Cardiovasc Intervent Radiol DOI 10.1007/s00270-012-0415-z
CASE REPORT
Intra-arterial Autologous Bone Marrow Cell Transplantation in a Patient with Upper-extremity Critical Limb Ischemia Juraj Madaric • Andrej Klepanec • Martin Mistrik Cestmir Altaner • Ivan Vulev
•
Received: 27 March 2012 / Accepted: 22 April 2012 Ó Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2012
Abstract Induction of therapeutic angiogenesis by autologous bone marrow mononuclear cell transplantation has been identified as a potential new option in patients with advanced lower-limb ischemia. There is little evidence of the benefit of intra-arterial cell application in upper-limb critical ischemia. We describe a patient with upper-extremity critical limb ischemia with digital gangrene resulting from hypothenar hammer syndrome successfully treated by intra-arterial autologous bone marrow mononuclear cell transplantation. Keywords Critical limb ischemia Hypothenar hammer syndrome Intra-arterial administration Therapeutic angiogenesis Upper extremity
Introduction Autologous bone marrow stem cell transplantation in patients with unreconstructable critical limb ischemia (CLI) is promising therapeutic modality. Growing evidence supports the positive effect of bone marrow cell (BMC) application in healing foot ulcers and preventing lowerlimb amputation [1–3]. However, information about the benefit of cell therapy in upper-limb critical ischemia is scarce and is oriented solely to intramuscular delivery [4, 5]. The best route for BMC administration in patients with CLI is controversial. Intra-arterial and intramuscular administration of BMCs has shown promising results in the prevention of limb amputation [2, 3]. We report a patient with advanced critical upper-limb ischemia caused by hypothenar hammer syndrome (HHS) treated successfully by intra-arterial BMC delivery.
Case Report J. Madaric (&) Department of Cardiology and Angiology, National Institute of Cardiovascular Diseases, NUSCH and Slovak Medical University, Pod Krasnou Horkou 1, 83348 Bratislava, Slovakia e-mail: jurmad@hotmail.com A. Klepanec I. Vulev Department of Diagnostic and Interventional Radiology, National Institute of Cardiovascular Diseases, Pod Krasnou Horkou 1, 83348 Bratislava, Slovakia M. Mistrik Clinic of Hematology and Transfusiology, Faculty Hospital, Antolska 11, 851 07 Bratislava, Slovakia C. Altaner Institute of Experimental Oncology, Slovak Academy of Science, Bratislava, Slovakia
Our patient was a 50-year-old man, a smoker with diabetes mellitus who worked in a mine and used a pneumatic hammer. He was referred to our center with a history of nonhealing necrosis, local pain in the third finger, and lividity of the second finger of the right hand (Fig. 1). Importantly, there was no improvement after management of risk factors and 3 months of anticoagulation therapy. Transcutaneous oxygen pressure (tcpO2) of the right hand was reduced to 23 mm Hg. The digital brachial index (DBI) was significantly decreased to 0.6. Patient-rated pain intensity on scale of 0–10 was 5. Upon computed tomographic angiography of the arterial system of the right upper extremity, obliteration of the distal part of ulnar artery with patent radial and
123
J. Madaric et al.: Autologous BMC Transplantation
Fig. 1 Nonhealing necrosis of the third finger and lividity of the second finger of the right hand
interosseous arteries was documented. Additionally, digital subtraction angiography revealed distal embolic occlusions of interdigital arteries, predominantly of the third finger (Fig. 2). These findings suggested that endovascular revascularization was not indicated, and the patient refused surgical revascularization. The laboratory results of an autoimmune assessment excluded other causes of digital ischemia. Physiologic and anatomic studies of the contralateral hand revealed no pathologic findings. The clinical and angiographic picture was classified as HHS. To prevent amputation due to progressive ischemia resistant to conservative therapy, administration of autologous intra-arterial bone marrow stem cells into the affected limb was undertaken. The procedure was carried out according to a study protocol approved by the local ethical committee [6]. The patient provided written informed consent before the procedure. Isolation of bone marrow was performed under aseptic conditions under analgosedation with propofol. A total of 240 mL of bone marrow was aspirated from both posterior iliac crests into an aspiration set prefilled with ACD-A anticoagulant (30 mL) and processed with a cell separator (SmartPreP2 Bone Marrow Aspirate Concentrate System; Harvest, Plymouth, MA, USA). This system uses gradient density centrifugation to provide 40 mL of BMC concentrate rich in all blood elements (predominantly white cells) within 15 min. Immediately after bone marrow aspiration and 15-min centrifugation of the aspirate, the puncture of the retrograde common femoral artery and introduction of a
123
4F catheter (Imager II Selective BERN; Boston Scientific, Fremont, CA, USA) into the distal part of the right brachial artery were performed. Afterward, the BMC concentrate was administered by continuous intra-arterial infusion (velocity of administration, 800 mL/h) nonselectively into the distal brachial artery. There were no complications on control angiography. The duration of complete procedure was approximately 1 h. The number of mononuclear cells in the administrated BMCs was 4.8 9 109, and the number of CD34? cells was 32 9 106. The patient was discharged the day after the procedure without complications with single antiaggregation therapy (aspirin). At 3 months’ follow-up, there was marked improvement in finger ischemia, with disappearance of lividity in the second finger and reduction of fingertip necrosis of the third finger. After 6 months, the third finger of the right hand was pink and warm with no signs of necrosis (Fig. 3). Patient-rated pain severity was 0, with no need for analgesics, after 3 months. There was a marked improvement in tcpO2 of the right hand after 3 months to 40 mm Hg; this was even more pronounced at 6 months (97 mm Hg). The DBI improved to 0.9 at 6 months.
Discussion In our patient with CLI of the upper extremity as a result of HHS with unreconstructable arterial disease, autologous intra-arterial BMC transplantation resulted in healing of digital necrosis and relief of ischemic pain at rest. Improved arterial perfusion of the affected extremity was documented by an increase in tcpO2 pressure after 3 months, with further improvement at 6 months’ followup and improvement in the DBI. CLI of the upper extremity is a relatively rare condition that can be caused by any of numerous entities. These include Raynaud disease, connective tissue disorders, vasculitis, arterial cardiac emboli, thromboangiitis obliterans (Buerger disease), atherosclerosis, and thoracic outlet syndrome [7]. HHS is a traumatic condition typically occurring in machinists, miners, sawmill workers, butchers, bricklayers, and carpenters. The angiographic features of HHS include tortuosity of the ulnar artery; aneurysm formation; occlusion of the ulnar artery segment overlying the hook of the hamate; and occluded digital arteries in the ulnar artery distribution, or the intraluminal emboli at the sites of digital obstruction. Standard treatment options include risk-factor management, medical treatment, bypass surgery, thrombectomy, and local thrombolysis. In patients in whom these therapeutic strategies fail or are not possible, amputation can become unavoidable. In our case, the patient experienced occlusion of the distal part of the ulnar artery with
J. Madaric et al.: Autologous BMC Transplantation
Fig. 2 Digital subtraction angiography reveals occlusion of the distal part of the ulnar artery (A) and distal parts of digital arteries in the middle and ring fingers (B)
embolic occlusions of distal parts of interdigital arteries. He refused bypass surgery, and local thrombolysis was not considered because of a 3-month history of digital ulcers. Over the past decade, therapeutic angiogenesis with autologous stem cell transplantation has shown promising results in promoting neovascularization and preventing limb amputation in patients with advanced CLI [8–10]. However, the optimal method of administration of stem cells remains unresolved. Intramuscular approach, intraarterial approach, or a combination of the two have been demonstrated to result in improved clinical status in patients with advanced lower limb ischemia [2, 9, 11]. Intramuscular application of BMCs seems to augment neovascularization with the creation of local depots of implanted cells in the ischemic area with cell transdifferentiation, cell migration, cell-to-cell contact and, importantly, paracrine mechanisms [12]. Conversely, BMCs delivered via the intra-arterial route can reach the
border zone of maximum ischemia by blood flow with preservation of the supply of nutrients and oxygen [13]. In patients with upper-extremity CLI, only intramuscular administration of autologous stem cells has been described [4, 5]. Comerota et al. [4] reported a patient with gangrene of both hands as a result of unreconstructable atherosclerotic disease of both upper extremities successfully treated by intramuscular application of autologous BMCs. Koshikawa et al. [5] reported clinical improvements after intramuscular administration of BMCs in patients with upper-extremity CLI as a result of thromboangiitis obliterans, or collagen vascular disease. In our patient, intra-arterial cell application resulted in healing of digital necrosis and relief of ischemic pain at rest. In conclusion, this case report demonstrates that intraarterial application of BMCs is a safe and effective treatment strategy for patients with advanced CLI, even of the upper extremity.
123
J. Madaric et al.: Autologous BMC Transplantation
2.
3.
4.
5.
6.
7.
8.
9.
10. Fig. 3 Complete improvement of the signs of ischemia of the right hand 6 months after BMC therapy 11. Conflict of interest of interest.
The authors declare that they have no conflict 12.
References 13. 1. Tateishi-Yuyama E, Matsubara H, Murohara T et al (2002) Therapeutic angiogenesis for patients with limb ischaemia by
123
autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360:427–435 Chochola M, Pytlı´k R, Kobylka P et al (2008) Autologous intraarterial infusion of bone marrow mononuclear cells in patients with critical limb ischemia. Int Angiol 27:281–290 Amann B, Luedemann C, Ratei R, Schmidt-Lucke JA (2009) Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transpl 18:371–380 Comerota AJ, Lin A, Douville J, Burchardt ER (2010) Upper extremity ischemia treated with tissue repair cells from adult bone marrow. J Vasc Surg 52:723–729 Koshikawa M, Shimodaira S, Yoshioka T et al (2006) Therapeutic angiogenesis by bone marrow implantation for critical hand ischemia in patients with peripheral arterial disease: a pilot study. Curr Med Res Opin 22:793–798 Madaric J, Klepanec A, Mistrik M et al (2011) Autologous bone marrow cells transplantation in patients with advanced critical limb ischemia: no difference in intra-arterial and intramuscular application. JACC 57:E1473 Chang BB, Roddy SP, Darling RC III et al (2003) Upper extremity bypass grafting for limb salvage in end-stage renal failure. J Vasc Surg 38:1313–1315 Procha´zka V, Gumulec J, Jalu˚vka F et al (2010) Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transpl 19:1413–1424 Lara-Hernandez R, Lozano-Vilardell P, Blanes P et al (2010) Safety and efficacy of therapeutic angiogenesis as a novel treatment in patients with critical limb ischemia. Ann Vasc Surg 24:287–294 Miyamoto K, Nishigami K, Nagaya N et al (2006) Unblinded pilot study of autologous transplantation of bone marrow mononuclear cells in patients with thromboangiitis obliterans. Circulation 114:2679–2684 Bartsch T, Brehm M, Zeus T et al (2007) Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study). Clin Res Cardiol 96:891–899 Zhou B, Poon MC, Pu WT, Han ZC (2007) Therapeutic neovascularisation for peripheral arterial disease: advances and perspectives. Histol Histopathol 22:677–686 Sprengers RW, Lips DJ, Moll FL, Verhaar MC (2008) Progenitor cell therapy in patients with critical limb ischemia without surgical options. Ann Surg 247:411–420