How can blood come into contact with negatively charged surfaces to activate factor XII?

Mechanisms of Factor XII Activation by Negatively Charged Surfaces

Factor XII is activated when blood comes into contact with negatively charged surfaces through the intrinsic pathway of coagulation, which occurs via specific interactions with activating surfaces that convert factor XII to factor XIIa. 1

Natural and Artificial Activating Surfaces

External/Artificial Surfaces

• Glass surfaces are a classic example of negatively charged surfaces that activate factor XII, which was commonly observed when glass tubes were used for blood collection 1
• Kaolin and sulfatides are other artificial negatively charged surfaces that can trigger factor XII activation 2
• Negatively charged surfaces protect factor XIIa from inhibition by C1 inhibitor, allowing it to hydrolyze its physiologic substrates 2

Biological Surfaces

• Misfolded protein aggregates that form by denaturation or surface adsorption can activate factor XII, specifically leading to kallikrein-kinin system activation without inducing coagulation 3
• Extracellular vesicles (EVs) that expose negatively charged phospholipids like phosphatidylserine can provide a surface for factor XII activation 1
• Platelet-derived EVs promote coagulation by generating additional procoagulant membrane surface 1

Molecular Mechanism of Activation

• When factor XII contacts negatively charged surfaces, it undergoes autoactivation to factor XIIa 4, 5
• This activation is triggered by conformational changes in the factor XII molecule upon binding to the negatively charged surface 1
• The intrinsic pathway activation begins with this contact activation, which then leads to the activation of factor XI to factor XIa 6

Physiological and Pathological Relevance

• In physiological settings, blood contact with extravascular tissue in a bleeding wound activates the extrinsic pathway, not the intrinsic pathway 1
• Factor XII activation is more relevant in pathological conditions than in normal hemostasis 4, 5
• Various biological substances can trigger FXII contact-activation in vivo, including:
  • Mast cell-derived heparin
  • Misfolded protein aggregates
  • Collagen
  • Nucleic acids
  • Polyphosphate 5

Role in Coagulation and Inflammation

• Factor XIIa initiates both the intrinsic coagulation pathway and the kallikrein-kinin inflammatory system 4, 5
• In systemic amyloidosis, factor XII activation occurs due to misfolded protein aggregates, leading to kallikrein formation without initiating coagulation 3
• Factor XIIa contributes to inflammation through activation of the bradykinin-producing kallikrein-kinin system 5

Clinical Implications

• Factor XII deficiency is not associated with bleeding disorders, suggesting it's not essential for normal hemostasis 4, 5
• However, factor XIIa plays a critical role in thromboembolic diseases 5
• Pharmacological inhibition of FXII/FXIIa may provide a promising therapeutic strategy for anticoagulation with additional anti-inflammatory effects 5
• In laboratory settings, anticoagulants that chelate Ca²⁺ ions prevent coagulation by impeding the formation of tenase and prothrombinase complexes that require negatively charged surfaces 1

Practical Considerations in Blood Collection

• Glass tubes were historically used for blood collection but are now avoided due to their ability to activate factor XII 1
• Plastic blood drawing tubes are recommended over glass tubes to avoid contact activation 1
• The use of a straight needle is preferred over butterfly needles, as the latter may induce contact activation 1