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Why the Blood Clotting Cascade Challenges Evolution

Image credit: Vector8DIY, via Pixabay.

Yesterday, in the first of a series of three articles (here), I summarized the details of the vertebrate blood clotting cascade. Now, in a second installment, I will review why coagulation presents a significant challenge to evolutionary explanations. This is to set the stage for part three where I will evaluate a particular attempt to offer an evolutionary account of blood clotting by biochemist Russell Doolittle. 

What components are essential to the coagulation cascade? If we limit our analysis, for simplicity, to those components that make up the common pathway (i.e., after the convergence of the intrinsic and extrinsic pathways), the essential proteins include fibrinogen, prothrombin, factor X, and factor V. In the absence of fibrinogen (a condition known as afibrinogenemia), the mesh-like network that stabilizes the blood clot will not form.1 In the absence of prothrombin, the result is a bleeding disorder called hypoprothrombinemia.2 Since no thrombin is produced, fibrinogen is not converted to fibrin and thus the system fails, again, to form the mesh-like network that is necessary for the formation of a stable clot. In the absence of factor V (known as Owren’s disease), the production of thrombin is significantly reduced, with a similar result.3 In the absence of factor X (known as Stuart-Prower disease), the production of thrombin is impaired, which again prevents blood clot formation.4

Carefully and Finely Tuned

Moreover, as Michael Behe explains in Darwin’s Black Box, the coagulation process needs to be carefully and finely tuned:

If only a small amount of fibrinogen were available it would not cover a wound; if a primitive fibrin formed a random blob instead of a meshwork, it would be unlikely to stop blood flow. If the initial action of antithrombin were too fast, the initial action of thrombin too slow, or the original Stuart factor [i.e., Factor X] or Christmas factor [i.e., Factor IX] or antihemophilic factor [i.e., Factor VIII] bound too loosely or too tightly (or if they bound to the inactive forms of their targets as well as the active forms), then the whole system would crash.5

Indeed, “the quality and character of the fibrin clots generated in fish and mammals do not appear to be significantly different.”6 Thus, the earliest vertebrates apparently formed fibrin clots that were not less effective or durable than those found in humans. How is this to be explained by a gradual trial-and-error process?

Furthermore, once the clotting has begun, there must be a mechanism to prevent excessive clotting and to confine the clot to the site of the injury. Otherwise, the result would be widespread clotting throughout the body’s blood vessels, leading to thrombosis and eventual death. Indeed, “this suppression of activity is very important; there is enough prothrombin in one milliliter of plasma to clot all the fibrinogen in the whole body if the prothrombin were all converted to thrombin.”7 Thus, the coagulation cascade cannot evolve unless there is simultaneously a mechanism in hand for controlling it to prevent excessive and widespread clotting. Both would have to arise at the same time. Thus, the coagulation cascade is balanced on a knife-edge. Maintaining this delicate balance requires intricate mechanisms, ensuring that clotting occurs when needed to prevent excessive bleeding, while also preventing unnecessary clot formation that could lead to harmful consequences such as thrombosis. Any disruptions or imbalances in these regulatory mechanisms can result in severe bleeding or clotting disorders.

A Proenzyme and an Activating Enzyme

Another difficulty is that, from the very start, any new step that was added to the cascade would need both a proenzyme and an activating enzyme to ensure that the proenzyme is turned on at the appropriate time. As Behe explains, while one might envision some simpler system where there is a direct pathway from factor X to fibrinogen, bypassing thrombin entirely, “If a new protein were inserted into the thrombinless system it would either turn the system on immediately — resulting in rapid death — or it would do nothing, and so have no reason to be selected. Because of the nature of a cascade, a new protein would immediately have to be regulated.”8 Thus, “since each step necessarily requires several parts, not only is the entire blood-clotting system irreducibly complex, but so is each step in the pathway.”9 A further problem with the hypothetical thrombinless system, entertained above, is that thrombin is highly effective in cleaving fibrinogen at specific sites, generating fibrin monomers that can polymerize to form a stable clot. Directly cutting fibrinogen with factor X alone would not produce the same reliable and robust fibrin network required for effective clot formation, unless an early form of factor X cut fibrinogen at the same sites that thrombin does.

One might try to explain the origins of new blood clotting factors by postulating successive rounds of gene duplication and divergence (where the duplicate copy would still be under the regulation of the enzyme regulating the original factor). However, a major problem here is that the duplication of a gene would create an excess of the protein that the gene codes for. But excessive expression of clotting factors can disrupt the delicate balance of the coagulation cascade, leading to an increased tendency for the formation of blood clots. To take one example, in humans, 2 to 4.5g/L is considered to be the normal range for the concentration of fibrinogen in blood plasma.10 Doubling this concentration, which occurs during pregnancy, significantly increases the risk of thrombosis — while halving it creates a risk of bleeding.11 Thus, the relative concentrations of coagulation factors is very precisely balanced. Upsetting this balance can result in conditions such as deep vein thrombosis, pulmonary embolism, or stroke. To take another example, it has been shown that, 

Elevated (pro)thrombin levels trigger the formation of densely-packed fibrin clots composed of thin fibrin fibers compared to normal clots. Increased thrombin generation in these individuals also increases activation of the thrombin-activatable fibrinolysis inhibitor (TAFI) in vitro. Activated TAFI downregulates fibrinolysis by cleaving C-terminal lysine residues from fibrin and reducing the number of tPA and plasminogen binding sites on fibrin. It has been suggested that the combination of abnormal structure and increased TAFI activation reduces the rate of fibrinolysis and contributes to the increased risk of thrombosis in these individuals.12

Thus, a duplicate blood clotting factor gene is likely to be deleterious and purged by purifying selection rather than preserved. Regarding this problem, one might retort that a gene duplication event that knocks the system out of balance might be compensated for by a second gene duplication event that creates a new activating enzyme, thereby bringing the system back into balance. However, among eukaryotic organisms, any particular gene has only a probability of being duplicated, over the span of one million years, of 0.01, “with rates in different species ranging from about 0.02 down to 0.002.”13 Moreover, “the vast majority of gene duplicates are silenced within a few million years, with the few survivors subsequently experiencing strong purifying selection.”14 Given the selection costs of carrying a duplicated gene, upsetting the delicate balance of the coagulation cascade, it is unlikely that it would be retained long enough for the appropriate gene to also be duplicated, restoring the balance of the system.

A Challenge to Evolutionary Mechanisms

In conclusion, the intricacies of vertebrate blood clotting represent a significant challenge to evolutionary mechanisms. The process of clot formation is itself irreducibly complex and must also emerge simultaneously with a mechanism to prevent excessive clotting and to confine the clot to the site of injury. From a neo-Darwinian perspective, it is difficult to envision such a system emerging one step at a time without passing through maladaptive intermediate stages. On the other hand, a complex integration of parts contributing towards a higher-level objective, such as we see associated with coagulation, is precisely what we might expect on a hypothesis of design. In the third and final installment in this series, I will review Russell Doolittle’s attempt to provide an evolutionary explanation for this pathway.


  1. Simurda T, Asselta R, Zolkova J, Brunclikova M, Dobrotova M, Kolkova Z, Loderer D, Skornova I, Hudecek J, Lasabova Z, Stasko J, Kubisz P. Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management. Diagnostics (Basel). 2021 Nov 19;11(11):2140.
  2. Mazodier K, Arnaud L, Mathian A, Costedoat-Chalumeau N, Haroche J, Frances C, Harlé JR, Pernod G, Lespessailles E, Gaudin P, Charlanne H, Hachulla E, Niaudet P, Piette JC, Amoura Z. Lupus anticoagulant-hypoprothrombinemia syndrome: report of 8 cases and review of the literature. Medicine (Baltimore). 2012 Sep;91(5):251-260.
  3. Ehtisham M, Shafiq MA, Shafique M, Mumtaz H, Shahzad MN. Owren’s Disease: A Rare Deficiency. Cureus. 2021 Aug 10;13(8):e17047.
  4. Chatterjee T, Philip J, Nair V, Mallhi RS, Sharma H, Ganguly P, Biswas AK. Inherited Factor X (Stuart-Prower Factor) deficiency and its management. Med J Armed Forces India. 2015 Jul;71(Suppl 1):S184-6.
  5. Behe, Michael J. Darwin’s Black Box: The Biochemical Challenge to Evolution. Free Press 1996, kindle.
  6. Doolittle RF. Step-by-step evolution of vertebrate blood coagulation. Cold Spring Harb Symp Quant Biol. 2009;74:35-40.
  7. Ibid., 17.
  8. Behe, Michael J. Darwin’s Black Box: The Biochemical Challenge to Evolution. Free Press 1996, kindle.
  9. Ibid.
  10. Grottke O, Mallaiah S, Karkouti K, Saner F, Haas T. Fibrinogen Supplementation and Its Indications. Semin Thromb Hemost. 2020 Feb;46(1):38-49.
  11. Ibid.
  12. Wolberg AS, Campbell RA. Thrombin generation, fibrin clot formation and hemostasis. Transfus Apher Sci. 2008 Feb;38(1):15-23.
  13. Lynch M, Conery JS. The evolutionary fate and consequences of duplicate genes. Science. 2000 Nov 10;290(5494):1151-5.
  14. Ibid.