Download PDF
Thromb Haemost 2025; 125(06): 553-562
DOI: 10.1055/a-2413-2966
Coagulation and Fibrinolysis

Unfavorably Altered Fibrin Clot Phenotype in Women Following Postpartum Hemorrhage of Unknown Cause: Effect of Lower Coagulation Factors

Magdalena Piróg 
1   Gynecological Endocrinology Department, Jagiellonian University Medical College, Krakow, Poland
,
Michał Ząbczyk
2   Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
3   Krakow Centre for Medical Research and Technologies, St. John Paul II Hospital, Krakow, Poland
,
Joanna Natorska
2   Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
3   Krakow Centre for Medical Research and Technologies, St. John Paul II Hospital, Krakow, Poland
,
Elżbieta Broniatowska
4   Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland
,
Robert Jach
1   Gynecological Endocrinology Department, Jagiellonian University Medical College, Krakow, Poland
,
Anetta Undas
2   Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
3   Krakow Centre for Medical Research and Technologies, St. John Paul II Hospital, Krakow, Poland
› Author Affiliations
Funding This work was supported by a grant from the Jagiellonian University Medical College (No. N41/DBS/001040, to A.U.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
› Further Information
Also available at
   Permissions and Reprints


Abstract

Background

Increased clot permeability and susceptibility to lysis have been reported in women with heavy menstrual bleeding. We hypothesized that similar alterations in fibrin clot properties may also be present in women with postpartum hemorrhage (PPH) of unknown cause.

Objective

To determine fibrin clot properties and their determinants in women after PPH of unknown cause.

Methods

We studied 52 consecutive women, aged 35 years (27–40), after at least 3 months since PPH of unknown cause and 52 matched controls for age, weight, and fibrinogen. Coagulation factors (F), antithrombin, thrombin generation, along with a comprehensive plasma fibrin clot analysis including fibrin polymerization, clot permeability (K s), and fibrinolysis efficiency were determined.

Results

Women with PPH showed reduced activity of FII (−10.3%), FV (−6.6%), FIX (−6.5%), FX (−7.2%), and FXI (−5.7%) compared with the controls, though all values were within ranges (all p < 0.05). There were no intergroup differences in fibrinogen, FVIII, FXIII, and thrombin generation. The PPH group formed with a delay looser plasma fibrin network (K s; +16.3%, p = 0.008) with lower maximum absorbance and shorter clot lysis time (CLT; −13.5%, p = 0.001) compared with the controls. On multivariable logistic regression, PPH was independently associated with higher C-reactive protein (per 1 mg/L, odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.09–2.68), lower FII (per 1%, OR = 0.93, 95% CI: 0.89–0.98), lower FV (per 1%, OR = 0.93, 95% CI: 0.89–0.97), and shorter CLT (per 1 minute, OR = 0.94, 95% CI: 0.90–0.98).

Conclusion

Prohemorrhagic fibrin clot properties, with lower, though normal coagulation factors, characterize women with PPH of unknown cause, which suggests novel mechanisms contributing to this type of bleeding.

Keywords

coagulation factors - fibrinolysis - fibrin clot - postpartum hemorrhage

Authors' Contribution

M.P.: preparation of samples, experimental design, data collection and analysis, drafting the manuscript; R.J.: analysis of the manuscript; M.Z.: laboratory investigations, statistical analysis, interpretation of data; J.N.: laboratory investigations, statistical analysis, interpretation of data; A.U: study design, data collection, interpretation of data and revision of the manuscript.




Publication History

Received: 18 July 2024

Accepted: 09 September 2024

Accepted Manuscript online:
11 September 2024

Article published online:
05 November 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Patek K, Friedman P. Postpartum hemorrhage-epidemiology, risk factors, and causes. Clin Obstet Gynecol 2023; 66 (02) 344-356
    CrossrefPubMedSearch in Google Scholar
  • 2 Creanga AA, Syverson C, Seed K, Callaghan WM. Pregnancy-related mortality in the United States, 2011-2013. Obstet Gynecol 2017; 130 (02) 366-373
    CrossrefPubMedSearch in Google Scholar
  • 3 Saluja B, Bryant Z. How implicit bias contributes to racial disparities in maternal morbidity and mortality in the United States. J Womens Health (Larchmt) 2021; 30 (02) 270-273
    CrossrefPubMedSearch in Google Scholar
  • 4 Schatz F, Guzeloglu-Kayisli O, Arlier S, Kayisli UA, Lockwood CJ. The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. Hum Reprod Update 2016; 22 (04) 497-515
    CrossrefPubMedSearch in Google Scholar
  • 5 Corbetta-Rastelli CM, Friedman AM, Sobhani NC, Arditi B, Goffman D, Wen T. Postpartum hemorrhage trends and outcomes in the United States, 2000-2019. Obstet Gynecol 2023; 141 (01) 152-161
    CrossrefPubMedSearch in Google Scholar
  • 6 de Moreuil C, Dargaud Y, Nougier C. et al. Women with severe postpartum hemorrhage have a decreased endogenous thrombin potential before delivery. J Thromb Haemost 2023; 21 (11) 3099-3108
    CrossrefPubMedSearch in Google Scholar
  • 7 Ruiter L, Kazemier BM, Mol BWJ, Pajkrt E. Incidence and recurrence rate of postpartum hemorrhage and manual removal of the placenta: a longitudinal linked national cohort study in The Netherlands. Eur J Obstet Gynecol Reprod Biol 2019; 238: 114-119
    CrossrefPubMedSearch in Google Scholar
  • 8 James AH, Jamison MG. Bleeding events and other complications during pregnancy and childbirth in women with von Willebrand disease. J Thromb Haemost 2007; 5 (06) 1165-1169
    CrossrefPubMedSearch in Google Scholar
  • 9 Main EK, Goffman D, Scavone BM. et al; National Partnership for Maternal Safety, Council on Patient Safety in Women's Health Care. National partnership for maternal safety: consensus bundle on obstetric hemorrhage. Obstet Gynecol 2015; 126 (01) 155-162
    PubMedSearch in Google Scholar
  • 10 Hugon-Rodin J, Carrière C, Claeyssens S. et al. Obstetrical complications in hereditary fibrinogen disorders: the Fibrinogest study. J Thromb Haemost 2023; 21 (08) 2126-2136
    CrossrefPubMedSearch in Google Scholar
  • 11 Stanton K, Philippou H, Ariëns RA. Ischaemic stroke, thromboembolism and clot structure. Neuroscience 2024; 550: 3-10
    CrossrefPubMedSearch in Google Scholar
  • 12 Pieters M, Wolberg AS. Fibrinogen and fibrin: an illustrated review. Res Pract Thromb Haemost 2019; 3 (02) 161-172
    CrossrefPubMedSearch in Google Scholar
  • 13 Mihalko E, Brown AC. Clot structure and implications for bleeding and thrombosis. Semin Thromb Hemost 2020; 46 (01) 96-104
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Szczepaniak P, Zabczyk M, Undas A. Increased plasma clot permeability and susceptibility to lysis are associated with heavy menstrual bleeding of unknown cause: a case-control study. PLoS One 2015; 10 (04) e0125069
    CrossrefPubMedSearch in Google Scholar
  • 15 Valke LLFG, Meijer D, Nieuwenhuizen L. et al. Fibrinolytic assays in bleeding of unknown cause: improvement in diagnostic yield. Res Pract Thromb Haemost 2022; 6 (02) e12681
    CrossrefPubMedSearch in Google Scholar
  • 16 Wolberg AS, Allen GA, Monroe DM, Hedner U, Roberts HR, Hoffman M. High dose factor VIIa improves clot structure and stability in a model of haemophilia B. Br J Haematol 2005; 131 (05) 645-655
    CrossrefPubMedSearch in Google Scholar
  • 17 de Moreuil C, Mehic D, Nopp S. et al. Hemostatic biomarkers associated with postpartum hemorrhage: a systematic review and meta-analysis. Blood Adv 2023; 7 (19) 5954-5967
    CrossrefPubMedSearch in Google Scholar
  • 18 Desborough MJR, Obaji S, Lowe GC, Doree C, Thomas W. Management of surgery, menorrhagia and child-birth for patients with unclassified bleeding disorders: a systematic review of cohort studies. Blood Coagul Fibrinolysis 2021; 32 (06) 366-372
    CrossrefPubMedSearch in Google Scholar
  • 19 Vogel JP, Oladapo OT, Dowswell T, Gülmezoglu AM. Updated WHO recommendation on intravenous tranexamic acid for the treatment of post-partum haemorrhage. Lancet Glob Health 2018; 6 (01) e18-e19
    CrossrefPubMedSearch in Google Scholar
  • 20 Ząbczyk M, Ariëns RAS, Undas A. Fibrin clot properties in cardiovascular disease: from basic mechanisms to clinical practice. Cardiovasc Res 2023; 119 (01) 94-111
    CrossrefPubMedSearch in Google Scholar
  • 21 American Diabetes Association. (2) Classification and diagnosis of diabetes. Diabetes Care 2015; 38 (Suppl): S8-S16
    CrossrefPubMedSearch in Google Scholar
  • 22 Singh S, Best C, Dunn S, Leyland N, Wolfman WL. CLINICAL PRACTICE – GYNAECOLOGY COMMITTEE. Abnormal uterine bleeding in pre-menopausal women. J Obstet Gynaecol Can 2013; 35 (05) 473-475
    CrossrefPubMedSearch in Google Scholar
  • 23 Zabczyk M, Plens K, Wojtowicz W, Undas A. Prothrombotic fibrin clot phenotype is associated with recurrent pulmonary embolism after discontinuation of anticoagulant therapy. Arterioscler Thromb Vasc Biol 2017; 37 (02) 365-373
    CrossrefPubMedSearch in Google Scholar
  • 24 Weisel JW, Nagaswami C. Computer modeling of fibrin polymerization kinetics correlated with electron microscope and turbidity observations: clot structure and assembly are kinetically controlled. Biophys J 1992; 63 (01) 111-128
    CrossrefPubMedSearch in Google Scholar
  • 25 Cieslik J, Mrozinska S, Broniatowska E, Undas A. Altered plasma clot properties increase the risk of recurrent deep vein thrombosis: a cohort study. Blood 2018; 131 (07) 797-807
    CrossrefPubMedSearch in Google Scholar
  • 26 Piróg M, Kacalska-Janssen O, Jach R, Ząbczyk M, Natorska J. Fibrin clot properties among women with endometriosis and the impact of ovarian stimulation. Reprod Biomed Online 2021; 43 (01) 81-90
    CrossrefPubMedSearch in Google Scholar
  • 27 Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003; 29 (02) 125-130
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Brummel-Ziedins KE, Branda RF, Butenas S, Mann KG. Discordant fibrin formation in hemophilia. J Thromb Haemost 2009; 7 (05) 825-832
    CrossrefPubMedSearch in Google Scholar
  • 29 Drabik L, Wołkow P, Undas A. Fibrin clot permeability as a predictor of stroke and bleeding in anticoagulated patients with atrial fibrillation. Stroke 2017; 48 (10) 2716-2722
    CrossrefPubMedSearch in Google Scholar
  • 30 Hofer S, Ay C, Rejtö J. et al. Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause. J Thromb Haemost 2019; 17 (09) 1478-1488
    CrossrefPubMedSearch in Google Scholar
  • 31 Driever EG, Larsen JB, Bos S, Bernal W, Hvas AM, Lisman T. Congruent identification of imbalanced fibrinolysis by 2 distinct clot lysis time assays. Res Pract Thromb Haemost 2023; 7 (01) 100043
    CrossrefPubMedSearch in Google Scholar
  • 32 Cortet M, Deneux-Tharaux C, Dupont C. et al. Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. Br J Anaesth 2012; 108 (06) 984-989
    CrossrefPubMedSearch in Google Scholar
  • 33 Pretorius E, Bronkhorst P, Briedenhann S, Smit E, Franz RC. Comparisons of the fibrin networks during pregnancy, nonpregnancy and pregnancy during dysfibrinogenaemia using the scanning electron microscope. Blood Coagul Fibrinolysis 2009; 20 (01) 12-16
    CrossrefPubMedSearch in Google Scholar
  • 34 Vries MJA, Macrae F, Nelemans PJ. et al. Assessment and determinants of whole blood and plasma fibrinolysis in patients with mild bleeding symptoms. Thromb Res 2019; 174: 88-94
    CrossrefPubMedSearch in Google Scholar
  • 35 Siniarski A, Baker SR, Duval C. et al. Quantitative analysis of clot density, fibrin fiber radius, and protofibril packing in acute phase myocardial infarction. Thromb Res 2021; 205: 110-119
    CrossrefPubMedSearch in Google Scholar
  • 36 Wolberg AS, Monroe DM, Roberts HR, Hoffman M. Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk. Blood 2003; 101 (08) 3008-3013
    CrossrefPubMedSearch in Google Scholar
  • 37 Antovic A, Mikovic D, Elezovic I, Zabczyk M, Hutenby K, Antovic JP. Improvement of fibrin clot structure after factor VIII injection in haemophilia A patients treated on demand. Thromb Haemost 2014; 111 (04) 656-661
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 Wolberg AS, Campbell RA. Thrombin generation, fibrin clot formation and hemostasis. Transfus Apher Sci 2008; 38 (01) 15-23
    CrossrefPubMedSearch in Google Scholar
  • 39 Gebhart J, Laczkovics C, Posch F. et al. Plasma clot properties in patients with a mild-to-moderate bleeding tendency of unknown cause. Ann Hematol 2015; 94 (08) 1301-1310
    CrossrefPubMedSearch in Google Scholar
  • 40 Brummel-Ziedins KE, Orfeo T, Rosendaal FR. et al. Empirical and theoretical phenotypic discrimination. J Thromb Haemost 2009; 7 (Suppl 1, Suppl 1): 181-186
    CrossrefPubMedSearch in Google Scholar
  • 41 Paszek E, Polak M, Bryk-Wiązania AH, Konieczyńska M, Undas A. Elevated plasma factor XI predicts cardiovascular events in patients with type 2 diabetes: a long-term observational study. Cardiovasc Diabetol 2023; 22 (01) 182
    CrossrefPubMedSearch in Google Scholar
  • 42 Zucker M, Seligsohn U, Salomon O, Wolberg AS. Abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe factor XI deficiency. J Thromb Haemost 2014; 12 (07) 1121-1130
    CrossrefPubMedSearch in Google Scholar
  • 43 Brummel-Ziedins K. Models for thrombin generation and risk of disease. J Thromb Haemost 2013; 11 (Suppl. 01) 212-223
    CrossrefPubMedSearch in Google Scholar
  • 44 Kwasny-Krochin B, Gluszko P, Undas A. Unfavorably altered fibrin clot properties in patients with active rheumatoid arthritis. Thromb Res 2010; 126 (01) e11-e16
    CrossrefPubMedSearch in Google Scholar
  • 45 Liu CN, Yu FB, Xu YZ. et al. Prevalence and risk factors of severe postpartum hemorrhage: a retrospective cohort study. BMC Pregnancy Childbirth 2021; 21 (01) 332
    CrossrefPubMedSearch in Google Scholar
  • 46 McQuilten ZK, Wood EM, Medcalf RL. When to use tranexamic acid for the treatment of major bleeding?. J Thromb Haemost 2024; 22 (03) 581-593
    CrossrefPubMedSearch in Google Scholar