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Thrombosis, Blood Clotting and Vascular Biology
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Thrombosis, Blood Clotting and Vascular Biology

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 47791

Special Issue Editor

Dr. Arijit Biswas

E-Mail Website
Guest Editor
Institute of Experimental Hematology and Transfusion Medicine, University Clinic of Bonn, Bonn, Germany
Interests: bleeding disorders; thrombosis; coagulation factor XIII; structure and function of coagulation proteins; genetic epidemiology of coagulation defects
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The physiological world of blood coagulation is an intricate maze of enzymes, regulators, and inhibitors, all of which network with each other to maintain normal hemostasis. Defects in these networks, inherited or acquired, can lead to thrombotic or bleeding risk, all of which pose a significant disease burden. Decades of investigations into coagulation research have vastly increased our understanding of this complex biological system and have aided in the development of medicinal, pharmaceutical, and research tools to address the defects in the system. However, the complexity of the system still presents a huge challenge to researchers, since several aspects of this system remain to be uncovered. In this Special Issue, we invite submissions that focus on the coagulation pathway, the thrombotic and bleeding complications resulting from defects in the coagulation pathway, and state of the art in the treatment and management of these deficiencies. Submissions can be in the form of reviews providing insights into the current knowledge and technical know-how as well as original research that addresses the key questions being asked in this area.

We look forward to receiving your submission.

Dr. Arijit Biswas
Guest Editor

Manuscript Submission Information

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Keywords

  • Coagulation
  • Thrombosis
  • Bleeding
  • Fibrinolysis
  • Coagulation proteins

Published Papers (15 papers)

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Research

Jump to: Review

8 pages, 774 KiB  
Article
The Relationship between Inflammatory Cytokines and Coagulopathy in Patients with COVID-19
by Fariba Rad, Ali Dabbagh, Akbar Dorgalaleh and Arijit Biswas
J. Clin. Med. 2021, 10(9), 2020; https://doi.org/10.3390/jcm10092020 - 09 May 2021
Cited by 17 | Viewed by 2976
Abstract
Coronavirus disease 2019 (COVID-19), with a broad range of clinical and laboratory findings, is currently the most prevalent medical challenge worldwide. In this disease, hypercoagulability and hyperinflammation, two common features, are accompanied by a higher rate of morbidity and mortality. We assessed the [...] Read more.
Coronavirus disease 2019 (COVID-19), with a broad range of clinical and laboratory findings, is currently the most prevalent medical challenge worldwide. In this disease, hypercoagulability and hyperinflammation, two common features, are accompanied by a higher rate of morbidity and mortality. We assessed the association between baseline inflammatory cytokine levels and coagulopathy and disease outcome in COVID-19. One hundred and thirty-seven consecutive patients hospitalized with COVID-19 were selected for the study. Baseline interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α) level were measured at time of admission. At the same time, baseline coagulation parameters were also assessed during the patient’s hospitalization. Clinical findings, including development of thrombosis and clinical outcome, were recorded prospectively. Out of 136 patients, 87 (~64%) had increased cytokine levels (one or more cytokines) or abnormal coagulation parameters. Among them, 58 (~67%) had only increased inflammatory cytokines, 12 (~14%) had only coagulation abnormalities, and 17 (19.5%) had concomitant abnormalities in both systems. It seems that a high level of inflammatory cytokines at admission points to an increased risk of developing coagulopathy, thrombotic events, even death, over the course of COVID-19. Early measurement of these cytokines, and timely co-administration of anti-inflammatories with anticoagulants could decrease thrombotic events and related fatal consequences. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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15 pages, 2557 KiB  
Article
Functional and Structural Characterization of Nucleic Acid Ligands That Bind to Activated Coagulation Factor XIII
by Nasim Shahidi Hamedani, Arijit Biswas, Oliver Rudan, Rosa Tönges, Carlotta Meyring, Fabian Tolle, Günter Mayer, Johannes Oldenburg, Jens Müller and Bernd Pötzsch
J. Clin. Med. 2021, 10(4), 677; https://doi.org/10.3390/jcm10040677 - 10 Feb 2021
Cited by 5 | Viewed by 2588
Abstract
Coagulation factor XIII (FXIII) is a protransglutaminase which plays an important role in clot stabilization and composition by cross-linking the α- and γ-chains of fibrin and increasing the resistance of the clot to mechanical and proteolytic challenges. In this study, we selected six [...] Read more.
Coagulation factor XIII (FXIII) is a protransglutaminase which plays an important role in clot stabilization and composition by cross-linking the α- and γ-chains of fibrin and increasing the resistance of the clot to mechanical and proteolytic challenges. In this study, we selected six DNA aptamers specific for activated FXIII (FXIIIa) and investigated the functional characterization of FXIIIa after aptamer binding. One of these aptamers, named FA12, efficiently captures FXIIIa even in the presence of zymogenic FXIII subunits. Furthermore, this aptamer inhibits the incorporation of FXIII and α2-antiplasmin (α2AP) into fibrin(ogen) with IC50-values of 38 nM and 17 nM, respectively. In addition to FA12, also another aptamer, FA2, demonstrated significant effects in plasma-based thromboelastometry (rotational thromboelastometry analysis, ROTEM)-analysis where spiking of the aptamers into plasma decreased clot stiffness and elasticity (p < 0.0001). The structure–function correlations determined by combining modeling/docking strategies with quantitative in vitro assays revealed spatial overlap of the FA12 binding site with the binding sites of two FXIII substrates, fibrinogen and α2AP, while FA2 binding sites only overlap those of fibrinogen. Taken together, these features especially render the aptamer FA12 as an interesting candidate molecule for the development of FXIIIa-targeting therapeutic strategies and diagnostic assays. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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13 pages, 1033 KiB  
Article
Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a Large Cohort of Patients—A Single-Center Experience in Genetic Diagnosis
by Barbara Preisler, Behnaz Pezeshkpoor, Atanas Banchev, Ronald Fischer, Barbara Zieger, Ute Scholz, Heiko Rühl, Bettina Kemkes-Matthes, Ursula Schmitt, Antje Redlich, Sule Unal, Hans-Jürgen Laws, Martin Olivieri, Johannes Oldenburg and Anna Pavlova
J. Clin. Med. 2021, 10(2), 347; https://doi.org/10.3390/jcm10020347 - 18 Jan 2021
Cited by 8 | Viewed by 2583
Abstract
Background: Familial multiple coagulation factor deficiencies (FMCFDs) are a group of inherited hemostatic disorders with the simultaneous reduction of plasma activity of at least two coagulation factors. As consequence, the type and severity of symptoms and the management of bleeding/thrombotic episodes vary among [...] Read more.
Background: Familial multiple coagulation factor deficiencies (FMCFDs) are a group of inherited hemostatic disorders with the simultaneous reduction of plasma activity of at least two coagulation factors. As consequence, the type and severity of symptoms and the management of bleeding/thrombotic episodes vary among patients. The aim of this study was to identify the underlying genetic defect in patients with FMCFDs. Methods: Activity levels were collected from the largest cohort of laboratory-diagnosed FMCFD patients described so far. Genetic analysis was performed using next-generation sequencing. Results: In total, 52 FMCFDs resulted from coincidental co-inheritance of single-factor deficiencies. All coagulation factors (except factor XII (FXII)) were involved in different combinations. Factor VII (FVII) deficiency showed the highest prevalence. The second group summarized 21 patients with FMCFDs due to a single-gene defect resulting in combined FV/FVIII deficiency or vitamin K–dependent coagulation factor deficiency. In the third group, nine patients with a combined deficiency of FVII and FX caused by the partial deletion of chromosome 13 were identified. The majority of patients exhibited bleeding symptoms while thrombotic events were uncommon. Conclusions: FMCFDs are heritable abnormalities of hemostasis with a very low population frequency rendering them orphan diseases. A combination of comprehensive screening of residual activities and molecular genetic analysis could avoid under- and misdiagnosis. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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24 pages, 7639 KiB  
Article
Enhanced Antifibrinolytic Efficacy of a Plasmin-Specific Kunitz-Inhibitor (60-Residue Y11T/L17R with C-Terminal IEK) of Human Tissue Factor Pathway Inhibitor Type-2 Domain1
by Kanagasabai Vadivel, Anne K. Zaiss, Yogesh Kumar, Frank M. Fabian, Ayman E. A. Ismail, Mark A. Arbing, Wallace G. Buchholz, William H. Velander and S. Paul Bajaj
J. Clin. Med. 2020, 9(11), 3684; https://doi.org/10.3390/jcm9113684 - 17 Nov 2020
Cited by 1 | Viewed by 2018
Abstract
Current antifibrinolytic agents reduce blood loss by inhibiting plasmin active sites (e.g., aprotinin) or by preventing plasminogen/tissue plasminogen activator (tPA) binding to fibrin clots (e.g., ε-aminocaproic acid and tranexamic acid); however, they have adverse side effects. Here, we expressed 60-residue (NH2NAE…IEK [...] Read more.
Current antifibrinolytic agents reduce blood loss by inhibiting plasmin active sites (e.g., aprotinin) or by preventing plasminogen/tissue plasminogen activator (tPA) binding to fibrin clots (e.g., ε-aminocaproic acid and tranexamic acid); however, they have adverse side effects. Here, we expressed 60-residue (NH2NAE…IEKCOOH) Kunitz domain1 (KD1) mutants of human tissue factor pathway inhibitor type-2 that inhibit plasmin as well as plasminogen activation. A single (KD1-L17R-KCOOH) and a double mutant (KD1-Y11T/L17R- KCOOH) were expressed in Escherichia coli as His-tagged constructs, each with enterokinase cleavage sites. KD1-Y11T/L17R-KCOOH was also expressed in Pichia pastoris. KD1-Y11T/L17R-KCOOH inhibited plasmin comparably to aprotinin and bound to the kringle domains of plasminogen/plasmin and tPA with Kd of ~50 nM and ~35 nM, respectively. Importantly, compared to aprotinin, KD1-L17R-KCOOH and KD1-Y11T/L17R-KCOOH did not inhibit kallikrein. Moreover, the antifibrinolytic potential of KD1-Y11T/L17R-KCOOH was better than that of KD1-L17R-KCOOH and similar to that of aprotinin in plasma clot-lysis assays. In thromboelastography experiments, KD1-Y11T/L17R-KCOOH was shown to inhibit fibrinolysis in a dose dependent manner and was comparable to aprotinin at a higher concentration. Further, KD1-Y11T/L17R-KCOOH did not induce cytotoxicity in primary human endothelial cells or fibroblasts. We conclude that KD1-Y11T/L17R-KCOOH is comparable to aprotinin, the most potent known inhibitor of plasmin and can be produced in large amounts using Pichia. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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10 pages, 898 KiB  
Communication
Dectin-1 and TIM3 Expression in Deep Vein Thrombosis of Lower Limbs (DVTLL)
by Vincenza Barresi, Salvatore Napoli, Giorgia Spampinato, Daniele Filippo Condorelli and Salvatore Santo Signorelli
J. Clin. Med. 2020, 9(11), 3466; https://doi.org/10.3390/jcm9113466 - 28 Oct 2020
Cited by 1 | Viewed by 1474
Abstract
The pathophysiological mechanisms of venous thromboembolism are venous stasis, endothelial damage, and hypercoagulability, while less attention has been given to the role of both innate and native immunity. In this paper, we investigate the involvement of the activated immune system detected through some [...] Read more.
The pathophysiological mechanisms of venous thromboembolism are venous stasis, endothelial damage, and hypercoagulability, while less attention has been given to the role of both innate and native immunity. In this paper, we investigate the involvement of the activated immune system detected through some indicators such as TIM3 and Dectin-1 expressed by T lymphocytes. TIM3 and Dectin-1, two surface molecules that regulate the fine-tuning of innate and adaptive immune responses, were evaluated in patients affected by deep vein thrombosis of lower limbs (DVTLL). CD3+, CD4+ and CD8+ T lymphocytes obtained from patients affected by DVTLL were analysed using fluorescence-conjugated antibodies for TIM3 and Dectin-1 by an imaging flow cytometer. DVTLL patients showed a higher number of CD4+ and CD8+ T lymphocytes. TIM3 expression in T lymphocytes was very low in both DVTLL patients and controls. On the contrary, an increase in Dectin-1+ cells among CD4+ and CD8+ T lymphocytes from DVTLL patients was observed. Dectin-1 is known to play a role in inflammation and immunity and our result suggests its potential involvement in thrombotic venous disease. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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17 pages, 2040 KiB  
Article
Comparative Analysis of Thrombin Calibration Algorithms and Correction for Thrombin-α2macroglobulin Activity
by William C. Chang, Joseph W. Jackson, Kellie R. Machlus, Alisa S. Wolberg and Mikhail V. Ovanesov
J. Clin. Med. 2020, 9(10), 3077; https://doi.org/10.3390/jcm9103077 - 24 Sep 2020
Cited by 6 | Viewed by 2498
Abstract
Background: The thrombin generation (TG) test is useful for characterizing global hemostasis potential, but fluorescence substrate artifacts, such as thrombin-α2macroglobulin (T-α2MG) signal, inner filter effect (IFE), substrate consumption, and calibration algorithms have been suggested as sources of intra- and inter-laboratory variance, which may [...] Read more.
Background: The thrombin generation (TG) test is useful for characterizing global hemostasis potential, but fluorescence substrate artifacts, such as thrombin-α2macroglobulin (T-α2MG) signal, inner filter effect (IFE), substrate consumption, and calibration algorithms have been suggested as sources of intra- and inter-laboratory variance, which may limit its clinical utility. Methods: Effects of internal vs. external normalization, IFE and T-α2MG on TG curves in normal plasma supplemented with coagulation factors, thrombomodulin, and tissue factor were studied using the Calibrated Automated Thrombinography (CAT; Diagnostica Stago, Parsippany, NJ, USA) and in-house software. Results: The various calibration methods demonstrated no significant difference in producing TG curves, nor increased the robustness of the TG assay. Several TG parameters, including thrombin peak height (TPH), produced from internal linear calibration did not differ significantly from uncalibrated TG parameters. Further, TPH values from internal linear and nonlinear calibration with or without T-α2MG correction correlated well with TPH from external calibration. Higher coefficients of variation (CVs) for TPH values were observed in both platelet-free and platelet-rich plasma with added thrombomodulin. Conclusions: Our work suggests minimal differences between distinct computational approaches toward calibrating and correcting fluorescence signals into TG levels, with most samples returning similar or equivalent TPH results. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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13 pages, 3014 KiB  
Article
Uninterrupted Dabigatran Administration Provides Greater Inhibition against Intracardiac Activation of Hemostasis as Compared to Vitamin K Antagonists during Cryoballoon Catheter Ablation of Atrial Fibrillation
by Zsuzsa Bagoly, Orsolya Hajas, Réka Urbancsek, Alexandra Kiss, Edit Fiak, Ferenc Sarkady, Noémi Klára Tóth, Rita Orbán-Kálmándi, Kitti Bernadett Kovács, László Nagy, Attila Nagy, János Kappelmayer, László Csiba and Zoltán Csanádi
J. Clin. Med. 2020, 9(9), 3050; https://doi.org/10.3390/jcm9093050 - 22 Sep 2020
Cited by 3 | Viewed by 2224
Abstract
Background. Cerebral thromboembolism is a rare but feared complication of transcatheter ablation in patients with atrial fibrillation (AF). Here, we aimed to test which pre-procedural anticoagulation strategy results in less intracardiac activation of hemostasis during ablation. Patients and methods. In this observational study, [...] Read more.
Background. Cerebral thromboembolism is a rare but feared complication of transcatheter ablation in patients with atrial fibrillation (AF). Here, we aimed to test which pre-procedural anticoagulation strategy results in less intracardiac activation of hemostasis during ablation. Patients and methods. In this observational study, 54 paroxysmal/persistent AF patients undergoing cryoballoon ablation were grouped according to their periprocedural anticoagulation strategy: no anticoagulation (oral anticoagulation (OAC) free; n = 24), uninterrupted vitamin K antagonists (VKA) (n = 11), uninterrupted dabigatran (n = 17). Blood was drawn from the left atrium before and immediately after the ablation procedure. Cryoablations were performed according to standard protocols, during which heparin was administered. Heparin-insensitive markers of hemostasis and endothelial damage were tested from intracardiac samples: D-dimer, quantitative fibrin monomer (FM), plasmin-antiplasmin complex (PAP), von Willebrand factor (VWF) antigen, chromogenic factor VIII (FVIII) activity. Results. D-dimer increased significantly in all groups post-ablation, with lowest levels in the dabigatran group (median [interquartile range]: 0.27 [0.36] vs. 1.09 [1.30] and 0.74 [0.26] mg/L in OAC free and uninterrupted VKA groups, respectively, p < 0.001). PAP levels were parallel to this observation. Post-ablation FM levels were elevated in OAC free (26.34 [30.04] mg/L) and VKA groups (10.12 [16.01] mg/L), but remained below cut-off in all patients on dabigatran (3.98 [2.0] mg/L; p < 0.001). VWF antigen and FVIII activity increased similarly post-ablation in all groups, suggesting comparable procedure-related endothelial damage. Conclusion. Dabigatran provides greater inhibition against intracardiac activation of hemostasis as compared to VKAs during cryoballoon catheter ablation. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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9 pages, 347 KiB  
Article
The Need for Red Cell Support During Non-Cardiac Surgery Is Associated to Pre-Transfusion Levels of FXIII and the Platelet Count
by Silke Listyo, Eric Forrest, Lukas Graf and Wolfgang Korte
J. Clin. Med. 2020, 9(8), 2456; https://doi.org/10.3390/jcm9082456 - 31 Jul 2020
Cited by 14 | Viewed by 2042
Abstract
Unexpected intraoperative bleeding is associated with a reduced availability of crosslinking capacity (provided through factor XIII (FXIII)) per unit of generated thrombin. Furthermore, FXIII deficiency and thrombocytopenia (but not fibrinogen deficiency) are the most prevalent modulators of clot firmness in the immediate postoperative [...] Read more.
Unexpected intraoperative bleeding is associated with a reduced availability of crosslinking capacity (provided through factor XIII (FXIII)) per unit of generated thrombin. Furthermore, FXIII deficiency and thrombocytopenia (but not fibrinogen deficiency) are the most prevalent modulators of clot firmness in the immediate postoperative setting. In this study, we therefore evaluated whether levels of FXIII, fibrinogen, or the platelet count influenced the probability of intraoperative red cell transfusions in patients in the operating theatre. This retrospective study was comprised of 1023 patients, which were in need of blood product support in the operating theatre and of which 443 received red cell transfusions. Due to standard operating procedures, FXIII activity, fibrinogen concentration, and platelet count were measured before transfusion took place, but without influencing the decision to transfuse. FXIII deficiency was frequent (50%), as was thrombocytopenia (49%), but not fibrinogen deficiency (9%). FXIII deficiency was associated with a significantly increased probability to receive red cell transfusions (OR 4.58, 95% CI 3.46–6.05) as was thrombocytopenia (OR 1.94, 95% CI 1.47–2.56), but not fibrinogen deficiency (OR 1.09, 95% CI 0.67–1.76). Similar results were seen for cut-off independent evaluations (receiver operating characteristics (ROC) curves, using continuously distributed variables), where the areas under the curves (AUC) of red cell transfusion for FXIII activity was 0.744 (95% CI 0.716–0.770)/0.632 (95% CI 0.601–0.661) for the platelet count, and 0.578 (95% CI 0.547–0.609) for fibrinogen concentration. All AUCs were significantly different from each other (p < 0.0001 and p = 0.0106, respectively), indicating that FXIII activity was a significantly better predictor of red blood cell (RBC) transfusion than platelet count and fibrinogen concentration. These results suggest that pre-transfusion FXIII activity and to a lesser extent the platelet count influence the probability of intraoperative red cell transfusions. Modifying FXIII activity and/or the platelet count might influence the need for downstream red cell transfusion, thus potentially reducing transfusion associated morbidity. This, however, needs confirmation in future studies. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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14 pages, 935 KiB  
Article
A Prospective Pilot Trial to Assess the Efficacy of Argatroban (Argatra®) in Critically Ill Patients with Heparin Resistance †
by Mirjam Bachler, Tobias Hell, Johannes Bösch, Benedikt Treml, Bettina Schenk, Benjamin Treichl, Barbara Friesenecker, Ingo Lorenz, Daniel Stengg, Stefan Hruby, Bernd Wallner, Elgar Oswald, Mathias Ströhle, Christian Niederwanger, Christian Irsara and Dietmar Fries
J. Clin. Med. 2020, 9(4), 963; https://doi.org/10.3390/jcm9040963 - 31 Mar 2020
Cited by 16 | Viewed by 3944
Abstract
The current study aims to evaluate whether prophylactic anticoagulation using argatroban or an increased dose of unfractionated heparin (UFH) is effective in achieving the targeted activated partial thromboplastin time (aPTT) of more than 45 s in critically ill heparin-resistant (HR) patients. Patients were [...] Read more.
The current study aims to evaluate whether prophylactic anticoagulation using argatroban or an increased dose of unfractionated heparin (UFH) is effective in achieving the targeted activated partial thromboplastin time (aPTT) of more than 45 s in critically ill heparin-resistant (HR) patients. Patients were randomized either to continue receiving an increased dose of UFH, or to be treated with argatroban. The endpoints were defined as achieving an aPTT target of more than 45 s at 7 h and 24 h. This clinical trial was registered on clinicaltrials.gov (NCT01734252) and on EudraCT (2012-000487-23). A total of 42 patients, 20 patients in the heparin and 22 in the argatroban group, were included. Of the patients with continued heparin treatment 55% achieved the target aPTT at 7 h, while only 40% of this group maintained the target aPTT after 24 h. Of the argatroban group 59% reached the target aPTT at 7 h, while at 24 h 86% of these patients maintained the targeted aPTT. Treatment success at 7 h did not differ between the groups (p = 0.1000), whereas at 24 h argatroban showed significantly greater efficacy (p = 0.0021) than did heparin. Argatroban also worked better in maintaining adequate anticoagulation in the further course of the study. There was no significant difference in the occurrence of bleeding or thromboembolic complications between the treatment groups. In the case of heparin-resistant critically ill patients, argatroban showed greater efficacy than did an increased dose of heparin in achieving adequate anticoagulation at 24 h and in maintaining the targeted aPTT goal throughout the treatment phase. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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9 pages, 264 KiB  
Article
Implications of Hemostasis Disorders in Patients with Critical Limb Ischemia—An In-Depth Comparison of Selected Factors
by Radosław Wieczór, Arleta Kulwas and Danuta Rość
J. Clin. Med. 2020, 9(3), 659; https://doi.org/10.3390/jcm9030659 - 29 Feb 2020
Cited by 9 | Viewed by 1921
Abstract
Background: Atherosclerosis is a systemic disease. Among patients with atherosclerosis, those suffering from peripheral arterial disease (PAD) represent a group of individuals with particularly high death risk, especially during the course of critical limb ischemia (CLI). In the pathogenesis of PAD/CLI complications, blood [...] Read more.
Background: Atherosclerosis is a systemic disease. Among patients with atherosclerosis, those suffering from peripheral arterial disease (PAD) represent a group of individuals with particularly high death risk, especially during the course of critical limb ischemia (CLI). In the pathogenesis of PAD/CLI complications, blood coagulation disorders play a significant role. The study aim was to examine the activation of the coagulation system depending on tissue factor (TF) in patients with CLI as compared with those with intermittent claudication (IC). Methods: Before initiating proper treatment (invasive or maintenance), blood samples were collected from 65 patients with CLI and 15 with IC to measure the following selected hemostasis parameters: concentrations and activation of tissue factor (TF Ag and TF Act) and tissue factor pathway inhibitor (TFPI Ag and TFPI Act), concentrations of thrombin–antithrombin complex (TAT Ag) and fibrinogen, platelet count (PLT), and concentrations of tissue-plasminogen activator (t-PA Ag), plasminogen activator inhibitor 1 (PAI-1), and D-dimer. The control group included 30 healthy volunteers (10 female/20 male). Results: The values of all analyzed parameters (except for lower TFPI Act) were significantly higher in the blood of PAD patients (with respect to PLT only in the CLI subgroup) in comparison with healthy subjects. The blood of patients with CLI as compared to the IC subgroup revealed much higher concentrations of TF Ag (p < 0.001), with slightly decreased TF Act, significantly lower concentrations of TFPI Ag (p < 0.001), slightly increased TFPI Act, and significantly higher levels of TAT Ag (p < 0.001), fibrinogen (p = 0.026), and D-dimer (p < 0.05). Conclusions: In patients with CLI, we can observe coagulation activation and a shifting balance toward prothrombotic processes. Furthermore, increased concentrations of D-dimer suggest a secondary activation of fibrinolysis and confirm the phenomenon as a prothrombotic condition with heightened fibrinolysis. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)

Review

Jump to: Research

19 pages, 1070 KiB  
Review
SARS-CoV-2 Infection: Modulator of Pulmonary Embolism Paradigm
by Mohammad Suhail Akhter, Hassan A. Hamali, Abdullah A. Mobarki, Hina Rashid, Johannes Oldenburg and Arijit Biswas
J. Clin. Med. 2021, 10(5), 1064; https://doi.org/10.3390/jcm10051064 - 04 Mar 2021
Cited by 8 | Viewed by 2797
Abstract
Pulmonary embolism (PE) is a life-threatening complication arising from venous thromboembolism with a difficult diagnosis and treatment and is often associated with increased mortality and morbidity. PE had a significantly low incidence prior to the COVID-19 epidemic. This condition saw a sharp surge [...] Read more.
Pulmonary embolism (PE) is a life-threatening complication arising from venous thromboembolism with a difficult diagnosis and treatment and is often associated with increased mortality and morbidity. PE had a significantly low incidence prior to the COVID-19 epidemic. This condition saw a sharp surge during the COVID-19 pandemic, indicating an evident viral influence on PE’s pathophysiology in COVID-19 patients. The hypercoagulable state induced by the viral load seems to be the major contributor, and the classical causative factors seem to play a lesser role. PE in COVID-19 infection has become a mammoth challenge since the diagnosis is quite challenging due to overlapping symptoms, lack of prior-known predisposing risk factors, limited resources, and viral transmittance risk. Numerous factors arising out of the viral load or treatment lead to an increased risk for PE in COVID-19 patients, besides the fact that certain unknown risk factors may also contribute to the incidence of PE in COVID-19 patients. The management of PE in COVID-19 infection mainly comprises thromboprophylaxis and anticoagulant therapy with mechanical ventilation, depending on the risk stratification of the patient, with a post-COVID-19 management that prevents recurrent PE and complications. This review aims to discuss various aspects of COVID-19-infection-associated PE and major differential aspects from non-COVID-19 PE. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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39 pages, 2542 KiB  
Review
Linking Labile Heme with Thrombosis
by Marie-Thérèse Hopp and Diana Imhof
J. Clin. Med. 2021, 10(3), 427; https://doi.org/10.3390/jcm10030427 - 22 Jan 2021
Cited by 21 | Viewed by 4169
Abstract
Thrombosis is one of the leading causes of death worldwide. As such, it also occurs as one of the major complications in hemolytic diseases, like hemolytic uremic syndrome, hemorrhage and sickle cell disease. Under these conditions, red blood cell lysis finally leads to [...] Read more.
Thrombosis is one of the leading causes of death worldwide. As such, it also occurs as one of the major complications in hemolytic diseases, like hemolytic uremic syndrome, hemorrhage and sickle cell disease. Under these conditions, red blood cell lysis finally leads to the release of large amounts of labile heme into the vascular compartment. This, in turn, can trigger oxidative stress and proinflammatory reactions. Moreover, the heme-induced activation of the blood coagulation system was suggested as a mechanism for the initiation of thrombotic events under hemolytic conditions. Studies of heme infusion and subsequent thrombotic reactions support this assumption. Furthermore, several direct effects of heme on different cellular and protein components of the blood coagulation system were reported. However, these effects are controversially discussed or not yet fully understood. This review summarizes the existing reports on heme and its interference in coagulation processes, emphasizing the relevance of considering heme in the context of the treatment of thrombosis in patients with hemolytic disorders. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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11 pages, 627 KiB  
Review
Inhibitor in Congenital Factor VII Deficiency; a Rare but Serious Therapeutic Challenge—A Systematic Literature Review
by Nahid Ramezanpour, Farhad Zaker, Arijit Biswas and Akbar Dorgalaleh
J. Clin. Med. 2021, 10(2), 211; https://doi.org/10.3390/jcm10020211 - 08 Jan 2021
Cited by 7 | Viewed by 4407
Abstract
Background: Congenital factor (F) VII deficiency is a rare coagulation factor deficiency with an estimated incidence of 1 per 500,000 individuals. Patients with severe FVII deficiency present a broad range of clinical presentations. Alloimmunization against exogenous FVII, as the main challenge of replacement [...] Read more.
Background: Congenital factor (F) VII deficiency is a rare coagulation factor deficiency with an estimated incidence of 1 per 500,000 individuals. Patients with severe FVII deficiency present a broad range of clinical presentations. Alloimmunization against exogenous FVII, as the main challenge of replacement therapy, is an extremely rare phenomenon that is accompanied by a high rate of life-threatening bleeding, that renders replacement therapy less effective. Due to the importance of the issue, we performed a systematic literature review in order to assess incidence, molecular basis, clinical presentations, and therapeutic challenge and management of inhibitor in congenital FVII deficiency. Strategy of search: This systematic review was performed in accordance with PRISMA guidelines. We performed an English-language literature review in the PubMed, EMBASE, Scopus, and Google Scholar databases, using the following keywords: “factor VII inhibitor”, “factor VII inhibitors”, “FVII inhibitors”, “congenital FVII deficiency”, “recombinant factor VII”, “anti rFVIIa”, “replacement therapy”, and “alloantibody”. Results: Out of 380 patients in the 13 studies, 27 had inhibitor against FVII; 18 were male, 7 were female, while the sex of 2 was not stated. The majority (92%) developed a high-titer inhibitor (Bethesda Unit > 5). All patients had severe FVII deficiency (FVII:C < 10%), and the majority received recombinant FVII prior to inhibitor development (N: 24, 89%). Among ten patients with a detected mutation, three subjects had a common non-sense (30%), and two had a deletion (20%). Conclusions: Inhibitor development is a relatively rare phenomenon seen only in severe FVII deficiency, where it is associated with severe and life-threatening presentations, treatment challenge, and economic burden on the patients and their families. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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11 pages, 1464 KiB  
Review
Stroke as a Potential Complication of COVID-19-Associated Coagulopathy: A Narrative and Systematic Review of the Literature
by István Szegedi, Rita Orbán-Kálmándi, László Csiba and Zsuzsa Bagoly
J. Clin. Med. 2020, 9(10), 3137; https://doi.org/10.3390/jcm9103137 - 28 Sep 2020
Cited by 21 | Viewed by 5313
Abstract
Coronavirus disease 2019 (COVID-19) is the most overwhelming medical threat of the past few decades. The infection, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause serious illness leading to respiratory insufficiency, and, in severely ill patients, it can progress to [...] Read more.
Coronavirus disease 2019 (COVID-19) is the most overwhelming medical threat of the past few decades. The infection, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause serious illness leading to respiratory insufficiency, and, in severely ill patients, it can progress to multiple organ failure leading to death. It has been noted from the earliest reports that the disease influences the hemostasis system and a hallmark of severe infection is elevated D-dimer levels. The profound coagulation changes in COVID-19 seem to be linked to inflammation-related events and severe endothelial cell injury. Besides the high incidence of venous thromboembolic events in SARS-CoV-2 infections, arterial events, including cerebrovascular events, were found to be associated with the disease. In this review, we aimed to summarize the available literature on COVID-19-associated coagulopathy and thrombosis. Furthermore, we performed a systematic search of the literature to identify the characteristics of stroke in COVID-19. Our findings showed that acute ischemic stroke (AIS) is the most frequent type of stroke occurring in infected patients. In most cases, stroke was severe (median NIHSS:16) and most of the patients had one or more vascular risk factors. Laboratory findings in AIS patients were consistent with COVID-19-associated coagulopathy, and elevated D-dimer levels were the most common finding. The outcome was unfavorable in most cases, as a large proportion of the reported patients died or remained bedridden. Limited data are available as yet on outcomes after acute vascular interventions in COVID-19 patients. In the future, well-designed studies are needed to better understand the risk of stroke in COVID-19, to optimize treatment, and to improve stroke care. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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18 pages, 629 KiB  
Review
A Review of the Incidence Diagnosis and Treatment of Spontaneous Hemorrhage in Patients Treated with Direct Oral Anticoagulants
by Kulothungan Gunasekaran, Venkat Rajasurya, Joe Devasahayam, Mandeep Singh Rahi, Arul Chandran, Kalaimani Elango and Goutham Talari
J. Clin. Med. 2020, 9(9), 2984; https://doi.org/10.3390/jcm9092984 - 15 Sep 2020
Cited by 17 | Viewed by 4626
Abstract
Anticoagulation carries a tremendous therapeutic advantage in reducing morbidity and mortality with venous thromboembolism and atrial fibrillation. For over six decades, traditional anticoagulants like low molecular weight heparin and vitamin K antagonists like warfarin have been used to achieve therapeutic anticoagulation. In the [...] Read more.
Anticoagulation carries a tremendous therapeutic advantage in reducing morbidity and mortality with venous thromboembolism and atrial fibrillation. For over six decades, traditional anticoagulants like low molecular weight heparin and vitamin K antagonists like warfarin have been used to achieve therapeutic anticoagulation. In the past decade, multiple new direct oral anticoagulants have emerged and been approved for clinical use. Since their introduction, direct oral anticoagulants have changed the landscape of anticoagulants. With increasing indications and use in various patients, they have become the mainstay of treatment in venous thromboembolic diseases. The safety profile of direct oral anticoagulants is better or at least similar to warfarin, but several recent reports are focusing on spontaneous hemorrhages with direct oral anticoagulants. This narrative review aims to summarize the incidence of spontaneous hemorrhage in patients treated with direct oral anticoagulants and also offers practical management strategies for clinicians when patients receiving direct oral anticoagulants present with bleeding complications. Full article
(This article belongs to the Special Issue Thrombosis, Blood Clotting and Vascular Biology)
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