Current evidence for outcomes of free-flap reconstruction in factor V Leiden

Background: Factor V Leiden is the most common form of inherited thrombophilic syndrome, affecting 5 per cent of caucasians. While increased rates of venous thromboembolic complications have been regularly reported in factor V Leiden patients, little is known about their risk of microvascular complications or flap failure rates in free-flap surgery. The aim of this review is to qualitatively review the published literature on outcomes of free-flap surgery in patients with factor V Leiden. Methods: MEDLINE®, PubMed, EMBASE and Cochrane were searched from their dates of inception to March 2017. Nine studies of level IV evidence were included in this qualitative review. In total, these studies included 22 patients who underwent 24 free-


Introduction
Factor V Leiden is a hereditary condition resulting in a mutation of the genetic composition of factor V, a clotting factor that forms part of the intrinsic clotting cascade. The mutation results in resistance against the normal degradation of factor V by activated protein C, leading to abnormally increased clotting. The risk of developing abnormal blood clots in heterozygous factor V Leiden patients is three to eight times the risk in the general population, while the risk for homogeneous patients can be as high as one in 12, or an 80-fold relative risk. 1,2 Of the inherited thrombophilias, factor V Leiden is the most common: 5 per cent of Caucasians are affected, although incidence rates in other races are much lower than this. 1 Inherited in an autosomal dominant manner, the incidence of those homozygous for the condition is estimated at less than 0.25 per cent, while the incidence of those heterozygous for the condition is 3-7 per cent. 3 The prevalence in Caucasian Australians is even higher, with a newborn screening study finding 9.5 per cent of the population to be heterozygous. 4 Microvascular free-flap reconstruction allows for the reconstruction of complex defects not amenable to repair by other reconstructive options. 5,6 Free-tissue transfer involves the reconstitution of blood supply to the transferred tissue via microanastomosis of the artery and/ or vein. The most significant morbidity in this process is flap failure due to thrombosis at the anastomotic site, both venous and arterial.
Prevention of thrombotic complications typically involves careful vessel dissection and handling, meticulous surgical technique and well-described adjuncts such as heparin, aspirin and dextran. 7,8 However, the literature supporting the use of these agents is varied and inconclusive. 7  duplicates. The two lead authors screened the titles and abstracts of these 217 articles and excluded studies that did not focus on free-flap surgery, did not differentiate between different types of hereditary thrombophilia, such that patients with factor V Leiden could be isolated out, or were not in English. Studies related to digit transplantation were excluded. Thirty-nine full-text studies were then assessed for eligibility, resulting in seven studies that met the inclusion criteria. Through examining the reference lists of these seven studies, three additional studies that met the inclusion criteria were identified. It was noted that Wang and colleagues wrote two case series in 2012 and both included a patient with factor V Leiden. 12,13 Only the case series with the greater number of patients with factor V Leiden was included in this review, since we did not want to count the same patient twice. Nine case studies or series (level IV evidence) were included in this review.

Results
Despite factor V Leiden being a relatively common and well-studied condition, literature on whether or not it affects outcomes in free-flap surgery is scant and limited to level IV evidence (case studies and reviews). Only nine studies, involving 22 patients in total, were found. These studies are outlined in Table 1.  including thrombophilias, has become more significant than the relative influence of surgical factors on free-flap outcomes.

Clinical implications: a role for preoperative screening strategies
Free-tissue transfer is the most complex technique in the reconstructive surgeon's armamentarium.   Such an approach has many merits: it is cost-saving, easy to implement and could foster stronger crossdiscipline collaboration between plastic surgeons and haematologists. Scope for further research includes whether or not adopting such a protocol would be cost-saving for an institution or lead to fewer free-flap complications. Further study should also be undertaken into the molecular pathways involved in microvascular thrombotic events and whether or not such pathways are altered in patients with factor V Leiden.

Disclosures
The authors have no financial or commercial conflicts of interest to disclose. This study was presented as a poster at Plastic Surgery: The Meeting, Chicago, 2018.