Welcome to this special issue of Seminars in Thrombosis & Hemostasis, which summarizes up-to-date knowledge on pathogenesis, diagnosis, and treatment
of thrombotic microangiopathies (TMAs) such as (enterohemorrhagic) E. coli (EHEC)–associated hemolytic uremic syndrome (HUS) (eHUS), atypical HUS (aHUS), (aHUS)
and thrombotic thrombocytopenic purpura (TTP). This issue also reviews C3 glomerulopathies
(C3G), emphasizing the expanding spectrum of TMAs.
The introduction to this issue is provided by Sethi and Fervenza who revise, from
a morphological and histological view, the current classification of C3G based on
renal pathology and explaining the typical features of the different complement-mediated
diseases on biopsy. They introduce the role of uncontrolled complement activation
of the alternative pathway in the pathogenesis of C3G, using new methods such as mass
spectrometry of microdissected glomeruli.[1]
de Cordoba et al then review up-to-date knowledge on the inherited form of aHUS and
thus on genetics, including recent findings such as complement factor H (CFH) and/or
factor H–related (CFHR) genomic rearrangements and mutations in the coagulation cascade.
It is commonly understood that multiple hits, involving genetic/autoimmune defects
of complement regulators and proteins, are likely required to impair protection of
endothelial cells. The genetic susceptibility is increased if an individual carries
a combination of inherited defects.[2]
For the acquired form of aHUS, Hofer et al describe in their review on CFH antibody–associated
HUS (CFH-Ab HUS) the current knowledge on CFH-Ab detection, the association with CFHR3-CFHR1 deletion, and the different treatment options. The significance of a rapid CFH-Ab
HUS diagnosis is crucial, as the treatment algorithm differs from other aHUS patients.[3]
Insights into endothelial cell activation and inflammation involved in TMA pathogenesis
are reviewed in detail by Riedl et al. Increasing knowledge on aHUS and an expanding
TMA spectrum have evolved over the last years ([Table 1]). Complement emerges as a crucial regulator, as it plays a central role in maintaining
this homeostasis within the microvasculature. Defects in the complement system, raising
the individual susceptibility to TMA evolvement, were discovered in affected patients.
The successful use of eculizumab in patients with aHUS or the extended TMA spectrum
corroborates the role of complement in TMA pathogenesis.[4]
Table 1
Classification of thrombotic microangiopathies
|
Infection induced TMA
• (Enterohemorrhagic) E. coli–associated HUS
• Shigella dysenteriae-associated HUS
• Streptococcus pneumonia-associated HUS
• Influenza A/H1N1-associated HUS
• HUS due to other pathogens: EBV, CMV, Mycoplasma pneumoniae, Bordetella pertussis, Parvovirus B19, HIV
|
|
TMA associated with disorders of complement regulation—atypical HUS
• Hereditary
• Autoimmune
|
|
TMA manifesting during pregnancy or postpartum
|
|
TMA associated with transplantation
• TMA developed de novo after solid organ transplantation
• TMA associated with bone-marrow or stem-cell transplantation
|
|
TMA associated with metabolic diseases
• Cobalamin C deficiency
|
|
TMA associated with other glomerulopathies/vasculitides
• Systemic lupus erythematosus/antiphospholipid syndrome
• C3 glomerulopathy
• Others: Immunoglobulin A nephropathy, focal segmental glomerulosclerosis, vasculitis
|
|
TMA associated with malignant hypertension
|
|
Drug induced TMA
• Calcineurin inhibitors
• Others: quinine, ticlopidine, chemotherapy
|
|
Other forms of TMA
• DGKE mutation
• Unknown
|
|
TMA associated with ADAMTS13 deficiency—thrombotic thrombocytopenic purpura
• Hereditary
• Autoimmune
|
Abbreviations: DGKE, diacylglycerol kinase epsilon; HUS, hemolytic uremic syndrome;
TMA, thrombotic microangiopathy.
Xiao et al focus on the functional aspects of the complement system and, in particular,
on the genetic complement disorders in C3G patients, such as CFH-related protein dimeri-zation
and complex formation. Abnormal CFHR proteins detected in patients with C3G may promote
formation of unusual dimers and/or multimers impacting complement control.[5]
Eculizumab, a monoclonal antibody binding C5, has been used in 11 C3G patients so
far, as reported by Vivarelli and Emma. A significant response was seen in eight patients
with evidence for terminal complement activation. As patients with C3G show a great
deal of interindividual variety, a patient-tailored complement-targeting treatment
might be the ideal approach in the future.[6]
Safouh and coworkers (Hofer et al) share the experience of a pediatric nephrologist
in Cairo, Egypt, in the review on HUS in the developing world. This is an important
contribution, as patients outnumber every cohort in the developed world and diagnostic
and therapeutic tools differ substantially. They introduce an overview on available
complement diagnostics, as well as recommendations on diagnosis and treatment tailored
for developing countries. Recommendations include a two-step approach, starting with
available resources locally and subsequent support of developed world for in-depth
analysis.[7]
The most prominent inherited form of TTP in children, the Upshaw–Schulman syndrome
(USS), is caused by homozygous or compound heterozygous mutations in the ADAMTS13 gene. Hassenpflug et al review current experience to highlight that the rare and
oligosymptomatic symptoms might obscure the diagnosis and that the pentad attributed
to this disease is much less frequent than commonly believed. Detailed analyses of
30 USS patients revealed mutations distributed over the whole ADAMTS13 gene, without any genotype–phenotype correlation.[8]
Considerable progress has been made in diagnosis and therapy of TTP. In acquired forms
of TTP, plasma exchange, immunosuppression and rituximab have improved outcome as
reviewed by Knöbl. New approaches including recombinant ADAMTS13, N-acetylcysteine,
and anti-von Willebrand factor A1 agents reflect promising treatments for the future.[9]
The role of complement in EHEC-associated HUS is reviewed by Orth-Höller and Würzner.
Complement activation had been observed in vivo in HUS patients. In vitro experiments
have then demonstrated that Shiga toxin 2 directly activates complement and interacts
with soluble complement regulators, namely, CFH, CFHR-1, and factor H-like protein
1, leading to an impaired complement control. Furthermore, Shiga toxin 2 also modulates
membrane-bound regulators by downregulating expression of CD59. These findings served
as a rationale for using eculizumab in patients with EHEC-associated HUS, especially
during the O104:H4 outbreak in Germany in 2011.[10]
Finally, Würzner et al[11] detail that in EHEC-associated HUS (or eHUS), antibiotic treatment should still
be avoided during the gastrointestinal phase. Complement inhibition, however, may
make the difference between favorable or detrimental outcome in severe cases. Experiences
on the use of eculizumab are discussed, recognizing that only a randomized trial can
answer the question of optimal treatment time, treatment duration, and patient population
which will benefit from treatment.[11]
