Circulating within blood plasma is a protein known as contact factor, or Factor XII. This protein, also called Hageman factor, is produced by the liver and exists as an inactive molecule waiting for a signal to participate in bodily processes. The name “contact factor” comes from its activation method, which involves physically touching certain surfaces.
The Role in Blood Clotting
Contact factor’s most understood function is initiating the intrinsic pathway of coagulation, a sequence of events leading to blood clot formation. This process begins when blood encounters a negatively charged surface, such as when a blood vessel’s inner lining is damaged and reveals underlying collagen. This direct contact causes the Factor XII protein to change its shape, converting it into its active form, Factor XIIa.
Once active, Factor XIIa triggers the next step in a cascade by activating another clotting factor, Factor XI. This sets off a chain reaction where each activated factor switches on the next, amplifying the signal at each step. The sequence culminates in the conversion of a soluble protein called fibrinogen into insoluble fibrin strands, which form a mesh that creates a stable blood clot to seal the injury.
This sequence is a part of how the body stops bleeding, a process called hemostasis. While other pathways can lead to clot formation, the intrinsic pathway is a significant contributor, particularly in laboratory settings. Cofactors like high-molecular-weight kininogen (HMWK) and prekallikrein help accelerate this initial activation, ensuring a timely response to vessel damage.
Beyond Coagulation
The functions of contact factor extend beyond initiating blood clots, as it is a participant in the kallikrein-kinin system. When Factor XII is activated, it initiates reactions that lead to the production of a peptide called bradykinin. This occurs when activated Factor XII (FXIIa) converts prekallikrein into its active form, kallikrein, which then liberates bradykinin from its precursor, HMWK.
Bradykinin is a molecule involved in inflammation, causing blood vessels to dilate and become more permeable, which can lead to swelling. Bradykinin is also involved in the sensation of pain and helps regulate blood pressure by causing vasodilation. This places contact factor at an intersection between the body’s clotting and inflammatory responses.
Contact factor also participates in fibrinolysis, the process that breaks down blood clots. Activated Factor XII can help convert plasminogen into plasmin, the enzyme responsible for dissolving a clot’s fibrin mesh. This dual function shows that the same protein that helps start clot formation also contributes to its eventual removal.
Contact Factor Deficiency
A deficiency in contact factor, or Hageman trait, is a rare genetic condition. It was first identified in 1955 in a patient named John Hageman, whose blood showed a prolonged clotting time during a routine test, despite him having no history of bleeding problems. This discovery revealed a perplexing aspect of the protein: its absence dramatically affects laboratory tests but not a person’s health.
Individuals with Factor XII deficiency typically do not experience abnormal bleeding, even during surgery or after trauma. This contrasts with deficiencies of other clotting factors, like hemophilia, which cause severe bleeding disorders. The lack of bleeding symptoms occurs because other bodily mechanisms compensate for the absence of Factor XII to ensure effective clot formation.
Because the condition is asymptomatic, it is often discovered by chance during routine blood work. Lab tests, like the activated partial thromboplastin time (PTT), will show a prolonged time for a clot to form in a test tube. This result does not reflect a bleeding risk for the patient, and treatment is not necessary.
Medical Relevance and Therapeutic Targeting
The nature of contact factor deficiency has opened up an area of medical research. The observation that its absence prevents pathological clot formation in animal models without causing bleeding has made Factor XII a target for new anticoagulant therapies. Current anti-clotting medications prevent thrombosis—the formation of unwanted blood clots—but carry a risk of causing bleeding, so a drug that blocks Factor XII could prevent thrombosis without this side effect.
Researchers are developing Factor XII inhibitors, including monoclonal antibodies, small molecules, and RNA-based therapeutics. These drugs aim to block Factor XIIa activity, halting the intrinsic coagulation pathway before it leads to a dangerous clot. This approach could be beneficial for preventing clots on artificial surfaces, like medical devices where contact activation is a trigger, and help manage deep vein thrombosis, pulmonary embolism, and stroke.
Contact factor’s role in the kallikrein-kinin system also makes it a target for other conditions. In hereditary angioedema (HAE), excessive Factor XII activity leads to the overproduction of bradykinin, causing recurrent swelling attacks. Therapies that inhibit Factor XII are being developed to prevent these attacks, and one inhibitor, the antibody garadacimab, has shown promise in clinical trials.