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Semin Thromb Hemost 2023; 49(04): 364-370
DOI: 10.1055/s-0042-1758819
Review Article

Thrombosis in Pregnant Women with Hemolytic Anemia

Emmanouil Papadakis
1   Thrombosis and Hemostasis Clinic, Genesis Hospital, Thessaloniki, Greece
,
Benjamin Brenner
2   Department of Hematology, Rambam Health Care Campus, Haifa, Israel
3   The Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
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Abstract

Hemolytic anemias are a group of uncommon disorders affecting both genders, frequently occurring at the reproductive age. While a link between hemolysis and hypercoagulability has been suggested based on the elucidation of certain involved pathophysiological mechanisms, the extent of thrombotic risk in pregnant women with hemolytic anemia remains debatable. Due to the paucity of pregnancy-related data, risk assessment of gestations in women with hemolytic anemia is complicated. This review will highlight the latest advances in the diagnosis and management of these challenging disorders in pregnancy.

Keywords

hemolytic anemias - pregnancy - venous thromboembolism


Publication History

Article published online:
21 November 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium – a register-based case-control study. Am J Obstet Gynecol 2008; 198 (02) 233.e1-233.e7
    CrossrefPubMedGoogle Scholar
  • 2 Jacobsen AF, Skjeldestad FE, Sandset PM. Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study. J Thromb Haemost 2008; 6 (06) 905-912
    CrossrefPubMedGoogle Scholar
  • 3 Aharon A, Brenner B, Katz T, Miyagi Y, Lanir N. Tissue factor and tissue factor pathway inhibitor levels in trophoblast cells: implications for placental hemostasis. Thromb Haemost 2004; 92 (04) 776-786
    PubMedGoogle Scholar
  • 4 Boer K, den Hollander IA, Meijers JC, Levi M. Tissue factor-dependent blood coagulation is enhanced following delivery irrespective of the mode of delivery. J Thromb Haemost 2007; 5 (12) 2415-2420
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 6 Wik HS, Jacobsen AF, Fagerland MW, Sandvik L, Sandset PM. Long-term mortality and incidence of cancer after pregnancy-related venous thrombosis: results of a population-based cohort study. Thromb Res 2013; 131 (06) 497-501
    CrossrefPubMedGoogle Scholar
  • 7 Wik HS, Jacobsen AF, Mowinckel MC, Sandset PM. The role of inflammation in post-thrombotic syndrome after pregnancy-related deep vein thrombosis: a population-based, cross-sectional study. Thromb Res 2016; 138: 16-21
    CrossrefPubMedGoogle Scholar
  • 8 Capecchi M, Ciavarella A, Artoni A, Abbattista M, Martinelli I. Thrombotic complications in patients with immune-mediated hemolysis. J Clin Med 2021; 10 (08) 1764
    CrossrefPubMedGoogle Scholar
  • 9 Hill QA, Stamps R, Massey E, Grainger JD, Provan D, Hill A. British Society for Haematology. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol 2017; 176 (03) 395-411
    CrossrefPubMedGoogle Scholar
  • 10 Amin C, Adam S, Mooberry MJ. et al. Coagulation activation in sickle cell trait: an exploratory study. Br J Haematol 2015; 171 (04) 638-646
    CrossrefPubMedGoogle Scholar
  • 11 Setty BN, Key NS, Rao AK. et al. Tissue factor-positive monocytes in children with sickle cell disease: correlation with biomarkers of haemolysis. Br J Haematol 2012; 157 (03) 370-380
    CrossrefPubMedGoogle Scholar
  • 12 van Beers EJ, Schaap MC, Berckmans RJ. et al; CURAMA Study Group. Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease. Haematologica 2009; 94 (11) 1513-1519
    CrossrefPubMedGoogle Scholar
  • 13 Karnell JL, Rieder SA, Ettinger R, Kolbeck R. Targeting the CD40-CD40L pathway in autoimmune diseases: humoral immunity and beyond. Adv Drug Deliv Rev 2019; 141: 92-103
    CrossrefPubMedGoogle Scholar
  • 14 Chamchoi A, Srihirun S, Paiboonsukwong K. et al. Hemoglobin-bound platelets correlate with the increased platelet activity in hemoglobin E/β-thalassemia. Int J Lab Hematol 2020; 42 (05) 518-525
    CrossrefPubMedGoogle Scholar
  • 15 Helms CC, Marvel M, Zhao W. et al. Mechanisms of hemolysis-associated platelet activation. J Thromb Haemost 2013; 11 (12) 2148-2154
    CrossrefPubMedGoogle Scholar
  • 16 Belcher JD, Beckman JD, Balla G, Balla J, Vercellotti G. Heme degradation and vascular injury. Antioxid Redox Signal 2010; 12 (02) 233-248
    CrossrefPubMedGoogle Scholar
  • 17 Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood 2014; 123 (24) 3818-3827
    CrossrefPubMedGoogle Scholar
  • 18 Burczyk G, Cichon I, Kolaczkowska E. Itaconate suppresses formation of neutrophil extracellular traps (NETs): involvement of hypoxia-inducible factor 1α (Hif-1α) and heme oxygenase (HO-1). Front Immunol 2022; 13: 864638
    CrossrefPubMedGoogle Scholar
  • 19 Jilma-Stohlawetz P, Lysy K, Belik S, Jilma B, Quehenberger P. Interference in specialized coagulation assays affecting the protein C pathway: effects of marked haemolysis, hyperbilirubinaemia and lipaemia on chromogenic and clotting tests on two coagulation platforms. Int J Lab Hematol 2019; 41 (03) 404-411
    CrossrefPubMedGoogle Scholar
  • 20 Gresele P, Momi S, Guglielmini G. Nitric oxide-enhancing or -releasing agents as antithrombotic drugs. Biochem Pharmacol 2019; 166: 300-312
    CrossrefPubMedGoogle Scholar
  • 21 Giles TD. Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease. J Clin Hypertens (Greenwich) 2006; 8 (12, Suppl 4): 2-16
    CrossrefPubMedGoogle Scholar
  • 22 Gladwin MT, Crawford JH, Patel RP. The biochemistry of nitric oxide, nitrite, and hemoglobin: role in blood flow regulation. Free Radic Biol Med 2004; 36 (06) 707-717
    CrossrefPubMedGoogle Scholar
  • 23 Cappellini MD. Coagulation in the pathophysiology of hemolytic anemias. Hematology (Am Soc Hematol Educ Program) 2007; 74-78
    CrossrefPubMedGoogle Scholar
  • 24 Ladeira VS, Barbosa AR, Oliveira MM. et al. ADAMTS-13-VWF axis in sickle cell disease patients. Ann Hematol 2021; 100 (02) 375-382
    CrossrefPubMedGoogle Scholar
  • 25 Keragala CB, Draxler DF, McQuilten ZK, Medcalf RL. Haemostasis and innate immunity - a complementary relationship: a review of the intricate relationship between coagulation and complement pathways. Br J Haematol 2018; 180 (06) 782-798
    CrossrefPubMedGoogle Scholar
  • 26 Frimat M, Tabarin F, Dimitrov JD. et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood 2013; 122 (02) 282-292
    CrossrefPubMedGoogle Scholar
  • 27 Ray JG, Burows RF, Ginsberg JS, Burrows EA. Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient. Haemostasis 2000; 30 (03) 103-117
    PubMedGoogle Scholar
  • 28 Devalet B, Mullier F, Chatelain B, Dogné JM, Chatelain C. Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review. Eur J Haematol 2015; 95 (03) 190-198
    CrossrefPubMedGoogle Scholar
  • 29 Griffin M, Munir T. Management of thrombosis in paroxysmal nocturnal hemoglobinuria: a clinician's guide. Ther Adv Hematol 2017; 8 (03) 119-126
    CrossrefPubMedGoogle Scholar
  • 30 Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121 (25) 4985-4996 , quiz 5105
    CrossrefPubMedGoogle Scholar
  • 31 Malato A, Saccullo G, Coco LL. et al. Thrombotic complications in paroxysmal nocturnal haemoglobinuria: a literature review. Blood Transfus 2012; 10 (04) 428-435
    PubMedGoogle Scholar
  • 32 Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers 2017; 3: 17028
    CrossrefPubMedGoogle Scholar
  • 33 Fieni S, Bonfanti L, Gramellini D, Benassi L, Delsignore R. Clinical management of paroxysmal nocturnal hemoglobinuria in pregnancy: a case report and updated review. Obstet Gynecol Surv 2006; 61 (09) 593-601
    CrossrefPubMedGoogle Scholar
  • 34 Sahin F, Akay OM, Ayer M. et al. Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res 2016; 6 (02) 19-27
    PubMedGoogle Scholar
  • 35 Alashkar F, Saner FH, Vance C. et al. Pregnancy in classical paroxysmal nocturnal hemoglobinuria and aplastic anemia-paroxysmal nocturnal hemoglobinuria: a high-risk constellation. Front Med (Lausanne) 2020; 7: 543372
    CrossrefPubMedGoogle Scholar
  • 36 Miyasaka N, Miura O, Kawaguchi T. et al. Pregnancy outcomes of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: a Japanese experience and updated review. Int J Hematol 2016; 103 (06) 703-712
    CrossrefPubMedGoogle Scholar
  • 37 Lee JW, Sicre de Fontbrune F, Wong Lee Lee L. et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood 2019; 133 (06) 530-539
    CrossrefPubMedGoogle Scholar
  • 38 Kulasekararaj AG, Griffin M, Langemeijer S. et al; 301/302 Study Group. Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies. Eur J Haematol 2022; 109 (03) 205-214
    CrossrefPubMedGoogle Scholar
  • 39 Lee SE, Lee JW. Safety of current treatments for paroxysmal nocturnal hemoglobinuria. Expert Opin Drug Saf 2021; 20 (02) 171-179
    CrossrefPubMedGoogle Scholar
  • 40 Hill A, Rother RP, Wang X. et al. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2010; 149 (03) 414-425
    CrossrefPubMedGoogle Scholar
  • 41 Scully M, Yarranton H, Liesner R. et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features. Br J Haematol 2008; 142 (05) 819-826
    CrossrefPubMedGoogle Scholar
  • 42 Fakhouri F, Roumenina L, Provot F. et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol 2010; 21 (05) 859-867
    CrossrefPubMedGoogle Scholar
  • 43 Fakhouri F, Scully M, Ardissino G, Al-Dakkak I, Miller B, Rondeau E. Pregnancy-triggered atypical hemolytic uremic syndrome (aHUS): a Global aHUS Registry analysis. J Nephrol 2021; 34 (05) 1581-1590
    CrossrefPubMedGoogle Scholar
  • 44 Amari Chinchilla K, Vijayan M, Taveras Garcia B, Jim B. Complement-mediated disorders in pregnancy. Adv Chronic Kidney Dis 2020; 27 (02) 155-164
    CrossrefPubMedGoogle Scholar
  • 45 Kelly RJ, Höchsmann B, Szer J. et al. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2015; 373 (11) 1032-1039
    CrossrefPubMedGoogle Scholar
  • 46 Neave L, Scully M. Microangiopathic hemolytic anemia in pregnancy. Transfus Med Rev 2018; 32 (04) 230-236
    CrossrefPubMedGoogle Scholar
  • 47 Middleton P, Shepherd E, Gomersall JC. Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period. Cochrane Database Syst Rev 2021; 3: CD001689
    PubMedGoogle Scholar
  • 48 Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis 2010; 5: 11
    CrossrefPubMedGoogle Scholar
  • 49 Nassar AH, Naja M, Cesaretti C, Eprassi B, Cappellini MD, Taher A. Pregnancy outcome in patients with beta-thalassemia intermedia at two tertiary care centers, in Beirut and Milan. Haematologica 2008; 93 (10) 1586-1587
    CrossrefPubMedGoogle Scholar
  • 50 Origa R, Piga A, Quarta G. et al. Pregnancy and beta-thalassemia: an Italian multicenter experience. Haematologica 2010; 95 (03) 376-381
    CrossrefPubMedGoogle Scholar
  • 51 Nourollahpour Shiadeh M, Cassinerio E, Modarres M, Zareiyan A, Hamzehgardeshi Z, Behboodi Moghadam Z. Reproductive health issues in female patients with beta-thalassaemia major: a narrative literature review. J Obstet Gynaecol 2020; 40 (07) 902-911
    CrossrefPubMedGoogle Scholar
  • 52 Cappellini MD, Robbiolo L, Bottasso BM, Coppola R, Fiorelli G, Mannucci AP. Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia. Br J Haematol 2000; 111 (02) 467-473
    CrossrefPubMedGoogle Scholar
  • 53 Mancuso A, Giacobbe A, De Vivo A, Ardita FV, Meo A. Pregnancy in patients with beta-thalassaemia major: maternal and foetal outcome. Acta Haematol 2008; 119 (01) 15-17
    CrossrefPubMedGoogle Scholar
  • 54 Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood 2002; 99 (01) 36-43
    CrossrefPubMedGoogle Scholar
  • 55 Nassar AH, Usta IM, Rechdan JB, Koussa S, Inati A, Taher AT. Pregnancy in patients with beta-thalassemia intermedia: outcome of mothers and newborns. Am J Hematol 2006; 81 (07) 499-502
    CrossrefPubMedGoogle Scholar
  • 56 Taher AT, Iolascon A, Matar CF. et al. Recommendations for pregnancy in rare inherited anemias. HemaSphere 2020; 4 (04) e446
    CrossrefPubMedGoogle Scholar
  • 57 James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006; 194 (05) 1311-1315
    CrossrefPubMedGoogle Scholar
  • 58 Naik RP, Streiff MB, Lanzkron S. Sickle cell disease and venous thromboembolism: what the anticoagulation expert needs to know. J Thromb Thrombolysis 2013; 35 (03) 352-358
    CrossrefPubMedGoogle Scholar
  • 59 Anyaegbu CC, Okpala IE, Aken'ova AY, Salimonu LS. Complement haemolytic activity, circulating immune complexes and the morbidity of sickle cell anaemia. Acta Pathol Microbiol Scand Suppl 1999; 107 (07) 699-702
    CrossrefPubMedGoogle Scholar
  • 60 Smith-Whitley K. Complications in pregnant women with sickle cell disease. Hematology (Am Soc Hematol Educ Program) 2019; 2019 (01) 359-366
    CrossrefPubMedGoogle Scholar
  • 61 Austin H, Key NS, Benson JM. et al. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 2007; 110 (03) 908-912
    CrossrefPubMedGoogle Scholar
  • 62 Folsom AR, Tang W, Roetker NS. et al. Prospective study of sickle cell trait and venous thromboembolism incidence. J Thromb Haemost 2015; 13 (01) 2-9
    CrossrefPubMedGoogle Scholar
  • 63 Wilson S, Ellsworth P, Key NS. Pregnancy in sickle cell trait: what we do and don't know. Br J Haematol 2020; 190 (03) 328-335
    CrossrefPubMedGoogle Scholar
  • 64 Hendrick AM. Auto-immune haemolytic anaemia – a high-risk disorder for thromboembolism?. Hematology 2003; 8 (01) 53-56
    CrossrefPubMedGoogle Scholar
  • 65 Lecouffe-Desprets M, Néel A, Graveleau J. et al. Venous thromboembolism related to warm autoimmune hemolytic anemia: a case-control study. Autoimmun Rev 2015; 14 (11) 1023-1028
    CrossrefPubMedGoogle Scholar
  • 66 Jäger U, Barcellini W, Broome CM. et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. Blood Rev 2020; 41: 100648
    CrossrefPubMedGoogle Scholar
  • 67 Pullarkat V, Ngo M, Iqbal S, Espina B, Liebman HA. Detection of lupus anticoagulant identifies patients with autoimmune haemolytic anaemia at increased risk for venous thromboembolism. Br J Haematol 2002; 118 (04) 1166-1169
    CrossrefPubMedGoogle Scholar
  • 68 Kokori SI, Ioannidis JP, Voulgarelis M, Tzioufas AG, Moutsopoulos HM. Autoimmune hemolytic anemia in patients with systemic lupus erythematosus. Am J Med 2000; 108 (03) 198-204
    CrossrefPubMedGoogle Scholar
  • 69 Zwaal RF, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 1997; 89 (04) 1121-1132
    CrossrefPubMedGoogle Scholar
  • 70 Ungprasert P, Tanratana P, Srivali N. Autoimmune hemolytic anemia and venous thromboembolism: a systematic review and meta-analysis. Thromb Res 2015; 136 (05) 1013-1017
    CrossrefPubMedGoogle Scholar
  • 71 Patriquin CJ, Kiss T, Caplan S. et al. How we treat paroxysmal nocturnal hemoglobinuria: a consensus statement of the Canadian PNH Network and review of the national registry. Eur J Haematol 2019; 102 (01) 36-52
    CrossrefPubMedGoogle Scholar
  • 72 Fakhouri F, Scully M, Provôt F. et al. Management of thrombotic microangiopathy in pregnancy and postpartum: report from an international working group. Blood 2020; 136 (19) 2103-2117
    CrossrefPubMedGoogle Scholar