4.6 Review

The Anticoagulant and Nonanticoagulant Properties of Heparin

Journal

THROMBOSIS AND HAEMOSTASIS
Volume 120, Issue 10, Pages 1371-1383

Publisher

GEORG THIEME VERLAG KG
DOI: 10.1055/s-0040-1715460

Keywords

heparin; anticoagulation; metastasis; inflammation

Ask authors/readers for more resources

Heparins represent one of the most frequently used pharmacotherapeutics. Discovered around 1926, routine clinical anticoagulant use of heparin was initiated only after the publication of several seminal papers in the early 1970s by the group of Kakkar. It was shown that heparin prevents venous thromboembolism and mortality from pulmonary embolism in patients after surgery. With the subsequent development of low-molecular-weight heparins and synthetic heparin derivatives, a family of related drugs was created that continues to prove its clinical value in thromboprophylaxis and in prevention of clotting in extracorporeal devices. Fundamental and applied research has revealed a complex pharmacodynamic profile of heparins that goes beyond its anticoagulant use. Recognition of the complex multifaceted beneficial effects of heparin underscores its therapeutic potential in various clinical situations. In this review we focus on the anticoagulant and nonanticoagulant activities of heparin and, where possible, discuss the underlying molecular mechanisms that explain the diversity of heparin's biological actions.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

Article Biochemistry & Molecular Biology

Structure-Based Cyclic Glycoprotein Ibα-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear

Johana Hrdinova, Delia I. Fernandez, Bogac Ercig, Bibian M. E. Tullemans, Dennis P. L. Suylen, Stijn M. Agten, Kerstin Jurk, Tilman M. Hackeng, Karen Vanhoorelbeke, Jan Voorberg, Chris P. M. Reutelingsperger, Kanin Wichapong, Johan W. M. Heemskerk, Gerry A. F. Nicolaes

Summary: This study designed and synthesized stable cyclic peptides to interfere with the interaction between VWF A1 domain and GPIb alpha. The selected peptides showed low binding free energy and retained their interference in the binding of VWF to GPIb-V-IX, as confirmed by flow cytometry. These peptides phenotypically mimicked the changes seen with the anti-VWF A1 domain antibody CLB-RAg35, although they were less potent. The improved peptide opt-mono-ORbIT demonstrated increased inhibitory activity under flow.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Article Biochemistry & Molecular Biology

Single Cell Analysis of Reversibility of the Cell Death Program in Ethanol-Treated Neuronal PC12 Cells

Wenting You, Tos T. J. M. Berendschot, Kevin Knoops, Marc A. M. J. van Zandvoort, Carroll A. B. Webers, Chris P. M. Reutelingsperger, Theo G. M. F. Gorgels

Summary: Neurodegenerative diseases are characterized by the loss of certain neurons and a slow progressive course. Our study indicates that damaged neurons in the process of cell death can be recovered.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Article Biochemical Research Methods

Structural anomalies in a published NMR-derived structure of IRAK-M

Hessel Poelman, Hans Ippel, Berke Gurkan, Rolf Boelens, Gert Vriend, Cornelis van 't Veer, Esther Lutgens, Gerry A. F. Nicolaes

Summary: Researchers elucidated the structure of IRAK-M death domain using NMR and performed docking studies to reveal its position in the Myddosome and the molecular basis for its selectivity towards IRAK1 over IRAK2 binding. They identified structural issues in the original model and built a more accurate homology model based on high-resolution crystal structures, which better matched known information about the death domain structure.

JOURNAL OF MOLECULAR GRAPHICS & MODELLING (2022)

Review Biochemistry & Molecular Biology

Vascular Smooth Muscle Cell Neutral Sphingomyelinase 2 in the Release of Exosomes and Vascular Calcification

Angelina Pavlic, Nasim Bahram Sangani, Johanna Kerins, Gerry Nicolaes, Leon Schurgers, Chris Reutelingsperger

Summary: Vascular calcification is the pathological deposition of calcium salts in blood vessel walls and is a risk factor for cardiovascular events and mortality. Vascular smooth muscle cells (VSMCs) play a crucial role in this process by releasing extracellular vesicles (EVs), but the underlying mechanisms are not fully understood. Understanding the molecular factors and mechanisms of EV release is essential for developing targeted pharmacological treatments for vascular calcification.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Article Medicine, General & Internal

Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients

Rickard Lagedal, Oskar Eriksson, Anna Sorman, Joram B. Huckriede, Bjarne Kristensen, Stephanie Franzen, Anders Larsson, Anders Bergqvist, Kjell Alving, Anders Forslund, Barbro Persson, Kristina N. Ekdahl, Pablo Garcia de Frutos, Bo Nilsson, Gerry A. F. Nicolaes, Miklos Lipcsey, Michael Hultstrom, Robert Frithiof

Summary: The antibody response in critically ill patients with COVID-19 is associated with organ failure, systemic histone release, and increased 30-day mortality.

JOURNAL OF CLINICAL MEDICINE (2022)

Article Biochemistry & Molecular Biology

Inhibition of Neutral Sphingomyelinase 2 by Novel Small Molecule Inhibitors Results in Decreased Release of Extracellular Vesicles by Vascular Smooth Muscle Cells and Attenuated Calcification

Angelina Pavlic, Hessel Poelman, Grzegorz Wasilewski, Kanin Wichapong, Petra Lux, Cecile Maassen, Esther Lutgens, Leon J. Schurgers, Chris P. Reutelingsperger, Gerry A. F. Nicolaes

Summary: Vascular calcification (VC) is an important factor in cardiovascular diseases, mediated by the release of extracellular vesicles by vascular smooth muscle cells (VSMCs) and the enzyme nSMase2. Inhibitors of nSMase2 have been identified through virtual ligand screening, and two compounds (ID 5728450 and ID 4011505) were found to inhibit EV release and calcification in vitro, potentially serving as therapeutic drugs for VC treatment or prevention.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

Review Medicine, General & Internal

The role of extracellular histones in COVID-19

Femke de Vries, Joram Huckriede, Kanin Wichapong, Chris Reutelingsperger, Gerry A. F. Nicolaes

Summary: This article reviews the cytotoxic mechanisms of extracellular histones in COVID-19 and discusses their role as potential drug targets and biomarkers. It provides important insights for the clinical treatment of COVID-19 patients.

JOURNAL OF INTERNAL MEDICINE (2023)

Article Multidisciplinary Sciences

Extracellular histone release by renal cells after warm and cold ischemic kidney injury: Studies in an ex-vivo porcine kidney perfusion model

Tim C. van Smaalen, Danielle M. H. Beurskens, Jasper J. H. F. M. Kox, Rasheendra Polonia, Rein Vos, Hans Duimel, Willine J. van de Wetering, Carmen Lopez-Iglesias, Chris P. Reutelingsperger, L. W. Ernest van Heurn, Carine J. Peutz-Kootstra, Gerry A. F. Nicolaes

Summary: Extracellular histones are released in warm ischemia and the resulting damage can be prevented by blocking histone release. The release of extracellular histones in patients receiving a renal transplant is associated with worse graft outcome. The findings suggest that targeting histones may be beneficial in preventing renal injury during transplantation.

PLOS ONE (2023)

Article Medicine, General & Internal

Annexin A1 Is Associated with Adverse Clinical Outcomes in Patients with COVID-19

Matthias H. Busch, Sjoerd A. M. E. G. Timmermans, Joop P. Aendekerk, Renee Ysermans, Jean Amiral, Jan G. M. C. Damoiseaux, Chris P. Reutelingsperger, Pieter van Paassen

Summary: Severe COVID-19 is characterized by hyperinflammation, vascular damage, and hypercoagulability. This study found that insufficient responses of Annexin A1 (AnxA1), a pro-resolving inhibitor, might contribute to the severe course of the disease. AnxA1 levels were significantly higher in moderate and severe COVID-19 cases compared to healthy controls, and elevated AnxA1 levels were associated with markers of inflammation and endothelial damage. AnxA1 was also higher in patients with thrombotic events and ICU admission. Baseline AnxA1 was identified as a predictor of thrombotic events, and the increase in AnxA1 over time was steeper in patients without adverse events.

JOURNAL OF CLINICAL MEDICINE (2022)

Article Cell Biology

Role of Annexin A1 Secreted by Neutrophils in Melanoma Metastasis

Silvana Sandri, Cristina Bichels Hebeda, Milena Fronza Broering, Marina de Paula Silva, Luciana Facure Moredo, Milton Jose de Barros e Silva, Andre Sapata Molina, Clovis Antonio Lopes Pinto, Joao Pedreira Duprat Neto, Chris P. Reutelingsperger, Cristiane Damas Gil, Sandra Helena Poliselli Farsky

Summary: Annexin A1 (AnxA1) is secreted by neutrophils and binds to formyl peptide receptors (FPRs) to trigger anti-inflammatory effects and efferocytosis. It is also expressed in the tumor microenvironment, mainly by cancer cells. In a study on lung melanoma metastasis, it was found that AnxA1 secreted by neutrophils promotes tumor invasion through FPR pathways.

CELLS (2023)

Article Biochemistry & Molecular Biology

Time Dependent Changes in the Ovine Neurovascular Unit; A Potential Neuroprotective Role of Annexin A1 in Neonatal Hypoxic-Ischemic Encephalopathy

Hyun Young Park, Valery L. E. van Bruggen, Carine J. Peutz-Kootstra, Daan R. M. G. Ophelders, Reint K. Jellema, Chris P. M. Reutelingsperger, Bart P. F. Rutten, Tim G. A. M. Wolfs

Summary: Perinatal brain injury following hypoxia-ischemia (HI) is characterized by loss of blood-brain barrier (BBB) integrity, which is associated with the depletion of Annexin A1, laminin, and collagen type IV, as well as vascular remodeling. Our study provides mechanistic insights into the dynamics of essential BBB structures after HI and suggests that strategies to restore BBB integrity should be applied within 48 hours after the injury. ANXA1 has great therapeutic potential for targeting HI-driven brain injury.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

Article Hematology

Crucial roles of red blood cells and platelets in whole blood thrombin generation

Siyu Sun, Elena Campello, Jinmi Zou, Joke Konings, Dana Huskens, Jun Wan, Delia I. Fernandez, Chris P. M. Reutelingsperger, Hugo ten Cate, Serena Toffanin, Cristiana Bulato, Philip G. de Groot, Bas de Laat, Paolo Simioni, Johan W. M. Heemskerk, Mark Roest

Summary: Red blood cells and platelets play a significant role in the clotting process, and the extent of phosphatidylserine exposure determines the coagulation activity.

BLOOD ADVANCES (2023)

Article Hematology

Design and characterization of novel activated protein C variants for the proteolysis of cytotoxic extracellular histone H3

Joram B. Huckriede, Danielle M. H. Beurskens, Karin C. C. A. Wildhagen, Chris P. M. Reutelingsperger, Kanin Wichapong, Gerry A. F. Nicolaes

Summary: This study investigated the interaction between human APC and human histone H3 and designed optimized APC variants through molecular docking and molecular dynamics simulation methods. The results showed that the designed APC variants had reduced anticoagulant activity, increased binding to histone H3, and similar ability to proteolyze histone H3 compared to the wild type-APC.

JOURNAL OF THROMBOSIS AND HAEMOSTASIS (2023)

No Data Available