Evaluating the definition of HELLP syndrome: Assessing LDH isoform activity
1
233 EVALUATING THE DEFINITION OF HELLP SYNDROME: ASSESSING LDH ISOFORM ACTIVITY JOHN O’BRIEN 1 , AIMEN SHILAD 2 , MILLIGAN DOUGLAS 3 , ALDO KHOURY 2 , JOHN R. BARTON 4 , 1 Baptist Health Care System, Lexington, Kentucky, 2 St. Jo- seph’s Hospital and Medical Center, Fairfield, New Jersey, 3 Central Baptist Hospital, Lexington, Kentucky, 4 Central Baptist Hospital, Perinatal Diagnostic Center, Lexington, Kentucky OBJECTIVE: Lactate dehydrogenase (LDH) activity has been utilized to define HELLP syndrome and can indicate both hepatocellular death and hemolysis. Our purpose was to compare LDH isoenzyme activity in women with HELLP syndrome to a control population. STUDY DESIGN: Patients were eligible for inclusion if they were diagnosed with HELLP syndrome defined as pregnancy-induced hypertensive disease accompanied by laboratory criteria: Platelet nadir !100 ! 10!3/supO/uL, maximum AST O70 U/L, and maximum LDH O600 U/L. A control population consisted of normotensive gravidas. LDH activity and its isoen- zymes were obtained in all study and control patients prior to delivery. RESULTS: Thirty-two patients were evaluated (16 in each group). The study group demonstrated a higher admission blood pressure and lower platelet count vs controls, all P%0.001. Total LDH activity was significantly higher in study patients (412G200 vs 199G34, P!.001). LDH activity was increased for all isoenzymes, see Table 1. The fraction of isoenzymes 1 and 2 were lower in the study group, LDH1 17.5G5.1 vs 20.8G3.8, P=.047 and LDH2 26.8G6.3 vs 33.8G4.1, P!0.001. No change in the fraction of LDH3 was observed between groups, 18.2G3.9 vs 19G1.4, P=.446. The fraction of LDH activity from liver, isoenzymes 4 and 5, increased significantly in patients with HELLP syndrome compared to controls (LDH4 13.2G4.3 vs 9.9G1.7, P=.008, and LDH5 24.3G10 vs 16.4G5.3, P=.009). CONCLUSION: Increased LDH activity in women with HELLP syndrome reflects both hepatic destruction and hemolysis. A greater proportion of this increased enzyme activity in women with HELLP syndrome however comes from hepatocellular death. If hemolysis is to be strictly defined in these patients, a more specific test is needed. LDH activity in HELLP syndrome LDH activity (Source) LDH1 (RBC) LDH2 (RBC) LDH3 (Lung) LDH4 (Liver) LDH5 (Liver) Study (n=16) 68G 24 102G27 73G29 56G36 113 G 120 Control (n=16) 42G12 67G12 38G6 20G5 33G 14 P value !.001 !.001 !.001 !.001 .013 234 THE EFFECT OF 2-MACROGLOBULIN ON VEGF-INDUCED ENDOTHELIN-1 UPREGU- LATION IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS MIN-JEONG OH 1 , JUNG-HO SHIN 1 , SANG-HEE CHUNG 2 , HYUN-JOO SEOL 1 , HAI-JOONG KIM 1 , 1 College of Medicine, Korea University, Department of Obstetrics and Gynecology, Seoul, South Korea, 2 Bundang CHA Hospital, Department of Obstetrics and Gynecology, Seongnam, South Korea OBJECTIVE: Studies of circulating concentrations of VEGF in preeclampsia have reported conflicting results. In studies that have measured free VEGF, levels were lower in preeclampsia than in controls of similar gestational age. However, studies that have measured total VEGF, including VEGF bound to proteins, have shown that concentrations are modestly elevated in preeclamp- sia. In addition to soluble Flt-1(sFlt-1), a potent antagonist of VEGF, a2- macroglobulin(a2M) is also known to be a major VEGF-binding protein and a highly conserved proteinase inhibitor. However, it is not clear whether a2M, present in human plasma at much higher concentration (2-4 mg/ml) than sFlt- 1, inhibits the action of VEGF when it binds to VEGF. This study is to clarify the effect of a2M on VEGF-induced endothelin-1(ET-1) upregulation. STUDY DESIGN: Human umbilical vein endothelial cells(HUVECs) were used in this study. Cells were treated with various concentration of sFlt-1(from 10 to 1000 ng/ml) or a2M (from 10 to 10000 ng/ml) in the presence of 10 ng/ml of VEGF for 24 hours. The mRNA levels of ET-1 were semiquantitatively determined by real time RT-PCR. RESULTS: sFlt-1 significantly decreased the mRNA expression of ET-1. At the concentration of 1000 ng/ml of sFlt-1, ET-1 mRNA was decreased by 90%. On the contrary, a2M did not affect the mRNA expression of ET-1, which suggests the biological function of VEGF might be preserved when VEGF binds to a2M. CONCLUSION: This study shows that a2M did not inhibit VEGF-induced ET-1 upregulation. Considering that a2M is present in human plasma at much higher concentration than sFlt-1, a portion of bound form of VEGF (that is, VEGF-a2M complex) might be able to exert the biological action. Therefore, this study suggests a2M, not only sFlt-1, should be considered in pathophys- iology of preeclampsia and further studies are needed to clarify the interaction of a2M and various VEGF actions. 235 POSTPARTUM COURSE OF GESTATIONAL HYPERTENSION AND PREECLAMPSIA TIINA PODYMOW 1 , PHYLLIS AUGUST 2 , 1 Cornell University Medical College, Nephrology and Hypertension, New York, New York, 2 Cornell University Medical College, Nephrology and Hypertension, Obstetrics and Gynecology, New York, New York OBJECTIVE: New onset hypertension (gestational hypertension and pree- clampsia) complicates 6-8% of pregnancies, yet little is known regarding the duration of elevated blood pressure in the post partum (PP) period. Hyper- tension clinic charts of women who developed gestational hypertension or preeclampsia (NHBPEP definitions) were reviewed to determine PP course. STUDY DESIGN: Hypertension clinic charts of 54 women who developed gestational hypertension or preeclampsia (NHBPEP definitions) were retro- spectively reviewed. Only those normotensive prior to pregnancy were included. Demographic data, gestational age at diagnosis, level of blood pressure (BP), BP medication use and number of weeks until BP normalized (BP%125/85 mm Hg) were recorded. RESULTS: 54 patients, (41 White, 5 Black, 5 Hispanic and 3 Asian) age 17- 51 (mean 35.7 G 7.1) were reviewed. Hypertension developed at gestational age 15-40 weeks, with 23 developing hypertension within three days of delivery, 29 developed 1-18 weeks prior to delivery and 2 postpartum. Infants were born at a gestational age 35 G 4.5 weeks. Average BP at treatment initiation was 157/93 mm Hg. Preeclampsia was diagnosed in 26 women. 47/52 were treated with BP medication in the puerperium. In 23 women BP normalized by 1 month PP; in 18 women BP normalized between 1-5 months PP, and 10 women remained hypertensive beyond 6 months. The 19% who remained hypertensive were slightly older (39.8 vs. 35.3 years). Hyperaldoste- ronism was diagnosed in a further 2 women and renovascular hypertension in one. CONCLUSION: Hypertension normalized in 81% of this sample, in some cases lasting for 5 months before normalizing. Those who remained hyper- tensive tended to be older than those who normalized. Secondary hypertension was detected in 3 patients. Further studies are needed to characterize those women most likely to benefit from postpartum antihypertensive treatment. 236 CHANGES IN ANGIOGENIC FACTORS LEVELS AND ACUTE PHASE REACTANTS CONCENTRATIONS THROUGHOUT PREGNANCY ANTOINE MALEK 1 , NICK BERSINGER 1 , ANTONELLA CROMI 2 , FABIO GHEZZI 2 , SILVIA TOMERA 2 , HENNING SCHNEIDER 1 , DANIEL SURBEK 1 , LUIGI RAIO 1 , 1 University of Bern, Obstetrics and Gynecology, Bern, Switzerland, 2 University of Insubria, Obstetrics and Gynecology, Varese, Italy OBJECTIVE: Either a systemic maternal inflammatory response and an alteration in the expression of angiogenenic molecules are implicated in the pathogenesis of preeclampsia and seem to precede clinical evidence of the disorder. Our aim was to describe the gestational patterns of circulating angiogenic factors (vascular endothelial growth factor [VEGF], placental growth factor [PlGF], and soluble fms-like tyrosine kinase1 [sFlt-1]) and acute phase reactants (C reactive protein [CRP] and interleukin-6 [IL-6]) throughout uncomplicated pregnancy and to assess whether a correlation exists between angiogenic markers and acute phase proteins levels. STUDY DESIGN: We performed a longitudinal study involving 16 consec- utive normotensive women with uncomplicated pregnancy attending our low- risk prenatal clinic. Serum specimens were obtained from each participant at 10-12 (period A), 18-20 (period B), 28-30 (period C) gestational weeks and at term (O37 wks, period D). The levels of VEGF, PlGF, sFlt-1, IL6 and CRP were measured by ELISA. Statistical analysis was performed with ANOVA for repeated measurement, Tukey´s test for post hoc analysis and Spearman correlation. RESULTS: CRP and IL-6 levels increased significantly at term compared to the early pregnancy (A vs. D and B vs. D, P!0.05). PlGF peaks in the third trimester (A vs C, B vs. C, and D vs C, P!0.05). VEGF concentration did not change throughout gestation and decreased significantly at term (B vs D and C vs D, P!0.05). No significant change was found in sFlt-1 levels throughout gestation, while a significant increase was observed at term (A vs. D and B vs. D, P!0.05). No significant correlation was found between angiogenic factors levels and both acute phase reactants concentration in any of the gestational age intervals. CONCLUSION: Circulating angiogenic molecules and acute phase reactants shows distinctive gestational patterns. The levels of inflammation markers (CRP and IL-6) are not correlated with the angiogenic profile in uncompli- cated pregnancy. S76 SMFM Abstracts
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Transcript of Evaluating the definition of HELLP syndrome: Assessing LDH isoform activity
233 EVALUATING THE DEFINITION OF HELLP SYNDROME: ASSESSING LDH ISOFORMACTIVITY JOHN O’BRIEN1, AIMEN SHILAD2, MILLIGAN DOUGLAS3, ALDO KHOURY2,JOHN R. BARTON4, 1Baptist Health Care System, Lexington, Kentucky, 2St. Jo-seph’s Hospital and Medical Center, Fairfield, New Jersey, 3Central BaptistHospital, Lexington, Kentucky, 4Central Baptist Hospital, PerinatalDiagnosticCenter, Lexington, Kentucky
OBJECTIVE: Lactate dehydrogenase (LDH) activity has been utilized todefine HELLP syndrome and can indicate both hepatocellular death andhemolysis. Our purpose was to compare LDH isoenzyme activity in womenwith HELLP syndrome to a control population.
STUDY DESIGN: Patients were eligible for inclusion if they were diagnosedwith HELLP syndrome defined as pregnancy-induced hypertensive diseaseaccompanied by laboratory criteria: Platelet nadir !100 ! 10!3/supO/uL,maximum AST O70 U/L, and maximum LDH O600 U/L. A controlpopulation consisted of normotensive gravidas. LDH activity and its isoen-zymes were obtained in all study and control patients prior to delivery.
RESULTS: Thirty-two patients were evaluated (16 in each group). The studygroup demonstrated a higher admission blood pressure and lower plateletcount vs controls, all P%0.001. Total LDH activity was significantly higher instudy patients (412G200 vs 199G34, P!.001). LDH activity was increased forall isoenzymes, see Table 1. The fraction of isoenzymes 1 and 2 were lower inthe study group, LDH1 17.5G5.1 vs 20.8G3.8, P=.047 and LDH2 26.8G6.3vs 33.8G4.1, P!0.001. No change in the fraction of LDH3 was observedbetween groups, 18.2G3.9 vs 19G1.4, P=.446. The fraction of LDH activityfrom liver, isoenzymes 4 and 5, increased significantly in patients with HELLPsyndrome compared to controls (LDH4 13.2G4.3 vs 9.9G1.7, P=.008, andLDH5 24.3G10 vs 16.4G5.3, P=.009).
CONCLUSION: Increased LDH activity in women with HELLP syndromereflects both hepatic destruction and hemolysis. A greater proportion of thisincreased enzyme activity in women with HELLP syndrome however comesfrom hepatocellular death. If hemolysis is to be strictly defined in thesepatients, a more specific test is needed.
LDH activity in HELLP syndrome
LDH activity(Source)
LDH1(RBC)
LDH2(RBC)
LDH3(Lung)
LDH4(Liver)
LDH5(Liver)
Study (n=16) 68G 24 102G27 73G29 56G36 113 G 120Control (n=16) 42G12 67G12 38G6 20G5 33G 14P value !.001 !.001 !.001 !.001 .013
234 THE EFFECT OF 2-MACROGLOBULIN ON VEGF-INDUCED ENDOTHELIN-1 UPREGU-LATION IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS MIN-JEONG OH1,JUNG-HO SHIN1, SANG-HEE CHUNG2, HYUN-JOO SEOL1, HAI-JOONG KIM1, 1Collegeof Medicine, Korea University, Department of Obstetrics and Gynecology,Seoul, South Korea, 2Bundang CHA Hospital, Department of Obstetrics andGynecology, Seongnam, South Korea
OBJECTIVE: Studies of circulating concentrations of VEGF in preeclampsiahave reported conflicting results. In studies that have measured free VEGF,levels were lower in preeclampsia than in controls of similar gestational age.However, studies that have measured total VEGF, including VEGF bound toproteins, have shown that concentrations are modestly elevated in preeclamp-sia. In addition to soluble Flt-1(sFlt-1), a potent antagonist of VEGF, a2-macroglobulin(a2M) is also known to be a major VEGF-binding protein and ahighly conserved proteinase inhibitor. However, it is not clear whether a2M,present in human plasma at much higher concentration (2-4 mg/ml) than sFlt-1, inhibits the action of VEGF when it binds to VEGF. This study is to clarifythe effect of a2M on VEGF-induced endothelin-1(ET-1) upregulation.
STUDY DESIGN: Human umbilical vein endothelial cells(HUVECs) wereused in this study. Cells were treated with various concentration of sFlt-1(from10 to 1000 ng/ml) or a2M (from 10 to 10000 ng/ml) in the presence of 10 ng/mlof VEGF for 24 hours. The mRNA levels of ET-1 were semiquantitativelydetermined by real time RT-PCR.
RESULTS: sFlt-1 significantly decreased the mRNA expression of ET-1. Atthe concentration of 1000 ng/ml of sFlt-1, ET-1 mRNA was decreased by90%. On the contrary, a2M did not affect the mRNA expression of ET-1,which suggests the biological function of VEGF might be preserved whenVEGF binds to a2M.
CONCLUSION: This study shows that a2M did not inhibit VEGF-inducedET-1 upregulation. Considering that a2M is present in human plasma at muchhigher concentration than sFlt-1, a portion of bound form of VEGF (that is,VEGF-a2M complex) might be able to exert the biological action. Therefore,this study suggests a2M, not only sFlt-1, should be considered in pathophys-iology of preeclampsia and further studies are needed to clarify the interactionof a2M and various VEGF actions.
235 POSTPARTUM COURSE OF GESTATIONAL HYPERTENSION AND PREECLAMPSIATIINA PODYMOW1, PHYLLIS AUGUST2, 1Cornell University Medical College,Nephrology and Hypertension, New York, New York, 2Cornell UniversityMedical College, Nephrology and Hypertension, Obstetrics and Gynecology,New York, New York
OBJECTIVE: New onset hypertension (gestational hypertension and pree-clampsia) complicates 6-8% of pregnancies, yet little is known regarding theduration of elevated blood pressure in the post partum (PP) period. Hyper-tension clinic charts of women who developed gestational hypertension orpreeclampsia (NHBPEP definitions) were reviewed to determine PP course.
STUDY DESIGN: Hypertension clinic charts of 54 women who developedgestational hypertension or preeclampsia (NHBPEP definitions) were retro-spectively reviewed. Only those normotensive prior to pregnancy wereincluded. Demographic data, gestational age at diagnosis, level of bloodpressure (BP), BP medication use and number of weeks until BP normalized(BP%125/85 mm Hg) were recorded.
RESULTS: 54 patients, (41 White, 5 Black, 5 Hispanic and 3 Asian) age 17-51 (mean 35.7 G 7.1) were reviewed. Hypertension developed at gestationalage 15-40 weeks, with 23 developing hypertension within three days ofdelivery, 29 developed 1-18 weeks prior to delivery and 2 postpartum. Infantswere born at a gestational age 35 G 4.5 weeks. Average BP at treatmentinitiation was 157/93 mm Hg. Preeclampsia was diagnosed in 26 women. 47/52were treated with BP medication in the puerperium. In 23 women BPnormalized by 1 month PP; in 18 women BP normalized between 1-5 monthsPP, and 10 women remained hypertensive beyond 6 months. The 19% whoremained hypertensive were slightly older (39.8 vs. 35.3 years). Hyperaldoste-ronism was diagnosed in a further 2 women and renovascular hypertension inone.
CONCLUSION: Hypertension normalized in 81% of this sample, in somecases lasting for 5 months before normalizing. Those who remained hyper-tensive tended to be older than those who normalized. Secondary hypertensionwas detected in 3 patients. Further studies are needed to characterize thosewomen most likely to benefit from postpartum antihypertensive treatment.
236 CHANGES IN ANGIOGENIC FACTORS LEVELS AND ACUTE PHASE REACTANTSCONCENTRATIONS THROUGHOUT PREGNANCY ANTOINE MALEK1, NICK BERSINGER1,ANTONELLA CROMI2, FABIO GHEZZI2, SILVIA TOMERA2, HENNING SCHNEIDER1,DANIEL SURBEK1, LUIGI RAIO1, 1University of Bern, Obstetrics and Gynecology,Bern, Switzerland, 2University of Insubria, Obstetrics and Gynecology, Varese,Italy
OBJECTIVE: Either a systemic maternal inflammatory response and analteration in the expression of angiogenenic molecules are implicated in thepathogenesis of preeclampsia and seem to precede clinical evidence of thedisorder. Our aim was to describe the gestational patterns of circulatingangiogenic factors (vascular endothelial growth factor [VEGF], placentalgrowth factor [PlGF], and soluble fms-like tyrosine kinase1 [sFlt-1]) and acutephase reactants (C reactive protein [CRP] and interleukin-6 [IL-6]) throughoutuncomplicated pregnancy and to assess whether a correlation exists betweenangiogenic markers and acute phase proteins levels.
STUDY DESIGN: We performed a longitudinal study involving 16 consec-utive normotensive women with uncomplicated pregnancy attending our low-risk prenatal clinic. Serum specimens were obtained from each participant at10-12 (period A), 18-20 (period B), 28-30 (period C) gestational weeks and atterm (O37 wks, period D). The levels of VEGF, PlGF, sFlt-1, IL6 and CRPwere measured by ELISA. Statistical analysis was performed with ANOVA forrepeated measurement, Tukeys test for post hoc analysis and Spearmancorrelation.
RESULTS: CRP and IL-6 levels increased significantly at term compared tothe early pregnancy (A vs. D and B vs. D, P!0.05). PlGF peaks in the thirdtrimester (A vs C, B vs. C, and D vs C, P!0.05). VEGF concentration did notchange throughout gestation and decreased significantly at term (B vs D and Cvs D, P!0.05). No significant change was found in sFlt-1 levels throughoutgestation, while a significant increase was observed at term (A vs. D and B vs.D, P!0.05). No significant correlation was found between angiogenic factorslevels and both acute phase reactants concentration in any of the gestationalage intervals.
CONCLUSION: Circulating angiogenic molecules and acute phase reactantsshows distinctive gestational patterns. The levels of inflammation markers(CRP and IL-6) are not correlated with the angiogenic profile in uncompli-cated pregnancy.
S76 SMFM Abstracts
