- Email: [email protected]
Parameters predicting complications in flap surgery
Vol. 115 No. 5 May 2013
Parameters predicting complications in flap surgery Jörg Handschel, PhD, MD, DDS,a Stefan Burghardt, MD, DDS,a Christian Naujoks, PhD, MD, DDS,a Norbert R. Kübler, PhD, MD, DDS,a and Günter Giers, PhD, MD, DDS,b Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany Objectives. The aim of this prospective study was to determine laboratory parameters predicting complications and/or failure in flap surgery. Study Design. Fifty-seven patients undergoing reconstructive surgery with cutaneous free and pedicled flaps were included. Blood samples were taken 2 days before surgery and 1, 3, 5, 7, and 14 days after. Parameters associated with thrombophilia, bleeding disorders, and wound healing were determined. Results. In 45 (77%) of 57 patients no complications occurred. Bleeding (9%) and venous thrombosis of the flaps (9%) led in 18% of the cases to surgical revisions. Activated protein C resistance showed a significant (P ⬍ .05) cluster in cases with venous thrombosis, whereas it was absent in all other cases. Fibrinogen, factor VIII:C, von Willebrand factor (vWF) activity, and VWF antigen were significantly (P ⬍ .05) higher in patients with venous thrombosis compared with all other patients. Conclusions. Laboratory parameters of thrombosis and bleeding appear to be associated with complications in flap surgery. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:589-594)
The therapy of squamous cell carcinomas and other malignancies1,2 of the head and neck area is dominated by surgical treatment, followed by radiotherapy.3 Owing to the fact that the management of head and neck cancer often creates extensive tissue defects, flap surgery has become a routine option during the past decades. Numerous flap designs (e.g., radial forearm, fibula, scapula, latissimus dorsi, etc.) have been introduced so far. The development and refinement of surgical instruments and methods have improved the reported success rates to 92%-96%.4,5 However, accounting for the difference in success is problematic. Khouri suggested in 1992 that it “rests upon a multitude of minute details,” and that is probably still true today.6,7 Indeed, there are many factors influencing the success of free or pedicled flap surgery. Besides the surgical technique, some other parameters influence the outcome. Interestingly, whereas older age8 and smoking6 do not have a significant effect on the success rate, the overall health condition9 as well as previously performed surgical treatment (e.g., neck dissection)9 in the head and neck area influence the outcome. Herold et al. reported that platelet count and leukocyte count had a significant effect on the complication rate and prognosis of free flaps.10 This is of significance because thrombosis and infection of the flap (or the recipient site) are the predominant reasons for complications requiring surgical revisions. Pohlenz et al. reported in their retroa
Department for Cranio- and Maxillofacial Surgery. Department of Laboratory Medicine, Medical Faculty. Received for publication Jul 24, 2012; returned for revision Aug 21, 2012; accepted for publication Sep 9, 2012. © 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2012.09.007
b
spective study including 1,000 flaps that venous thrombosis and hematoma are the most common complications at the recipient site and are mainly responsible for flap failure.5 Kruse et al. evaluated 81 radial forearm flaps. The main reason for flap failure was venous thrombosis (3 out of 81 flaps) followed by 1 arterial thrombosis.11 In another study evaluating 4,965 flaps it was shown that thrombotic events are a major risk for flap failure.12 Taken together, thrombosis, infection, and bleeding complications seem to play a major role regarding failure or complications in flap surgery. To further improve the success rate of free flaps it could be advantageous to select patients with risk factors regarding these causes in advance. Therefore, the aim of the present prospective study was to determine laboratory parameters predicting complications and/or failure in flap surgery.
MATERIALS AND METHODS Study design and patients This investigation was designed and performed as a prospective study. From March 2011 to March 2012 all patients undergoing reconstructive surgery with cutaneous free and pedicled flaps were included if their informed consent was given to participate. Patients receiving bonecontaining flaps without a cutaneous flap (e.g., fibula without skin island) were excluded. Postoperative care was performed following our standard procedure. Patients were kept sedated for 1 night on the intensive care unit and afterward transfered on our surgical ward. For the postoperative period, antithrombotic prophylaxis with low-molecular-weight heparin was used. Flap monitoring was performed regarding clinical parameters such as color, turgor, and capillary refill. This study was approved by the local Ethical Committee. 589
ORAL AND MAXILLOFACIAL SURGERY 590 Handschel et al.
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Fig. 1. Distribution of revisions by causes.
Sampling and parameters Blood samples were taken 2 days before surgery and 1, 3, 5, 7, and 14 days after. Parameters describing thrombophilia, bleeding disorders, and wound healing were determined: Parameters of thrombophilia: cardiolipin antibodies,13 lupus anticoagulant,14 2-glycoprotein I antibodies,15,16 activated protein C (APC) resistance,17 prothrombin mutation G20210A,17 factor V Leiden,17 lipoprotein (a),18 low antithrombin,16 low protein C,18 low protein S,18 high factor VIII:C, high von Willebrand factor (VWF) activity/antigen. Parameter of hemorrhagic diathesis:18 in vitro bleeding time (closure time with the use of platelet function analyzer [PFA]),19 low von Willebrand factor antigen/ activity.20,21 General parameters of coagulation: partial thromboplastin time (PTT),22 prothrombin time (Quick value, in %),23 thrombin time,24 fibrinogen,25 factor XIII,26 factor VIII,27 D dimer.28 Parameters of wound healing:29 high-sensitivity C-reactive protein (CRP),30 carbohydrate-deficient transferrin (CDT),31 neuron-specific enolase (NSE).32 Statistical analysis For statistical analysis, SPSS 20.0 software was used. Descriptive statistics were used to describe the baseline characteristics of the patients. To detect any statistical differences, the Mann-Whitney U test and the 2 test were performed. A P value of ⬍.05 was considered to be statistically significant.
RESULTS Fifty-seven patients (23 female/34 male) participated in the study. In total, 61 flaps were used to perform
the surgical reconstruction. The predominant type of flap was the radial forearm flap (n ⫽ 44 [72%]), followed by scapula (7 [11%]) and the pectoralis major flap (6 [10%]) (Figure 1) Three flaps in 2 patients had to be removed, so the total failures numbered 3 (4.9%). However, various complications were observed that made surgical revision necessary. In 77%, no complications and revisions occurred, but bleeding (9%) and venous thrombosis (9%) led in 18% of the cases to surgical revisions. Other reasons were thrombosis of the artery (2%) and partial necrosis of the flap (3%). Most revisions (9 out of 14) were performed during the first 4 days. Whereas on days 1 and 2, a total of 8 surgical interventions (57%) were necessary, only 5 revisions were performed after postoperative day 5. Interestingly, APC resistance, which was determined before surgery, showed a cluster in cases with venous thrombosis whereas it was absent in all other cases (Figure 2). Moreover, the preoperatively determined values for fibrinogen, factor VIII:C, VWF activity, and VWF antigen showed significant differences between the various revision groups (Figures 3 and 4). Interestingly, in all of these parameters, the values in patients with venous thrombosis were significantly higher than in patients with an unremarkable follow-up the cases with bleeding events had significant lower values than patients without complications. Thus, these parameters were correlated with the clinical follow-up. It is important to know that the commonly evaluated parameters describing the risk for bleeding disorders or thrombophilia (prothrombin time [Quick value, %], activated PTT) showed no significant differences between the revision groups. Finally, the last values of the above-mentioned parameters before a surgical
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ORIGINAL ARTICLE Handschel et al. 591
Fig. 2. Distributions of patients with (positive) and without (negative) activated protein C resistance according to the revision groups.
Fig. 3. Preoperative values with significant differences between the complication groups. Note that the values of the bleeding group are significantly higher and those of the venous thrombosis group significantly lower than the control group (white bars, no revisions). VIIIC, Factor VIII:C; vW, von Willebrand factor.
revision were compared at this time point with all other cases without a revision. There were no statistical significant differences (data not shown).
DISCUSSION The purpose of this prospective study was to determine laboratory parameters predicting complications and/or failure in flap surgery. The overall failure rate in this investigation is similar to other published data of
5%-10%.5,9,11 Moreover, the need for surgical revision reported in the literature is similar to our rate (10%-20%).5,9 Despite generally excellent results, a small but clinically relevant risk remains necessitating urgent reexplorations because of complications (bleeding, thrombosis, etc). In view of this situation and to further optimize the clinical outcome in flap surgery, it seems reasonable to search for risk factors predicting flap revisions or failure.
ORAL AND MAXILLOFACIAL SURGERY 592 Handschel et al.
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Fig. 4. Preoperative values of fibrinogen with significant differences between complication groups. Note that the values of the bleeding group are significantly higher and those of the venous thrombosis group significantly lower than the control group (white bar, no revisions).
In the present study, we found a higher rate of prothrombotic risk factors in patients with complications. These prothrombotic risk factor were resistance to APC and increased activities of fibrinogen, factor VIII:C, VWF activity, and VWF antigen. Resistance to APC was first described in 1993 and subsequently shown to be caused by a mutation in clotting factor V, factor V Leiden.33,34 When factor V has a mutation at one of the cleavage sites for APC (factor VR506Q, or factor V Leiden), it is less sensitive to the natural anticoagulant protein C–protein S system, i.e., there is resistance to APC. This mutation leads to gain of function rather than loss of function, increasing the risk by ⬃8-fold among heterozygous carriers.35 Increased activities of fibrinogen, factor VIII:C, VWF activity, and VWF antigen are typically found in inflammatory reactions of different kinds, such as infection, malignancy, autoimmune diseases, etc. High concentrations of clotting factor VIII are associated with a 6-fold increased risk of thrombosis,35 and high concentrations of fibrinogen are associated with a 4-fold increased risk of thrombosis.36 High concentrations of clotting factor VIII are related to increased risk of thrombosis. Factor VIII concentrations that exceed 150% compared with those below 1,000 IU/L were associated with a 6-fold increased risk of thrombosis.35 In some individuals, increased levels of factor VIII are found independently from an inflammatory response. Concentrations of factor VIII are determined mostly by blood group, which accounts for the old observation of a relation between non-O blood groups and risk of thrombosis.37,38 High concentrations of clotting factors are not caused by a mutation that has disrupted the
normal sequence of a gene, as is the case with the deficiencies, but are the result of more subtle changes in the regulation of gene activity. Several genetic loci influence the concentrations of clotting factors. For example, for factor VIII there are at least 3 sets of genes involved. The first are the genes that code for ABO blood group, because people with blood group O have lower concentrations of factor VIII (and VWF) than those with non-O blood groups. The second are genes for VWF, the carrier protein for factor VIII. Finally, there is an unknown set of genes, because even when blood group and VWF are taken into account, there is still a familial tendency to aggregation of factor VIII concentrations, for which no cause has yet been found within the factor VIII gene.39 A limitation of the present prospective study is the number of patients. Although 57 patients are included, many more patients would be necessary to detect smaller effects of laboratory parameters on the overall success rate. Finally, it is interesting to discuss what these results mean for clinical practice. To be honest, our study gives a hint that there could be changes in practice that might improve the outcome, but our study is not and interventional trial. However, based on our findings it might be reasonable to change the anticoagulation strategies in patients with risk for bleeding or thrombosis. Therefore, the above-mentioned parameters should be determined before surgical treatment. The advantage of those treatment changes can be determined only in clinical trials. Taken together, the above-mentioned laboratory parameters of thrombosis and bleeding appear to be as-
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sociated with complications in flap surgery. However, our study results are preliminary and of a descriptive nature. Confirmation with larger patient numbers are desirable.
ORIGINAL ARTICLE Handschel et al. 593
19. 20.
REFERENCES 1. Handschel J, Herbst H, Brand B, Meyer U, Piffko J. Intraoral sebaceous carcinoma. Br J Oral Maxillofac Surg 2003;41:84-7. 2. Handschel JG, Depprich RA, Zimmermann AC, Braunstein S, Kübler NR. Adenomatoid odontogenic tumor of the mandible: review of the literature and report of a rare case. Head Face Med 2005;1:3. 3. Prott FJ, Handschel J, Micke O, Sunderkötter C, Meyer U, Piffko J. Long-term alterations of oral mucosa in radiotherapy patients. Int J Radiat Oncol Biol Phys 2002;54:203-10. 4. Genden EM, Rinaldo A, Suárez C, Wei WI, Bradley PJ, Ferlito A. Complications of free flap transfers for head and neck reconstruction following cancer resection. Oral Oncol 2004;40:979-84. 5. Pohlenz P, Klatt J, Schön G, Blessmann M, Li L, Schmelzle R. Microvascular free flaps in head and neck surgery: complications and outcome of 1000 flaps. Int J Oral Maxillofac Surg 2012; 41:739-43. 6. Gardiner MD, Nanchahal J. Strategies to ensure success of microvascular free tissue transfer. J Plast Reconstr Aesthet Surg 2010;63:e665-673. 7. Khouri RK. Avoiding free flap failure. Clin Plast Surg 1992;19: 773-81. 8. Kim HK, Park B, Bae TH, Kim WS. Comparative study of the postoperative complications of microvascular surgery in elderly and young patients. J Reconstr Microsurg 2011;27: 219-24. 9. Mücke T, Rau A, Weitz J, Ljubic A, Rohleder N, Wolff KD, et al. Influence of irradiation and oncologic surgery on head and neck microsurgical reconstructions. Oral Oncol 2012;48:367-71. 10. Herold C, Gohritz A, Meyer-Marcotty M, Steiert A, Jokuszies A, Vaske B, Vogt PM. Is there an association between comorbidities and the outcome of microvascular free tissue transfer? J Reconstr Microsurg 2011;27:127-32. 11. Kruse AL, Bredell MG, Lübbers HT, Jacobsen C, Grätz KW, Obwegeser JA. Clinical reliability of radial forearm free-flap procedure in reconstructive head and neck surgery. J Craniofac Surg 2011;22:822-5. 12. Selber JC, Soto M, Liu J, Robb G. The survival curve: factors impacting the outcome of free flap take-backs. Plast Reconstr Surg 2012;130:105-13. 13. Sallai KK, Nagy E, Bodó I, Mohl A, Gergely P. Thrombosis risk in systemic lupus erythematosus: the role of thrombophilic risk factors. Scand J Rheumatol 2007;36:198-205. 14. Gris JC, Bouvier S, Molinari N, Galanaud JP, Cochery-Nouvellon E, Mercier E, et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood 2012;119:2624-32. 15. Fischer-Betz R, Specker C, Brinks R, Schneider M. Pregnancy outcome in patients with antiphospholipid syndrome after cerebral ischemic events: an observational study. Lupus 2012. 16. Rahman A, Islam AM and Husnayen S, Husnayen S. Recurrent deep vein thrombosis due to thrombophilia. Korean Circ J 2012;42:345-8. 17. Johnson NV, Khor B, van Cott EM. Advances in laboratory testing for thrombophilia. Am J Hematol 2012;87(Suppl 1): S108-112. 18. Kenet G, Lütkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, et al. Impact of thrombophilia on risk of arterial
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ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation 2010;121:1838-47. Rand ML, Leung R, Packham MA. Platelet function assays. Transfus Apher Sci 2003;28:307-17. Heilmann C, Geisen U, Beyersdorf F, Nakamura L, Benk C, Trummer G, et al. Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS). Intensive Care Med 2012;38:62-8. Lasne D, Dey C, Dautzenberg MD, Cherqaoui Z, Monge F, Aouba A, et al. Screening for von Willebrand disease: contribution of an automated assay for von Willebrand factor activity. Haemophilia 2012;18:e158-63. Mathis AS, Davé N, Shah NK, Friedman GS. Bleeding and thrombosis in high-risk renal transplantation candidates using heparin. Ann Pharmacother 2004;38:537-43. Sølbeck S, Ostrowski SR, Johansson PI. A review of the clinical utility of INR to monitor and guide administration of prothrombin complex concentrate to orally anticoagulated patients. Thromb J 2012;10:5. Flanders MM, Crist R, Rodgers GM. Comparison of five thrombin time reagents. Clin Chem 2003;49:169-72. Sørensen B, Larsen OH, Rea CJ, Tang M, Foley JH, FengerEriksen C. Fibrinogen as a hemostatic agent. Semin Thromb Hemost 2012;38:268-73. Muszbek L, Bereczky Z, Bagoly Z, Komáromi I, Katona E, XIII F. A coagulation factor with multiple plasmatic and cellular functions. Physiol Rev 2011;91:931-72. Dimitrov JD, Christophe OD, Kang J, Repessé Y, Delignat S, Kaveri SV, Lacroix-Desmazes S. Thermodynamic analysis of the interaction of factor VIII with von Willebrand factor. Biochemistry 2012;51:4108-16. Lukas PS, Neugebauer A, Schnyder S, Biasiutti FD, Krummenacher R, Ferrari ML, von Känel R. Depressive symptoms, perceived social support, and prothrombotic measures in patients with venous thromboembolism. Thromb Res 2012;130, Nos.:374-380. Julovi SM, Xue M, Dervish S, Sambrook PN, March L, Jackson CJ. Protease activated receptor-2 mediates activated protein Cinduced cutaneous wound healing via inhibition of p38. Am J Pathol 2011;179:2233-42. Malpartida F, Vivancos R, Urbano C, Mora J. [Inflammation and plaque instability]. Arch Cardiol Mex 2007;77(Suppl 4):S4-16.-22. McKinzie BP, Worrall CL, Simpson KN, Couillard DJ, Leon SM. Impact of elevated per cent carbohydrate-deficient transferrin at hospital admission on outcomes in trauma patients. Am Surg 2010;76:492-6. Chabok SY, Moghadam AD, Saneei Z, Amlashi FG, Leili EK, Amiri ZM. Neuron-specific enolase and S100BB as outcome predictors in severe diffuse axonal injury. J Trauma Acute Care Surg 2012;72:1654-7. Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 1993;90:1004-8. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369:64-7. Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993;342:1503-6. Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briët E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors
ORAL AND MAXILLOFACIAL SURGERY 594 Handschel et al. for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms—the Leiden thrombophilia study (LETS). Thromb Haemost 1994;71:719-22. 37. Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345:152-5. 38. Jick H, Slone D, Westerholm B, Inman WH, Vessey MP, Shapiro S, et al. Venous thromboembolic disease and ABO blood type. A cooperative study. Lancet 1969;1:539-42. 39. Kamphuisen PW, Houwing-Duistermaat JJ, van Houwelingen HC, Eikenboom JC, Bertina RM, Rosendaal FR. Familial clus-
OOOO May 2013 tering of factor VIII and von Willebrand factor levels. Thromb Haemost 1998;79:323-7. Reprint requests: Priv.-Doz.Dr. Dr. Jörg Handschel Department for Cranio- and Maxillofacial Surgery Heinrich-Heine-University Düsseldorf Moorenstraße 5 (Geb. 18.73) D-40225 Düsseldorf Germany [email protected]
Parameters predicting complications in flap surgery Jörg Handschel, PhD, MD, DDS,a Stefan Burghardt, MD, DDS,a Christian Naujoks, PhD, MD, DDS,a Norbert R. Kübler, PhD, MD, DDS,a and Günter Giers, PhD, MD, DDS,b Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany Objectives. The aim of this prospective study was to determine laboratory parameters predicting complications and/or failure in flap surgery. Study Design. Fifty-seven patients undergoing reconstructive surgery with cutaneous free and pedicled flaps were included. Blood samples were taken 2 days before surgery and 1, 3, 5, 7, and 14 days after. Parameters associated with thrombophilia, bleeding disorders, and wound healing were determined. Results. In 45 (77%) of 57 patients no complications occurred. Bleeding (9%) and venous thrombosis of the flaps (9%) led in 18% of the cases to surgical revisions. Activated protein C resistance showed a significant (P ⬍ .05) cluster in cases with venous thrombosis, whereas it was absent in all other cases. Fibrinogen, factor VIII:C, von Willebrand factor (vWF) activity, and VWF antigen were significantly (P ⬍ .05) higher in patients with venous thrombosis compared with all other patients. Conclusions. Laboratory parameters of thrombosis and bleeding appear to be associated with complications in flap surgery. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:589-594)
The therapy of squamous cell carcinomas and other malignancies1,2 of the head and neck area is dominated by surgical treatment, followed by radiotherapy.3 Owing to the fact that the management of head and neck cancer often creates extensive tissue defects, flap surgery has become a routine option during the past decades. Numerous flap designs (e.g., radial forearm, fibula, scapula, latissimus dorsi, etc.) have been introduced so far. The development and refinement of surgical instruments and methods have improved the reported success rates to 92%-96%.4,5 However, accounting for the difference in success is problematic. Khouri suggested in 1992 that it “rests upon a multitude of minute details,” and that is probably still true today.6,7 Indeed, there are many factors influencing the success of free or pedicled flap surgery. Besides the surgical technique, some other parameters influence the outcome. Interestingly, whereas older age8 and smoking6 do not have a significant effect on the success rate, the overall health condition9 as well as previously performed surgical treatment (e.g., neck dissection)9 in the head and neck area influence the outcome. Herold et al. reported that platelet count and leukocyte count had a significant effect on the complication rate and prognosis of free flaps.10 This is of significance because thrombosis and infection of the flap (or the recipient site) are the predominant reasons for complications requiring surgical revisions. Pohlenz et al. reported in their retroa
Department for Cranio- and Maxillofacial Surgery. Department of Laboratory Medicine, Medical Faculty. Received for publication Jul 24, 2012; returned for revision Aug 21, 2012; accepted for publication Sep 9, 2012. © 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2012.09.007
b
spective study including 1,000 flaps that venous thrombosis and hematoma are the most common complications at the recipient site and are mainly responsible for flap failure.5 Kruse et al. evaluated 81 radial forearm flaps. The main reason for flap failure was venous thrombosis (3 out of 81 flaps) followed by 1 arterial thrombosis.11 In another study evaluating 4,965 flaps it was shown that thrombotic events are a major risk for flap failure.12 Taken together, thrombosis, infection, and bleeding complications seem to play a major role regarding failure or complications in flap surgery. To further improve the success rate of free flaps it could be advantageous to select patients with risk factors regarding these causes in advance. Therefore, the aim of the present prospective study was to determine laboratory parameters predicting complications and/or failure in flap surgery.
MATERIALS AND METHODS Study design and patients This investigation was designed and performed as a prospective study. From March 2011 to March 2012 all patients undergoing reconstructive surgery with cutaneous free and pedicled flaps were included if their informed consent was given to participate. Patients receiving bonecontaining flaps without a cutaneous flap (e.g., fibula without skin island) were excluded. Postoperative care was performed following our standard procedure. Patients were kept sedated for 1 night on the intensive care unit and afterward transfered on our surgical ward. For the postoperative period, antithrombotic prophylaxis with low-molecular-weight heparin was used. Flap monitoring was performed regarding clinical parameters such as color, turgor, and capillary refill. This study was approved by the local Ethical Committee. 589
ORAL AND MAXILLOFACIAL SURGERY 590 Handschel et al.
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Fig. 1. Distribution of revisions by causes.
Sampling and parameters Blood samples were taken 2 days before surgery and 1, 3, 5, 7, and 14 days after. Parameters describing thrombophilia, bleeding disorders, and wound healing were determined: Parameters of thrombophilia: cardiolipin antibodies,13 lupus anticoagulant,14 2-glycoprotein I antibodies,15,16 activated protein C (APC) resistance,17 prothrombin mutation G20210A,17 factor V Leiden,17 lipoprotein (a),18 low antithrombin,16 low protein C,18 low protein S,18 high factor VIII:C, high von Willebrand factor (VWF) activity/antigen. Parameter of hemorrhagic diathesis:18 in vitro bleeding time (closure time with the use of platelet function analyzer [PFA]),19 low von Willebrand factor antigen/ activity.20,21 General parameters of coagulation: partial thromboplastin time (PTT),22 prothrombin time (Quick value, in %),23 thrombin time,24 fibrinogen,25 factor XIII,26 factor VIII,27 D dimer.28 Parameters of wound healing:29 high-sensitivity C-reactive protein (CRP),30 carbohydrate-deficient transferrin (CDT),31 neuron-specific enolase (NSE).32 Statistical analysis For statistical analysis, SPSS 20.0 software was used. Descriptive statistics were used to describe the baseline characteristics of the patients. To detect any statistical differences, the Mann-Whitney U test and the 2 test were performed. A P value of ⬍.05 was considered to be statistically significant.
RESULTS Fifty-seven patients (23 female/34 male) participated in the study. In total, 61 flaps were used to perform
the surgical reconstruction. The predominant type of flap was the radial forearm flap (n ⫽ 44 [72%]), followed by scapula (7 [11%]) and the pectoralis major flap (6 [10%]) (Figure 1) Three flaps in 2 patients had to be removed, so the total failures numbered 3 (4.9%). However, various complications were observed that made surgical revision necessary. In 77%, no complications and revisions occurred, but bleeding (9%) and venous thrombosis (9%) led in 18% of the cases to surgical revisions. Other reasons were thrombosis of the artery (2%) and partial necrosis of the flap (3%). Most revisions (9 out of 14) were performed during the first 4 days. Whereas on days 1 and 2, a total of 8 surgical interventions (57%) were necessary, only 5 revisions were performed after postoperative day 5. Interestingly, APC resistance, which was determined before surgery, showed a cluster in cases with venous thrombosis whereas it was absent in all other cases (Figure 2). Moreover, the preoperatively determined values for fibrinogen, factor VIII:C, VWF activity, and VWF antigen showed significant differences between the various revision groups (Figures 3 and 4). Interestingly, in all of these parameters, the values in patients with venous thrombosis were significantly higher than in patients with an unremarkable follow-up the cases with bleeding events had significant lower values than patients without complications. Thus, these parameters were correlated with the clinical follow-up. It is important to know that the commonly evaluated parameters describing the risk for bleeding disorders or thrombophilia (prothrombin time [Quick value, %], activated PTT) showed no significant differences between the revision groups. Finally, the last values of the above-mentioned parameters before a surgical
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ORIGINAL ARTICLE Handschel et al. 591
Fig. 2. Distributions of patients with (positive) and without (negative) activated protein C resistance according to the revision groups.
Fig. 3. Preoperative values with significant differences between the complication groups. Note that the values of the bleeding group are significantly higher and those of the venous thrombosis group significantly lower than the control group (white bars, no revisions). VIIIC, Factor VIII:C; vW, von Willebrand factor.
revision were compared at this time point with all other cases without a revision. There were no statistical significant differences (data not shown).
DISCUSSION The purpose of this prospective study was to determine laboratory parameters predicting complications and/or failure in flap surgery. The overall failure rate in this investigation is similar to other published data of
5%-10%.5,9,11 Moreover, the need for surgical revision reported in the literature is similar to our rate (10%-20%).5,9 Despite generally excellent results, a small but clinically relevant risk remains necessitating urgent reexplorations because of complications (bleeding, thrombosis, etc). In view of this situation and to further optimize the clinical outcome in flap surgery, it seems reasonable to search for risk factors predicting flap revisions or failure.
ORAL AND MAXILLOFACIAL SURGERY 592 Handschel et al.
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Fig. 4. Preoperative values of fibrinogen with significant differences between complication groups. Note that the values of the bleeding group are significantly higher and those of the venous thrombosis group significantly lower than the control group (white bar, no revisions).
In the present study, we found a higher rate of prothrombotic risk factors in patients with complications. These prothrombotic risk factor were resistance to APC and increased activities of fibrinogen, factor VIII:C, VWF activity, and VWF antigen. Resistance to APC was first described in 1993 and subsequently shown to be caused by a mutation in clotting factor V, factor V Leiden.33,34 When factor V has a mutation at one of the cleavage sites for APC (factor VR506Q, or factor V Leiden), it is less sensitive to the natural anticoagulant protein C–protein S system, i.e., there is resistance to APC. This mutation leads to gain of function rather than loss of function, increasing the risk by ⬃8-fold among heterozygous carriers.35 Increased activities of fibrinogen, factor VIII:C, VWF activity, and VWF antigen are typically found in inflammatory reactions of different kinds, such as infection, malignancy, autoimmune diseases, etc. High concentrations of clotting factor VIII are associated with a 6-fold increased risk of thrombosis,35 and high concentrations of fibrinogen are associated with a 4-fold increased risk of thrombosis.36 High concentrations of clotting factor VIII are related to increased risk of thrombosis. Factor VIII concentrations that exceed 150% compared with those below 1,000 IU/L were associated with a 6-fold increased risk of thrombosis.35 In some individuals, increased levels of factor VIII are found independently from an inflammatory response. Concentrations of factor VIII are determined mostly by blood group, which accounts for the old observation of a relation between non-O blood groups and risk of thrombosis.37,38 High concentrations of clotting factors are not caused by a mutation that has disrupted the
normal sequence of a gene, as is the case with the deficiencies, but are the result of more subtle changes in the regulation of gene activity. Several genetic loci influence the concentrations of clotting factors. For example, for factor VIII there are at least 3 sets of genes involved. The first are the genes that code for ABO blood group, because people with blood group O have lower concentrations of factor VIII (and VWF) than those with non-O blood groups. The second are genes for VWF, the carrier protein for factor VIII. Finally, there is an unknown set of genes, because even when blood group and VWF are taken into account, there is still a familial tendency to aggregation of factor VIII concentrations, for which no cause has yet been found within the factor VIII gene.39 A limitation of the present prospective study is the number of patients. Although 57 patients are included, many more patients would be necessary to detect smaller effects of laboratory parameters on the overall success rate. Finally, it is interesting to discuss what these results mean for clinical practice. To be honest, our study gives a hint that there could be changes in practice that might improve the outcome, but our study is not and interventional trial. However, based on our findings it might be reasonable to change the anticoagulation strategies in patients with risk for bleeding or thrombosis. Therefore, the above-mentioned parameters should be determined before surgical treatment. The advantage of those treatment changes can be determined only in clinical trials. Taken together, the above-mentioned laboratory parameters of thrombosis and bleeding appear to be as-
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sociated with complications in flap surgery. However, our study results are preliminary and of a descriptive nature. Confirmation with larger patient numbers are desirable.
ORIGINAL ARTICLE Handschel et al. 593
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OOOO May 2013 tering of factor VIII and von Willebrand factor levels. Thromb Haemost 1998;79:323-7. Reprint requests: Priv.-Doz.Dr. Dr. Jörg Handschel Department for Cranio- and Maxillofacial Surgery Heinrich-Heine-University Düsseldorf Moorenstraße 5 (Geb. 18.73) D-40225 Düsseldorf Germany [email protected]