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

Abstract

Left ventricular assist device (LVAD) therapy is associated with thrombophilia despite anticoagulation. Of interest, LVAD patients have increased carboxyhemoglobin, a measure of upregulated heme oxygenase (Hmox) activity that releases carbon monoxide (CO) and iron. Given that CO and iron enhance plasmatic coagulation, we determined if LVAD patients had hypercoagulability and decreased fibrinolytic vulnerability with measurable CO and iron-mediated effects. Blood samples were obtained a month or more after implantation of the LVAD. Thrombelastographic methods to assess coagulation kinetics, fibrinolytic kinetics, formation of carboxyhemefibrinogen, and iron-mediated enhancement of clot growth were utilized. Coagulation and fibrinolytic parameter normal individual (n = 30) plasma values were determined. Sixteen LVAD patients were studied. CO and iron enhancement of coagulation were observed in the majority of LVAD patients, contributing to hypercoagulation. However, most patients demonstrated abnormally increased rates of clot lysis. Critically, hemolysis as assessed by circulating lactate dehydrogenase activity was small in this cohort, and only four patients without comorbid states (e.g., obesity, diabetes, sleep apnea) were hypercoagulable with evidence of Hmox upregulation. However, seven patients with comorbidities were hypercoagulable with Hmox upregulation. Future investigation of CO and iron-related thrombophilia and comorbid disease is warranted to define its role in LVAD-related thrombosis.

Carbon Monoxide and Its Controlled Release: Therapeutic Application, Detection, and Development of Carbon Monoxide Releasing Molecules (CORMs)

“…For instance, patients with left ventricular assist devices (LVAD) are associated with thrombophilia despite anticoagulation. Blood samples from LVAD patients were obtained a month or more after LVAD implantation, and CO enhancement of coagulation was observed in most of them . Morbid obesity is associated with significant thrombophilia.…”

“…Blood samples from LVAD patients were obtained a month or more after LVAD implantation, and CO enhancement of coagulation was observed in most of them. 101 Morbid obesity is associated with significant thrombophilia. In 2015, Nielsen et al 101 conducted an investigation to determine whether morbidly obese patients undergoing bariatric surgery showed increased endogenous CO production and plasmatic hypercoagulability.…”

“…101 Morbid obesity is associated with significant thrombophilia. In 2015, Nielsen et al 101 conducted an investigation to determine whether morbidly obese patients undergoing bariatric surgery showed increased endogenous CO production and plasmatic hypercoagulability. The results indicated that the plasma coagulation kinetics of these bariatric patients was obviously upregulated and the COHb concentration and carboxy heme fibrinogen (COHF) formation were increased.…”

Erythrocyte aging as a mechanism of anemia and a biomarker of device thrombosis in continuous-flow left ventricular assist devices

“…This subsequently accelerated thrombus formation in a self-propelling feedback mechanism. 36,37 Erythropoiesis-stimulating agents, which increase erythrocyte production, were associated with a 235% increased hazard for pump thrombosis. 38 The altered high shear stress forces in the thrombosed device likely increased erythrocyte damage and CO production, contributing to thrombosis.…”

The Gilded Clot: Review of Metal-Modulated Platelet Activation, Coagulation, and Fibrinolysis

“…An additional study localized the binding site of Fe 3+ on fibrinogen to be its alpha chain [ 35 ]. The clinical presence of iron-mediated hypercoagulability has been demonstrated in inflammatory conditions involving HO-1 upregulation as assessed with the aforementioned thrombelastograph-based chelation assay [ 33 , 34 ], which include calcific valvulopathy [ 93 ], Alzheimer’s disease [ 94 ], ventricular assist device therapy [ 95 ], sickle cell disease [ 96 ], and chronic migraine headache [ 97 ].…”