Complement Activation in Pregnancy: Too Much of a Good Thing?

Gilbert, Jeffrey S.; Banek, Christopher T.; Katz, Vern L.; Babcock, Sara A.; Regal, Jean F.

doi:10.1161/hypertensionaha.112.202747

Cited by 8 publications

(5 citation statements)

References 12 publications

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“…It remains unclear what triggers complement activation and which complement pathways are principally involved. Based on our findings (Bb but not C4a elevated) we speculate that there may be stronger links with the alternative complement pathway activation, as previously also proposed by others [ 21 , 35 ].…”

Section: Discussionsupporting

confidence: 87%

Complement Split Products in Amniotic Fluid in Pregnancies Subsequently Developing Early-Onset Preeclampsia

et al. 2015

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Objective. To determine the second-trimester amniotic fluid concentrations of complement split products in pregnancies subsequently affected by early-onset preeclampsia. Study Design. Cohort of 731 women with singleton pregnancies undergoing second-trimester genetic amniocentesis followed up to delivery and analyzed as a nested case-control study. Cases of preeclampsia developing before 34 weeks' gestation (n = 15) were compared with 47 uncomplicated term controls. Amniotic fluid collected at amniocentesis was tested for complement split products Bb, C4a, C3a, and C5a. Results. Women who developed early-onset preeclampsia as compared with the term pregnant controls had significantly higher (P = 0.04) median amniotic fluid C3a levels (318.7 ng/mL versus 254.5 ng/mL). Median amniotic fluid Bb levels were also significantly higher (P = 0.03) in preeclamptic women than in normal pregnant women (1127 ng/mL versus 749 ng/mL). Median levels of C4a and C5a were not significantly different between the groups. Conclusion. Our data suggest that complement activation in early pregnancy is associated with early-onset preeclampsia. We believe this to be the first prospective study to link complement activation in amniotic fluid in early pregnancy and later development of preeclampsia. Our findings provide evidence that immune dysregulation may precede the clinical manifestations of preeclampsia and that the alternative complement pathway is principally involved.

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Section: Discussionsupporting

confidence: 87%

Complement Split Products in Amniotic Fluid in Pregnancies Subsequently Developing Early-Onset Preeclampsia

et al. 2015

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“…Critical illnesses are well known to cause an injury to ECs, leading to endotheliopathy and endothelial dysfunction [ 62 , 63 ]. Now, the evidence shows that complement activation plays the major role in molecular pathogenesis of inflammation and DIT [ 1 – 3 , 55 , 58 – 61 , 64 ]. Based on endotheliopathy that promotes several biomolecular events, the “two-activation theory of the endothelium” is proposed and illustrated in Fig.…”

Section: Introductionmentioning

confidence: 99%

TTP-like syndrome: novel concept and molecular pathogenesis of endotheliopathy-associated vascular microthrombotic disease

Chang

2018

Thrombosis J

145

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TTP is characterized by microangiopathic hemolytic anemia and thrombocytopenia associated with brain and kidney dysfunction. It occurs due to ADAMTS13 deficiency. TTP-like syndrome occurs in critically ill patients with the similar hematologic changes and additional organ dysfunction syndromes. Vascular microthrombotic disease (VMTD) includes both TTP and TTP-like syndrome because their underlying pathology is the same disseminated intravascular microthrombosis (DIT). Microthrombi are composed of platelet-unusually large von Willebrand factor multimers (ULVWF) complexes. TTP occurs as a result of accumulation of circulating ULVWF secondary to ADAMTS13 deficiency. This protease deficiency triggers microthrombogenesis, leading to “microthrombi” formation in microcirculation. Unlike TTP, TTP-like syndrome occurs in critical illnesses due to complement activation. Terminal C5b-9 complex causes channel formation to endothelial membrane, leading to endotheliopathy, which activates two different molecular pathways (i.e., inflammatory and microthrombotic). Activation of inflammatory pathway triggers inflammation. Activation of microthrombotic pathway promotes platelet activation and excessive endothelial exocytosis of ULVWF from endothelial cells (ECs). Overexpressed and uncleaved ULVWF become anchored to ECs as long elongated strings to recruit activated platelets, and assemble “microthrombi”. In TTP, circulating microthrombi typically be lodged in microvasculature of the brain and kidney, but in TTP-like syndrome, microthrombi anchored to ECs of organs such as the lungs and liver as well as the brain and kidneys, leading to multiorgan dysfunction syndrome. TTP occurs as hereditary or autoimmune disease and is the phenotype of ADAMTS13 deficiency-associated VMTD. But TTP-like syndrome is hemostatic disorder occurring in critical illnesses and is the phenotype of endotheliopathy-associated VMTD. Thus, this author’s contention is TTP and TTP-like syndrome are two distinctly different disorders with dissimilar underlying pathology and pathogenesis.

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“…Although the complement system is essential for fetal survival (Usami et al, 2010) and normal placental development (Singh et al, 2011), excessive complement activation is associated with recurrent miscarriages, preterm labor, and pre-eclampsia (Lynch and Salmon, 2010). During pregnancies complicated with pre-eclampsia, there is strong evidence of excessive complement activation in the circulation, with a decrease in C3 concentration and an increase in C5a, soluble C5b-9, and the ratio of C3a to C3 (Derzsy et al, 2010;Soto et al, 2010), as well as excessive complement activation in placenta (Buurma et al, 2012;Gilbert et al, 2012c) and urine . A recent case report suggests that complement contributes to pre-eclamptic symptoms because depletion of complement component C5 in a severely pre-eclamptic woman was able to prolong pregnancy by .2 weeks .…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Complement Activation Products C3a and C5a on Cardiovascular Function in Hypertensive Pregnant Rats

Lillegard¹,

Loeks-Johnson²,

Opacich³

et al. 2014

J Pharmacol Exp Ther

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Early-onset pre-eclampsia is characterized by decreased placental perfusion, new-onset hypertension, angiogenic imbalance, and endothelial dysfunction associated with excessive activation of the innate immune complement system. Although our previous studies demonstrated that inhibition of complement activation attenuates placental ischemia-induced hypertension using the rat reduced uterine perfusion pressure (RUPP) model, the important product(s) of complement activation has yet to be identified. We hypothesized that antagonism of receptors for complement activation products C3a and C5a would improve vascular function and attenuate RUPP hypertension.

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Complement Activation in Pregnancy: Too Much of a Good Thing?

Cited by 8 publications

References 12 publications

Complement Split Products in Amniotic Fluid in Pregnancies Subsequently Developing Early-Onset Preeclampsia

Complement Split Products in Amniotic Fluid in Pregnancies Subsequently Developing Early-Onset Preeclampsia

TTP-like syndrome: novel concept and molecular pathogenesis of endotheliopathy-associated vascular microthrombotic disease

Differential Effects of Complement Activation Products C3a and C5a on Cardiovascular Function in Hypertensive Pregnant Rats

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