrance; can present at any age; “trigger” requiredHereditary: heterozygous mutations in CFH, CFI, CD46, C3, and CFB (27,28)If eculizumab is not available: PE, liver transplantation may be considered.
Acquired: anti-FH Ab aHUS more common in childrenAcquired: anti-FH Ab (19,21)
TTP/ADAMTS13 deficiency mediated TMAIncidence (US): 0.37 per 100,000 per yr (46); adults 2.9 per million per yr, children 0.1 per million per yr (2)ADAMTS13 deficiency caused by: Hereditary: recessive (homozygous or compound heterozygous) ADAMTS13 mutationsPE
Female>Male (44)Immunosuppression (steroids/rituximab) indicated if acquired
Adults > children (2)Acquired: autoantibody-mediated inhibition
Cobalamin C deficiencyIncidence of cblC deficiency: 1:37,000–1:100,000 births (50)Disorder of cblC metabolism results from recessive (homozygous or compound heterozygous) mutations in the MMACHC geneMetabolic therapy recommended: efficacy of hydroxocobalamin and betaine established (50)
Can present in adulthood as well as childhoodPathogenic mechanisms causing TMA remain undetermined
DGKE TMARareRecessive (homozygous or compound heterozygous) mutations in DGKE (36)Insufficient evidence to determine optimal management
Presents aged <1 yr (36)Loss of DGKE results in prothrombotic state independently of complement activation (51)Reports of both nonresponse (36) and response (31) to eculizumab
STEC-HUSE. coli O157 predominant causative pathogen: incidence (UK): 7.1 per million per yr; Latin America, 10–17 per 100,000 children per yr (113)Enteric infection with Stx-producing pathogensSupportive care is recommended; high proportion may require dialysis. No intervention evaluated in an RCT was superior to supportive care for any outcome (systematic review [114])
Peak incidence in children <5 yr (115) and approximately 15% of children with enteric infection develop HUS (59)Stx binds to Gb3, which is highly expressed in the kidney, is internalized, and inhibits protein synthesis (63)Antibiotics: controversy remains, studies inconclusive, may worsen outcome, therefore currently not recommended; RCT of azithromycin ongoing (NCT02336516)
E. coli O104: European outbreak in 2011 exceptional for high HUS occurrence rate (24%), severity, and high proportion of adults (60)The consequent endothelial injury results in intravascular fibrin generation (59)PE: not recommended, no benefit established (no RCTs) (46)
Other Stx producing pathogens e.g., Shigella dysenteriaeComplement activation observed (116) but role is not definedEculizumab: not recommended; no benefit demonstrated in retrospective analyses (60,68,69); RCT ongoing (NCT02205541)
Outbreaks and sporadic cases
Pneumococcal HUSRare. Limited data available from published cohorts, and incidence unknown (117,118). 10-yr cumulative incidence rate of 1.2 per 100,000 children reported (NZ) (119). Associated with pneumonia and empyema in children <2 yr (72)Neuraminidase cleaves sialic acid residues from glycoproteins on erythrocyte, platelet, and endothelial cell membranes, exposing the cryptic T antigen to which IgM in the plasma can then bind, resulting in cell damage and TMA (73).Supportive management and treatment of infection recommended
HIV-associated TMAPre-HAART era: incidence of 1.5%–7% (75,120)Pathogenic mechanisms remain undeterminedSupportive management and treatment of infection recommended
HAART era: incidence 0.3% (77)
Pregnancy-associated TMAComplement-mediated aHUS: pregnancy triggers complement-mediated TMA in approximately 20% of women with aHUS (81)Complement gene mutations in up to 86% (81)Eculizumab; start immediately (do not wait for genetic analysis) if TTP has been excluded and presentation is not suggestive of HELLP
A proportion are primary TMAs; differential diagnosis includes complement-mediated aHUS, TTP, and HELLPTTP: 10%–36% of women with TTP present during pregnancy (44)vWf increases in normal pregnancy and consumes ADAMTS13; in women with a genetic predisposition, its activity can fall low enough for TTP to manifest (81)PE
HELLP: incidence: 0.5%–0.9% of all pregnancies; complicates 5%–10% of cases of severe preeclampsia (121)Mechanisms are poorly understood (80)Definitive treatment is delivery (86). No role for PE (46)
Increased levels of endoglin and sFlt-1 may play a role in endothelial dysfunction (79,86).
Drug-mediated TMATrue incidence unknownImmune mediated: drug-dependent antibodies, e.g., quinine (2)Recommendation is drug discontinuation
Reported incidences of TMA include:Toxicity mediated: multiple mechanisms, e.g., CNIs, IFN, chemotherapy agents, VEGF inhibitors (2)Ticlopidine-associated TMA: as per TTP (46,92) (PE)
Approximately 1:1000 patient-yr for high-dose IFN-β (90)Ticlopidine-associated TMA is mediated by acquired ADAMTS13 deficiency (92)
2%–10% of patients treated with mitomycin (122)
1%–4.7% of patients treated with tacrolimus (122)
VEGF inhibitors: unknown (91)
De novo TMA after solid organ transplantIncidence after kidney transplantation: 0.8% in USRDS data (123); up to 14% in single-center studies (94)MultifactorialTreatment of precipitating factors, e.g., AMR, infection, drug withdrawal
Incidence: 4% in liver transplant and 2.3% in lung transplant recipients (93)Complement gene mutations reported in up to 29% (renal transplants) (96)Eculizumab where complement-mediated aHUS is possible
TMA after bone marrow transplantMultisystem TMA complicates 10%–40% of allogenic BMTs (97,98)MultifactorialNo evidence-based effective management strategy
No established benefit with PE (46)
Favorable outcomes with eculizumab compared with historical controls reported in retrospective analysis (101), but prospective trials needed to establish consensus
Severe hypertension-associated TMAIncidence: variously reported; case series of severe hypertension have identified TMA in 27%–44% (13,124127)Pathogenic mechanisms unclearNo evidence supporting any strategy other than BP management
Malignancy-associated TMAUnknownMultifactorialDiscontinuation of causative chemotherapy agents
TMA with glomerular diseasesTMA can occur in association with IgA nephropathy, ANCA-associated vasculitis, membranous nephropathy, FSGS, and MPGN/C3G (13)Pathogenic mechanisms unclearLimited evidence for management of the TMA
Hereditary and acquired complement defects in MPGN/C3GRole of complement inhibition in C3G/aHUS crossover unclear
TMA with autoimmune conditionsSLE: concurrent TMA reported in up to 8%–15% of biopsies (9,128)Pathogenic mechanisms unclearSLE: no evidence for specific TMA management in addition to SLE management as recommended in international guidelines
CAPS: TMA in 14% in international registry (112)Some evidence of complement activation in SLE and CAPS (13)CAPS: efficacy of eculizumab suggested in case reports and series; prospective trial (not RCT) to enable renal transplantation ongoing (NCT01029587)
SRC: occurs in approximately 10% of people with SSc; TMA in 45%–50% (111,129)SRC: ACEIs significantly reduce mortality (111)
  • aHUS, atypical hemolytic uremic syndrome; UK, United Kingdom; PE, plasma exchange; FH, factor H; Ab, antibody; TTP, thrombotic thrombocytopenic purpura; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; TMA, thrombotic microangiopathy; US, United States; cblC, cobalamin C type; STEC-HUS, hemolytic uremic syndrome caused by shiga toxin–producing Escherichia coli; Stx, shiga toxin; RCT, randomized controlled trial; HUS, hemolytic uremic syndrome; Gb3, globotriaosylceramide; NZ, New Zealand; T antigen, Thomsen–Friedenreich antigen; HAART, highly active antiretroviral therapy; HELLP, syndrome of hemolysis, elevated liver enzymes, and low platelets; CNI, calcineurin inhibitor; VEGF, vascular endothelial growth factor; USRDS, United States Renal Data System; AMR, antibody-mediated rejection; BMT, bone marrow transplants; MPGN, mesangioproliferative GN; C3G, C3 glomerulopathy; CAPS, catastrophic antiphospholipid syndrome; SRC, scleroderma renal crisis; SSc, systemic sclerosis; ACEI, angiotensin-converting enzyme inhibitor.