Increased Carbon Monoxide Production by Hemeoxygenase‐1 Caused by Device‐Mediated Hemolysis: Thrombotic Phantom Menace?

Abstract

Replacement of key components of the circulatory system with artificial devices has become the mainstay of therapy for conditions such as end-stage valvular disease or congestive heart failure. Unfortunately, device thrombosis and thromboembolic morbidity persist despite optimized anticoagulation. This work reviews the commonly known causes of device-associated thrombophilia, introduces recent literature concerning the effect of carbon monoxide on coagulation, and presents new patient data linking endogenously produced carbon monoxide with device-associated thrombosis. A new paradigm involving the interaction of red blood cell lysis-induced upregulation of hemoxygenase-1, increased endogenous carbon monoxide, hyperfibrinogenemia, and contact protein/microparticle-induced thrombin generation is presented.

Iron and carbon monoxide enhance coagulation and attenuate fibrinolysis by different mechanisms

“…Given that both iron and carbon monoxide are products of HO-1 activity, it is likely that they coexist in various micromolar concentrations in conditions such as cancer [27][28][29][30][31], diabetes mellitus [21], rheumatoid arthritis [22], and mechanical circulatory support [18,26]. Although it is not possible to directly extrapolate our findings as the underpinning of hypercoagulability in these various settings [18,22,[26][27][28][29][30][31], it is possible that exposure of circulating fibrinogen to various combinations of iron and carbon monoxide may be enhancing coagulation in these disease states.…”

“…Both viscoelastic and SEM data demonstrate distinct kinetic and ultrastructural profile effects, respectively, of iron, carbon monoxide, and their combination on thrombus formation. Future in-vitro and in-vivo investigations of these phenomena are planned, especially in settings that may involve upregulation of HO-1 activity [18,22,[26][27][28][29][30][31].…”

“…Upregulation of HO-1 occurs in a variety of situations that involve red blood cell lysis and release of heme, such as in the case of biomaterial-blood interaction during mechanical circulatory support [18]. Catalytically released iron may also contribute to hydroxyl radical modification of fibrinogen [19] or bind directly to fibrinogen [20] as recently demonstrated.…”

Left Ventricular Assist Device–Associated Carbon Monoxide and Iron-Enhanced Hypercoagulation

“…6 With regard to LDH as a measure of hemolysis during normal operation of various devices or after pump thrombosis, typical values are displayed in Table 1 derived from recent reports. [7][8][9][10][11][12][13] There is significant device and center variability in low grade, hemolysis-generated LDH values, possibly indicative of differences in anticoagulation or blood flow characteristics dependent on surgical implantation and pump management. 14,15 This indolent but persistent process of device-mediated hemolysis is potentially biochemically important from a coagulation perspective, as free heme will upregulate heme oxygenase (Hmox, isoform 1 inducible, isoform 2 constitutive) activity and increase carbon monoxide (CO) and iron release during heme catabolism.…”

“…16,17 This has been recently reported with patients implanted with the HMII LVAD, with increased endogenous CO release documented by abnormal carboxyhemoglobin concentrations ranging from 1.9% to 4.0%. 7 This is potentially critical, as plasmatic coagulation is enhanced by CO via binding with a heme group(s) associated with fibrinogen in humans and rabbits, in vitro and in vivo. [18][19][20][21][22][23] Carbon monoxide also decreases tissue-type plasminogen activator (tPA)-induced fibrinolysis by enhancing α 2 -antiplasmin activity and decreasing plasmin activity.…”