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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.

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