Decreased Levels of Histidine-Rich Glycoprotein in Advanced Lung Cancer: Association with Prothrombotic Alterations

Abstract

Background . Histidine-rich glycoprotein (HRG) displays anticoagulant and antifibrinolytic properties in animal models, but its effects in humans are unclear. We investigated serum HRG levels and their associations with the disease stage and prothrombotic alterations in lung cancer (LC) patients. Methods . In 148 patients with advanced LC prior to anticancer therapy (87 non-small-cell LC and 61 small-cell LC) versus 100 well-matched controls, we measured HRG levels in association with clot permeability (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:msub><mml:mrow><mml:mi>K</mml:mi></mml:mrow><mml:mrow><mml:mtext>s</mml:mtext></mml:mrow></mml:msub></mml:math>), clot turbidimetry (lag phase and maximum absorbance), and clot lysis time (CLT). Results . Compared to controls, LC patients had 45.9% lower HRG levels with no associations with demographics and comorbidities. Decreased HRG, defined as the 90 th percentile of control values (&lt;52.7 μ g/ml), was 16 times more common in subjects with than without LC (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mtext>OR</mml:mtext><mml:mo>=</mml:mo><mml:mn>16.4</mml:mn></mml:math>, 95% CI 9.2-23.5,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.01</mml:mn></mml:math>).<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mtext>HRG</mml:mtext><mml:mo>&lt;</mml:mo><mml:mn>38</mml:mn></mml:math> μ g/ml discriminated stage IIIAB/limited disease from IV/extensive disease (ED) LC. In LC patients, HRG correlated inversely with CLT (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mi>r</mml:mi><mml:mrow><mml:mo>=</mml:mo></mml:mrow><mml:mrow><mml:mo>−</mml:mo></mml:mrow><mml:mn>0.41</mml:mn></mml:math>,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.001</mml:mn></mml:math>), but not with other fibrin variables. Among stage IV/ED LC, HRG correlated significantly with<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"><mml:msub><mml:mrow><mml:mi>K</mml:mi></mml:mrow><mml:mrow><mml:mtext>s</mml:mtext></mml:mrow></mml:msub></mml:math>and lag phase (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"><mml:mi>r</mml:mi><mml:mo>=</mml:mo><mml:mn>0.28</mml:mn></mml:math>and<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"><mml:mi>r</mml:mi><mml:mo>=</mml:mo><mml:mn>0.33</mml:mn></mml:math>, respectively, both<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.001</mml:mn></mml:math>). LC patients with low<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"><mml:msub><mml:mrow><mml:mi>K</mml:mi></mml:mrow><mml:mrow><mml:mtext>s</mml:mtext></mml:mrow></mml:msub></mml:math>(10 th percentile of control values) combined with prolonged CLT (90 th percentile of control values) had reduced HRG levels compared to the remainder (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M12"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.003</mml:mn></mml:math>). No such observations were noted in controls. Conclusions . Our study is the first to show that decreased HRG levels occur in advanced LC and are associated with the disease stage and hypofibrinolysis.