Thrombosis in Pregnant Women with Hemolytic Anemia

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

• 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
• 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
• 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
• 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
• 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 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 15 Helms CC, Marvel M, Zhao W. et al. Mechanisms of hemolysis-associated platelet activation. J Thromb Haemost 2013; 11 (12) 2148-2154
• 16 Belcher JD, Beckman JD, Balla G, Balla J, Vercellotti G. Heme degradation and vascular injury. Antioxid Redox Signal 2010; 12 (02) 233-248
• 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
• 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
• 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
• 20 Gresele P, Momi S, Guglielmini G. Nitric oxide-enhancing or -releasing agents as antithrombotic drugs. Biochem Pharmacol 2019; 166: 300-312
• 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
• 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
• 23 Cappellini MD. Coagulation in the pathophysiology of hemolytic anemias. Hematology (Am Soc Hematol Educ Program) 2007; 74-78
• 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
• 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
• 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
• 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
• 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
• 29 Griffin M, Munir T. Management of thrombosis in paroxysmal nocturnal hemoglobinuria: a clinician's guide. Ther Adv Hematol 2017; 8 (03) 119-126
• 30 Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121 (25) 4985-4996 , quiz 5105
• 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
• 32 Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers 2017; 3: 17028
• 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
• 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
• 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
• 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
• 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
• 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
• 39 Lee SE, Lee JW. Safety of current treatments for paroxysmal nocturnal hemoglobinuria. Expert Opin Drug Saf 2021; 20 (02) 171-179
• 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
• 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
• 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
• 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
• 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
• 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
• 46 Neave L, Scully M. Microangiopathic hemolytic anemia in pregnancy. Transfus Med Rev 2018; 32 (04) 230-236
• 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
• 48 Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis 2010; 5: 11
• 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
• 50 Origa R, Piga A, Quarta G. et al. Pregnancy and beta-thalassemia: an Italian multicenter experience. Haematologica 2010; 95 (03) 376-381
• 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
• 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
• 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
• 54 Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood 2002; 99 (01) 36-43
• 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
• 56 Taher AT, Iolascon A, Matar CF. et al. Recommendations for pregnancy in rare inherited anemias. HemaSphere 2020; 4 (04) e446
• 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
• 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
• 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
• 60 Smith-Whitley K. Complications in pregnant women with sickle cell disease. Hematology (Am Soc Hematol Educ Program) 2019; 2019 (01) 359-366
• 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
• 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
• 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
• 64 Hendrick AM. Auto-immune haemolytic anaemia – a high-risk disorder for thromboembolism?. Hematology 2003; 8 (01) 53-56
• 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
• 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
• 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
• 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
• 69 Zwaal RF, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 1997; 89 (04) 1121-1132
• 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
• 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
• 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