Perioperative bleeding: understanding causes, mechanisms and novel management approaches

1. Introduction

Perioperative bleeding is a significant challenge for clinicians, especially as the global population ages and more patients require anticoagulants or antiplatelet therapy. The demand for surgeries in individuals on anticoagulants or with coagulopathies has increased substantially. Despite advances in surgical and anaesthetic techniques, the risk of perioperative bleeding remains, impacting the complexity of surgeries and postoperative recovery. Excessive bleeding threatens patient safety, prolongs hospital stays, increases healthcare costs, and can be fatal [1].

The heightened awareness of the need for effective anticoagulation therapy, along with the rising use of direct oral anticoagulants (DOACs), has amplified concerns about managing perioperative bleeding. The growing incidence of anticoagulant-associated bleeding is troubling, particularly due to the absence of reversal agents for some drugs [2]. Concurrently, the need for effective blood management has driven the development of new treatments and technologies to mitigate bleeding risks. Innovations include point-of-care diagnostic systems for rapid coagulation assessment, advanced hemoadsorption technologies (used in extracorporeal blood purification) and new anticoagulant reversal agents [3, 4].

This review explores the multifactorial nature of perioperative bleeding, the role of anticoagulants in increasing bleeding risks and current management strategies. We focus on advancements in managing anticoagulated patients, novel therapies such as hemoadsorption, and strategies for reversing anticoagulant effects. The increasing complexity of perioperative bleeding management, especially in patients with coagulopathies, underscores the need for individualized treatment plans to optimize outcomes in these high-risk populations [5].

2. Methods

We searched multiple databases and resources, including PubMed, Scopus, Google Scholar, and clinical guidelines from medical societies such as the International Society on Thrombosis and Haemostasis (ISTH). The search terms used were “perioperative anticoagulation management”, “anticoagulant reversal” and “antithrombotic therapy in surgery”, with a focus on studies published between 2014 and 2024 to ensure the information was up to date. We also consulted the latest guidelines, including the 2024 European Association for Cardio-Thoracic Surgery/European Association for Cardio-Thoracic Anaesthesiology and Intensive Care (EACTS/EACTAIC) Guidelines on patient blood management in adult cardiac surgery in collaboration with European Board of Cardiovascular Perfusion (EBCP) [6] and Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists/American Society of ExtraCorporeal Technology/Society for the Advancement of Blood Management (STS/SCA/AmSECT/SABM) recommendations [7], to ensure comprehensive coverage of current best practices.

We included studies published in the English language and peer-reviewed journals that focused on anticoagulation management during surgery, the use of anticoagulants such as warfarin and direct oral anticoagulants, and strategies for reversing anticoagulation.

From the selected studies, we extracted data on the types of anticoagulants, management strategies during surgery, available reversal methods, and clinical outcomes such as bleeding or clotting events. We identified 55 relevant references, which we classified by type to provide a clearer overview of the sources used. The classification of references is presented in Table 1, which differentiates them according to type and key topic/focus.

The studies highlighted the lack of clear guidelines for managing anticoagulation before and after surgery, with gaps noted in bridging therapy and the availability of reversal agents [8, 9, 10, 11]. The findings emphasize the need for standardized protocols, particularly regarding the perioperative management of newer direct oral anticoagulants such as idarucizumab and andexanet alfa.

3. Coagulation cascade and haemostasis

Understanding normal haemostasis is crucial to managing perioperative bleeding. Haemostasis prevents excessive blood loss after a blood vessel injury and involves vascular constriction, platelet aggregation and the coagulation cascade, resulting in a stable fibrin clot [9, 10].

4. Congenital and acquired coagulation disorders

Patients with congenital or acquired coagulation disorders face a significantly higher risk of perioperative bleeding, complicating surgical management due to their impaired ability to form stable clots [17].

5. Anticoagulant therapy and reversal strategies

Anticoagulants are widely used in clinical practice to prevent thromboembolic events in patients with conditions such as atrial fibrillation, deep vein thrombosis and pulmonary embolism. While effective in reducing the risk of thrombosis and stroke, their use complicates perioperative bleeding management [24]. During surgery, balancing bleeding risks with the need to prevent thromboembolic complications is critical [25]. Novel anticoagulants present additional challenges due to the lack of readily available reversal agents [25]. This section reviews major anticoagulants, their mechanisms of action and reversal strategies [26] (Table 2).

6. Blood products and adjunct therapies

Blood products and adjunct therapies are essential in managing anticoagulant-induced bleeding [40, 41, 42] (Table 3):

● Fresh Frozen Plasma (FFP): Provides a broad spectrum of clotting factors but has a slower onset of action and risks such as fluid overload and transfusion-related complications.

● Prothrombin Complex Concentrates (PCCs): Offer rapid correction of coagulopathy with fewer complications and lower volume requirements compared to Fresh Frozen Plasma (FFP). PCCs contain the vitamin K–dependent coagulation factors II, VII, IX and X, as well as the natural anticoagulants protein C and protein S, making them particularly useful for immediate reversal of elevated INR in patients receiving vitamin K antagonists (e.g., warfarin) who present with severe bleeding or require emergency surgery. PCCs are also useful for replacing multiple coagulation factors when FFP is unavailable or time-consuming to administer, and for off-label reversal of direct oral anticoagulants like apixaban and rivaroxaban in cases of severe bleeding or urgent interventions.

● Platelet Transfusions: Can help restore platelet function in patients on antiplatelet agents, though they are less effective for irreversible inhibitors unless combined with adjuncts like DDAVP.

● Tranexamic Acid (TXA): An antifibrinolytic that stabilises clots and reduces bleeding, though it may increase thrombotic risk in predisposed patients.

● Cryoprecipitate: This is derived from thawed fresh frozen plasma and is a pooled blood product containing fibrinogen, von Willebrand factor, factor VIII, factor XIII and fibronectin—thus offering a broader spectrum of clotting factors. While there can be variability in fibrinogen content, many transfusion medicine laboratories measure and report the exact fibrinogen concentration, allowing clinicians to order Cryoprecipitate by specifying the desired grams of fibrinogen. In modern practice, Cryoprecipitate can be prepared in a volume of approximately 250–300 mL to match the necessary fibrinogen dose without causing significant volume overload. Additionally, its content of factor XIII is crucial for stable clot formation.

● Fibrinogen concentrate: By comparison, it is a purified, lyophilized product that provides a standardized, precisely dosed supply of fibrinogen, facilitating rapid reconstitution and potentially reducing transfusion-related complications. This can be especially advantageous in critically ill patients who require timely, exact correction of hypofibrinogenemia. Both Cryoprecipitate and fibrinogen concentrate play important roles in managing fibrinogen deficiency, with the choice often guided by patient factors, laboratory availability and institutional protocols.

In life-threatening bleeding, off-label agents such as rFVIIa (NovoSeven) or factor XIII (which stabilises fibrin clots) may be used, though they carry thrombotic risks [43, 44]. In addition, cryoprecipitate (rich in fibrinogen, factor VIII, factor XIII and vWF) is useful in massive transfusion protocols—which often employ fixed ratios (e.g., 1:1:1 for red blood cells, plasma and platelets)—to preempt coagulopathy, especially in trauma or cardiovascular surgery.

7. Novel diagnostic tests in perioperative bleeding management

The management of perioperative bleeding is evolving rapidly with the development of new therapies and technologies designed to improve bleeding control, particularly in patients receiving anticoagulant therapy. These advances aim to enhance the precision of bleeding management and improve outcomes in high-risk surgeries. Point-of-care testing (POCT) provides clinicians with real-time information about a patient’s coagulation status during surgery, enabling more precise and timely treatment decisions. Viscoelastic devices such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) assess the viscoelastic properties of blood, offering insights into clot formation, stabilization and dissolution. For example, ROTEM provides comprehensive information on the dynamics of clot formation, while TEG reports parameters such as R-time, K-time, α-angle and maximum amplitude (MA) to help target deficiencies in platelets, fibrinogen, or clotting factors for optimal transfusion therapy [44, 45].

Viscoelastic testing, performed by devices such as TEG and ROTEM, provides real-time insights into the dynamics of clot formation and stability. In TEG, R-time represents the time until the initial fibrin formation, serving as an indicator of clotting factor activity—prolonged R-time may suggest a deficiency. The maximum amplitude (MA) in TEG reflects the ultimate strength of the clot, primarily influenced by platelet function and fibrinogen levels; a lower MA can indicate issues such as platelet dysfunction or low fibrinogen. Similarly, in ROTEM, clotting time (CT) is the equivalent parameter to TEG’s R-time, marking the period until clot initiation, while maximum clot firmness (MCF) corresponds to the overall clot strength, analogous to TEG’s MA. ROTEM also includes specific assays: EXTEM uses tissue factor to activate the extrinsic coagulation pathway, and INTEM employs ellagic acid to stimulate the intrinsic pathway. These distinctions enable clinicians to better understand and manage coagulation abnormalities, tailoring interventions to the patient’s specific needs [44, 45].

8. Novel treatment options in perioperative bleeding management

CytoSorb is an innovative hemoadsorption device that removes anticoagulants and other harmful substances from the bloodstream. This technology shows promise—particularly in patients undergoing cardiopulmonary bypass or other high-risk surgeries—by adsorbing drugs such as rivaroxaban and ticagrelor, thereby reducing plasma concentrations and mitigating bleeding risk [46, 47]. Studies have demonstrated that CytoSorb can significantly reduce plasma concentrations of anticoagulants like rivaroxaban and ticagrelor, resulting in fewer transfusions and reduced bleeding complications [48]. Experimental data also suggest that agents such as dabigatran, edoxaban, and ticagrelor can be effectively removed in vitro; however, larger randomised trials are needed to optimise protocols and assess cost-effectiveness [49, 50, 51, 52, 53]. Additional hemoadsorption technologies are under investigation for their ability to adsorb anticoagulants and antiplatelet medications during the perioperative period. These devices offer an alternative to traditional reversal strategies—such as specific antidotes or blood product transfusions—and may become critical tools for managing perioperative bleeding, particularly when specific reversal agents are unavailable or ineffective [53, 54].

The major advantage of these technologies is their ability to rapidly and effectively remove anticoagulants from the circulation, thereby reducing bleeding complications without relying solely on slower processes such as drug metabolism or antidote administration. However, many hemoadsorption devices remain in pilot phases or early clinical trials, and factors such as cost, availability, and the risk of excessive removal (which may promote thrombosis) must be carefully considered.

Recent evidence suggests that hemoadsorption devices, such as CytoSorb, can effectively reduce plasma concentrations of various anticoagulants—most notably rivaroxaban and ticagrelor—by adsorbing these agents from the bloodstream during high-risk surgical procedures like cardiopulmonary bypass. This reduction in drug levels may translate into a decreased risk of perioperative bleeding and a lower need for transfusions. Preliminary studies have also indicated potential for removing other anticoagulants, including dabigatran and edoxaban, though much of this data comes from in vitro experiments or small-scale clinical trials. Despite these promising findings, larger randomized controlled studies are required to confirm their clinical efficacy, determine optimal usage protocols, and evaluate cost-effectiveness before hemoadsorption devices can be widely adopted in clinical practice [50, 51, 52, 53, 54].

9. Our experiences with novel techniques

The use of hemoadsorption devices has attracted considerable attention in recent years, particularly for managing complex cases requiring CPB. Among these devices, Cytosorb has shown promise in removing excess anticoagulants and antithrombotic agents in situations where precise control of blood coagulation is paramount. Early experience in our center has been encouraging, and we are now organizing a formal study to further investigate the effectiveness and safety of Cytosorb in this context.

The study aims to: assess perioperative bleeding rates, transfusion requirements and short-term outcomes; evaluate any device-related complications or adverse events; and, optimize protocols for integrating the Cytosorb cartridge into standard CPB circuits.

We anticipate that this investigation will help delineate best practices, including patient selection criteria, dosing adjustments for anticoagulants, and standardized timelines for cartridge use. Furthermore, long-term follow-up data will clarify whether the benefits of intraoperative adsorption translate to faster postoperative recovery and decreased healthcare costs.

10. Challenges and future directions

Managing drug-induced haemostatic disorders remains complex. The limited availability and high costs of specific reversal agents (such as idarucizumab and andexanet alfa) restrict their use. Further research is needed to develop affordable alternatives and to establish standardised protocols for reversal timing and blood product utilisation. Long-term studies should also assess the impact of perioperative bleeding on outcomes such as infection risk and wound healing.

Emerging interest in universal reversal agents that target multiple anticoagulants may simplify management, and the development of shorter-acting anticoagulants with predictable pharmacokinetics could reduce reliance on reversal strategies, thereby improving safety in both elective and emergency surgical settings.

11. Limitations

Our review aimed to comprehensively cover current knowledge and emerging approaches to perioperative bleeding, but it has several limitations. First, our literature search was confined to English-language studies from 2014–2024, possibly overlooking relevant findings published outside these constraints. Second, we did not conduct a formal meta-analysis, relying on narrative synthesis and expert consensus, which may affect the strength of our recommendations. Third, the cited studies were heterogeneous in design, populations and surgical settings, complicating direct comparisons and limiting generalizability. Fourth, because the field of anticoagulation therapy and related technologies evolves rapidly, certain off-label uses may quickly become outdated. Fifth, many novel therapies, such as hemoadsorption devices, have limited real-world data and short follow-up durations. Sixth, the predominance of research from high-income settings restricts applicability to regions with different resources and patient demographics. Finally, although we underscore personalized strategies, we could not address all patient-specific factors, emphasizing the need for multidisciplinary evaluation and further large-scale research to validate and refine these emerging approaches.

12. Conclusions

Perioperative bleeding management is a multifaceted challenge that requires careful consideration of a patient’s medical history, coagulation status and current medications. The advent of newer anticoagulants and the rising incidence of bleeding disorders necessitate the development of more targeted, personalised approaches. Modern diagnostic systems—including point-of-care testing—along with innovative hemoadsorption therapies (such as Cytosorb) and other novel technologies, show great potential for improving outcomes by enabling more precise and effective management of bleeding risks.

Abbreviations

ADP, Adenosine Diphosphate; aPCC, activated Prothrombin Complex Concentrate; aPTT, activated Partial Thromboplastin Time; APS, Antiphospholipid Syndrome; aVWD, acquired von Willebrand disease; CKD, Chronic Kidney Disease; COX-1, cyclooxygenase-1; CPB, Cardiopulmonary Bypass; DDAVP, Desmopressin; DOACs, Direct Oral Anticoagulants; FFP, Fresh Frozen Plasma; FVIIa, activated Factor VII; FX, Factor X; HIT, Heparin-Induced Thrombocytopenia; LMWH, Low-Molecular-Weight Heparin; MA, Maximum Amplitude; MCF, Maximum Clot Firmness; P2Y12, Platelet ADP Receptor; PCCs, Prothrombin Complex Concentrates; POCT, Point-of-Care Testing; RBC, Red Blood Cell; rFVIIa, recombinant Factor VIIa; ROTEM, Rotational Thromboelastometry; STAR, Safe and Timely Antithrombotic Removal; TEG, Thromboelastography; TF, Tissue Factor; TFPI, Tissue Factor Pathway Inhibitor; TXA, Tranexamic Acid; TXA₂, Thromboxane A₂; UFH, Unfractionated Heparin; VKA, Vitamin K Antagonist; vWD, von Willebrand Disease; vWF, von Willebrand Factor; CT, clotting time; ISTH, International Society on Thrombosis and Haemostasis; EACTS, European Association for Cardio-Thoracic Surgery; EACTAIC, European Association of Cardiothoracic Anaesthesiology and Intensive Care; EBCP, European Board of Cardiovascular Perfusion; STS, Society of Thoracic Surgeons; SCA, Society of Cardiovascular Anesthesiologists; AmSECT, American Society of ExtraCorporeal Technology; SABM, Society for the Advancement of Blood Management.

Availability of data and materials

Not applicable.

Author contributions

GTŠ and IP—conceived and designed the review, collected and analyzed the literature, and wrote the manuscript. GTŠ and IP—contributed equally to all aspects of the work and share first authorship. Both authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Acknowledgment

We would like to thank the researchers conducting all the studies mentioned in the article for exploring the field of coagulation, perioperative bleeding and anticoagulant drugs.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest. Specifically, none of the authors has any financial or personal relationship with any hemoadsorption device manufacturer (including CytoSorb), nor did we receive any sponsorship or honorarium related to this work.