Accelerated Fibrinolysis: A Tendency to Bleed?

Abstract

Hyperfibrinolysis is rarely investigated as an underlying mechanism in patients with mild-to-moderate bleeding disorders (MBDs) and bleeding disorders of unknown cause (BDUC). Hereditary hyperfibrinolytic disorders, including α2-antiplasmin (α2-AP) deficiency, plasminogen activator inhibitor type 1 (PAI-1) deficiency, Quebec platelet disorder, and tissue plasminogen activator (tPA) excess, present with mild-to-moderate bleeding symptoms that are common in patients with MBD or BDUC, but may also manifest as life-threatening bleeding. This review summarizes the available data on hyperfibrinolysis in MBD and BDUC patients, and its assessment by various methods such as measurement of fibrinolytic factors, global hemostatic assays (e.g., viscoelastic testing, turbidity-based plasma clot lysis), and fluorogenic plasmin generation (PG). However, evidence on the relationship between hyperfibrinolytic profiles and bleeding severity is inconsistent, and, although found in some coagulation factor deficiencies, has not been universally observed. In BDUC, increased tPA activity and paradoxical increases in thrombin-activatable fibrinolysis inhibitor and α2-AP have been reported. Some studies reported no change in PAI-1 levels, while others observed reduced PAI-1 levels in a significant subset of patients. The tPA-ROTEM (tPA-rotational thromboelastometry) assay identified a hyperfibrinolytic profile in up to 20% of BDUC patients. PG analysis revealed a paradoxically reduced peak plasmin, but showed strong predictive power in differentiating BDUC patients from healthy controls. Although global fibrinolytic assays may help identify hyperfibrinolytic profiles as a potential cause of increased bleeding in some MBD or BDUC patients, the utility of measuring fibrinolytic factors requires further investigation. Tranexamic acid is commonly used to treat hereditary hyperfibrinolysis and is also recommended in MBD/BDUC patients prior to hemostatic challenges.

Keywords

fibrinolytic disorders - fibrinogen/fibrin - plasminogen activator inhibitor - coagulation factor - von Willebrand disease

Introduction

Severe bleeding disorders, such as hemophilia and profound platelet function disorder (PFD) are typically diagnosed in early childhood because of their marked clinical presentation.[1] Most adult patients are referred to hematologists for evaluation of mild-to-moderate bleeding disorders (MBD). Of these patients, the majority remain undiagnosed after testing, with only 30 to 40% receiving a diagnosis, such as von Willebrand disease (VWD), milder forms of PFD, or mild coagulation factor deficiencies (CFDs).[2] [3] [4] The significant proportion of patients with MBD who remain without a specific diagnosis are classified as having a bleeding disorder of unknown cause (BDUC).[2] [5] These patients experience clinically significant bleeding tendencies, including mucocutaneous bleeding, postpartum hemorrhage (PPH), and surgical bleeding, which often result in anemia. Heavy menstrual bleeding is prevalent in up to 60% of all women with BDUC and reflects a high burden on physical and mental health.[2] [6] Bleeding scores such as the bleeding assessment tool of the International Society on Thrombosis and Haemostasis (ISTH-BAT) are recommended for the evaluation of medical history but are not considered binding, as they depend on whether patients have undergone surgeries or childbirth.[5] [7] [8] Since BDUC is considered a “diagnosis of exclusion,” an extensive diagnostic workup, including assessments of plasmatic coagulation and platelet function, is essential to rule out other MBDs.

Hyperfibrinolysis is a pathological condition characterized by excessive breakdown of fibrin clots ([Fig. 1]).[9] The serine protease plasmin, which degrades fibrin into fibrin degradation products such as D-dimer, is the central enzyme in this process.[10] Plasmin is generated from its zymogen, plasminogen, through the activation by tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA). Fibrinolysis is tightly regulated by thrombin-activatable fibrinolysis inhibitor (TAFI), which attenuates plasmin formation by removing carboxy-terminal lysine residues from fibrin, thereby limiting plasminogen binding and activation.[11] This process is notably enhanced when thrombin binds to thrombomodulin, as demonstrated in patients with high levels of soluble thrombomodulin, as seen in thrombomodulin-associated coagulopathy.[12] Other inhibitors of fibrinolysis include α2-antiplasmin (α2-AP) and α2-macroglobulin (α2-M), both of which directly inhibit plasmin activity, and plasminogen activator inhibitor type 1 (PAI-1), which inhibits tPA and uPA.[9]

Fig. 1 The fibrinolytic system and hereditary fibrinolytic disorders. α2-AP, α2-antiplasmin; PAI-1, plasminogen activator inhibitor type 1; TAFI, thrombin-activatable fibrinolysis inhibitor; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator.

Hereditary hyperfibrinolytic states have been described in a limited number of families,[13] and hyperfibrinolysis is thought to contribute to the bleeding diathesis in some BDUC patients.[14] However, the investigation of fibrinolytic abnormalities is currently not included in the standard work-up of patients with a hereditary bleeding disorder and/or a lifelong bleeding tendency.[5] [15] [16] [17] Furthermore, acquired hyperfibrinolysis, as seen in liver cirrhosis, acute promyelocytic leukemia, trauma, and PPH, should be excluded as a cause for bleeding.[9] [18]

In this comprehensive narrative review, we aim to provide an overview of bleeding disorders related to accelerated fibrinolysis. In the first section, we present a detailed overview of the current knowledge on hereditary hyperfibrinolysis. In the second section, we explore the current understanding of the potential role of hyperfibrinolysis in patients with MBD and BDUC.

Search Strategy

A comprehensive literature search was conducted in the MEDLINE database to identify relevant studies on the relationship between fibrinolysis and bleeding disorders, with a particular focus on bleeding disorders of unknown cause. The search strategy included the terms fibrinolysis, hyperfibrinolysis, mild to moderate bleeding disorders, bleeding disorder of unknown cause, plasmin generation (PG), clot lysis time, plasminogen, PAI-1, α2-AP, α2-M, Quebec platelet syndrome, TAFI, tPA, uPA, and tranexamic acid (TXA). The search was designed to capture systematic reviews, peer-reviewed clinical trials, and high-quality observational studies published up to June 2024, as well as clinical guidelines and recommendations available through the same period.

Laboratory Investigation of Hyperfibrinolysis

Assessing fibrinolytic function in vitro remains a challenge, as few standardized methods comprehensively evaluate fibrinolysis in clinical practice.[19] For example, plasma-based turbidimetric assays require the addition of tPA to initiate fibrinolysis, which reduces sensitivity to endogenous plasminogen activator levels. Conversely, the euglobulin clot lysis time (ECLT) method removes key fibrinolytic inhibitors, such as α2-AP and TAFI, limiting its utility for detecting deficiencies in these inhibitors. Rotational thromboelastometry (ROTEM), frequently used as a point-of-care test during surgery, does not typically require the addition of tPA but has yet to be validated as a reliable diagnostic tool for hyperfibrinolytic disorders. Fluorogenic PG assays provide a more holistic overview of fibrinolytic dysfunction and offer insights into the relationship between abnormal fibrin dissolution and disease pathogenesis. The complexity of the fibrinolytic system, along with its interactions with coagulation, inflammation, and cellular elements, further complicates the development of robust diagnostic assays.[20]

Hereditary Hyperfibrinolysis

Hereditary hyperfibrinolysis, a rare condition characterized by aberrations in fibrinolytic pathways, has been described in a limited number of individuals and families. In a comprehensive review by Saes et al, the clinical manifestations of various fibrinolytic bleeding disorders were detailed.[13] These include α2-AP deficiency, PAI-1 deficiency, Quebec platelet disorder, and excess tPA ([Fig. 1]). The total cases outlined included 14 homozygous and 104 heterozygous α2-AP deficiency cases, 26 cases of PAI-1 deficiency, 23 cases of Quebec platelet disorder, and 4 cases of tPA excess.[13]

The severity of bleeding varies from mild to moderate phenotypes, as commonly seen in BDUC patients, to even severe and life-threatening bleeding episodes.[13] Diagnosing these very rare disorders can be challenging and most of the disorders need to be confirmed by genetic analysis.[13] [18] [19]

α2-Antiplasmin Deficiency

α2-AP deficiency is an autosomal recessive disorder caused by mutations in the SERPINF2 gene located on chromosome 17.[21] [22] This condition can be classified into two subtypes: type 1, characterized by a quantitative deficiency (reduced antigen and activity levels), and type 2, a qualitative deficiency (reduced functional activity with normal antigen levels). However, distinguishing between these subtypes has limited clinical relevance.

Homozygous individuals (α2-AP levels <10%) experience a significant bleeding tendency, often presenting with spontaneous bleeding episodes, such as prolonged wound bleeding, hematomas, hematuria, or even central nervous system bleeding. Bleeding can also occur following surgical procedures, trauma, or childbirth. In contrast, heterozygotes (α2-AP levels between 20 and 50%) generally experience hemorrhagic events only after trauma, dental extractions, or surgery. In heterozygous individuals, symptoms primarily manifest following hemostatic challenges, with α2-AP levels typically around 50% of normal.[13] [23] [24] To the best of our knowledge, studies investigating the clinical relevance of plasmin–antiplasmin levels in bleeding patients are lacking, highlighting a gap that warrants further research.

Global coagulation assays generally yield normal values, with the exception of a shortened ECLT, which can also be normal in certain cases.[13] [23] Diagnostic confirmation often relies on assays targeted to measure α2-AP levels and activity, particularly due to the lack of α2-AP enrichment in the euglobulin fraction following plasma acidification.[18] Nevertheless, others and we found limited value of unbiased testing of α2-AP in MBD patients,[25] [26] which might be due the very low prevalence of α2-AP deficiencies. The main treatment option for bleeding events in patients with α2-AP is TXA.[27]

Plasminogen Activator Inhibitor-1 Deficiency

PAI-1 deficiency is another rare autosomal recessive disorder, which can present with either quantitative or qualitative defects. Mutations leading to this condition typically involve variations in the SERPINE1 gene. Menorrhagia is the most common bleeding symptom associated with PAI-1 deficiency. Patients also suffer from major bleeding after trauma or surgery. Obstetric complications are also prevalent in PAI-1-deficient women, with a reported high incidence of miscarriage and preterm birth. While only 24% of pregnancies reach full term, the same number results in miscarriages. Most preterm births occur between gestational weeks 31 and 36.[28] [29] The exact reason for the high rates of miscarriages and preterm births in PAI deficiency remains unclear; however, animal studies indicate that PAI-1 and its proteolytic activity may contribute to the breakdown of the follicular wall during ovulation and may impair crucial processes in fertilization, embryo implantation, embryogenesis, and angiogenesis.[30] [31] Bleeding complications were described in most patients during the first trimester.[31] Family studies have shown that only a minority of heterozygous family members exhibit bleeding symptoms.[28] [29]

While the ECLT is typically shortened in these patients, the diagnosis is complicated by the fact that this assay may occasionally appear normal, despite PAI-1 being enriched in the euglobulin fraction.[28] On the other hand, measurement of PAI-1 levels remains challenging, as it is unclear whether the lower PAI-1 levels can be detected in commercially available ELISAs.[32] In addition, PAI-1 levels may be influenced by various factors such as age,[33] body mass index,[34] [35] as well as genetic polymorphisms.[36] Furthermore, due to circadian fluctuation of plasma PAI-1 antigen levels, it should be measured early in the morning.[37]

TXA is serving as an effective treatment, especially as prophylaxis before hemostatic challenges or for women with heavy menstrual bleeding.[28] [38] [39] On the other hand, desmopressin (DDAVP) should be avoided in these patients, as it induces secretion of tPA from endothelial cells.[18]

Quebec Platelet Disorder

Quebec platelet disorder is an autosomal dominant condition associated with elevated uPA levels in platelet α-granules.[40] [41] This results in abnormal fibrinolysis, along with reductions in both factor V (FV) and platelet FV due to increased intraplatelet PG that degrades diverse α-granule proteins.[42] Patients present with a variety of bleeding symptoms including postinterventional bleedings, hematomas, or epistaxis.[13] [18] [41] Although nine pregnancies have been documented in affected individuals, none resulted in miscarriage, and antenatal bleeding was not reported. However, two women required blood transfusions following delivery. Similar to PAI-1 deficiency, impaired wound healing has been reported, correlating with lower platelet counts.[13] [18] [41]

Platelet function, as assessed by light transmission aggregation using epinephrine, is typically impaired, along with abnormal α-granule release. The disorder can also be associated with mild thrombocytopenia.[13] [18] [41]

The administration of platelets usually does not mitigate bleeding, and TXA remains the recommended treatment.[13] [18] [41]

Tissue Plasminogen Activator Excess

Excess tPA, though exceedingly rare with only about four documented cases, has been linked to abnormal bleeding following surgery, trauma, or spontaneous bleeding events such as bruising.[43] [44] [45] To the best of our knowledge, no genetic explanations have been identified for tPA excess, and the underlying pathophysiological mechanism remains unclear.

Patients with tPA excess typically display normal results on global coagulation assays but have a shortened ECLT.[13] [18] Prior to the recognition of PAI-1 deficiency, some cases of tPA excess may have been misdiagnosed. In suspected cases, both tPA levels and its complexes with PAI-1 should be measured to confirm the diagnosis.[13]

Due to the low number of cases, little evidence is available on how to treat patients with tPA excess. Nevertheless, TXA should be considered from a pathophysiological point of view.[13]

Recent efforts to systematically evaluate hyperfibrinolysis in MBD and BDUC patients have been hindered by the absence of reliable in vitro assays that can accurately assess the fibrinolytic potential in vivo.[14] Nevertheless, identifying hyperfibrinolytic states is critical, as such conditions can be effectively managed with antifibrinolytic agents, such as TXA or aminocaproic acid.[46] Data from several groups, including our data from the Vienna Bleeding Biobank,[14] [26] [47] have measured fibrinolytic factors, performed global hemostatic assays as well as genetic tests to identify patients with a hyperfibrinolytic phenotype, as discussed below.

Hyperfibrinolysis in Patients with Established Bleeding Disorders

We previously performed high-throughput whole-exome sequencing of 96 genes associated with coagulation/fibrinolysis and platelet function in our large cohort of MBD from the Vienna Bleeding Biobank.[48] While the analysis identified pathological genetic variants in only approximately 3% of more than 600 BDUC patients, none of these were associated with fibrinolytic disorders, underscoring the rarity of these disorders. The involvement of hyperfibrinolysis as a factor potentially influencing the bleeding phenotype in various established bleeding disorders has been extensively studied, as previously reviewed by our group.[14] For example, Agren et al investigated fibrinolytic factors in 586 patients with MBD, including 24.4% with PFD, 10.1% with VWD, 1.2% with thrombocytopenia, 2.7% with CFD, and 57% with BDUC.[33] Their results showed reduced PAI-1 activity but no significant difference in tPA–PAI-1 complex levels when comparing MBD patients with 100 healthy blood donors and 100 matched controls. Hyperfibrinolysis has also been investigated in more severe bleeding conditions: Grünewald et al found an association between elevated levels of tPA antigen and TAFI and a more severe bleeding phenotype in patients with severe hemophilia.[49] Colucci et al found that plasma from patients with factor XI (FXI) deficiency had reduced thrombin generation and TAFIa levels, as well as shorter clot lysis times compared with controls.[50] Similarly, Gidley et al reported an association between reduced clot stability and decreased resistance to fibrinolysis in individuals with FXI deficiency, which was associated with a higher bleeding tendency.[51]

Several studies have also focused on PG in rare bleeding disorders. Most studies were performed with the Nijmegen Hemostasis Assay (NHA), where both thrombin generation and PG were performed simultaneously, as previously described.[52] [53] [54] Similar to our performed assay established by Wolberg and colleagues (see below), the NHA assay compares arbitrary fluorescence values to a calibration curve and correct for the inner filter effect.[10] In contrast to our PGA assay by Wolberg and colleagues,[47] which uses calibration with α2M-plasmin, the NHA performs calibration with plasmin. On the other hand, Matsumoto et al performed a modified simultaneous thrombin and PG assay (STA), which does not correct neither for substrate consumption, nor for the inner filter effect.[55]

Valke et al observed an increase in PG potential, as indicated by peak plasmin levels in the NHA, in patients with severe hemophilia A compared with those with mild hemophilia A or healthy controls.[52] However, Matsumoto et al found no differences in PG in the STA between patients with severe hemophilia and healthy controls.[55] Predictably, PG potential was minimal or undetectable in individuals with plasminogen deficiency using the NHA, whereas patients with homozygous PAI-1 deficiency showed increased plasmin potential, consistent with a hyperfibrinolytic bleeding disorder profile.[54] Interestingly, other rare bleeding disorders, specifically 41 patients affected with deficiencies in prothrombin, factor (F) V, FVII, FX, FXIII, and fibrinogen, showed a reduction of PG potential in the NHA, which could be explained by a simultaneous reduced thrombin generation potential in these patients.[53]

Investigating Hyperfibrinolysis in Bleeding Disorder of Unknown Cause

Several studies have investigated the role of hyperfibrinolysis as an underlying cause in patients with BDUC, as summarized in [Fig. 2]. Our group previously reported elevated levels of tPA activity and a paradoxical increase in TAFI and α2-AP, without significant differences in PAI-1 levels between 270 BDUC patients and 98 healthy controls.[26] A study of 193 patients with mucocutaneous bleeding, including 81.1% with BDUC, also revealed a paradoxical increase in TAFI levels, compared with 143 controls.[56] Wiewel-Verschueren et al also found elevated TAFI and α2-AP levels in women with heavy menstrual bleeding compared with controls.[57] All described studies used different functional chromogenic assays to measure TAFI activity. These increases might reflect a compensatory response to bleeding, possibly balancing elevated tPA activity, though the exact mechanism remains unclear.[26] [56] On the other hand, Valke et al retrospectively identified abnormal ECLT and/or reduced PAI-1 antigen and activity in 39% of 160 BDUC patients.[58]

Fig. 2 The role of hyperfibrinolysis in patients with BDUC. α2-AP, α2-antiplasmin; BDUC, bleeding disorder of unknown cause; PAI-1, plasminogen activator inhibitor type 1; TAFI, thrombin-activatable fibrinolysis inhibitor; tPA tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator. [rerif]

Several groups applied distinct global assays to investigate for hyperfibrinolysis in BDUC patients. Generally, measurement of the fibrinolytic capacity in vitro is challenging,[19] as previously discussed.[14] In a study of 382 BDUC patients, we observed, using an in-house turbidity assay dependent on the addition of tPA, a lower clot formation rate and a shorter clot lysis time compared with age- and sex-matched controls, indicating increased clot susceptibility to fibrinolysis.[59] Also Szczepaniak et al demonstrated increased clot permeability and lysis susceptibility in heavy menstrual bleeding patients using a plasma clot turbidity assay with tPA. These findings suggest that altered clot characteristics may contribute to the bleeding phenotype.[60] Conversely, Veen et al reported prolonged clot lysis time in a smaller cohort of 109 BDUC patients, with no significant differences in ROTEM parameters.[61] Similarly, Vries et al did not identify variations in clot formation or strength in a cohort of 240 self-reported bleeding patients versus 95 nonbleeding controls scheduled for elective surgery.[62]

Our recent data, presented at the ISTH 2024 meeting, revealed counterintuitive findings in BDUC patients using ROTEM analysis. Specifically, we observed an unexpected increase in maximum clot firmness and a decrease in maximum lysis in 436 BDUC patients compared with 100 age-matched healthy controls. In contrast, Monard et al utilized a tPA-ROTEM assay and identified a hyperfibrinolytic profile in 20% of BDUC patients, as presented at the American Society of Hematology 2023 conference.[63] These hyperfibrinolytic patients also exhibited reduced PAI-1 activity and antigen levels, alongside lower α2-AP levels.

To the best of our knowledge, data on PG, which gives a holistic overview the fibrinolytic potential, in BDUC other bleeding patients are lacking.[10] That is why we recently conducted a novel PG assay on 375 BDUC patients in comparison to 100 age-matched controls.[47] Very interestingly, in this study, BDUC patients exhibited decreased PG potential with lower velocity and peak plasmin, but a higher endogenous plasmin potential compared with controls.

In addition, confocal microscopy of six patients revealed that BDUC patients appear to have thicker fibers and a tendency toward denser clots. Peak plasmin correlated with higher clot density and FXIII levels, and inversely with fibrin fiber thickness. Overall, our data indicate that the counterintuitively reduced peak plasmin in BDUC patients might be potentially related to altered clot structure. Nevertheless, this has to be validated externally in larger cohorts.

Generally, the discrepancies across various studies could be attributed to the smaller sample sizes in some cohorts, the heterogeneity of the patient populations studied, and inter-laboratory variations in fibrinolytic assays. As shown in the tPA-ROTEM data by Morad et al, BDUC patients represent a heterogeneous group, with only a subset displaying a distinct hyperfibrinolytic profile. Several innovative global assays designed to measure global fibrinolytic capacity in patients with bleeding disorders have shown promise.[64] [65] However, these tests require extensive validation in independent study groups before they can be reliably integrated into routine clinical practice.

Antifibrinolytic Treatment in Mild to Moderate Bleeding Disorders?

The use of antifibrinolytics, particularly TXA, in MBD such as VWD or CFD has been studied and suggested to be an effective treatment to prevent bleeding.[66] [67] [68] Retrospective data from the Vienna Bleeding Biobank and from other groups also suggest the use of TXA (with or without DDAVP) in patients with BDUC, showing efficacy in reducing bleeding events during both minor and major hemostatic challenges,[69] [70] though most studies included a low number of patients. On the other hand, a study by Veen et al reported a high incidence of post-interventional bleeding despite prophylactic treatment with TXA and/or DDAVP.[71] They found that 23% of patients treated prophylactically still developed bleeding, with similar frequencies observed in both BDUC and MBD patients.[71] Also in our study, 28.9% of patients experienced post-surgical bleeding, with 27.3% of these cases occurring despite receiving prophylaxis.[72] Retrospective data from the United Kingdom also indicated that while prophylactic TXA and DDAVP reduced the risk of PPH in women with BDUC, they did not eliminate the risk entirely.[73] Comparable findings were reported for women with VWD and hemophilia carriers, who continued to experience postpartum bleeding despite prophylaxis.[74]

In women with heavy menstrual bleeding, TXA appears to be effective and safe, regardless the underlying cause of the bleeding.[75]

A survey of 216 respondents from 39 countries revealed that TXA was the preferred choice for prophylaxis in 71% of minor surgeries, 59% of major surgeries, and 58% of pregnancies in patients with BDUC. Nevertheless, treatment approaches for acute bleeding in BDUC remain highly variable and inconsistent across different settings.[76] Overall, large randomized controlled trials in MBD and especially BDUC are lacking.

Currently, the ISTH recommends a pragmatic approach to administering TXA, especially for invasive surgical procedures and childbirth. In cases of higher bleeding risk, DDAVP can be added. A multidisciplinary team should ideally formulate personalized management plans for patients prior to invasive procedures or deliveries, preferably in a specialized center.[5] [77]

Conclusion

Hereditary disorders associated with hyperfibrinolysis should be considered when clinical suspicion is high, though these disorders are exceedingly rare.[13] [17] Given the shared bleeding phenotype, it has been hypothesized that alterations in the fibrinolytic system may contribute to the bleeding tendency in some patients with MBD or BDUC. However, data on fibrinolytic factor levels and global assays remain inconsistent.[14] Performing PG and tPA-ROTEM may assist in identifying patients with a hyperfibrinolytic profile. Given the rarity of hereditary fibrinolytic disorders, the utility of measuring fibrinolytic factors in all BDUC patients requires further investigation. Overall, investigating hyperfibrinolysis in all MBD and BDUC patients as a uniform group may not be the most effective approach. Tailoring diagnostic efforts to specific subgroups may yield more accurate insights into the underlying mechanisms of bleeding in these patients.

Despite limited prospective data, TXA has emerged as a key therapeutic option for BDUC patients, particularly during hemostatic challenges such as surgery or childbirth. However, clinical validation of existing fibrinolytic assays in larger BDUC populations is needed to refine diagnostic approaches for more rapidly identifying hyperfibrinolysis and to better evaluate the efficacy of TXA in this patient population.

Conflicts of Interest

D.M. received honoraria for advisory board meetings and lectures from CSL Behring and Sobi, a research grant from CSL Behring (Prof. Heimburger award), and travel support by Sobi, Novo Nordisk, Pfizer, and Roche.

I.P. received a grant from CSL Behring for the Medical University of Vienna, honoraria from CSL Behring, Sobi, Takeda, and Pfizer, for lectures and advisory board meetings, as well as travel support by Sobi.

J.G. received research grants from CSL Behring, Sobi, Takeda, Amgen, and Novartis for the Medical University of Vienna, honoraria for lectures and advisory board meetings from CSL Behring, Sobi, Novartis, and Amgen.

Contribution

D.M., J.G., and I.P. performed a literature review and wrote and revised the manuscript.

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Publication History

Received: 03 December 2024

Accepted: 18 March 2025

Article published online:
27 April 2025