From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
Schematic representation of mitochondrial pathways affected by genetic defects in congenital SAs. Genes mutated in congenital SAs (in red) are involved in several pathways: heme synthesis, mitochondrial iron homeostasis, tRNA biosynthesis. Nonsyndromic congenital SAs: 1, XLSA; 2, SLC25A38 deficiency; 5, glutaredoxin 5 deficiency; 6, erythropoietic protoporphyria. Syndromic congenital SAs: 3, thiamine-responsive megaloblastic anemia; 4, X-linked congenital SA with ataxia; 7, Pearson marrow-pancreas syndrome; 8, myopathy, lactic acidosis, and SA; 9. SA, SIFD. ABCB7, mitochondrial transporter for cytosolic Fe-S cluster; ALA, 5-aminlevulinic acid; ALAS2, d-aminolevulinate synthase 2; Co-A, coenzyme A; CP gen III, coproporphyrinogen III; FECH, ferrochelatase; GLRX5, glutaredoxin 5; PPIX, protoporphyrin IX; PUS1, pseudouridylate synthase 1; SLC19A2, transporter of TPP; SLC25A38, transporter of glycine; TPP, thiamine pyrophosphate; TRNT1, tRNA-nucleotidyltransferase 1.
deletion of mitochondrial tRNA genes. In accordance, TRNT1 is essential for the tRNA maturation, and its reduced activity, as in other syndromic SA, is predicted to have profound effects on cell viability by affecting overall protein biosynthesis and causing a plethora of dysfunctions in patients. In conclusion, the article by Chakraborty et al opens new frontiers for molecular diagnosis in the pre- and postnatal periods and genetic treatment of patients with SIFD, although many efforts still need to be undertaken to understand the molecular mechanism underlying this complex disease phenotype. Conflict-of-interest disclosure: The author declares no relevant conflict of interest. n REFERENCES 1. Chakraborty PK, Schmitz-Abe K, Kennedy EK, et al. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood. 2014;124(18): 2867-2871. 2. Wiseman DH, May A, Jolles S, et al. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Blood. 2013;122(1):112-123. 3. Bottomley SS, Fleming MD. Sideroblastic anemia: diagnosis and management. Hematol Oncol Clin North Am. 2014;28(4):653-670.
2764
4. Bergmann AK, Campagna DR, McLoughlin EM, et al. Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations. Pediatr Blood Cancer. 2010;54(2): 273-278.
6. Russo R, Esposito MR, Iolascon A. Inherited hematological disorders due to defects in coat protein (COP)II complex. Am J Hematol. 2013;88(2):135-140.
5. Narla A, Ebert BL. Ribosomopathies: human disorders of ribosome dysfunction. Blood. 2010;115(16): 3196-3205.
7. Arosio P, Levi S. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim Biophys Acta. 2010;1800(8):783-792. © 2014 by The American Society of Hematology
l l l THROMBOSIS & HEMOSTASIS
Comment on Abdul Sultan et al, page 2872
Postpartum venous thromboembolic risk: one size may not fit all ----------------------------------------------------------------------------------------------------Hilary S. Gammill
UNIVERSITY OF WASHINGTON; FRED HUTCHINSON CANCER RESEARCH CENTER
In this issue of Blood, Abdul Sultan et al describe risk factors for venous thromboembolism (VTE) after pregnancy with consideration of duration of risk in differing clinical circumstances.1 They provide essential information toward a data-driven foundation on which clinical guidelines may be refined.
P
regnancy-related VTE represents one of the leading causes of maternal mortality and morbidity worldwide.2,3 In pregnancy and postpartum, several factors converge to increase VTE risk, including altered
coagulation factors, mechanical obstruction by the enlarged uterus, and pregnancy-related endothelial changes. Pregnancy-related VTE occurs in ;1 to 2 of every 1000 deliveries.3,4 Relative to nonpregnant, reproductive age
BLOOD, 30 OCTOBER 2014 x VOLUME 124, NUMBER 18
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
Conceptual model of levels of risk factors for postpartum VTE, based on hierarchical analysis used by Abdul Sultan et al. Professional illustration by Luk Cox, Somersault18:24.
women, pregnant women have a 4-fold higher risk of VTE,4 and postpartum risk is further increased, with estimates ranging from 9-fold to 84-fold higher.4,5 Clinical guidelines addressing VTE risk and thromboprophylaxis aim to target high-risk populations to effectively prevent these complications.6,7 However, the data on which guidelines have been developed rely on observational studies, extrapolation from other populations, and expert opinion. In fact, the primary conclusion of the guidelines from the American College of Chest Physicians was that there is an urgent need for improved data to address these questions.7 In the last few years, several investigators have sought to address this identified need, but many questions remain. Clinical factors associated with VTE risk are well established2-5,7-9 and, as suggested by Abdul Sultan et al, may be best considered in a hierarchical framework (see figure). Patient characteristics prior to pregnancy that may influence risk include maternal age, race, genetic thrombophilias, obesity, and smoking.
Disease conditions prior to pregnancy that are associated with higher risk include prior VTE, anemia, systemic lupus erythematosus, heart disease, and sickle cell disease. During pregnancy, antepartum hemorrhage, infection, hyperemesis, hospitalization, bed rest or other immobilization, preeclampsia, fetal growth restriction, and multiple gestation are associated with higher risk. At the time of delivery and in the immediate postpartum time frame, risk factors include cesarean section, postpartum hemorrhage, infection, and other serious systemic illness. To optimize thromboprophylaxis strategies, an understanding of the variance in risk over time and in particular the duration of risk postpartum is essential. In prior work, Abdul Sultan et al established that overall, VTE risk is highest in the third trimester of pregnancy and in the first 3 weeks postpartum.2 However, other studies have suggested that in some clinical scenarios, postpartum risk may persist for up to 12 weeks after delivery.5,8
BLOOD, 30 OCTOBER 2014 x VOLUME 124, NUMBER 18
It is clear that VTE risk varies over time and with clinical circumstances and that thromboprophylaxis guidelines therefore cannot fall into a one-size-fits-all category. The need for comprehensive, prospective data with which to customize recommendations remains; however, in the current study, Abdul Sultan et al have uniquely addressed the intersection of risk factors and timing of risk. Using a conceptual hierarchical modeling approach, the authors evaluated data from linked primary and secondary medical information from a large study population representative of the general United Kingdom population. Their statistical technique allowed exploration of the complex interactions between confounding variables and estimation of VTE risk in specific postpartum time periods, up to 12 weeks postpartum. Overall, they found that women with obesity, preeclampsia, infection, and cesarean delivery had a higher risk of VTE that persisted for 6 weeks after delivery. In contrast, the higher risk of VTE seen in women with postpartum hemorrhage or preterm birth persisted for 3 weeks postpartum. Prospective—ideally, randomized—studies remain essential to optimize postpartum thromboprophylaxis guidelines. However, this study by Abdul Sultan et al demonstrates the importance of tailoring recommendations according to each patient’s clinical circumstances and constellation of risk factors and provides needed data on which such decisions may be informed. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Abdul Sultan A, Grainge MJ, West J, Fleming KM, Nelson-Piercy C, Tata LJ. Impact of risk factors on the timing of first postpartum venous thromboembolism: a population-based cohort study from England. Blood. 2014;124(18):2872-2880. 2. Abdul Sultan A, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol. 2012; 156(3):366-373. 3. Virkus RA, Løkkegaard E, Lidegaard Ø, et al. Risk factors for venous thromboembolism in 1.3 million pregnancies: a nationwide prospective cohort. PLoS ONE. 2014;9(5):e96495. 4. Ghaji N, Boulet SL, Tepper N, Hooper WC. Trends in venous thromboembolism among pregnancy-related hospitalizations, United States, 1994-2009. Am J Obstet Gynecol. 2013;209(5):433.e1–433.e8.
2765
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
5. Kamel H, Navi BB, Sriram N, Hovsepian DA, Devereux RB, Elkind MS. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med. 2014; 370(14):1307-1315. 6. American College of Obstetricians and Gynecologists Women’s Health Care Physicians. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol. 2013;122(3):706-717.
2766
7. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e691S–e736S.
9. Abdul Sultan A, Tata LJ, West J, et al. Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom. Blood. 2013;121(19): 3953-3961.
8. Tepper NK, Boulet SL, Whiteman MK, et al. Postpartum venous thromboembolism: incidence and risk factors. Obstet Gynecol. 2014;123(5):987-996.
© 2014 by The American Society of Hematology
BLOOD, 30 OCTOBER 2014 x VOLUME 124, NUMBER 18
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 124: 2764-2766 doi:10.1182/blood-2014-09-599217
Postpartum venous thromboembolic risk: one size may not fit all Hilary S. Gammill
Updated information and services can be found at: http://www.bloodjournal.org/content/124/18/2764.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
Schematic representation of mitochondrial pathways affected by genetic defects in congenital SAs. Genes mutated in congenital SAs (in red) are involved in several pathways: heme synthesis, mitochondrial iron homeostasis, tRNA biosynthesis. Nonsyndromic congenital SAs: 1, XLSA; 2, SLC25A38 deficiency; 5, glutaredoxin 5 deficiency; 6, erythropoietic protoporphyria. Syndromic congenital SAs: 3, thiamine-responsive megaloblastic anemia; 4, X-linked congenital SA with ataxia; 7, Pearson marrow-pancreas syndrome; 8, myopathy, lactic acidosis, and SA; 9. SA, SIFD. ABCB7, mitochondrial transporter for cytosolic Fe-S cluster; ALA, 5-aminlevulinic acid; ALAS2, d-aminolevulinate synthase 2; Co-A, coenzyme A; CP gen III, coproporphyrinogen III; FECH, ferrochelatase; GLRX5, glutaredoxin 5; PPIX, protoporphyrin IX; PUS1, pseudouridylate synthase 1; SLC19A2, transporter of TPP; SLC25A38, transporter of glycine; TPP, thiamine pyrophosphate; TRNT1, tRNA-nucleotidyltransferase 1.
deletion of mitochondrial tRNA genes. In accordance, TRNT1 is essential for the tRNA maturation, and its reduced activity, as in other syndromic SA, is predicted to have profound effects on cell viability by affecting overall protein biosynthesis and causing a plethora of dysfunctions in patients. In conclusion, the article by Chakraborty et al opens new frontiers for molecular diagnosis in the pre- and postnatal periods and genetic treatment of patients with SIFD, although many efforts still need to be undertaken to understand the molecular mechanism underlying this complex disease phenotype. Conflict-of-interest disclosure: The author declares no relevant conflict of interest. n REFERENCES 1. Chakraborty PK, Schmitz-Abe K, Kennedy EK, et al. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood. 2014;124(18): 2867-2871. 2. Wiseman DH, May A, Jolles S, et al. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Blood. 2013;122(1):112-123. 3. Bottomley SS, Fleming MD. Sideroblastic anemia: diagnosis and management. Hematol Oncol Clin North Am. 2014;28(4):653-670.
2764
4. Bergmann AK, Campagna DR, McLoughlin EM, et al. Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations. Pediatr Blood Cancer. 2010;54(2): 273-278.
6. Russo R, Esposito MR, Iolascon A. Inherited hematological disorders due to defects in coat protein (COP)II complex. Am J Hematol. 2013;88(2):135-140.
5. Narla A, Ebert BL. Ribosomopathies: human disorders of ribosome dysfunction. Blood. 2010;115(16): 3196-3205.
7. Arosio P, Levi S. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim Biophys Acta. 2010;1800(8):783-792. © 2014 by The American Society of Hematology
l l l THROMBOSIS & HEMOSTASIS
Comment on Abdul Sultan et al, page 2872
Postpartum venous thromboembolic risk: one size may not fit all ----------------------------------------------------------------------------------------------------Hilary S. Gammill
UNIVERSITY OF WASHINGTON; FRED HUTCHINSON CANCER RESEARCH CENTER
In this issue of Blood, Abdul Sultan et al describe risk factors for venous thromboembolism (VTE) after pregnancy with consideration of duration of risk in differing clinical circumstances.1 They provide essential information toward a data-driven foundation on which clinical guidelines may be refined.
P
regnancy-related VTE represents one of the leading causes of maternal mortality and morbidity worldwide.2,3 In pregnancy and postpartum, several factors converge to increase VTE risk, including altered
coagulation factors, mechanical obstruction by the enlarged uterus, and pregnancy-related endothelial changes. Pregnancy-related VTE occurs in ;1 to 2 of every 1000 deliveries.3,4 Relative to nonpregnant, reproductive age
BLOOD, 30 OCTOBER 2014 x VOLUME 124, NUMBER 18
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
Conceptual model of levels of risk factors for postpartum VTE, based on hierarchical analysis used by Abdul Sultan et al. Professional illustration by Luk Cox, Somersault18:24.
women, pregnant women have a 4-fold higher risk of VTE,4 and postpartum risk is further increased, with estimates ranging from 9-fold to 84-fold higher.4,5 Clinical guidelines addressing VTE risk and thromboprophylaxis aim to target high-risk populations to effectively prevent these complications.6,7 However, the data on which guidelines have been developed rely on observational studies, extrapolation from other populations, and expert opinion. In fact, the primary conclusion of the guidelines from the American College of Chest Physicians was that there is an urgent need for improved data to address these questions.7 In the last few years, several investigators have sought to address this identified need, but many questions remain. Clinical factors associated with VTE risk are well established2-5,7-9 and, as suggested by Abdul Sultan et al, may be best considered in a hierarchical framework (see figure). Patient characteristics prior to pregnancy that may influence risk include maternal age, race, genetic thrombophilias, obesity, and smoking.
Disease conditions prior to pregnancy that are associated with higher risk include prior VTE, anemia, systemic lupus erythematosus, heart disease, and sickle cell disease. During pregnancy, antepartum hemorrhage, infection, hyperemesis, hospitalization, bed rest or other immobilization, preeclampsia, fetal growth restriction, and multiple gestation are associated with higher risk. At the time of delivery and in the immediate postpartum time frame, risk factors include cesarean section, postpartum hemorrhage, infection, and other serious systemic illness. To optimize thromboprophylaxis strategies, an understanding of the variance in risk over time and in particular the duration of risk postpartum is essential. In prior work, Abdul Sultan et al established that overall, VTE risk is highest in the third trimester of pregnancy and in the first 3 weeks postpartum.2 However, other studies have suggested that in some clinical scenarios, postpartum risk may persist for up to 12 weeks after delivery.5,8
BLOOD, 30 OCTOBER 2014 x VOLUME 124, NUMBER 18
It is clear that VTE risk varies over time and with clinical circumstances and that thromboprophylaxis guidelines therefore cannot fall into a one-size-fits-all category. The need for comprehensive, prospective data with which to customize recommendations remains; however, in the current study, Abdul Sultan et al have uniquely addressed the intersection of risk factors and timing of risk. Using a conceptual hierarchical modeling approach, the authors evaluated data from linked primary and secondary medical information from a large study population representative of the general United Kingdom population. Their statistical technique allowed exploration of the complex interactions between confounding variables and estimation of VTE risk in specific postpartum time periods, up to 12 weeks postpartum. Overall, they found that women with obesity, preeclampsia, infection, and cesarean delivery had a higher risk of VTE that persisted for 6 weeks after delivery. In contrast, the higher risk of VTE seen in women with postpartum hemorrhage or preterm birth persisted for 3 weeks postpartum. Prospective—ideally, randomized—studies remain essential to optimize postpartum thromboprophylaxis guidelines. However, this study by Abdul Sultan et al demonstrates the importance of tailoring recommendations according to each patient’s clinical circumstances and constellation of risk factors and provides needed data on which such decisions may be informed. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Abdul Sultan A, Grainge MJ, West J, Fleming KM, Nelson-Piercy C, Tata LJ. Impact of risk factors on the timing of first postpartum venous thromboembolism: a population-based cohort study from England. Blood. 2014;124(18):2872-2880. 2. Abdul Sultan A, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol. 2012; 156(3):366-373. 3. Virkus RA, Løkkegaard E, Lidegaard Ø, et al. Risk factors for venous thromboembolism in 1.3 million pregnancies: a nationwide prospective cohort. PLoS ONE. 2014;9(5):e96495. 4. Ghaji N, Boulet SL, Tepper N, Hooper WC. Trends in venous thromboembolism among pregnancy-related hospitalizations, United States, 1994-2009. Am J Obstet Gynecol. 2013;209(5):433.e1–433.e8.
2765
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
5. Kamel H, Navi BB, Sriram N, Hovsepian DA, Devereux RB, Elkind MS. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med. 2014; 370(14):1307-1315. 6. American College of Obstetricians and Gynecologists Women’s Health Care Physicians. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol. 2013;122(3):706-717.
2766
7. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e691S–e736S.
9. Abdul Sultan A, Tata LJ, West J, et al. Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom. Blood. 2013;121(19): 3953-3961.
8. Tepper NK, Boulet SL, Whiteman MK, et al. Postpartum venous thromboembolism: incidence and risk factors. Obstet Gynecol. 2014;123(5):987-996.
© 2014 by The American Society of Hematology
BLOOD, 30 OCTOBER 2014 x VOLUME 124, NUMBER 18
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 124: 2764-2766 doi:10.1182/blood-2014-09-599217
Postpartum venous thromboembolic risk: one size may not fit all Hilary S. Gammill
Updated information and services can be found at: http://www.bloodjournal.org/content/124/18/2764.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
