Interaction of the immune and haemostatic systems in immunogenesis

The immune and haemostatic systems interact closely in immunohaemostasis, which provides reliable protection against diseases of various origins. This protection depends on the balance between both systems. Increased immune activity can lead to excessive blood clotting, while suppression of the haemostatic system can lead to a risk of bleeding. To maintain balance, each system has mechanisms to influence the other. The immune system affects homeostasis in several ways. Certain immune cells, such as macrophages and neutrophils, can release clotting factors (factor VII and factor X), which can affect blood clots [9]. Immune complexes, consisting of antibodies to pathogens, affect the activation of the blood coagulation cascade through complement activation [10]. The opposite effect is demonstrated by other immune cells, such as T-suppressors and B cells, which can produce inhibitors of clotting factors, such as antithrombin III and protein C, which prevent blood clots [11].

The effect of immune cells on platelets, which are important cells for blood clotting, has different effects depending on their type. Thus, macrophages can inhibit platelet activation and thus prevent blood clots; neutrophils, as phagocytic leukocytes, can activate platelets in response to infection; depending on the type of T-cell, some can activate platelets, while others can slow down activation; B-cells, as lymphocytes responsible for the production of antibodies, have several ways of interacting with platelets – they can activate these cells by binding to them and produce complexes that, depending on the immune processes, can activate or inhibit their activation; dendritic cells are not directly related to platelet function, however, by releasing cytokines and other inflammatory mediators and activating T cells, they have an indirect effect on their activation [12, 13].

The fibrinolytic system, which is responsible for dissolving blood clots, can be affected by immune cells due to their ability to produce activators or inhibitors of the key fibrinolytic enzyme plasminogen. Depending on the type and stage of the infection, immune cells can release both plasminogen activators and inhibitors [14]. Macrophages can release tissue plasminogen activator (t-PA), which converts it into the active enzyme plasmin, which breaks down fibrin, the main component of blood clots, and leads to their dissolution. However, macrophages also can release plasmin inhibitors, specifically α2-antiplasmin (α2-AP), which prevents excessive dissolution of blood clots [15]. Neutrophils and T cells can release both plasminogen activators and plasmin inhibitors. The effect of B cells on plasminogen lies in its ability to produce antibodies that bind to activators or inhibitors of this enzyme [16]. The effect of dendritic cells on the fibrinolytic system, by analogy with the effect on platelets, is indirect and is manifested by their ability to activate T cells and other immune cells [17].

Endothelial cells, which line the inner surface of blood vessels, play a significant role in blood clotting, bleeding, and inflammation [18]. Immune cells can affect changes in endothelial cell function through the release of cytokines tumour necrosis factor-alpha (TNF-α), Interleukin-1 factor-beta (IL-1β), and Interferon-γ (IFN-γ), which can stimulate the expression of adhesion molecules on the surface of endothelial cells, leading to leukocyte adhesion and transmigration [19]. Immune cells also can interact directly with endothelial cells through receptor-ligand interactions, which can activate signalling pathways in endothelial cells and lead to changes in their function [20]. The effect of immune complexes on endothelial cells is manifested in their ability to bind to receptors on the surface of these cells, activating them. This can trigger inflammation, endothelial dysfunction, and blood clots [21]. Another mechanism of communication between immune cells and the endothelium of blood vessels is their effect on microvascular blood flow by regulating the expansion and contraction of these vessels, which can affect the delivery of oxygen and nutrients to the surrounding tissues and the excretion of waste products [22].

In the context of the global pandemic caused by the novel Covid-19, the interaction between the immune and haemostatic systems has attracted significant attention due to the virus's profound impact on endothelial function and the resulting immunohaemostasis dysfunction. The virus responsible for the disease known as Covid-19, has been observed to infect endothelial cells, resulting in a state of widespread endothelial inflammation and dysfunction. This results in the development of a cytokine storm, characterised by the excessive release of pro-inflammatory cytokines, including IL-6, TNF-α and IL-1β. The overactivation of the immune response has been observed to increase endothelial permeability, which in turn contributes to vascular leakage and promotes hypercoagulability, a hallmark of severe cases of coronavirus disease 2019. This dysregulation can result in extensive microvascular clotting and severe complications, including thrombosis in the lungs and other organs. Consequently, the Covid-19 exemplifies how viral infections can disrupt immunohaemostasis, thereby underscoring the clinical relevance of understanding immune and haemostatic interactions in the context of managing coagulopathies associated with infectious diseases [23].

The haemostatic system also has mechanisms to influence the immune system [24]. As components of the haemostatic system, blood coagulation factors are most closely related to the components of the immune system – immune cells. These components, specifically thrombin, can activate immune cells such as macrophages and neutrophils, which can lead to the production of cytokines and an enhanced immune response [25, 26]. In addition, clotting factors and fibrin are involved in stimulating the migration of immune cells to sites of infection or inflammation, thus helping the immune system to fight pathogens, and affect the production of antibodies by B cells, enhancing the protective function of humoral immunity [27, 28].

The haemostatic system is essential for maintaining immune tolerance and does so in several ways. Antithrombin III, protein C, and some other proteins of the haemostatic system can inhibit the activation of macrophages and neutrophils, preventing an excessive immune response to the body's own antigens [29]. The ability of fibrinogen and fibrin to bind to and promote the removal of immune complexes from the circulation helps prevent the activation of immune cells by these complexes and eliminate the potential threat to healthy cells [30]. Certain proteins of the haemostatic system, specifically thrombin and thrombin receptor activating protein (TRAP), are involved in regulating immune cell apoptosis, thereby controlling their count and excessive activation [31]. By regulating the expansion and contraction of blood vessels, the haemostatic system can affect microvascular blood flow, increasing or restricting the access of immune cells to antigens in certain tissues [32].

There are also several mechanisms by which the haemostatic system can influence the formation of immune memory. Thrombin, TRAP, and some other proteins of the haemostatic system can stimulate the activation of memory immune cells, such as B cells and T cells, which can further enhance the immune response to reinfection [33]. The ability of fibrinogen and fibrin to bind to antigens makes it possible for them to “get to know” the memory immune cells and provide an accelerated immune response when they encounter these antigens [34]. An analogous effect is achieved when blood clotting factors and fibrin stimulate the migration of immune cells to sites of repeated infection [35]. Extracellular vesicles are membrane-bound particles released by a variety of cell types, including platelets, immune cells, and endothelial cells [36]. They play a crucial role in intercellular communication, influencing both coagulation and immune responses. Extracellular vesicles transport a diverse range of bioactive molecules, including proteins, lipids, and nucleic acids, which reflect the physiological state of their cell of origin. In the context of coagulation, platelet-derived extracellular vesicles are of particular significance. The expression of phosphatidylserine on the surface of these vesicles provides a negatively charged platform that facilitates the assembly of coagulation complexes, thereby promoting thrombin generation and fibrin formation. Furthermore, these extracellular vesicles are capable of carrying tissue factor, the primary initiator of the coagulation cascade, thereby further enhancing their procoagulant activity [37].

Extracellular vesicles also modulate immune functions beyond their role in coagulation. They are also capable of transferring antigens and major histocompatibility complex molecules between cells, which in turn affects antigen presentation and subsequent T-cell activation. For example, dendritic cell-derived extracellular vesicles have the capacity to present antigens to T cells, thereby initiating immune responses. Conversely, tumour-derived extracellular vesicles may carry immunosuppressive molecules, thereby aiding in immune evasion. The dual role of extracellular vesicles in coagulation and immune modulation underscores their importance in maintaining immunohaemostatic balance. Dysregulation of extracellular vesicle production or function can contribute to pathological conditions, such as thrombosis or impaired immune responses. A comprehensive understanding of the specific roles and mechanisms of extracellular vesicles in these processes is crucial for developing targeted therapeutic strategies [38].

Dysfunction of the immune or haemostatic system can lead to immunohaemostasis disorders, which can result in the development of thrombosis, bleeding, infectious, and autoimmune diseases. Therefore, it is vital to investigate the mechanisms that can be effectively used to regulate blood clotting processes. The mechanisms through which immune cells and haemostatic factors interact to regulate immunohaemostasis have been elucidated, with each element playing a specific role in sustaining balance. The findings underscore the dual nature of immune cells, whereby they may either promote or inhibit blood clotting, contingent on the specific type of cell and the stage of infection. These insights are of great importance for the comprehension of disease processes and the development of therapeutic strategies that take into account both immune and haemostatic functions.

Significance of immune reactions in the regulation of blood coagulation processes

Blood clotting is a complex process involving the interaction of blood components such as platelets, clotting factors, and fibrinogen. Immune responses play a vital role in the regulation of this process, which is carried out through platelet activation, regulation of coagulation factors, and influence on fibrinolysis and immune tolerance. Platelets can be activated by immune complexes that bind to Fc receptors on the platelet surface and activate them, while the already activated platelets release clotting factors and biologically active molecules that stimulate blood clots. There are two types of Fc receptors on the surface of platelets. The most common of them, FcγRIIA receptors, activate platelets by binding to IgG immune complexes formed in the body in response to infections. FcγRIIB receptors are a less common type of Fc receptor. They also can bind to IgG complexes, but their binding strength is lower than that of FcγRIIA [39]. The activation of these receptors, depending on the type of immune complex, microenvironment, genetic factors, and existing diseases, can lead to platelet activation or inhibition. Depending on the ratio of antigens to antibodies, IgG immune complexes can activate platelets (in the case of an excess of antigens) or inhibit them (in the case of an excess of antibodies). The effect of platelet activation via FcγRIIB receptors may be influenced by the presence of other mediators in the microenvironment, such as thrombin, adrenaline, and prostaglandin. Polymorphisms of FcγRIIB genes can affect its activity in binding to immune complexes by altering its affinity, localisation, or signal transduction. The presence of autoimmune diseases and infections also has a bearing on changes in FcγRIIB activity and, accordingly, will affect platelet activation. A significant factor in platelet activation is its current activation state: platelets that are already activated by other stimulants are more likely to be activated by FcγRIIB, while inactivated platelets are more likely to be inhibited by these receptors [40].

The increased reactivity of platelets in a range of pathological conditions is underpinned by intricate metabolic and molecular mechanisms, including alterations in platelet metabolism and interactions with inflammatory molecules. It has been demonstrated that platelet metabolism, particularly with regard to energy pathways such as glycolysis and oxidative phosphorylation, exerts an influence on platelet activation. In conditions of inflammation and hyperglycaemia, as observed in diabetes, there is an increase in glycolytic flux within platelets, leading to heightened ATP production and an enhanced aggregation response. Similarly, alterations in oxidative metabolism contribute to the generation of reactive oxygen species, which further prime platelets for activation and aggregation. Furthermore, the interaction between platelets and inflammatory molecules, including cytokines, chemokines, and adhesion molecules, serves to exacerbate this reactivity. The binding of inflammatory mediators such as interleukin-6 (IL-6) and TNF-α to platelet receptors amplifies the release of granules containing prothrombotic agents and increases the expression of surface receptors that are critical for platelet adhesion. This inflammation-driven reactivity underscores the necessity for the implementation of personalized thrombosis management strategies that take into account the distinctive metabolic and inflammatory factors present in individual patient conditions, such as diabetes, chronic kidney disease, and inflammatory disorders. Inhibition of these pathways may facilitate the development of more efficacious and personalized strategies for the management of thrombotic risk [41].

In pathological conditions such as diabetes and chronic kidney disease, there are notable alterations in platelet behaviour that elevate the risk of thrombosis. It is established that both conditions induce platelet hyperreactivity, which is manifested as an increased tendency for platelet aggregation and contributes to a prothrombotic state. In diabetes, elevated blood glucose levels and oxidative stress result in enhanced platelet activation through mechanisms involving the upregulation of thromboxane A2 and a reduction in nitric oxide bioavailability. Both of these contribute to platelet adhesion and aggregation. Similarly, chronic kidney disease affects platelet function due to uremic toxins that alter platelet surface receptors, particularly FcγRIIB/FcγRIIA, which are crucial for platelet aggregation. These pathophysiological changes highlight the necessity for targeted therapeutic strategies to manage thrombotic risk in patients with these underlying conditions.

Apart from Fc, other receptors can also interact with immune complexes and affect the activation of platelets on which they are located, leading to the formation of blood clots. These include Toll-like receptors (TLRs), C-type lectin receptors (CLECs), and complement receptors [42]. Platelets can also be activated by microbial components. For instance, bacterial endotoxins and viral proteins can activate them through TLRs, CLECs, and other receptors that bind to these components, contributing to the launch of an innate immune response and blood clots [43]. Certain immune cells, such as macrophages and neutrophils, can actively stimulate platelet activation through direct contact or the release of soluble mediators, while other cells, such as regulatory T cells, can inhibit platelet activation and reduce blood clots. Direct interaction between immune cells and platelets occurs through several mechanisms. Immune cells and platelets express receptors on their surface that can bind to ligands secreted by other cells. Thus, GPIb and αIIbβ3 receptors expressed by platelets can bind to fibrinogen and other plasma proteins; CD40L and CD154 ligands secreted by immune cells can bind to platelet surface receptors CD40 and CD40L, respectively. This connection can activate platelets and change their functions of aggregation and granule release [44]. Platelets can interact with immune cells through direct contact of their plasma membranes, which is ensured by the transmission of signals from one cell to another through transdermal proteins and secondary messengers. An example of such contact is the transmission of a signal from immune cells to platelets via the nuclear factor kappa-B (NF-κB) factor, which results in the activation of the latter [45]. Contact between immune cells and platelets also occurs through the formation of specialised structures on their surfaces – immune synapses, which contain an elevated concentration of receptors, ligands, and signalling molecules that allow for effective transmission of signals between cells. The formation of immune synapses has a considerable impact on platelet activation, which leads to platelet aggregation, granule release, and cytokine production [46].

Platelet activation can be influenced by certain components of the complement system. C5a, as a fragment of complement component C5, can bind to the C5aR receptor on the platelet surface, which leads to platelet activation, aggregation, granule release, and production of pro-inflammatory mediators. An analogous binding mechanism occurs with C3a, a fragment of complement component C3, and the platelet receptor C3aR. The membrane attack complex formed in the complement cascade can treat platelets as a target and lead to their death [47]. Depending on the type, cytokines can either activate platelets or inhibit their activation. The relationship between cytokines and platelets is presented in Table 1.

Immune reactions also affect the blood clotting process through the regulation of clotting factors. Immune cells can produce clotting factors and their inhibitors, which control the speed and intensity of blood clotting. They have a different mechanism of communication, but have an analogous effect on the clotting process, which is the production of blood clotting factors – factor VIII, factor IX, thrombin, and factor XIII; production of blood clotting factor inhibitors – antithrombin III and protein C. Macrophages provide this effect by binding to the antigen-antibody complex and activating the complement system, monocytes – by circulating in the blood and migrating to the site of inflammation, dendritic cells – by presenting antigens to T lymphocytes, T lymphocytes – by stimulating the immune response, B lymphocytes – by producing antibodies that can activate or inhibit the complement system [48]. Immune reactions also affect the regulation of blood clotting through fibrinolysis. This effect is exerted through the ability of immune cells to produce fibrinolysis activators and inhibitors that control the rate of blood clot dissolution. The role of immune cells in fibrinolysis is presented in Table 2.

Macrophages and monocytes have much in common in the regulation of fibrinolysis, but there are also substantial differences between them. Monocytes circulate in the bloodstream and migrate to sites of inflammation or infection, producing uPA and tPA in the early stages of inflammation, while macrophages are located in the liver, spleen, lungs, and bone marrow tissues and produce uPA and tPA over a longer period. Apart from those listed in Table 2, other immune cells can affect the fibrinolysis process. Dendritic cells can activate T-lymphocytes and influence fibrinolytic activity through the release of cytokines. Mast cells release histamine and other mediators that can affect plasminogen activity and fibrinolytic activity. Immune cells are essential for maintaining immune tolerance to blood components. It can be achieved by selecting immature T-lymphocytes in the thymus. During this process, those T-lymphocytes that respond to the body's own tissue antigens are programmed to die or transform into regulatory T-lymphocytes capable of suppressing the immune response. In addition to T-lymphocytes, B-lymphocytes with regulatory functions and dendritic cells with immunosuppressive properties can suppress the immune response to their own antigens [49]. Apoptosis, although it cannot be unequivocally considered an immune response, plays a significant role in the removal of damaged or infected cells that can become a source of autoimmunity. Some blood components, such as red blood cells, plasma proteins, blood progenitor cells, platelets, may be partially ignored by the immune system due to ineffective presentation to the immune system [50]. Certain immune cells can secrete factors that inhibit the activation of other immune cells, preventing the development of inflammation and indirectly affecting the blood clotting process [51].

One of the most crucial elements of immunohaemostasis is its dynamic nature, which is shaped by the continuous interplay between the immune and haemostatic systems. These interactions are not static but vary in response to diverse stimuli, such as infections, injuries, and autoimmune disorders, resulting in fluctuations in immune response and coagulation mechanisms. This dynamic behaviour has a significant impact on clinical outcomes, as the equilibrium between pro-coagulant and anticoagulant forces determines the risk of thrombosis or bleeding. It is therefore imperative to gain an understanding of this adaptability in order to be able to tailor treatment approaches.

For example, in patients with sepsis, immunohaemostasis is dysregulated due to systemic inflammation, which elevates the risk of thrombosis through mechanisms such as immunothrombosis. Similarly, in autoimmune diseases, immune cells can erroneously activate coagulation pathways, thereby exacerbating thrombosis risks. An understanding of this dynamic interplay may facilitate the development of more effective and personalised treatments. As an illustration, targeted cytokine modulation strategies (e.g. TNF-α or IL-1 blockers) may prevent excessive platelet activation without increasing the risk of bleeding, which is particularly advantageous for autoimmune patients prone to thrombosis. Similarly, complement inhibitors that target specific receptors on immune cells or platelets show promise for the management of immune-triggered coagulation in conditions such as sepsis. This approach has the potential to reduce thrombotic events while preserving essential immune functions.

In conclusion, the integration of the adaptive nature of immunohaemostasis into clinical practices will facilitate more accurate prediction, monitoring and treatment of coagulation-related disorders. This approach has the potential to enhance outcomes for patients with complex inflammatory or immune-mediated thrombotic conditions, thereby facilitating advancements in immunotherapy strategies for blood coagulation disorders.

Modern approaches in the treatment of patients at risk of developing thrombosis and bleeding

Preventing the risk of thrombosis and bleeding is associated with maintaining haemostasis. When choosing a treatment method for patients at risk of blood clotting disorders, it is important to maintain a balance between thrombosis and fibrinolysis. An additional difficulty in treatment is that thrombosis and bleeding can occur simultaneously due to the development of disseminated intravascular coagulation. Therefore, this group of patients requires an individual and thorough approach. Modern treatment methods accommodate the balance between preventing thrombosis and minimising the risk of bleeding. These include anticoagulant therapy, antiplatelet therapy, dual antiplatelet therapy, platelet infusion, surgery, endovascular techniques, medical prophylaxis of bleeding, and coagulation monitoring.

Espinola-Klein [52] studied anticoagulants and antiplatelet agents and found when and how they can be combined. Anticoagulants are commonly used for venous thromboembolism, atrial fibrillation, and technical heart valves, while antiplatelet agents are used for atherosclerosis. The combination of both drugs in therapy may be relevant to reduce the risk in patients with atherosclerosis, atrial fibrillation, and in patients with an indication for long-term anticoagulation. This combination reduces the risk of myocardial infarction, stroke, cardiovascular death, and serious adverse effects on the extremities. The disadvantage of this combination is an increased risk of bleeding, and therefore when prescribing individual drugs or a combination of drugs, the existing risks of thrombosis and bleeding must be weighed against the risk of haemostasis. We can agree with the researcher's conclusions about the effectiveness of antiplatelet and anticoagulant therapy, considering that these methods use a mechanism of inhibition of thrombin activity, which for some reason is not provided or is provided incorrectly by immune cells.

Considering the risk of bleeding during anticoagulant therapy, scientists and doctors are looking for approaches to reduce it. Sinnaeve and Adriaenssens [53] reviewed strategies for de-escalation of dual antiplatelet therapy. The principle of this therapy is to combine antiplatelet agents (aspirin or clopidogrel) with oral anticoagulants (P2Y 12 inhibitor) to minimise the risk of thrombosis. The strategy to reduce the risk of bleeding, analysed by the researchers, is to change the conventional recommended antithrombotic combination to a less potent one at an earlier time point, and includes the following de-escalation options: switching from potent P2Y12 inhibitors to a lower dose while maintaining aspirin in the combination; changing dual antiplatelet therapy to a single antiplatelet drug at an earlier time point. In conclusion, the researchers emphasise that the search for ways to reduce risks in anticoagulation therapy is still evolving, and the proposed de-escalation methods, while reducing bleeding risks, do not demonstrate an increase in ischaemic benefit, and therefore their use should be considered as an adjunct to proven existing treatments. Agreeing with the researchers' conclusions, we can emphasise their validity and note the significance of finding safe and equally effective alternatives to conventional approaches to thrombosis therapy.

Platelet infusion is a transfusion of platelet concentrate to correct thrombocytopenia and reduce the risk of bleeding in patients with low platelet counts [54]. Devey and Gothot [55] proved the efficacy of platelet infusion in patients resistant to platelet transfusion in a retrospective study. Scientists analysed the clinical and biological changes in 13 patients after continuous transfusion of platelet concentrates and found that the average platelet count increased in the cohort, and in 61% of cases there was an improvement in bleeding symptoms. We can agree with the researchers' findings, but to understand the safety of the method, it is important to investigate the risk of thrombosis in patients undergoing this therapy.

Currently, one of the crucial areas in the study of platelet infusion is to determine the effectiveness of its use to improve the functioning of the female reproductive system. Intrauterine infusion of platelet-rich plasma is considered an advanced approach to stimulate endometrial growth and blood circulation in the uterus. The effectiveness of this method is conditioned by the following properties: the release of growth factors by platelets, which promote the formation of new blood vessels in the uterus, improving blood circulation, and oxygen supply to the endometrium; reduction of inflammation in the uterus; wound healing and restoration of damaged endometrium. Gonzalo et al. [56] analysed the clinical case of a patient with Asherman syndrome, whose successful treatment with an intrauterine infusion of autologous platelet-rich plasma allowed restoring endometrial thickness and function and led to a successful pregnancy.

In a systematic review, Panda et al. [57] reported the positive results of the use of intra-ovarian infusion of autologous platelet-rich plasma for patients with poor ovarian reserve or ovarian failure. Indicators of the effectiveness of this therapy include the fertilisation rate, the number of embryos at the cleavage stage, and the number of good quality embryos. While agreeing with the researchers' findings on the effectiveness of the platelet invasion method for solving certain problems of the reproductive system, it is essential to note that excessive platelet activation can lead to blood clots and bleeding. Therefore, during this procedure, the platelet count should be carefully monitored, and their dose and concentration should be adjusted.

Removal of a blood clot from blood vessels (thrombectomy) is used in acute myocardial infarction to quickly remove the clot and restore blood flow to the heart (primary coronary intervention), stroke – to remove the clot and restore blood flow to the brain, deep vein thrombosis – to reduce the risk of further complications, pulmonary thrombosis – to restore blood flow to the lungs, peripheral ischaemia – to remove a blood clot blocking the blood flow to the leg or arm and, accordingly, to save the limb. Xiong et al. [58], studying advances in the treatment of acute ischaemic stroke, proved that endovascular therapy with mechanical thrombectomy is effective within the first day after the onset of stroke, is useful for patients with occlusions of distal vessels and proximal large vessels, as well as for patients with milder neurological deficits.

Endovascular methods are used in the treatment of thrombophlebitis in complex cases or when other methods are not efficacious. Depending on the complexity and location of the thrombus, endovascular methods have several types. Catheter thrombolysis involves the injection of a thrombolytic agent into a blocked vein to dissolve a blood clot. Catheter angioplasty and stenting involves the insertion of a catheter with a balloon that inflates and dilates the vessel into a narrowed or blocked vessel, while in some cases, a stent is inserted into the vein to help keep it open. Mechanical thrombectomy is used to remove a blood clot from a vein using a special catheter [59]. This procedure includes rotational and aspiration thrombectomy. The advantages of endovascular methods of treating thrombophlebitis are minimal invasiveness, rapid recovery of the patient after the procedure, and effectiveness, while the disadvantage is the inability to use them for all patients. The use of these methods is limited by the patient's severe general condition, anatomical features of the vessels, the presence of infections in the blocked vein, injuries in the area of thrombophlebitis, allergic reactions to contrast dye, or medications used during endovascular procedures.

For patients with an elevated risk of thrombosis and bleeding, important aspects of treatment include medical prophylaxis of bleeding, including antiplatelet drugs, anticoagulants, fibrinolytics, vitamin K, and desmopressin, and coagulation monitoring, which provides regular monitoring of coagulation parameters to optimise anticoagulation or antiplatelet therapy [60]. All the methods discussed above are not universal and have certain risks and limitations, and therefore, considering the complexity of the processes that lead to haemostatic disorders, it is essential to use an individual approach to the treatment of these disorders, factoring in the causes of their development, medical history, and severity of the patient's condition at the time of examination. The significance of immune reactions in the regulation of blood coagulation processes can be used to develop and implement new areas in the diagnosis, prevention, and treatment of thrombosis and bleeding, or to improve the efficacy and safety of existing therapeutic strategies, which will help to increase the survival rate in patients at risk of these disorders.

The potential of emerging therapies based on immune modulation to treat coagulation disorders is being explored through the targeting of specific interactions between the immune and haemostatic systems. For instance, anti-inflammatory approaches that diminish cytokine-induced platelet activation may assist in the management of thrombotic disorders, particularly in patients with systemic inflammation or autoimmune diseases. Clinical trials could focus on the use of cytokine inhibitors (such as IL-1 or TNF-α blockers) to prevent excessive platelet aggregation in autoimmune thrombosis, thereby reducing the risk of thrombosis without the need for traditional anticoagulants that carry bleeding risks. Another potential avenue for translation into clinical practice is the modulation of complement pathways that are involved in immune-triggered coagulation. The use of complement inhibitors that are specifically designed to block the C5a receptor on platelets could prove an effective method of preventing inappropriate platelet activation while simultaneously preserving other immune functions. This selective approach may prove beneficial in reducing thrombotic complications in patients with sepsis, where immune-driven coagulation is prevalent.

Furthermore, immune tolerance induction strategies, such as those involving regulatory T cell expansion or cytokine modulation, have the potential to provide therapeutic benefits in haemophilia and other bleeding disorders. The objective of these strategies is to maintain immune tolerance towards the therapeutic clotting factors, thereby reducing the occurrence of inhibitory antibodies that complicate treatment. The preliminary results of studies utilising low-dose immune-modulating agents in conjunction with clotting factor infusions suggest the potential for a safer and more efficacious long-term management of bleeding risks in these patients.

The current treatment strategies and their limitations in managing thrombosis and bleeding are discussed, with particular emphasis on the importance of a tailored approach. The development of novel therapeutic strategies, including immune modulation and cytokine inhibition, has the potential to provide safer and more effective treatment options, particularly in cases involving complex haemostatic and immune interactions.