Editorial Compilation VIII

Welcome to the latest issue of Seminars in Thrombosis and Hemostasis (STH) published under the “banner” of “Editorial Compilation,” this being the eighth such issue. Although STH is primarily a theme-driven publication, ongoing opportunities arise to publish issues containing more wide-ranging contributions of current interest and controversy, and which do not quite match a current themed issue in progress. We also require a medium to enable publication of contributions from our Eberhard F. Mammen Young Investigator Award winners ([Table 1]). As now standard for this compilation series, the current issue has a mixture of content that comprises such elements, as well as broadly fitting within the separate themes of “thrombosis” and “bleeding.”

Table 1 Past STH editorials related to Eberhard F. Mammen award announcements

1. Favaloro EJ. 2011 Eberhard F. Mammen award announcements. Semin Thromb Hemost 2011;37(5):431–439.

2. Favaloro EJ. 2012 Eberhard F. Mammen award announcements. Semin Thromb Hemost 2012;38(5):425–432.

3. Favaloro EJ. 2013 Eberhard F. Mammen award announcements. Semin Thromb Hemost 2013;39(6):567–574.

4. Favaloro EJ. 2014 Eberhard F. Mammen award announcements: Part II—Young Investigator Awards. Semin Thromb Hemost 2014;40(7):718–723.

5. Favaloro EJ. 2015 Eberhard F Mammen award announcements: Part II—Young Investigator Awards. Semin Thromb Hemost 2015;41(8):809–815.

6. Favaloro EJ. 2016 Eberhard F. Mammen Award Announcements: Part II—Young Investigator Awards. Semin Thromb Hemost 2017;43(3):235–241.

7. Favaloro EJ. 2017 Eberhard F. Mammen Award Announcements: Part II—Young Investigator Awards. Semin Thromb Hemost 2018;44(2):81–88.

8. Favaloro EJ. 2018 Eberhard F. Mammen Award Announcements: Part II—Young Investigator Awards. Semin Thromb Hemost 2019;45(2):123–129.

9. Favaloro EJ. 2019 Eberhard F. Mammen Award Announcements: Part I—Most Popular Articles. Semin Thromb Hemost 2019;45(3):215–224.

10. Favaloro EJ. 2019 Eberhard F. Mammen Award Announcements: Part II—Young Investigator Awards. Semin Thromb Hemost 2020;46(2):105–113.

This issue begins with the most recent guidance document from the International Council for Standardization in Haematology (ICSH), this contribution related to recommendations for hemostasis critical values, tests, and reporting.[1] This guidance document has been developed by an ad hoc committee, comprised of an international collection of both clinical and laboratory experts. The purpose of this ICSH document is to provide laboratory guidance for (1) identifying hemostasis (“coagulation”) tests that have potential patient risk based on analysis, test result, and patient presentations, (2) critical test result thresholds; (3) acceptable reporting and documenting mechanisms, and (4) developing laboratory policies. The basis for these recommendations was derived from published data, expert opinion, and good laboratory practice. The committee realizes that regional and local regulations, institutional stakeholders (e.g., physicians, laboratory personnel, hospital managers), and patient types (e.g., adults, pediatric, surgical) will be additional confounders for a given laboratory in generating a critical test list, critical value thresholds, and policy. Nevertheless, we expect this guidance document to be helpful as a framework for local practice. A previous ICSH document providing recommendations for laboratory measurement of direct oral anticoagulants (DOACs) may also be of interest to readers.[2]

Next is the contribution around the topic of using artificial intelligence (AI) for managing thrombosis research, diagnosis, and clinical management, by Mishra and Ashraf.[3] Thrombosis development in either arterial or venous system remains a major cause of death and disability worldwide. This poorly controlled in vivo clotting may result in many severe complications, including myocardial infarction, venous thromboembolism, stroke, and cerebral venous thrombosis. Appropriate understanding of these conditions is challenging, as they are multifactorial and involve several and often different risk factors. It therefore requires collective effort and data from numerous research studies to fully comprehend molecular mechanisms for prediction, prevention, treatment, and overall management of these conditions. To help accomplish this, a comprehensive approach that can compile thousands of available experimental data and transform these into more applicable and purposeful findings would be useful. Thus, large datasets can be utilized to generate models that could be predictive of how an individual would respond when subjected to any kind of additional risk factors or surgery, hospitalization, etc., or in the presence of some susceptible genetic variations. AI-based methods harness the capabilities of computer software to imitate human behaviors such as decision making, language translation, visual perception, and most importantly, decision making. These emerging tools, if appropriately explored, might assist in processing of large data and tackle the complexities of identifying novel or interesting pathways that could otherwise be hidden due to their enormity. This narrative review attempts to compile the applications of various subfields of AI and machine learning in the context of thrombosis research to date. It further reflects on the potential of AI in transforming enormous research data into translational application in the form of predictive computational models.

This issue of STH continues with an exploration of antifactor Xa-based anticoagulation during extracorporeal membrane oxygenation (ECMO) by Ranucci et al.[4] ECMO represents a difficult situation to manage.[5] [6] Choices for monitoring of unfractionated heparin (UFH) anticoagulation in ECMO patients include activated clotting time (CT), activated partial thromboplastin time, reaction times of viscoelastic tests, and antifactor Xa activity (between 0.3 and 0.7 IU/mL). Recent studies propose the antifactor Xa to be the gold standard for monitoring UFH anticoagulation in ECMO. However, many extraneous factors combined question the utility of antifactor Xa as the sole method of monitoring of UFH effects in ECMO. Antifactor Xa is a chromogenic assay, which may be biased by the frequently elevated values of bilirubin and free hemoglobin in ECMO patients. The test may alternatively underestimate UFH effects in cases of low antithrombin values. More importantly, the antifactor Xa assay is a plasma-based test, which does not consider the role of platelets and fibrinogen in forming a stable clot. Thrombocytopenia and platelet dysfunction are common features in ECMO patients, and under-considering their role may lead to over-anticoagulation, should only antifactor Xa guiding be used to adjust the UFH dose. Conversely, fibrinogen is an acute phase protein, and some patients may experience high levels of this protein during ECMO course. In this case a UFH monitoring based on antifactor Xa is insensitive to this condition, although it may potentially be associated with thrombotic complications. Finally, the generally suggested range of 0.3 to 0.7 IU/mL is a somewhat arbitrary estimate, based on the desired range for treating and preventing thrombotic events in non-ECMO patients. In conclusion, the authorship group believe that antifactor Xa may offer useful information on the real effects of UFH only when combined with a whole blood test capable of assessing the relative contribution of platelets and fibrinogen to clot formation.

Continuing the exploration of “whole blood” monitoring, this time in neonates with perinatal hypoxia, is the original contribution from Konstantinidi et al.[7] Perinatal hypoxia is associated with increased risk of coagulation disorders by enhancing consumption of platelets and some clotting factors, due to the associated severe hypoxemia, acidemia, and compromised oxygen and blood supply to the neonatal liver and bone marrow. Thromboelastometry (TEM), which estimates the dynamics of blood coagulation, may represent an attractive tool for studying the coagulation status of these neonates.[8] The authors aimed at assessing the hemostatic profile of neonates with perinatal hypoxia, using the standard extrinsically activated thromboelastometry (ex-TEM) assay. In total, 164 hospitalized neonates with perinatal asphyxia and/or fetal distress comprised the study subjects, and 273 healthy neonates served as controls. Ex-TEM assay was performed, Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE) was calculated, and clinical findings and laboratory results were recorded in all study subjects. Hypoxic neonates expressed prolonged CT, clot formation time (CFT), and reduced amplitude at 10 minutes (A10), α angle, and maximum clot firmness compared with healthy neonates. Furthermore, asphyxiated neonates had significantly prolonged CT and CFT, and reduced A10 and α angle, compared with neonates with fetal distress. The authors conclude that hypoxic neonates display a hypocoagulable ex-TEM profile relative to healthy neonates, indicating a potential role of TEM in early detection of coagulation derangement in perinatal hypoxia.

The “neonate” theme continues with the contribution from Politou et al, on high-risk pregnancies and their impact on neonatal primary hemostasis.[9] Primary hemostasis, similar to other systems in the adjusting and transitioning neonate, undergoes developmental adaptations in the first days of life. Although platelets of neonates do not differ quantitatively compared with those of adults, they functionally present with major differences, thus supporting the theory of a “hypofunctional” phenotype that is counterbalanced by high hematocrit and more potent von Willebrand factor (VWF) multimers. No clinical effect of bleeding tendency has hence been established so far for healthy term neonates. However, discrepancies in functionality have been noted, associated with gestational age, with more pronounced platelet hyporesponsiveness in preterm neonates. Multiple methods of in vitro platelet function evaluation such as platelet function analyzer-100/200, platelet aggregometry, flow cytometry and cone, and platelet analyzer have been used for the assessment of neonatal primary hemostasis. Several pregnancies are characterized as “high risk,” when risk factors preexist in maternal history or evolve during pregnancy. These pregnancies require specific observation as they may have unpredictable outcomes. High-risk pregnancies include clinical entities such as preeclampsia, pregnancy-induced smoking during pregnancy, gestational diabetes mellitus (GDM), autoimmune diseases, and other maternal hematological conditions. In some cases, like systemic lupus erythematosus, antiphospholipid antibody syndrome, and maternal immunologically-based thrombocytopenia, neonatal thrombocytopenia is regarded as a prominent hemostasis defect, while in others, like pregnancy-induced hypertension and preeclampsia, both quantitative and qualitative disorders of neonatal platelets have been reported. In other pathologies, like GDM, neonatal primary hemostasis remains vastly unexplored, which raises the need for further investigation. The extent to which primary hemostasis is affected in neonates of high-risk pregnancies is the main objective of this narrative review.

The issue changes focus with the next contribution from Larsen et al, who explore the benefits and harm of treatment with P2Y12-inhibitors beyond 12 months, in patients with coronary artery disease (CAD).[10] The trade-off between the relative benefits versus harm in this setting after percutaneous coronary intervention (PCI) remains controversial. The authors present a review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed and Embase were searched without time restrictions to identify randomized controlled trials comparing > 12 months P2Y12-inhibition versus ≤ 12 months treatment in patients with acute coronary syndrome (ACS) or stable CAD undergoing PCI. A qualitative assessment was performed using the assessment tool from the National Heart, Lung and Blood Institute of the National Institutes of Health. The authors also performed a meta-analysis of the following end points: primary outcome (primarily major cardiovascular events), all-cause death, and major bleeding. Eight trials, comprising 40,218 patients, were finally included. Five studies were rated “good,” two studies “fair,” and one study “poor.” The meta-analysis showed that > 12-month P2Y12-inhibition significantly reduced the primary outcomes compared with ≤ 12-month treatment (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.75–0.97; p = 0.01). No significant difference was demonstrated between groups in all-cause death (HR: 1.02, 95% CI: 0.76–1.36; p = 0.91) or major bleedings (HR: 1.26; 95% CI: 0.93–1.70; p = 0.14). The I ² test showed low to moderate heterogeneity among the included studies (between 21.6 and 62.3%). This systematic review and meta-analysis therefore demonstrate a reduction in major cardiovascular events during extended P2Y12-inhibitor treatment beyond 12 months compared with ≤ 12 months in patients with ACS or stable CAD undergoing PCI. There was no significant difference in all-cause death or major bleedings. This report is an extension to the previous recent publications in this journal on the harms and benefits of aspirin therapy for primary prevention of cardiovascular disease (CVD) events.[11] [12]

Also discussing therapeutic treatment is the next contribution, by Lippi et al, this time in relation to the potential utility of DOACs for therapy in at least some forms of disseminated intravascular coagulation (DIC).[13] DIC is a relatively rare but life-threatening condition, the outcome of which depends largely on timely and accurate therapeutic management.[14] Inhibiting the activation of blood coagulation is an effective option for limiting the burden of diffuse intravascular thrombosis, for attenuating consumption of clotting factors and platelets, and for ultimately preventing massive bleeding. As readers of this journal know, DOACs are a relatively new generation of drugs which specifically inhibit activated factor II (thrombin) and X (FXa), thus providing effective anticoagulation while concomitantly limiting the hemorrhagic risk compared with other conventional anticoagulant agents.[15] The peculiar mechanism of action would therefore at least theoretically support their use in some patients with DIC, especially in those with a more pronounced thrombotic phenotype. A comprehensive literature search on use of DOACs in patients with intravascular coagulopathies currently yields only 15 documents, all case reports, totaling 21 patients (dabigatran, n = 5; rivaroxaban, n = 13; apixaban, n = 3; edoxaban, n = 0). Taken together, the current literature data suggest that these drugs may have low prophylaxis efficacy, and thereby their indication for preventing DIC in high-risk patients may be limited. Nevertheless, DOACs seem at least therapeutically equivalent to heparin in some forms of DIC, especially in those with prevalent thrombotic phenotype, while having more favorable oral administration. The inherent risk of hemorrhages from heparin injection is also shared by DOACs, so that their use in DIC patients with prevalent bleeding phenotype will probably remain unwarranted. Major caution should also be used in patients with impaired drug metabolism, especially those progressing toward liver or renal failure or receiving aggressive antimicrobial treatment. Where potentially indicated, further clinical trials should be planned to test the therapeutic efficacy of these drugs in patients with different forms of DIC.

We move this issue of STH back to CVD, this time in relation to the central role of acute phase proteins in rheumatoid arthritis, and their involvement in disease autoimmunity and inflammatory responses, which then lead to heightened risk of CVD in affected patients. The team of Bezuidenhout and Pretorius provides a State-of-the-Art discussion on this topic, and albeit focused on rheumatoid arthritis provides lessons for other autoimmune disorders.[16] Rheumatoid arthritis is an autoimmune disease of complex etiopathogenic origin and traditionally characterized by chronic synovitis and articular erosions. Furthermore, there is strong evidence that infectious agents, including those that become dormant within the host, play a major role in much of the etiology of rheumatoid arthritis and its hallmark of inflammation. A combination of genetic predisposition, environmental exposure, and presence of infectious agents may therefore lead to a loss of immune tolerance to citrullinated proteins, which present as self-antigens to the human immune system. This results in generation of highly rheumatoid arthritis-specific autoantibodies, known as anticitrullinated protein antibodies (ACPAs). Protein citrullination occurs via posttranslational deamination of arginine residues by peptidylarginine deaminase enzymes, which have confirmed sources of both endogenous and infectious origins. A recognized plasma protein target of citrullination and RA autoantibody generation is fibrin and its soluble precursor fibrinogen, both key components of hemostasis and acute phase reaction. Increased titers of ACPAs that accompany rapid progression to clinical RA disease have been shown to drive a variety of proinflammatory processes, and therefore result in aberrant fibrin clot formation and increased cardiovascular risk. However, the full extent to which hemostasis is affected in RA remains controversial, owing to the differential impact that citrullinated fibrin(ogen) and concurrent systemic inflammation may have on resulting hemostatic outcome. This review highlights key events in initiation of autoimmune-driven inflammatory events, including the role of bacterial infectious agents, which subsequently result in clinical RA disease and associated secondary CVD risk, with specific focus on plasma proteins that are heavily involved throughout the immunopathological progression process.

The final full-length paper in this issue of the journal is by Zolkova et al, a comprehensive assessment of the genetic background of von Willebrand disease (VWD),[17] and complementing the content of a recent issue in this journal on molecular and genetic testing in thrombosis and hemostasis.[18] Sequencing of the gene encoding for VWF has brought new insight into the physiology of VWF as well as its pathophysiology in the context of VWD.[19] Molecular testing in VWD patients has shown high variability in its overall genetic background, with almost 600 mutations and many disease-causing mechanisms have been described in 35 years since the VWF gene was identified. Genetic testing in VWD patients is now available in many centers as a part of the VWD diagnostic algorithm. Molecular mechanisms leading to type 2 and 3 VWD are well characterized; thus, information from genetic analysis in these VWD types may be beneficial for their correct classification. However, the molecular basis of type 1 VWD is still not fully elucidated, and most likely represents a multifactorial disorder reflecting a combined impact of environmental and genetic factors, both within and outside of VWF. Regarding sequencing methods, the previous gold-standard Sanger sequencing is gradually being replaced with next generation sequencing methods that are more cost and time effective.[20] Instead of gene-by-gene approaches, gene panels of genes for coagulation factors and related proteins have recently become a center of attention in patients with inherited bleeding disorders, especially because a high proportion of VWD patients, mainly those with low VWF plasma levels (“type 1”), appear to be free of mutations in VWF. Whole exome and whole genome sequencing are accessible in a very limited number of laboratories. Results from these studies have presented several genes other than VWF or ABO, as possibly affecting VWF levels and such findings will need further validation studies. Readers may be interested to learn that the lead author of this new contribution was a recent Eberhard F. Mammen Young Investigator Award winner.

As is usual for these nonthematic issues of STH, we present here also some correspondence. First, the team of Sokol and colleagues take the opportunity to comment on a previous review in the journal,[21] in the context of their strong belief in the importance of “Sticky Platelet syndrome.”[22] Then, Hong et al report on a small study of red blood cell distribution width, and its association with collateral flow and final infarct volume in patients suffering from acute stroke within the context of large artery atherosclerosis.[23] Yang and colleagues then describe a case of lupus anticoagulant-hypoprothrombinemia syndrome in which positivity for antiphosphatidylserine/prothrombin complex IgM antibodies was found.[24] This case represents an unusual presentation of the antiphospholipid syndrome.[25] Next, Lippi and Favaloro provide an update on biological and clinical associations between e-cigarettes and myocardial infarction.[26] The original report[27] continues to be a regular favorite with readers of this journal. Finally, Gosselin et al report on a small study on the effect of multiple freeze-thaw cycles on coagulation testing.[28] Although historically, it has been indicated in reagent manufacturer package inserts that plasma samples for coagulation should avoid multiple freeze thaw processes, since sample integrity may be compromised, solid evidence for any effects are largely lacking. Thus, this report should be of interest to laboratory personnel who otherwise may struggle on the number of “acceptable” freeze-thaw cycles for hemostasis testing, and this report provides specific insight into other preanalytical variables in coagulation testing.[29]

We again thank all the authors of this latest issue of “Editorial Compilations” for their original and comprehensive contributions, and we hope our readership enjoys this new installment in this series.

• References

• 1 Gosselin RC, Adcock D, Dorgalaleh A. , et al. International Council for Standardization in Haematology (ICSH) recommendations for hemostasis critical values, tests and reporting. Semin Thromb Hemost 2020; 46 (04) 398-409
• 2 Gosselin RC, Adcock DM, Bates SM. , et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 2018; 118 (03) 437-450
• 3 Mishra A, Ashraf MZ. Using artificial intelligence to manage thrombosis research, diagnosis and clinical management. Semin Thromb Hemost 2019; 46 (04) 410-418
• 4 Ranucci M, Cotza M, Isgrò G, Carboni G, Ballotta A, Baryshnikova E. Anti-factor Xa-based anticoagulation during extracorporeal membrane oxygenation. Potential problems and possible solutions. Semin Thromb Hemost 2020; 46 (04) 419-427
• 5 Thomas J, Kostousov V, Teruya J. Bleeding and thrombotic complications in the use of extracorporeal membrane oxygenation. Semin Thromb Hemost 2018; 44 (01) 20-29
• 6 Arachchillage DRJ, Passariello M, Laffan M. , et al. Intracranial hemorrhage and early mortality in patients receiving extracorporeal membrane oxygenation for severe respiratory failure. Semin Thromb Hemost 2018; 44 (03) 276-286
• 7 Konstantinidi A, Sokou R, Tsantes A. , et al. Thromboelastometry variables in neonates with perinatal hypoxia. Semin Thromb Hemost 2020; 46 (04) 428-434
• 8 Konstantinidi A, Sokou R, Parastatidou S. , et al. Clinical application of thromboelastography/thromboelastometry (TEG/TEM) in the neonatal population: a narrative review. Semin Thromb Hemost 2019; 45 (05) 449-457
• 9 Politou M, Mougiou V, Kollia M. , et al. High-risk pregnancies and their impact on neonatal primary hemostasis. Semin Thromb Hemost 2020; 46 (04) 435-445
• 10 Larsen ML, Grove EL, Kristensen SD, Hvas A-M. Benefits and harm of treatment with P2Y12-inhibitors beyond 12 months in patients with coronary artery disease. Semin Thromb Hemost 2020; 46 (04) 446-456
• 11 Lippi G, Danese E, Favaloro EJ. Harms and benefits of using aspirin for primary prevention of cardiovascular disease: a narrative overview. Semin Thromb Hemost 2019; 45 (02) 157-163
• 12 Christiansen M, Grove EL, Hvas AM. Primary prevention of cardiovascular events with aspirin: toward more harm than benefit-a systematic review and meta-analysis. Semin Thromb Hemost 2019; 45 (05) 478-489
• 13 Lippi G, Langer F, Favaloro EJ. DOACs for DIC: an alliterative wordplay or potentially valuable therapeutic interventions?. Semin Thromb Hemost 2020; 46 (04) 457-464
• 14 Thachil J. The elusive diagnosis of disseminated intravascular coagulation: does a diagnosis of DIC exist anymore?. Semin Thromb Hemost 2019; 45 (01) 100-107
• 15 Lippi G, Gosselin R, Favaloro EJ. Current and emerging direct oral anticoagulants: state-of-the-art. Semin Thromb Hemost 2019; 45 (05) 490-501
• 16 Bezuidenhout JA, Pretorius E. The central role of acute phase proteins in rheumatoid arthritis: involvement in disease autoimmunity, inflammatory responses and the heightened risk of cardiovascular disease. Semin Thromb Hemost 2020; 46 (04) 465-483
• 17 Zolkova J, Sokol J, Simurda T. , et al. Genetic background of von Willebrand disease: history, current state, and future perspectives. Semin Thromb Hemost 2020; 46 (04) 484-500
• 18 Rabbolini DJ, Othman M. Molecular and genetic testing in thrombosis and hemostasis. Semin Thromb Hemost 2019; 45 (07) 657-660
• 19 Batlle J, Pérez-Rodríguez A, Corrales I. , et al; PCM-EVW-ES Investigators Team. Update on molecular testing in von Willebrand disease. Semin Thromb Hemost 2019; 45 (07) 708-719
• 20 Kumar KR, Cowley MJ, Davis RL. Next-generation sequencing and emerging technologies. Semin Thromb Hemost 2019; 45 (07) 661-673
• 21 Arachchillage DRJ, Makris M. Inherited thrombophilia and pregnancy complications: should we test?. Semin Thromb Hemost 2019; 45 (01) 50-60
• 22 Sokol J, Kubisz P, Stasko J. Comment on: inherited thrombophilia and pregnancy complications: should we test?. Semin Thromb Hemost 2020; 46 (04) 501-501
• 23 Hong L, Fang K, Ling Y. , et al. Red blood cell distribution width is associated with collateral flow and final infarct volume in acute stroke with large artery atherosclerosis. Semin Thromb Hemost 2020; 46 (04) 502-506
• 24 Fei Y, Tang N, Zhang H, Li G, Zhang H, Zhang C. Significantly prolonged PT and APTT with no bleeding tendency: a patient with lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) positive for anti-phosphatidylserine/prothrombin (aPS/PT) complex IgM antibodies. Semin Thromb Hemost 2020; 46 (04) 507-511
• 25 Sacharidou A, Shaul PW, Mineo C. New insights in the pathophysiology of antiphospholipid syndrome. Semin Thromb Hemost 2018; 44 (05) 475-482
• 26 Lippi G, Favaloro EJ. An update on biological and clinical associations between e-cigarettes and myocardial infarction. Semin Thromb Hemost 2020; 46 (04) 512-514
• 27 Lippi G, Favaloro EJ, Meschi T, Mattiuzzi C, Borghi L, Cervellin G. E-cigarettes and cardiovascular risk: beyond science and mysticism. Semin Thromb Hemost 2014; 40 (01) 60-65
• 28 Gosselin RC, Honeychurch K, Kang HJ, Dwyre DW. Effect of multiple freeze-thaw cycles on coagulation testing. Semin Thromb Hemost 2020; 46 (04) 515-520
• 29 Gosselin RC, Marlar RA. Preanalytical variables in coagulation testing: setting the stage for accurate results. Semin Thromb Hemost 2019; 45 (05) 433-448