Case report 621
Left atrial myxoma presenting as pulmonary embolism: potential role of heme oxygenase-1 Daniel T. Redforda, Jess L. Thompsonb, James C. McCullocha and Vance G. Nielsena We present the case of a patient with left atrial myxoma that presented with pulmonary embolism. The patient did not have any intracardiac communication between right and left sides of the heart. Using thrombelastography, the patient was determined to have an abnormally large velocity of plasma thrombus growth and strength with reduced vulnerability to lysis. Critically, increased carboxyhemoglobin concentrations were present, likely secondary to hemolysis from the tumor and engagement of systemic heme oxygenase-1. It was determined that the patient’s plasmatic hypercoagulability was in part due to carboxyhemefibrinogen formation via a thrombelastographic method. In addition to circulating hypercoagulability, the patient also had an area of chronic venous stasis in his left ankle that had not changed for over a decade prior to this thrombophilic episode. In conclusion, we present the first case of paradoxical pulmonary embolism in the presence of a left atrial myxoma, potentially secondary to a combination of hemolysis, heme
Introduction Cardiac myxoma is the most frequent nonmalignant tumor of the heart, but its incidence is still quite rare, with an incidence of 0.5 per million per annum [1–3]. The vast majority (75–83%) occur in the left atrium, a very small percentage (1.3–2.5%) of myxomas are in both atria, most patients are women (56–64%), and embolic symptoms can occur (16–40%) [1–4]. To date, the only case of pulmonary embolism occurring in the presence of a left atrial myxoma involved the tumor crossing a large type II atrial septal defect [5]. In sum, these rare tumors usually elicit embolic phenomena into the same-sided circulation (e.g. right atrial tumor causes pulmonary embolism, left atrial tumor causes systemic arterial embolization). Whereas it is intuitive that same-sided embolism can accompany the symptoms associated with cardiac myxomas, the potential hemostatic impact of consequent red cell lysis secondary to turbulent flow, such as that seen with circulatory devices [6], has not been appreciated. Such lysis would be expected to up-regulate systemic heme oxygenase-1 (HO-1) activity, which in turn would result in greater endogenous carbon monoxide production [7], potentially enhancing coagulation [8] and decreasing fibrinolytic vulnerability [9]. We subsequently present a case wherein this mechanism may have been at play in a patient who presented with 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
oxygenase-1 up-regulation, systemic hypercoagulability/ hypofibrinolysis, and regional venous stasis. Blood Coagul Fibrinolysis 25:621–624 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:621–624 Keywords: atrial myxoma, carbon monoxide, heme oxygenase-1, pulmonary embolism, thrombelastography a Department of Anesthesiology and bDepartment of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
Correspondence to Vance G. Nielsen, MD, Department of Anesthesiology, The University of Arizona College of Medicine, P.O. Box 245114, 1501 North Campbell Avenue, Tucson, AZ 85724-5114, USA Tel: +1 520 626 7999; fax: +1 520 626 6943; e-mail: [email protected] Received 28 October 2013 Revised 30 December 2013 Accepted 15 January 2014
pulmonary embolism and subsequently found to be afflicted with a left atrial myxoma.
Case report Our patient was a 65-year-old man who had never smoked tobacco and who presented with complaints of left ankle and leg swelling with shortness of breath. He had suffered thrombophlebitis of his left ankle a decade earlier, which had resolved, albeit with residual focal varicosities. Pulmonary computerized tomography with contrast angiography revealed bilateral upper and lower segmental emboli. An incidental finding of a left atrial myxoma was made during this study. The patient was treated with warfarin for 2 months and referred to us for surgical removal of the myxoma. He discontinued his warfarin therapy for 1 week prior to operation as instructed by his surgeon. Physical exam just prior to surgery revealed residual left ankle phlebitis. Upon learning about this patient’s history, we suspected that an important change in his circulating hemostatic status had been inflicted by the myxoma, perhaps by induction of HO-1 activity. We approached him concerning this possibility, and he freely gave his informed written consent to be assessed and have this report published. As per our custom, a radial arterial catheter was placed for monitoring and blood sampling, and 4.5 ml of whole blood was collected and anticoagulated with DOI:10.1097/MBC.0000000000000097
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
622 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 6
sodium citrate (9 parts whole blood to 1 part 0.105 mol/l sodium citrate) for thrombelastographic analyses subsequently described. The patient was thereafter taken to the operating room. Intraoperative cardiac imaging was obtained after induction of anesthesia and following placement of a transesophageal echocardiographic probe (Philips Diagnostic Ultrasound System Model # IE33, adult probe 3D X7–2t; Philips Diagnostic, Bothel, Washington, USA) into the patient’s esophagus. A comprehensive examination was performed. In particular, a careful color flow Doppler examination of the atrial and ventricular septum was performed to rule out intracardiac shunting. To further rule out any intracardiac shunting, an agitated saline bubble study was also performed. All studies were negative for the presence of a patent foramen ovalis, atrial septal defect, as well as all types of ventricular septal defects. The size and location of the myxoma were established to be on the left side of the atrial septum in close proximity to the anterior mitral valve leaflet, as well as the left main and noncoronary cusps of the aortic valve. The dissection was completed and valve function was determined to be normal, and there were no new intracardiac shunts by both color flow Doppler and again a negative bubble study. Images of the myxoma obtained echocardiographically and with photography intraoperatively are displayed in Fig. 1.
With regard to standard coagulation studies obtained by our clinical laboratory prior to incision, the patient was found to have a platelet count of 184 000/ml (normal range 150 000–424 000), a prothrombin time of 12.3 s (normal 11.9–15.0), an activated partial thromboplastin time of 30.3 s (normal 22.6–35.5), a fibrinogen concentration of 405 mg/dl (normal 200–430), and a D-dimer concentration below 0.5 mg/ml (considered a negative result). Perioperative arterial blood gas analyses demonstrated a normal hemoglobin concentration of 14.1 g/dl (normal 14.0–17.5) and carboxyhemoglobin concentrations of 1.5–2.0% (normal 0–1.5%). With regard to thrombelastographic analyses, a 326 ml aliquot of whole blood, 10 ml of tissue factor (TF) reagent (0.1% final concentration in dH2O; Diagnostica Stago S.A.S., Asnieres sur Seine, France), 3.6 ml dH2O, and 20 ml of 200 mmol/l CaCl2 were placed in a disposable cup in a computer-controlled thrombelastograph hemostasis system (Model 5000; Haemoscope Corp., Niles, Illinois, USA), with addition of CaCl2 as the last step to initiate clotting. Coagulation kinetics were determined for 15 min at 378C. The remaining blood was centrifuged for 15 min at 3000g at room temperature plasma subjected to further analyses to determine hypercoagulability and the presence of carboxyhemefibrinogen (COHF) formation as previously described [10,11]. In brief, plasma samples consisted of 326 ml of plasma; 10 ml of TF
Fig. 1
Images of left atrial myxoma. (a) This image was acquired in the midesophageal aortic valve long axis view (ME-AV-LAX) with the white arrow pointing at the myxoma. (b) View showing surgical removal of the myxoma through the left atrial wall; black arrow identifies myxoma. (c) Three-dimensional image of the myxoma from the midesophageal bicaval view (ME bicaval) is displayed, with the image rotated with the ultrasound machines software to obtain a left-to-right coronal view. Myxoma measurements were 2.58 2.91 cm. (d) Three-dimensional image of the myxoma from the ME bicaval, with image rotated to view the sagittal plane. The myxoma measured 2.38 2.84 cm in this view. Note the stippled surface of the tumor in panels c and d.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Myxoma and heme oxygenase-1 Redford et al. 623
reagent (0.1% final concentration in dH2O), 3.6 ml of dH2O or carbon monoxide-releasing molecule-2 (CORM-2) (100 mmol/l final concentration; Sigma-Aldrich, Saint Louis, Missouri, USA) or phenylhydroxylamine (PHA, 10 mmol/l final concentration; Sigma-Aldrich); and 20 ml of 200 mmol/l CaCl2. This concentration of CORM-2 reliably increases clot strength in the absence of carbon monoxide, and the concentration of PHA used reliably converted heme groups associated with fibrinogen to a metheme state, significantly decreasing the effects of carbon monoxide already present [10,11]. Lastly, one sample of plasma underwent analyses to determine fibrinolytic vulnerability with the addition of tissue-type plasminogen activator (tPA). Its sample consisted of 316 ml of plasma; 10 ml of TF reagent (0.1% final concentration in dH2O); 10 ml tPA (580 U/mg; Genentech, Inc., San Francisco, California, USA), diluted with 50 mmol/l potassium phosphate buffer (pH 7.4), for a final activity of 100 U/ml; 3.6 ml of dH2O; and 20 ml of 200 mmol/l CaCl2 as per our previously described assay [12]. Data were collected for this sample until clot lysis time was observed. Thrombelastographic assay results are displayed in Table 1. First, the patient’s whole blood sample did not have abnormal velocity of clot growth or strength compared to previously presented normal values for whole blood [13]. However, the patient’s plasma sample had greater velocity of clot growth and strength compared to the 5–95% confidence interval (CI) values of our laboratory’s normal patient, generated as previously cited [10,11]. Critically, the plasma thrombus strength accounted for 62% of the whole blood clot strength, whereas normal individuals usually have only 33% of clot strength secondary to plasma proteins [13]. As for fibrinolytic vulnerability, the patient’s plasma showed a strong hypofibrinolytic tendency, with prolongation of clot growth time, clot lysis time, and clot lifespan, despite an increased maximum rate of clot lysis. With regard to COHF formation, it was determined that the elastic Table 1 Parameter TMRTG MRTG TTG TMRL MRL CGT CLT CLS
Coagulation parameters in a patient with left atrial myxoma Whole blood
Plasma
2.4 8.5 752 – – – – –
2.6 (2.2, 3.9) 13.9 (3.5, 8.6) 465 (131, 208) – – – – –
Plasma þ tPA 2.7 13.1 450 15.4 2.6 13.2 27.2 40.4
(1.4, 1.7) (6.7, 13.2) (95, 201) (3.0, 15.7) (0.9, 2.3) (1.9, 6.2) (6.1, 24.0) (8.0, 27.8)
CGT, clot growth time (min); CLS, clot lifespan (min); CLT, clot lysis time (min); MRL, maximum rate of lysis (dynes/cm2 per s); MRTG, maximum rate of thrombus generation (dynes/cm2 per s), a measure of the velocity of clot growth; TMRL, time to maximum rate of lysis (min), a measure of the onset of fibrinolysis; TMRTG, time to maximum rate of thrombus generation (min), a measure of speed to onset of coagulation; tPA, addition of 100 U/ml tissue-type plasminogen activator; TTG, total thrombus generation (dynes/cm2), a measure of clot strength. Values in parentheses represent the 5 and 95% confidence interval values for the parameter derived from 30 normal individuals.
modulus (G) values for the patient’s unmodified plasma was 4728 dynes/cm2, for CORM-2-exposed plasma was 7315 dynes/cm2, and for PHA-exposed plasma was 3606 dynes/cm2. Thus, the patient’s plasma was hypercoagulable, with CORM-2-mediated increase in strength being 55% and PHA-mediated decrease in strength being 24%, compared to unmodified plasma. We have defined the presence of COHF as an increase in G secondary to CORM-2 exposure as less than the mean sum value of the percentage increase in clot strength secondary to CORM-2 with the percentage decrease in clot strength secondary to PHA addition seen in normal individuals, which was 112%, and is denoted as the fibrinogen redox gap (FRG) [10,11]. Thus, our patient’s FRG was 79%, which is less than 112% observed in normal individuals. In sum, our patient had plasmatic hypercoagulability with the presence of a measurable COHF-mediated component of clot strength, and also displayed reduced fibrinolytic vulnerability. The patient had an uneventful postoperative course, and was discharged home after 4 days. Pathological examination confirmed that the tumor was a nonvillous myxoma. Lastly, at the 6-week follow-up postoperative examination, the patient was found to recover, with left ankle phlebitis resolved, and was advised to continue a 6-month course of warfarin anticoagulation.
Discussion Our case report is the first identification of myxomaassociated hypercoagulability/hypofibrinolysis with a detectable COHF-mediated strength component secondary to abnormally increased endogenous carbon monoxide production by HO-1. The most likely source of increased systemic carboxyhemoglobin (COHb) concentration was low-grade hemolysis secondary to turbulent flow across tumor. As can be seen in Fig. 1, the tumor was attached by a pedicle to the atrial septum, and the three-dimensional images show an irregular stippled surface. Lysis of red blood cells with consequent increases in free heme most likely caused the increase in HO-1 activity responsible for increased COHb concentrations, which is similar to that observed with circulatory devices [6]. Although circulatory hypercoagulability was present, another critical thrombophilic element afflicted our patient – the chronic venous stasis around his ankle. This remote region of stasis and indolent thrombin generation may have been the ‘prothrombotic match’ needed to start the ‘circulating thrombophilic fire’ that resulted in pulmonary embolism. Although this cannot be definitively determined in our case, our data support a new paradigm to consider when paradoxical thromboembolic phenomena occur. In conclusion, we present a patient with systemic hypercoagulability, increased COHb concentrations, and increased COHF production undergoing surgical removal of a left atrial myxoma that presented with
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
624 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 6
paradoxical pulmonary embolism. Future investigations of the role played by HO-1 in myxoma or other haemolytic-associated hypercoagulability are warranted.
5
Acknowledgements
7
6
Grant support: This investigation was supported by the Department of Anesthesiology.
8
Conflicts of interest
9
There are no conflicts of interest. 10
References 1
2
3
4
Pinede L, Duhaut P, Loire R. Clinical presentation of left atrial cardiac myxoma: a series of 112 cases. Medicine 2001; 80: 159–172. Garatti A, Nano G, Canziani A, Gagliardotto P, Mossuto E, Frigiola A, Menicanti L. Surgical excision of cardiac myxomas: twenty years experience at a single institution. Ann Thorac Surg 2012; 93:825–831. Zheng JJ, Geng XG, Wang HC, Yan Y, Wang HY. Clinical and histopathological analysis of 66 cases with cardiac myxoma. Asian Pacific J Cancer Prev 2013; 14:1742–1746. Irani AD, Estrera AL, Buja LM, Safi HJ. Biatrail myxoma: a case report and review of the literature. J Card Surg 2008; 23:385–390.
11
12
13
Nagele R, Bonetti PO, Mayer KA. A patient with pulmonary embolism and a mass in the left atrium. Heart 2012; 98:1260. Nielsen VG, Pearson T, Smith MC. Increased carbon monoxide production by hemeoxygenase-1 caused by device-mediated hemolysis: thrombotic phantom menace? Artif Organs 2013; 37:1008–1014. Landaw SA, Callahan EW, Schmid R. Catabolism of heme in vivo: comparison of the simultaneous production of bilirubin and carbon monoxide. J Clin Invest 1970; 49:914–925. Nielsen VG, Kirklin JK, George JF. Carbon monoxide releasing molecule-2 increases the velocity of thrombus growth and strength in human plasma. Blood Coagul Fibrinolysis 2009; 20:377–380. Nielsen VG, Kirklin JK, George JF. Carbon monoxide releasing molecule-2 (CORM-2) decreases fibrinolysis in human plasma. Blood Coagul Fibrinolysis 2009; 20:448–455. Nielsen VG, Garol BD, Zelman EA, Guerrero MA. Hemeoxygenase-1 mediated hypercoagulability in a patient with thyroid cancer. Blood Coagul Fibrinolysis 2013; 24:663–665. Nielsen VG, Ley MLB, Waer AL, Alger PW, Matika RW, Steinbrenner EB. Plasmatic hypercoagulation in patients with breast cancer: role of hemeoxygenase-1. Blood Coagul Fibrinolysis 2013; 24:809–813. Nielsen VG, Hafner DT, Steinbrenner EB. Can divergent plasminantiplasmin-carbon monoxide interactions in young, healthy tobacco smokers explain the ‘smoker’s paradox’? Blood Coagul Fibrinolysis 2013; 24:381–385. Ellis TC, Nielsen VG, Marques MB, Kirklin JK. Thrombelastographic measures of clot propagation: a comparison of alpha to maximum rate of thrombus generation. Blood Coagul Fibrinolysis 2007; 18:45–48.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Left atrial myxoma presenting as pulmonary embolism: potential role of heme oxygenase-1 Daniel T. Redforda, Jess L. Thompsonb, James C. McCullocha and Vance G. Nielsena We present the case of a patient with left atrial myxoma that presented with pulmonary embolism. The patient did not have any intracardiac communication between right and left sides of the heart. Using thrombelastography, the patient was determined to have an abnormally large velocity of plasma thrombus growth and strength with reduced vulnerability to lysis. Critically, increased carboxyhemoglobin concentrations were present, likely secondary to hemolysis from the tumor and engagement of systemic heme oxygenase-1. It was determined that the patient’s plasmatic hypercoagulability was in part due to carboxyhemefibrinogen formation via a thrombelastographic method. In addition to circulating hypercoagulability, the patient also had an area of chronic venous stasis in his left ankle that had not changed for over a decade prior to this thrombophilic episode. In conclusion, we present the first case of paradoxical pulmonary embolism in the presence of a left atrial myxoma, potentially secondary to a combination of hemolysis, heme
Introduction Cardiac myxoma is the most frequent nonmalignant tumor of the heart, but its incidence is still quite rare, with an incidence of 0.5 per million per annum [1–3]. The vast majority (75–83%) occur in the left atrium, a very small percentage (1.3–2.5%) of myxomas are in both atria, most patients are women (56–64%), and embolic symptoms can occur (16–40%) [1–4]. To date, the only case of pulmonary embolism occurring in the presence of a left atrial myxoma involved the tumor crossing a large type II atrial septal defect [5]. In sum, these rare tumors usually elicit embolic phenomena into the same-sided circulation (e.g. right atrial tumor causes pulmonary embolism, left atrial tumor causes systemic arterial embolization). Whereas it is intuitive that same-sided embolism can accompany the symptoms associated with cardiac myxomas, the potential hemostatic impact of consequent red cell lysis secondary to turbulent flow, such as that seen with circulatory devices [6], has not been appreciated. Such lysis would be expected to up-regulate systemic heme oxygenase-1 (HO-1) activity, which in turn would result in greater endogenous carbon monoxide production [7], potentially enhancing coagulation [8] and decreasing fibrinolytic vulnerability [9]. We subsequently present a case wherein this mechanism may have been at play in a patient who presented with 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
oxygenase-1 up-regulation, systemic hypercoagulability/ hypofibrinolysis, and regional venous stasis. Blood Coagul Fibrinolysis 25:621–624 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:621–624 Keywords: atrial myxoma, carbon monoxide, heme oxygenase-1, pulmonary embolism, thrombelastography a Department of Anesthesiology and bDepartment of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
Correspondence to Vance G. Nielsen, MD, Department of Anesthesiology, The University of Arizona College of Medicine, P.O. Box 245114, 1501 North Campbell Avenue, Tucson, AZ 85724-5114, USA Tel: +1 520 626 7999; fax: +1 520 626 6943; e-mail: [email protected] Received 28 October 2013 Revised 30 December 2013 Accepted 15 January 2014
pulmonary embolism and subsequently found to be afflicted with a left atrial myxoma.
Case report Our patient was a 65-year-old man who had never smoked tobacco and who presented with complaints of left ankle and leg swelling with shortness of breath. He had suffered thrombophlebitis of his left ankle a decade earlier, which had resolved, albeit with residual focal varicosities. Pulmonary computerized tomography with contrast angiography revealed bilateral upper and lower segmental emboli. An incidental finding of a left atrial myxoma was made during this study. The patient was treated with warfarin for 2 months and referred to us for surgical removal of the myxoma. He discontinued his warfarin therapy for 1 week prior to operation as instructed by his surgeon. Physical exam just prior to surgery revealed residual left ankle phlebitis. Upon learning about this patient’s history, we suspected that an important change in his circulating hemostatic status had been inflicted by the myxoma, perhaps by induction of HO-1 activity. We approached him concerning this possibility, and he freely gave his informed written consent to be assessed and have this report published. As per our custom, a radial arterial catheter was placed for monitoring and blood sampling, and 4.5 ml of whole blood was collected and anticoagulated with DOI:10.1097/MBC.0000000000000097
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
622 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 6
sodium citrate (9 parts whole blood to 1 part 0.105 mol/l sodium citrate) for thrombelastographic analyses subsequently described. The patient was thereafter taken to the operating room. Intraoperative cardiac imaging was obtained after induction of anesthesia and following placement of a transesophageal echocardiographic probe (Philips Diagnostic Ultrasound System Model # IE33, adult probe 3D X7–2t; Philips Diagnostic, Bothel, Washington, USA) into the patient’s esophagus. A comprehensive examination was performed. In particular, a careful color flow Doppler examination of the atrial and ventricular septum was performed to rule out intracardiac shunting. To further rule out any intracardiac shunting, an agitated saline bubble study was also performed. All studies were negative for the presence of a patent foramen ovalis, atrial septal defect, as well as all types of ventricular septal defects. The size and location of the myxoma were established to be on the left side of the atrial septum in close proximity to the anterior mitral valve leaflet, as well as the left main and noncoronary cusps of the aortic valve. The dissection was completed and valve function was determined to be normal, and there were no new intracardiac shunts by both color flow Doppler and again a negative bubble study. Images of the myxoma obtained echocardiographically and with photography intraoperatively are displayed in Fig. 1.
With regard to standard coagulation studies obtained by our clinical laboratory prior to incision, the patient was found to have a platelet count of 184 000/ml (normal range 150 000–424 000), a prothrombin time of 12.3 s (normal 11.9–15.0), an activated partial thromboplastin time of 30.3 s (normal 22.6–35.5), a fibrinogen concentration of 405 mg/dl (normal 200–430), and a D-dimer concentration below 0.5 mg/ml (considered a negative result). Perioperative arterial blood gas analyses demonstrated a normal hemoglobin concentration of 14.1 g/dl (normal 14.0–17.5) and carboxyhemoglobin concentrations of 1.5–2.0% (normal 0–1.5%). With regard to thrombelastographic analyses, a 326 ml aliquot of whole blood, 10 ml of tissue factor (TF) reagent (0.1% final concentration in dH2O; Diagnostica Stago S.A.S., Asnieres sur Seine, France), 3.6 ml dH2O, and 20 ml of 200 mmol/l CaCl2 were placed in a disposable cup in a computer-controlled thrombelastograph hemostasis system (Model 5000; Haemoscope Corp., Niles, Illinois, USA), with addition of CaCl2 as the last step to initiate clotting. Coagulation kinetics were determined for 15 min at 378C. The remaining blood was centrifuged for 15 min at 3000g at room temperature plasma subjected to further analyses to determine hypercoagulability and the presence of carboxyhemefibrinogen (COHF) formation as previously described [10,11]. In brief, plasma samples consisted of 326 ml of plasma; 10 ml of TF
Fig. 1
Images of left atrial myxoma. (a) This image was acquired in the midesophageal aortic valve long axis view (ME-AV-LAX) with the white arrow pointing at the myxoma. (b) View showing surgical removal of the myxoma through the left atrial wall; black arrow identifies myxoma. (c) Three-dimensional image of the myxoma from the midesophageal bicaval view (ME bicaval) is displayed, with the image rotated with the ultrasound machines software to obtain a left-to-right coronal view. Myxoma measurements were 2.58 2.91 cm. (d) Three-dimensional image of the myxoma from the ME bicaval, with image rotated to view the sagittal plane. The myxoma measured 2.38 2.84 cm in this view. Note the stippled surface of the tumor in panels c and d.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Myxoma and heme oxygenase-1 Redford et al. 623
reagent (0.1% final concentration in dH2O), 3.6 ml of dH2O or carbon monoxide-releasing molecule-2 (CORM-2) (100 mmol/l final concentration; Sigma-Aldrich, Saint Louis, Missouri, USA) or phenylhydroxylamine (PHA, 10 mmol/l final concentration; Sigma-Aldrich); and 20 ml of 200 mmol/l CaCl2. This concentration of CORM-2 reliably increases clot strength in the absence of carbon monoxide, and the concentration of PHA used reliably converted heme groups associated with fibrinogen to a metheme state, significantly decreasing the effects of carbon monoxide already present [10,11]. Lastly, one sample of plasma underwent analyses to determine fibrinolytic vulnerability with the addition of tissue-type plasminogen activator (tPA). Its sample consisted of 316 ml of plasma; 10 ml of TF reagent (0.1% final concentration in dH2O); 10 ml tPA (580 U/mg; Genentech, Inc., San Francisco, California, USA), diluted with 50 mmol/l potassium phosphate buffer (pH 7.4), for a final activity of 100 U/ml; 3.6 ml of dH2O; and 20 ml of 200 mmol/l CaCl2 as per our previously described assay [12]. Data were collected for this sample until clot lysis time was observed. Thrombelastographic assay results are displayed in Table 1. First, the patient’s whole blood sample did not have abnormal velocity of clot growth or strength compared to previously presented normal values for whole blood [13]. However, the patient’s plasma sample had greater velocity of clot growth and strength compared to the 5–95% confidence interval (CI) values of our laboratory’s normal patient, generated as previously cited [10,11]. Critically, the plasma thrombus strength accounted for 62% of the whole blood clot strength, whereas normal individuals usually have only 33% of clot strength secondary to plasma proteins [13]. As for fibrinolytic vulnerability, the patient’s plasma showed a strong hypofibrinolytic tendency, with prolongation of clot growth time, clot lysis time, and clot lifespan, despite an increased maximum rate of clot lysis. With regard to COHF formation, it was determined that the elastic Table 1 Parameter TMRTG MRTG TTG TMRL MRL CGT CLT CLS
Coagulation parameters in a patient with left atrial myxoma Whole blood
Plasma
2.4 8.5 752 – – – – –
2.6 (2.2, 3.9) 13.9 (3.5, 8.6) 465 (131, 208) – – – – –
Plasma þ tPA 2.7 13.1 450 15.4 2.6 13.2 27.2 40.4
(1.4, 1.7) (6.7, 13.2) (95, 201) (3.0, 15.7) (0.9, 2.3) (1.9, 6.2) (6.1, 24.0) (8.0, 27.8)
CGT, clot growth time (min); CLS, clot lifespan (min); CLT, clot lysis time (min); MRL, maximum rate of lysis (dynes/cm2 per s); MRTG, maximum rate of thrombus generation (dynes/cm2 per s), a measure of the velocity of clot growth; TMRL, time to maximum rate of lysis (min), a measure of the onset of fibrinolysis; TMRTG, time to maximum rate of thrombus generation (min), a measure of speed to onset of coagulation; tPA, addition of 100 U/ml tissue-type plasminogen activator; TTG, total thrombus generation (dynes/cm2), a measure of clot strength. Values in parentheses represent the 5 and 95% confidence interval values for the parameter derived from 30 normal individuals.
modulus (G) values for the patient’s unmodified plasma was 4728 dynes/cm2, for CORM-2-exposed plasma was 7315 dynes/cm2, and for PHA-exposed plasma was 3606 dynes/cm2. Thus, the patient’s plasma was hypercoagulable, with CORM-2-mediated increase in strength being 55% and PHA-mediated decrease in strength being 24%, compared to unmodified plasma. We have defined the presence of COHF as an increase in G secondary to CORM-2 exposure as less than the mean sum value of the percentage increase in clot strength secondary to CORM-2 with the percentage decrease in clot strength secondary to PHA addition seen in normal individuals, which was 112%, and is denoted as the fibrinogen redox gap (FRG) [10,11]. Thus, our patient’s FRG was 79%, which is less than 112% observed in normal individuals. In sum, our patient had plasmatic hypercoagulability with the presence of a measurable COHF-mediated component of clot strength, and also displayed reduced fibrinolytic vulnerability. The patient had an uneventful postoperative course, and was discharged home after 4 days. Pathological examination confirmed that the tumor was a nonvillous myxoma. Lastly, at the 6-week follow-up postoperative examination, the patient was found to recover, with left ankle phlebitis resolved, and was advised to continue a 6-month course of warfarin anticoagulation.
Discussion Our case report is the first identification of myxomaassociated hypercoagulability/hypofibrinolysis with a detectable COHF-mediated strength component secondary to abnormally increased endogenous carbon monoxide production by HO-1. The most likely source of increased systemic carboxyhemoglobin (COHb) concentration was low-grade hemolysis secondary to turbulent flow across tumor. As can be seen in Fig. 1, the tumor was attached by a pedicle to the atrial septum, and the three-dimensional images show an irregular stippled surface. Lysis of red blood cells with consequent increases in free heme most likely caused the increase in HO-1 activity responsible for increased COHb concentrations, which is similar to that observed with circulatory devices [6]. Although circulatory hypercoagulability was present, another critical thrombophilic element afflicted our patient – the chronic venous stasis around his ankle. This remote region of stasis and indolent thrombin generation may have been the ‘prothrombotic match’ needed to start the ‘circulating thrombophilic fire’ that resulted in pulmonary embolism. Although this cannot be definitively determined in our case, our data support a new paradigm to consider when paradoxical thromboembolic phenomena occur. In conclusion, we present a patient with systemic hypercoagulability, increased COHb concentrations, and increased COHF production undergoing surgical removal of a left atrial myxoma that presented with
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
624 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 6
paradoxical pulmonary embolism. Future investigations of the role played by HO-1 in myxoma or other haemolytic-associated hypercoagulability are warranted.
5
Acknowledgements
7
6
Grant support: This investigation was supported by the Department of Anesthesiology.
8
Conflicts of interest
9
There are no conflicts of interest. 10
References 1
2
3
4
Pinede L, Duhaut P, Loire R. Clinical presentation of left atrial cardiac myxoma: a series of 112 cases. Medicine 2001; 80: 159–172. Garatti A, Nano G, Canziani A, Gagliardotto P, Mossuto E, Frigiola A, Menicanti L. Surgical excision of cardiac myxomas: twenty years experience at a single institution. Ann Thorac Surg 2012; 93:825–831. Zheng JJ, Geng XG, Wang HC, Yan Y, Wang HY. Clinical and histopathological analysis of 66 cases with cardiac myxoma. Asian Pacific J Cancer Prev 2013; 14:1742–1746. Irani AD, Estrera AL, Buja LM, Safi HJ. Biatrail myxoma: a case report and review of the literature. J Card Surg 2008; 23:385–390.
11
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