Microparticles in hemophilia : friend or foe? To improve hemostasis or to induce atherothrombosis?
Author: Zong, Yanan
Date: 2020-12-18
Location: Wretlindsalen, Tomtebodavägen 18A, Karolinska Institutet, Solna
Time: 10.00
Department: Inst för molekylär medicin och kirurgi / Dept of Molecular Medicine and Surgery
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Thesis (2.266Mb)
Abstract
As one of the most well-known inherited bleeding disorders, hemophilia A (HA) is caused by the deficiency or dysfunction of coagulation factor VIII (FVIII). Patients with HA (PWHA) suffer from abnormal bleeding after injuries or surgeries, or even spontaneous bleeding in severe cases, particularly at joints and muscles. The main treatment for PWHA is FVIII replacement therapy. Patients with the same residual FVIII levels may present different clinical bleeding phenotypes, thus individualized adjustment of the treatment is necessary. Moreover, the risks of cardiovascular disease (CVD) are increased in middle-aged or elderly patients. The management of CVD in PHWA has become a new clinical challenge. Circulating microparticles (MPs) are small membrane vesicles that originate mostly from platelets in healthy individuals. MPs play important roles in hemostasis and thrombosis and are reported to participate in the development of CVD. However, the role of MPs in hemostasis of HA as well as in the development of CVD in PWHA remains unclear. The overall aim of this thesis was to investigate the role of MPs in HA. The first part focused on the effect of MPs on hemostasis of HA in vitro and in vivo. In the second part, the prevalence of CVD, the profiles of MPs, as well as their correlations in the middle-aged and elderly PWHA were investigated. In another study, fibrin formation for combinations of a new bispecific antibody and bypassing agents (aPCC or rFVIIa) was studied using in vitro approaches.
In Paper I, we characterized the fibrin formation and fibrin clot structure in a human plasma model of severe HA after the addition of sequence-identical analogue (SIA) of emicizumab, alone or in combinations with bypassing agents (aPCC or rFVIIa). The combination of SIA and aPCC exhibited hypercoagulable patterns, suggesting that this combination might introduce thrombotic risk when used to treat PWHA. In Papers II and IV, the procoagulant effect of MPs in HA was studied using in vitro plasma models and in vivo mouse models of HA, respectively. MPs improved hemostasis and were found to be incorporated into the fibrin network in both in vitro and in vivo HA models. In Paper III, the prevalence of subclinical CVD in a Swedish PWHA (≥40 years old) cohort was determined using the advanced electrocardiography (A-ECG) technique, retrospectively. PWHA were found to have higher probabilities of developing CVD compared to the age-matched male control. In Paper V, a cross-sectional study with a Chinese cohort of PWHA treated on-demand (≥30 years old) was conducted. PWHA treated on-demand were not protected from developing subclinical CVD. No correlations between the CVD risks and MPs profiles were observed. In addition, the hypercoagulable state might lead to increased platelet activation in PWHA.
Taken together, this thesis has provided new insights to understand the procoagulant effect of MPs in HA and confirmed that PWHA are not protected from developing CVD. MPs may modify the clinical bleeding phenotypes in PWHA. Moreover, MPs might be a potential biomarker for individualized therapy in PWHA, particularly for aging patients, who have increased risk of CVD.
In Paper I, we characterized the fibrin formation and fibrin clot structure in a human plasma model of severe HA after the addition of sequence-identical analogue (SIA) of emicizumab, alone or in combinations with bypassing agents (aPCC or rFVIIa). The combination of SIA and aPCC exhibited hypercoagulable patterns, suggesting that this combination might introduce thrombotic risk when used to treat PWHA. In Papers II and IV, the procoagulant effect of MPs in HA was studied using in vitro plasma models and in vivo mouse models of HA, respectively. MPs improved hemostasis and were found to be incorporated into the fibrin network in both in vitro and in vivo HA models. In Paper III, the prevalence of subclinical CVD in a Swedish PWHA (≥40 years old) cohort was determined using the advanced electrocardiography (A-ECG) technique, retrospectively. PWHA were found to have higher probabilities of developing CVD compared to the age-matched male control. In Paper V, a cross-sectional study with a Chinese cohort of PWHA treated on-demand (≥30 years old) was conducted. PWHA treated on-demand were not protected from developing subclinical CVD. No correlations between the CVD risks and MPs profiles were observed. In addition, the hypercoagulable state might lead to increased platelet activation in PWHA.
Taken together, this thesis has provided new insights to understand the procoagulant effect of MPs in HA and confirmed that PWHA are not protected from developing CVD. MPs may modify the clinical bleeding phenotypes in PWHA. Moreover, MPs might be a potential biomarker for individualized therapy in PWHA, particularly for aging patients, who have increased risk of CVD.
List of papers:
I. Yanan Zong, Aleksandra Antovic, Nida Mahmoud Hourani Soutari, Jovan Antovic, Iva Pruner. Synergistic effect of bypassing agents and sequence identical analogue of emicizumab and fibrin clot structure in the in vitro model of hemophilia A. TH Open. 2020,4(2):e94-e103.
Fulltext (DOI)
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II. Yanan Zong, Iva Pruner, Aleksandra Antovic, Apostolos Taxiarchis, Zara Pons Vila, Nida Soutari, Fariborz Mobarrez, Roza Chaireti, Jerker Widengren, Joachim Piguet & Jovan P. Antovic. Phosphatidylserine positive microparticles improve hemostasis in in-vitro hemophilia A plasma models. Scientific Reports. 2020;10(1):7871.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Yanan Zong, MarenMaanja, Roza Chaireti, Todd T. Schlegel, Martin Ugander, Jovan P. Antovic. Substantial prevalence of subclinical cardiovascular diseases in patients with hemophilia A evaluated by advanced electrocardiography. Journal of Electocardiology. 2020;58:171–175.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Yanan Zong, Iva Pruner, Apostolos Taxiarchis, Jun Wan, Marisa Ninivaggi, Nida Soutari, Agnes Rasmuson, Bas de Laat, Jovan P. Antovic. Procoagulant microparticles improve hemostasis and accumulate at the injured site in hemophilia A mice. [Manuscript]
V. Yanan Zong, Hongfei Kang, Maren Maanja, Shengmei Chen, Todd Schelegel, Roza Chaireti, Marin Ugander, Jovan P. Antovic, Xiangdong Kong. Subclinical cardiac diseases and the role of microparticles (MPs) in patients with hemophilia A treated on-demand. [Manuscript]
I. Yanan Zong, Aleksandra Antovic, Nida Mahmoud Hourani Soutari, Jovan Antovic, Iva Pruner. Synergistic effect of bypassing agents and sequence identical analogue of emicizumab and fibrin clot structure in the in vitro model of hemophilia A. TH Open. 2020,4(2):e94-e103.
Fulltext (DOI)
Pubmed
II. Yanan Zong, Iva Pruner, Aleksandra Antovic, Apostolos Taxiarchis, Zara Pons Vila, Nida Soutari, Fariborz Mobarrez, Roza Chaireti, Jerker Widengren, Joachim Piguet & Jovan P. Antovic. Phosphatidylserine positive microparticles improve hemostasis in in-vitro hemophilia A plasma models. Scientific Reports. 2020;10(1):7871.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Yanan Zong, MarenMaanja, Roza Chaireti, Todd T. Schlegel, Martin Ugander, Jovan P. Antovic. Substantial prevalence of subclinical cardiovascular diseases in patients with hemophilia A evaluated by advanced electrocardiography. Journal of Electocardiology. 2020;58:171–175.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Yanan Zong, Iva Pruner, Apostolos Taxiarchis, Jun Wan, Marisa Ninivaggi, Nida Soutari, Agnes Rasmuson, Bas de Laat, Jovan P. Antovic. Procoagulant microparticles improve hemostasis and accumulate at the injured site in hemophilia A mice. [Manuscript]
V. Yanan Zong, Hongfei Kang, Maren Maanja, Shengmei Chen, Todd Schelegel, Roza Chaireti, Marin Ugander, Jovan P. Antovic, Xiangdong Kong. Subclinical cardiac diseases and the role of microparticles (MPs) in patients with hemophilia A treated on-demand. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Antovic, Jovan
Co-supervisor: Chaireti, Roza; Pruner, Iva; Mobarrez, Fariborz; Strålfors, Annelie
Issue date: 2020-11-27
Rights:
Publication year: 2020
ISBN: 978-91-8016-074-2
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