Natural anticoagulants: A missing link in mild to moderate bleeding tendencies

Abstract

Introduction There is a growing interest in natural anticoagulants as a cause of mild to moderate bleeding disorders (MBDs), particularly in patients with bleeding of unknown cause (BUC), which is defined as having a mild to moderate bleeding phenotype without a definite diagnosis despite exhaustive and repeated laboratory investigations. Recently, abnormalities in two natural anticoagulant pathways, thrombomodulin (TM), and tissue factor pathway inhibitor (TFPI), were identified in single patients or families as the underlying cause for a bleeding tendency. Aim The objective of this review is to discuss the current understanding of the role of natural anticoagulants in MBDs using available clinical and translational data. Methods A Cochrane Library and PubMed (MEDLINE) search focusing on selected natural anticoagulants and their role in MBDs was conducted. Results Data on the influence of natural anticoagulants including protein C, protein S, antithrombin, TM, and TFPI or factors with anticoagulant properties like fibrinogen gamma prime (γ’) on MBDs are scarce. Observations from sepsis treatment and from translational research highlight their importance as regulators of the haemostatic balance, especially via the activated protein C‐related pathway, and suggest a role in some MBDs. Conclusion Similar to the distinct genetic variants of natural anticoagulants linked to thrombosis, we hypothesize that novel variants may be associated with a bleeding tendency and could be identified using next generation sequencing.

Thrombomodulin in patients with mild to moderate bleeding tendency

“…In these patients with a known haemostatic defect, the individual bleeding phenotype often is independent of residual coagulation factor levels 4,28 . Amongst other factors, also natural anticoagulants have been shown to impact the individual bleeding tendency in patients with an established bleeding disorder 29 . Nevertheless, in this analysis we could not observe an impact of sTM on the bleeding severity in patients irrespective of the diagnosis of a bleeding disorder.…”

Bleeding Disorder of Unknown Cause: A Diagnosis of Exclusion

“…Additionally, consideration must be given to the possibility of rare bleeding disorders attributed to hyperfibrinolysis or heightened levels of natural anticoagulants in specific patient populations. 19,20 Within the VIBB, our diagnostic approach combines evidence-based principles with practicality. While we adhere to current guidelines and draw from published data in literature, certain analyses, particularly for PFD, necessitate a pragmatic perspective.…”

“…In recent years, translational and genetic studies have unveiled novel bleeding disorders, shedding light on different aspects of the hemostatic system. 20 However, it is important to note that certain rare bleeding disorders, which do not manifest through standard global coagulation tests, may go unnoticed unless specifically investigated. These uncommon bleeding disorders, including those marked by enhanced natural anticoagulant function and hyperfibrinolysis, 19,20 often exhibit a bleeding pattern similar to BDUC.…”

“…Additionally, consideration must be given to the possibility of rare bleeding disorders attributed to hyperfibrinolysis or heightened levels of natural anticoagulants in specific patient populations. 19 20…”

Activated protein C and free protein S in patients with mild to moderate bleeding disorders

“…The underlying mechanisms for bleeding and impaired thrombin generation (TG) and plasma clot formation (PCF) in BDUC is unknown 2 . Natural anticoagulants might play an important role in BDUC patients 3 . The contribution of the pivotal anticoagulants activated protein C (APC) and protein S (PS) to the hemostatic profile of patients with BDUC has yet not been explored 4 .…”