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Factor XII Deficiency and Thrombosis

Janice Richardson asks, “Why does a low factor XII cause clotting?”

Factor XII was described in 1955 by Ratnoff and Colopy who recognized its deficiency in an American male, John Hageman. Factor XII deficiency causes a markedly prolonged activated partial thromboplastin time (APTT, PTT) but paradoxically does not associate with bleeding. Most of us know Mr. Hageman died of a pulmonary embolism after a hip fracture, implying the deficiency has no protective effect and could be prothrombotic. Factor XII is one of the contact factors, along with prekallikrein (PK, Fletcher factor), and high molecular weight kininogen (HMWK, Fitzgerald factor). Some include factor XI and a complement pathway control protein, C1 inhibitor (C1-INH), which binds factor XII.

For an authoritative secondary reference that summarizes the association of factor XII deficiency with myocardial infarction, coronary artery disease, miscarriage, and coronary stent thrombosis, see Colman RW: Contact activation (kallikrein-kinin) pathway: Multiple physiologic and pathophysiologic activities (Chapter 6) in Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ. Hemostasis and Thrombosis Basic Principles and Clinical Practice, 5th Edition, Lippincott, 2005. In his chapter, despite these associations, Colman suggests factor XII does not currently rise to the level of a clinical thrombosis risk factor, as he writes, “Careful prospective investigations with age- and sex-matched controls will be required to determine whether factor XII deficiency should be added to the ever-increasing list of inherited risk factors for thrombosis.”

In another part of chapter 6, Colman writes that factor XII cleaves plasminogen, making it a minor player in fibrinolysis. He doesn’t draw any conclusion, however I suggest it may be that factor XII deficiency slows fibrinolysis, promoting thrombosis. The weakness in my theory is that most reports of factor XII deficiency and thrombosis document arterial-side, not venous clotting. Geo.

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