This chapter is relevant to Section Q1(v) of the 2017 CICM Primary Syllabus, which expects the exam candidates to be able to "describe the mechanisms of preventing thrombosis including endothelial factors and natural anticoagulants". It probably also has some relevance to the "fibrinolysis" part of Section Q1(iv), "describe the process and regulation of haemostasis, coagulation and fibrinolysis". Of course, one might argue that this topic has minimal meaning for the intensivist, as in the critically ill these natural mechanisms of preventing thrombosis are either totally absent or so dysfunctional that they are not to be trusted, and everybody is on some combination of chemical and mechanical VTE prophylaxis. Still, people have to answer SAQs like Question 10 from the first paper of 2019, where for 50% of the marks we had to "discuss the role of naturally occurring anticoagulants in preventing clot formation in-vivo". Discuss, they asked, as if this were some chat over coffee, rather than a stressful barrier exam. Fortunately, the events of haemostasia - though they are simultaneous and interlinked - when beheld as sequential processes present themselves as a handy structure for an answer such as this. What follows is an attempt to use that structure to produce a short summary for revision purposes.
- Factors that prevent the initiation of thrombosis
- Normal endothelium does not contain any clotting cascade activators (eg. TF)
- Endothelial glycocalyx contains antithrombotic molecules:
- Heparin-like oligosaccharides
- Blood flow produces shear stress which opposes regional clotting factor concentration and platelet aggregation
- Factors that prevent primary haemostasis
- Extrinsic pathway inhibitors:
- Tissue factor pathway inhibitor (TFPI) antagonises the TF-FVIIa complex and prevents extrinsic pathway activation
- Platelet activation/aggregation inhibitors:
- Prostacyclin (PGI2), via GS-protein-coupled receptor
- Nitric oxide (less iCa2+, also inhibits TXA2 receptor)
- Fibrin degradation products (bind GPIIb/IIa receptors)
- Factors that prevent secondary haemostasis
- Antithrombin III antagonises the activity of thrombin
- Protein C:
- Activated by thrombin
- Inhibits thrombin, Factor Va and Factor VIIIa
- Protein S: co-factor for Protein C
- Thrombomodulin: co-factor for Protein C
- Factors which promote fibrinolysis
- Tissue plasminogen activator and urokinase activate plasminogen
- Plasminogen is activated into plasmin
- Plasmin degrades fibrin into fibrin degradation products
An excellent, though somewhat dated, paper by the Rosenbergs (1984) can be recommended as the best peer-reviewed alternative to this unreliable online resource. It is still current enough for CICM First Part Exam purposes, as the expected answers to CICM questions will likely be based on what is written in popular med-school-level textbooks, and these have a tendency to reference each other, such that the lineage of every stated fact can be traced back to the first editions of the 1960s. In case one is not convinced, Yau et al (2016) is a more modern alternative which covers the topic to a satisfactory depth. Fibrinolysis is also done well by Chapin & Hajjar (2015) and Longstaff & Kolev (2015)
Recalling the self-amplifying proteolytic cascade of haemostasis (such as the "thrombin burst" for example), the attentive reader will immediately realise that there must be some kind of regulatory process limiting this, because if there was not, the runaway sorceror's apprentice effect of this organic nanomachinery would result in the immediate and complete filling of the entire circulatory volume with clot. That this does not happen is a gratitude we owe to a number of naturally occurring factors that can be classified according to the part of the haemostatic process they are intended to oppose.
Question 19 from the second paper of 2015 asked complicated questions about fibrinolysis specifically and judging from the college examiners' notes, the expectations were high. The pass rate was a depressing 8%. This is not surprising, considering that there is a lot of material to cover. In short:
Rosenberg, R. D., and J. S. Rosenberg. "Natural anticoagulant mechanisms." The Journal of clinical investigation 74.1 (1984): 1-6.
Longstaff, Colin, and K. Kolev. "Basic mechanisms and regulation of fibrinolysis." Journal of Thrombosis and Haemostasis 13 (2015): S98-S105.
Yau, Jonathan W., Hwee Teoh, and Subodh Verma. "Endothelial cell control of thrombosis." BMC cardiovascular disorders 15.1 (2015): 1-11.
Ezihe-Ejiofor, J. Adanma, and Nevil Hutchinson. "Anticlotting mechanisms 1: physiology and pathology." Continuing Education in Anaesthesia, Critical Care & Pain 13.3 (2013): 87-92.
Ezihe-Ejiofor, J. Adanma, and Nevil Hutchinson. "Anticlotting mechanisms 2: pharmacology and clinical implications." Continuing Education in Anaesthesia, Critical Care & Pain 13.3 (2013): 93-97.
Broze Jr, George J. "Tissue factor pathway inhibitor." Thrombosis and haemostasis 74.07 (1995): 090-093.
Wood, Jeremy P., et al. "Biology of tissue factor pathway inhibitor." Blood, The Journal of the American Society of Hematology 123.19 (2014): 2934-2943.
Jin, Richard C., Barbara Voetsch, and Joseph Loscalzo. "Endogenous mechanisms of inhibition of platelet function." Microcirculation 12.3 (2005): 247-258.
Loscalzo, Joseph, and Eugene Braunwald. "Tissue plasminogen activator." New England Journal of Medicine 319.14 (1988): 925-931.
Jilani, Talha N., and Abdul H. Siddiqui. "Tissue plasminogen activator." StatPearls [Internet] (2021).
Chapin, John C., and Katherine A. Hajjar. "Fibrinolysis and the control of blood coagulation." Blood reviews 29.1 (2015): 17-24.
Masola, Valentina, et al. "Endothelial Glycocalyx as a Regulator of Fibrotic Processes." International Journal of Molecular Sciences 22.6 (2021): 2996.
Hathcock, James J. "Flow effects on coagulation and thrombosis." Arteriosclerosis, thrombosis, and vascular biology 26.8 (2006): 1729-1737.