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Article ; Online: Personalized Approaches to the Treatment of Hemostatic Disorders.

Preston, Roger J S / O'Sullivan, Jamie M

2021 Volume 47, Issue 2, Page(s) 117–119

MeSH term(s)	Hemostatic Disorders ; Hemostatics ; Humans
Chemical Substances	Hemostatics
Language	English
Publishing date	2021-02-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	196901-8
ISSN	1098-9064 ; 0094-6176
ISSN (online)	1098-9064
ISSN	0094-6176
DOI	10.1055/s-0041-1723800
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Article ; Online: Potential mechanisms of resistance to current anti-thrombotic strategies in Multiple Myeloma.

Comerford, Claire / Glavey, Siobhan / O'Sullivan, Jamie M / Quinn, John

Cancer drug resistance (Alhambra, Calif.)

2022 Volume 5, Issue 1, Page(s) 214–228

Abstract: ... of immunoglobulins/"M-proteins" on both the endothelium and on fibrin fibre polymerisation. It thus appears clear ...

Abstract	Multiple Myeloma (MM) is a common haematological malignancy that is associated with a high rate of venous thromboembolism (VTE) with almost 10% of patients suffering thrombosis during their disease course. Recent studies have shown that, despite current thromboprophylaxis strategies, VTE rates in MM remain disappointingly high. The pathophysiology behind this consistently high rate of VTE is likely multifactorial. A number of factors such as anti-thrombin deficiency or raised coagulation Factor VIII levels may confer resistance to heparin in these patients, however, the optimal method of clinically evaluating this is unclear at present, though some groups have attempted its characterisation with thrombin generation testing (TGT). In addition to testing for heparin resistance, TGT in patients with MM has shown markedly varied abnormalities in both endogenous thrombin potential and serum thrombomodulin levels. Apart from these thrombin-mediated processes, other mechanisms potentially contributing to thromboprophylaxis failure include activated protein C resistance, endothelial toxicity secondary to chemotherapy agents, tissue factor abnormalities and the effect of immunoglobulins/"M-proteins" on both the endothelium and on fibrin fibre polymerisation. It thus appears clear that there are a multitude of factors contributing to the prothrombotic milieu seen in MM and further work is necessitated to elucidate which factors may directly affect and inhibit response to anticoagulation and which factors are contributing in a broader fashion to the hypercoagulability phenotype observed in these patients so that effective thromboprophylaxis strategies can be employed.
Language	English
Publishing date	2022-03-07
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2578-532X
ISSN (online)	2578-532X
DOI	10.20517/cdr.2021.115
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Article ; Online: The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies.

Comerford, Claire / Glavey, Siobhan / Quinn, John / O'Sullivan, Jamie M

Journal of thrombosis and haemostasis : JTH

2022 Volume 20, Issue 8, Page(s) 1766–1777

Abstract: Cancer associated thrombosis (CAT) is associated with significant morbidity and mortality, highlighting an unmet clinical need to improve understanding of the pathophysiology of CAT. Multiple myeloma (MM) is associated with one of the highest rates of ... ...

Abstract	Cancer associated thrombosis (CAT) is associated with significant morbidity and mortality, highlighting an unmet clinical need to improve understanding of the pathophysiology of CAT. Multiple myeloma (MM) is associated with one of the highest rates of thrombosis despite widespread use of thromboprophylactic agents. The pathophysiology of thrombosis in MM is multifactorial and patients with MM appear to display a hypercoagulable phenotype with potential contributory factors including raised von Willebrand factor (VWF) levels, activated protein C resistance, impaired fibrinolysis, and abnormal thrombin generation. In addition, the toxic effect of anti-myeloma therapies on the endothelium and contribution to thrombosis has been widely described. Elevated VWF/factor VIII (FVIII) plasma levels have been reported in heterogeneous cohorts of patients with MM and other hematological malignancies. In specific studies, high plasma VWF levels have been shown to associate with VTE risk and reduced overall survival. While the mechanisms underpinning this remain unclear, dysregulation of the VWF and A Disintegrin And Metalloprotease Thrombospondin type 1, motif 13 (ADAMTS-13) axis is evident in certain solid organ malignancies and correlates with advanced disease and thrombosis. Furthermore, thrombotic microangiopathic conditions arising from deficiencies in ADAMTS-13 and thus an accumulation of prothrombotic VWF multimers have been reported in patients with MM, particularly in association with specific myeloma therapies. This review will discuss current evidence on the pathophysiological mechanisms underpinning thrombosis in MM and in particular summarize the role of VWF/FVIII in hematological malignancies with a focus on thrombotic risk and emerging evidence for contribution to disease progression.
MeSH term(s)	ADAMTS13 Protein ; Factor VIII/therapeutic use ; Hematologic Neoplasms/complications ; Hematologic Neoplasms/drug therapy ; Hemostatics ; Humans ; Multiple Myeloma/complications ; Multiple Myeloma/drug therapy ; Thrombosis ; von Willebrand Factor/metabolism
Chemical Substances	Hemostatics ; von Willebrand Factor ; Factor VIII (9001-27-8) ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2022-06-23
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.15773
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Zs.A 5805: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 295: Show issues

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Article ; Online: Antithrombin inhibition using nanobodies to correct bleeding in hemophilia.

O'Sullivan, Jamie M / O'Donnell, James S

EMBO molecular medicine

2020 Volume 12, Issue 4, Page(s) e12143

Abstract: In this issue of EMBO Molecular Medicine, Barbon et al describe a new approach to rebalancing coagulation in patients with hemophilia (PWH) through targeted inhibition of anticoagulant antithrombin (AT) (Barbon et al, 2020). In contrast to previous ... ...

Abstract	In this issue of EMBO Molecular Medicine, Barbon et al describe a new approach to rebalancing coagulation in patients with hemophilia (PWH) through targeted inhibition of anticoagulant antithrombin (AT) (Barbon et al, 2020). In contrast to previous studies that used RNA interference (RNAi) therapy to reduce AT levels (Sehgal et al, 2015; Pasi et al, 2017), the authors utilized llama-derived single-domain antibodies (sdAbs or nanobodies) to inhibit AT activity (Fig 1). These engineered sdAbs successfully restored thrombin generation in hemophilic plasma and corrected bleeding phenotype in a murine hemophilia model. Furthermore, long-term AAV8-mediated hepatic expression of the sdAb was well tolerated and associated with a sustained correction in bleeding in hemophilia A and B mice. Collectively, these exciting data uncover a novel AT-targeting approach that may be useful as an alternative therapy for restoring normal hemostasis in PWH.
MeSH term(s)	Animals ; Anticoagulants/pharmacology ; Blood Coagulation/drug effects ; Hemophilia A/drug therapy ; Hemorrhage ; Humans ; Mice ; Single-Domain Antibodies/pharmacology
Chemical Substances	Anticoagulants ; Single-Domain Antibodies
Language	English
Publishing date	2020-03-25
Publishing country	England
Document type	News ; Comment
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202012143
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Zs.A 6784: Show issues

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Article ; Online: The Biological Significance of von Willebrand Factor O-Linked Glycosylation.

Ward, Soracha / O'Sullivan, Jamie M / O'Donnell, James S

Seminars in thrombosis and hemostasis

2021 Volume 47, Issue 7, Page(s) 855–861

Abstract: ... of all secreted proteins in man. As such, the role of N- and O-linked glycan structures in modulating various ... linked and 10 O-linked glycans. Together, these carbohydrate chains account for 20% of VWF monomeric mass ... on the specific role played by O-linked glycans in modulating VWF biology. Specifically, VWF O-linked glycans have ...

Abstract	Glycosylation is a key posttranslational modification, known to occur on more than half of all secreted proteins in man. As such, the role of N- and O-linked glycan structures in modulating various aspects of protein biology is an area of much research. Given their prevalence, it is perhaps unsurprising that variations in glycan structures have been demonstrated to play critical roles in modulating protein function and have been implicated in the pathophysiology of human diseases. von Willebrand factor (VWF), a plasma glycoprotein that is essential for normal hemostasis, is heavily glycosylated, containing 13 N-linked and 10 O-linked glycans. Together, these carbohydrate chains account for 20% of VWF monomeric mass, and have been shown to modulate VWF structure, function, and half-life. In this review, we focus on the specific role played by O-linked glycans in modulating VWF biology. Specifically, VWF O-linked glycans have been shown to modulate tertiary protein structure, susceptibility to ADAMTS13 proteolysis, platelet tethering, and VWF circulatory half-life.
MeSH term(s)	ADAMTS13 Protein ; Blood Platelets/metabolism ; Glycosylation ; Humans ; Polysaccharides ; Protein Processing, Post-Translational ; von Willebrand Factor/metabolism
Chemical Substances	Polysaccharides ; von Willebrand Factor ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2021-06-15
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	196901-8
ISSN	1098-9064 ; 0094-6176
ISSN (online)	1098-9064
ISSN	0094-6176
DOI	10.1055/s-0041-1726373
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Article ; Online: von Willebrand factor promotes wound healing.

O'Donnell, James S / O'Sullivan, Jamie M

Blood

2019 Volume 133, Issue 24, Page(s) 2553–2555

MeSH term(s)	Factor VIII ; Heparin ; Humans ; Wound Healing ; von Willebrand Diseases ; von Willebrand Factor
Chemical Substances	von Willebrand Factor ; Factor VIII (9001-27-8) ; Heparin (9005-49-6)
Language	English
Publishing date	2019-06-13
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2019001175
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Zs.MO 364: Show issues

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Article: Personalized Approaches to the Treatment of Hemostatic Disorders

Preston, Roger J.S. / O'Sullivan, Jamie M.

Seminars in Thrombosis and Hemostasis

(Personalized Approaches to Bleeding and Thrombotic Disorders)

2021 Volume 47, Issue 02, Page(s) 117–119

Series title	Personalized Approaches to Bleeding and Thrombotic Disorders
Language	English
Publishing date	2021-02-26
Publisher	Thieme Medical Publishers, Inc.
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	196901-8
ISSN	1098-9064 ; 0094-6176
ISSN (online)	1098-9064
ISSN	0094-6176
DOI	10.1055/s-0041-1723800
Database	Thieme publisher's database

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Article ; Online: Advances in the Management of Cancer-Associated Thrombosis.

Dhami, Sukhraj Pal Singh / Patmore, Sean / O'Sullivan, Jamie M

Seminars in thrombosis and hemostasis

2021 Volume 47, Issue 2, Page(s) 139–149

Abstract: The association between cancer and venous thromboembolism (VTE) has been established for more than 150 years. Nevertheless, cancer-associated thrombosis still remains a major clinical challenge and is associated with significant morbidity and mortality ... ...

Abstract	The association between cancer and venous thromboembolism (VTE) has been established for more than 150 years. Nevertheless, cancer-associated thrombosis still remains a major clinical challenge and is associated with significant morbidity and mortality for patients with cancer. The clinical presentation of cancer-associated thrombosis can be distinct from that of a patient without an underlying malignancy. Moreover, specific cancer types, including pancreatic cancer and hematological malignancies, as well as advanced stage disease can confer a significant thrombotic risk. This risk is further augmented by specific anticancer treatment modalities. The pathophysiology of cancer-associated thrombosis is complex and multifactorial. However, understanding the biological mechanisms underpinning VTE risk may provide insight into novel targeted prophylaxis in cancer patients. Over the last decade, low-molecular-weight heparin has been the preferred anticoagulant agent for patients with cancer-associated thrombosis due to improved efficacy compared with vitamin K antagonists. However, the advent of direct oral anticoagulants (DOACs) has added to the repertoire of ammunition now at the disposal of clinicians to aid in the management of cancer-associated thrombosis. Several randomized controlled trials have now been published, demonstrating DOAC as a noninferior alternative for both the treatment and prevention of cancer-associated thrombosis. Notwithstanding this, limitations for their widespread use remain, with the potential for increased bleeding risk, drug interactions, and poor DOAC metabolism. This review discusses the evidence base for the incidence and risk factors associated with VTE in cancer, development, and refinement of risk prediction models and novel advances in the therapeutic management of cancer-associated thrombosis.
MeSH term(s)	Anticoagulants/pharmacology ; Anticoagulants/therapeutic use ; Humans ; Neoplasms/complications ; Risk Factors ; Thrombosis/drug therapy ; Thrombosis/etiology
Chemical Substances	Anticoagulants
Language	English
Publishing date	2021-02-26
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	196901-8
ISSN	1098-9064 ; 0094-6176
ISSN (online)	1098-9064
ISSN	0094-6176
DOI	10.1055/s-0041-1722863
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Article ; Online: Platelets in malaria pathogenesis.

O'Sullivan, Jamie M / O'Donnell, James S

Blood

2018 Volume 132, Issue 12, Page(s) 1222–1224

MeSH term(s)	Animals ; Blood Platelets ; Humans ; Malaria ; Parasites ; Plasmodium
Language	English
Publishing date	2018-09-20
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2018-08-865618
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Article: Hamstring Injury Rehabilitation and Prevention in the Female Athlete.

O'Sullivan, Lucy / Preszler, Jamie / Tanaka, Miho

International journal of sports physical therapy

2022 Volume 17, Issue 6, Page(s) 1184–1193

Abstract: Hamstring injuries (HSIs) are common in female athletes and are associated with a lengthy recovery period and a high rate of reinjury. Currently, the majority of existing literature investigating HSI rehabilitation has been conducted using male ... ...

Abstract	Hamstring injuries (HSIs) are common in female athletes and are associated with a lengthy recovery period and a high rate of reinjury. Currently, the majority of existing literature investigating HSI rehabilitation has been conducted using male participants. However, female athletes display intrinsic anatomical and biomechanical differences compared to males that influences the way this population experiences HSIs and HSI rehabilitation. HSI rehabilitation and injury prevention guidelines for female athletes must take these differences into account. Female athletes display anatomical differences such as increased anterior pelvic tilting, gluteus maximus weakness, an increased pelvic width-to-femoral length ratio, and an increased degree of femoral anteversion, all of which can predispose females to HSIs. Maneuvers designed to strengthen the gluteal musculature and transverse abdominis can overcome these risk factors. Females show increased joint laxity and a greater range of motion of hip flexion and internal rotation compared to males. Females have lower passive hamstring stiffness than males, therefore hamstring flexibility exercises may not be as necessary during rehabilitation for females as in the male athlete population. Female athletes may instead benefit from trunk stabilization exercises and agility training due to neuromuscular control deficits that arise from the maturation and growth of the female pelvis. Existing literature on hamstring injury prevention shows consistent use of the Nordic Hamstring Exercise and balance exercises may reduce the risk of sustaining an HSI in both males and females, though more studies are needed to ascertain the optimal regimen for injury prevention in the female athlete population specifically. The goal of this clinical commentary is to discuss sex-specific anatomic and biomechanical differences of the lumbar, pelvic, and hip regions with the aim of providing guidelines for rehabilitation and injury prevention of HSIs in female athletes. Level of evidence: 5.
Language	English
Publishing date	2022-10-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2628664-6
ISSN	2159-2896
ISSN	2159-2896
DOI	10.26603/001c.38254
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