Human Evolution: Between Hemorrhage and Thrombosis

The human coagulation system has resulted from thousands of years of evolutionary pressure, finely balancing the competing risks of lethal hemorrhage and catastrophic thrombosis. There are several examples of the close interaction between the two opposing sides of hemostasis. A paradigmatic case is offered by the factor V Leiden mutation. Emerging approximately 22,000 years ago, this gain-of-function variant is now expressed in approximately 5% of Caucasians. While it now significantly elevates the risk of venous thromboembolism, it historically provided crucial evolutionary advantages, including reduced peripartum blood loss, enhanced iron stores, improved fertility, and increased embryo implantation rates. Conversely, congenital hypocoagulable states, such as hemophilia, demonstrate the other side of the coin. With modern therapeutic advances now extend the life expectancy of individuals with hemophilia, clinicians are increasingly managing age-related comorbidities. While experimental models suggest a chr onic hypocoagulable state might mitigate the risk of occlusive cardiovascular events or suppress cancer metastasis, clinical and epidemiological data remain conflicting. Mild factor deficiencies may offer some protection against ischemic heart disease, but overall cardiovascular and oncological risk profiles in patients with hemophilia increasingly mirror those of the aging general population. This review explores the genetic and environmental forces that shape this homeostatic equilibrium, illustrating how historical survival mechanisms influence modern disease patterns.