- Email: [email protected]
Regarding “Altered fibrin clot structure and function in individuals with intermittent claudication”
LETTERS TO THE EDITOR Regarding “Altered fibrin clot structure and function in individuals with intermittent claudication” We recently demonstrated that healthy first-degree relatives of individuals with intermittent claudication formed ex-vivo fibrin clots that are less porous, have significantly thicker fibers, increased factor XIII crosslinking, and are more resistant to fibrinolysis compared with a control group.1 This study suggested a mechanism through which a positive family history may produce deleterious effects and may have implications in the future cardiovascular risk of what is apparently a healthy subgroup of the population.1 Previous studies demonstrated abnormal fibrin clot structure in individuals with myocardial infarction2 and diabetes mellitus.3 Young postinfarct patients produced clots with a tighter, less porous rigid structure,2 and diabetic patients also formed a thin-fiber, low-porosity clot network.3 Fatah et al2 declared that the tight, rigid fibrin gel networks might be important for the formation and progression of coronary lesions. Furthermore, they suggested that clot resiliency, or resistance to lysis, could also affect plaque growth and the formation of hemodynamically significant stenoses.2 It was therefore expected that claudicant patients would form clots that were significantly different compared with a control group. In addition, fibrin clot structure has not been previously studied in claudicant patients. We performed assays for clot permeation, fiber thickness by turbidity and laser scanning confocal microscopy, factor XIII crosslinking, and fibrinolysis, as described previously.1 Assays were performed on 34 individuals who represented a relatively young group of patients with mild to moderate peripheral arterial disease (PAD) whose intervention rate and concomitant generalized atherosclerotic disease was comparable with the PAD population as a whole. Assays were only performed on this number due to financial and time constraints. In addition, there were potentially confounding factors because participants had established clinically significant disease and were receiving cardiovascular medications, which are known to affect clot structure.3-5 These medications have been shown to have a beneficial effect on clot structure and so would not introduce a positive bias. In addition, because the group of firstdegree relatives mainly consisted of sons, the intermittent claudication study group was significantly older than the other groups.1 The claudicant patients have the least permeable, most rigid clots, which are made up of the thickest fibers and are most resistant to fibrinolysis, compared with the other groups (Table). This novel work has characterized an abnormal fibrin clot structure in claudicant patients and supports the work of others indicating abnormal clot structures in individuals with atherothrombotic disease.2,3 The literature clearly shows that intermittent claudication is independently associated with up to a sixfold increase in risk of
cardiovascular mortality compared with the healthy population.6 This abnormal clot structure may also explain an aspect of the development, clinical manifestation, and progression of PAD, along with the increased frequency of cardiovascular events in these patients. This research was funded by a British Heart Foundation Junior Research Fellowship (FS/03/061/15883). Neeraj Bhasin, MD, MRCS(Eng) Duncan J. Parry, MD, FRCS(Ed) D. Julian A. Scott, MD, FRCS(Eng), FEBVS Division of Cardiovascular and Diabetes Research University of Leeds Leeds Vascular Institute Leeds General Infirmary Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom Robert A.S. Ariëns, PhD Peter J. Grant, MD, FRCP Division of Cardiovascular and Diabetes Research University of Leeds Leeds, United Kingdom Robert M. West, DPhil Biostatistics Unit University of Leeds Leeds, United Kingdom REFERENCES 1. Bhasin N, Ariëns RAS, West RM, Parry DJ, Grant PJ, Scott DJA. Altered fibrin clot structure and function in the healthy first degree relatives of subjects with intermittent claudication. J Vasc Surg Article [Epub ahead of print]. 2. Fatah K, Silveira A, Tornvall P, Karpe F, Blomback M, Hamsten A. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost 1996;76:535-40. 3. Nair CH, Azhar A, Dhall DP. Studies of fibrin network structure in human plasma. Part II: Clinical application–Diabetes and Antidiabetic drugs. Thromb Res 1991;64:477-485. 4. Undas A, Celinska-Löwenhoff M, Löwenhoff T, Szczeklik A. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. J Thromb Haemost 2006; 4:1029-36.
Table. Fibrin clot structure and function data P Clot variable
Control
FDR
Claudicant
Ks ⫻10⫺9 cm2a 15.6 (14.7-16.6) 14.6 (13.9-15.3) 13.8 (12.3-15.2) MAb 0.75 (0.67-0.93) 0.86 (0.75-0.98) 0.95 (0.82-1.07) F XIII activity, %b 105 (87-141) 133 (103-155) 129 (97-156) Fiber thickness on LSCM,a nm 315.8 (307.0-324.6) 405.1 (397.6-412.6) 480.2 (466.9-493.6) a Lysis front velocity, m/min 12.66 (6.38-18.94) 4.83 (2.50-7.17) 4.37 (2.89-5.84)
Control vs Control vs FDR vs FDR claudicant claudicant .259 ⬍.001 ⬍.001 ⬍.001 .018
FDR, First-degree relative; Ks, average pore size; LSCM, laser scanning confocal microscopy; MA, fiber thickness by turbidity. a Parametric data are expressed as the mean (95% confidence interval). b Nonparametric data are expressed as median (IQR).
1088
.087 ⬍.001 .042 ⬍.001 .008
.963 .130 ⬎.99 ⬍.001 ⬎.99
JOURNAL OF VASCULAR SURGERY Volume 49, Number 4
5. Williams S, Fatah K, Hjemdahl P, Blomback M. Better increase in fibrin gel porosity by low dose than intermediate dose acetylsalicylic acid. Eur Heart J 1998;19:1666-72. 6. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381-6. doi:10.1016/j.jvs.2008.11.028
Regarding “Strategies to improve spinal cord ischemia in endovascular thoracic aortic repair: Outcomes of a prospective cerebrospinal fluid drainage protocol” We read with interest the recent article by Hnath et al1 on outcomes after routine cerebrospinal fluid (CSF) drainage to prevent spinal cord ischemia (SCI) in patients undergoing thoracic endovascular aneurysm repair (TEVAR). We routinely use CSF drainage and maintain a high mean arterial pressure to prevent SCI in all patients having open thoracoabdominal aneurysm repair. We perform TEVAR under epidural anesthesia, which provides a good sensory block but preserves motor function, allowing assessment of spinal cord function intraoperatively and postoperatively. We do not, therefore, use prophylactic CSF drainage. We have found emergency CSF drainage with elevation of mean arterial pressure can reverse symptoms if SCI develops after endovascular aneurysm repair.2 Of 260 cases in our center, SCI developed in 10 patients (3.8%) and was reversed by CSF drainage in 7. We agree that the risk of SCI is higher in patients who have had a previous abdominal aortic aneurysm repair, patients in whom a long length of the thoracic aorta will be covered, and in procedures that require coverage of the left subclavian artery without revascularization. It should be pointed out, however, that CSF drainage is not without its complications. We have had three major complications to date from CSF drains placed for patients having both open repair and TEVAR. One patient developed a temperature and had raised inflammatory markers 48 hours after insertion of the CSF drain. A magnetic resonance imaging scan showed an epidural abscess at the site of drain placement (Fig, A). This resolved after antibiotic treatment, but the patient has residual paraparesis, with lower limb weakness and urinary incontinence. Two other patients were found to have retained CSF drains on routine follow-up scans where a residual portion of the catheter had broken off inside the spinal canal (Fig, B and C). They are currently symptomless,
Letters to the Editor 1089
however, and after consultation with neurologists and neurosurgeons, no further treatment is planned. Subdural hematomas have been reported as a direct result of lumbar spinal drainage.3,4 Settepani et al5 also reported intracerebellar hematomata in two patients after drainage of large volumes of CSF. Complications secondary to spinal drains are relatively rare, and in high-risk patients and open thoracoabdominal aneurysm repair, prophylactic CSF drainage should be considered. This may be an unnecessary risk, however, in patients having TEVAR who have not had previous abdominal aneurysm repair and in whom the subclavian artery is not being covered or those who have had prior subclavian artery revascularization. We, therefore, agree that mandatory CSF drainage for all patients undergoing TEVAR is unnecessary. Ashish S. Patel, MRCS, MBBS, BSc Bijan Modarai, PhD, MRCS Rachel Bell, MS, FRCS Peter Taylor, MA, MCh, FRCS Department of Vascular Surgery Guy’s & St. Thomas’ Hospital London, United Kingdom REFERENCES 1. Hnath JC, Mehta M, Taggert JB, Sternbach Y, Roddy SP, Kreienberg PB, et al. Strategies to improve spinal cord ischemia in endovascular thoracic aortic repair: outcomes of a prospective cerebrospinal fluid drainage protocol. J Vasc Surg 2008;48:836-40. 2. Bajwa A, Davis M, Moawad M, Taylor PR. Paraplegia following elective endovascular repair of abdominal aortic aneurysm: reversal with cerebrospinal fluid drainage. Eur J Vasc Endovasc Surg 2008;35:46-8. 3. Dardik A, Perler BA, Roseborough GS, Williams GM. Subdural hematoma after thoracoabdominal aortic aneurysm repair: an underreported complication of spinal fluid drainage? J Vasc Surg 2002;36:47-50. 4. Weaver KD, Wiseman DB, Farber M, Ewend MG, Marston W, Keagy BA. Complications of lumbar drainage after thoracoabdominal aortic aneurysm repair. J Vasc Surg 2001;34:623-7. 5. Settepani F, van Dongen EP, Schepens MA, Morshuis WJ. Intracerebellar hematoma following thoracoabdominal aortic repair: an unreported complication of cerebrospinal fluid drainage. Eur J Cardiothorac Surg 2003;24:659-61. doi:10.1016/j.jvs.2008.11.064
Fig. A, Patient 1: Magnetic resonance scan shows collection at the site of the spinal drain (arrow). B, Patient 2: Retained catheter (arrow) found on routine follow-up computed tomography scan. C, Patent 3: Retained catheter found on routine follow-up computed tomography scan.
cardiovascular mortality compared with the healthy population.6 This abnormal clot structure may also explain an aspect of the development, clinical manifestation, and progression of PAD, along with the increased frequency of cardiovascular events in these patients. This research was funded by a British Heart Foundation Junior Research Fellowship (FS/03/061/15883). Neeraj Bhasin, MD, MRCS(Eng) Duncan J. Parry, MD, FRCS(Ed) D. Julian A. Scott, MD, FRCS(Eng), FEBVS Division of Cardiovascular and Diabetes Research University of Leeds Leeds Vascular Institute Leeds General Infirmary Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom Robert A.S. Ariëns, PhD Peter J. Grant, MD, FRCP Division of Cardiovascular and Diabetes Research University of Leeds Leeds, United Kingdom Robert M. West, DPhil Biostatistics Unit University of Leeds Leeds, United Kingdom REFERENCES 1. Bhasin N, Ariëns RAS, West RM, Parry DJ, Grant PJ, Scott DJA. Altered fibrin clot structure and function in the healthy first degree relatives of subjects with intermittent claudication. J Vasc Surg Article [Epub ahead of print]. 2. Fatah K, Silveira A, Tornvall P, Karpe F, Blomback M, Hamsten A. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost 1996;76:535-40. 3. Nair CH, Azhar A, Dhall DP. Studies of fibrin network structure in human plasma. Part II: Clinical application–Diabetes and Antidiabetic drugs. Thromb Res 1991;64:477-485. 4. Undas A, Celinska-Löwenhoff M, Löwenhoff T, Szczeklik A. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. J Thromb Haemost 2006; 4:1029-36.
Table. Fibrin clot structure and function data P Clot variable
Control
FDR
Claudicant
Ks ⫻10⫺9 cm2a 15.6 (14.7-16.6) 14.6 (13.9-15.3) 13.8 (12.3-15.2) MAb 0.75 (0.67-0.93) 0.86 (0.75-0.98) 0.95 (0.82-1.07) F XIII activity, %b 105 (87-141) 133 (103-155) 129 (97-156) Fiber thickness on LSCM,a nm 315.8 (307.0-324.6) 405.1 (397.6-412.6) 480.2 (466.9-493.6) a Lysis front velocity, m/min 12.66 (6.38-18.94) 4.83 (2.50-7.17) 4.37 (2.89-5.84)
Control vs Control vs FDR vs FDR claudicant claudicant .259 ⬍.001 ⬍.001 ⬍.001 .018
FDR, First-degree relative; Ks, average pore size; LSCM, laser scanning confocal microscopy; MA, fiber thickness by turbidity. a Parametric data are expressed as the mean (95% confidence interval). b Nonparametric data are expressed as median (IQR).
1088
.087 ⬍.001 .042 ⬍.001 .008
.963 .130 ⬎.99 ⬍.001 ⬎.99
JOURNAL OF VASCULAR SURGERY Volume 49, Number 4
5. Williams S, Fatah K, Hjemdahl P, Blomback M. Better increase in fibrin gel porosity by low dose than intermediate dose acetylsalicylic acid. Eur Heart J 1998;19:1666-72. 6. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381-6. doi:10.1016/j.jvs.2008.11.028
Regarding “Strategies to improve spinal cord ischemia in endovascular thoracic aortic repair: Outcomes of a prospective cerebrospinal fluid drainage protocol” We read with interest the recent article by Hnath et al1 on outcomes after routine cerebrospinal fluid (CSF) drainage to prevent spinal cord ischemia (SCI) in patients undergoing thoracic endovascular aneurysm repair (TEVAR). We routinely use CSF drainage and maintain a high mean arterial pressure to prevent SCI in all patients having open thoracoabdominal aneurysm repair. We perform TEVAR under epidural anesthesia, which provides a good sensory block but preserves motor function, allowing assessment of spinal cord function intraoperatively and postoperatively. We do not, therefore, use prophylactic CSF drainage. We have found emergency CSF drainage with elevation of mean arterial pressure can reverse symptoms if SCI develops after endovascular aneurysm repair.2 Of 260 cases in our center, SCI developed in 10 patients (3.8%) and was reversed by CSF drainage in 7. We agree that the risk of SCI is higher in patients who have had a previous abdominal aortic aneurysm repair, patients in whom a long length of the thoracic aorta will be covered, and in procedures that require coverage of the left subclavian artery without revascularization. It should be pointed out, however, that CSF drainage is not without its complications. We have had three major complications to date from CSF drains placed for patients having both open repair and TEVAR. One patient developed a temperature and had raised inflammatory markers 48 hours after insertion of the CSF drain. A magnetic resonance imaging scan showed an epidural abscess at the site of drain placement (Fig, A). This resolved after antibiotic treatment, but the patient has residual paraparesis, with lower limb weakness and urinary incontinence. Two other patients were found to have retained CSF drains on routine follow-up scans where a residual portion of the catheter had broken off inside the spinal canal (Fig, B and C). They are currently symptomless,
Letters to the Editor 1089
however, and after consultation with neurologists and neurosurgeons, no further treatment is planned. Subdural hematomas have been reported as a direct result of lumbar spinal drainage.3,4 Settepani et al5 also reported intracerebellar hematomata in two patients after drainage of large volumes of CSF. Complications secondary to spinal drains are relatively rare, and in high-risk patients and open thoracoabdominal aneurysm repair, prophylactic CSF drainage should be considered. This may be an unnecessary risk, however, in patients having TEVAR who have not had previous abdominal aneurysm repair and in whom the subclavian artery is not being covered or those who have had prior subclavian artery revascularization. We, therefore, agree that mandatory CSF drainage for all patients undergoing TEVAR is unnecessary. Ashish S. Patel, MRCS, MBBS, BSc Bijan Modarai, PhD, MRCS Rachel Bell, MS, FRCS Peter Taylor, MA, MCh, FRCS Department of Vascular Surgery Guy’s & St. Thomas’ Hospital London, United Kingdom REFERENCES 1. Hnath JC, Mehta M, Taggert JB, Sternbach Y, Roddy SP, Kreienberg PB, et al. Strategies to improve spinal cord ischemia in endovascular thoracic aortic repair: outcomes of a prospective cerebrospinal fluid drainage protocol. J Vasc Surg 2008;48:836-40. 2. Bajwa A, Davis M, Moawad M, Taylor PR. Paraplegia following elective endovascular repair of abdominal aortic aneurysm: reversal with cerebrospinal fluid drainage. Eur J Vasc Endovasc Surg 2008;35:46-8. 3. Dardik A, Perler BA, Roseborough GS, Williams GM. Subdural hematoma after thoracoabdominal aortic aneurysm repair: an underreported complication of spinal fluid drainage? J Vasc Surg 2002;36:47-50. 4. Weaver KD, Wiseman DB, Farber M, Ewend MG, Marston W, Keagy BA. Complications of lumbar drainage after thoracoabdominal aortic aneurysm repair. J Vasc Surg 2001;34:623-7. 5. Settepani F, van Dongen EP, Schepens MA, Morshuis WJ. Intracerebellar hematoma following thoracoabdominal aortic repair: an unreported complication of cerebrospinal fluid drainage. Eur J Cardiothorac Surg 2003;24:659-61. doi:10.1016/j.jvs.2008.11.064
Fig. A, Patient 1: Magnetic resonance scan shows collection at the site of the spinal drain (arrow). B, Patient 2: Retained catheter (arrow) found on routine follow-up computed tomography scan. C, Patent 3: Retained catheter found on routine follow-up computed tomography scan.