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Factor XIII levels correlate with fibrinogen concentrations in patients with venous malformations

Venous malformations (VM) are congenital slow-flow vascular malformations, with a prevalence of ∼1%. The term encapsulates structural anomalies of varying size and severity, which may be unifocal or multifocal.1,2 Symptoms and clinical features tend to progress with age. Coagulopathy can be a significant problem for patients with very large or multiple lesions,1–3 taking the form of a localised intravascular coagulopathy (LIC), often with palpable phleboliths, which can be demonstrated on MRI.4 The coagulopathy can lead to disseminated intravascular coagulation (DIC), heralded by rising D-dimers.5 Complications may include embolization and bleeding.6 D-dimers are elevated in the majority of cases.5 In severe cases fibrinogen levels are reduced.3,7 There is a paucity of data on extended coagulation factor screens. However, where these are available, factor V is occasionally decreased, and there is conflicting data on the role of von Willebrand factor.2,7 A recent paper has shown a mild decrease in factor XIII levels in ∼20% of patients, but with no levels below 53 IU/dL (lower limit of normal in study 76 IU/dl).8 The cause of depleted factor XIII levels is speculative at present but may include endothelial activation and enhanced fibrinolysis, aswell as a potential role for causativemutations in endothelial receptors.7,8 In our hospital we have a large multidisciplinary VM service involving dermatology, plastic, general, ENT and vascular surgery teams, urology, interventional radiology and haematology, with experience in the coagulopathy associated with these disorders. We have previously been alerted to a correlation between fibrinogen and factor XIII in VM patients. In order to formally review our practice, we performed a single-centre retrospective study to assess the coagulation defects seen in patients with VMs. We collected data on all patients seen in our hospital who had factor XIII checked between June 2014 and June 2021(n= 190). Of these, 84 had a diagnosis of VM: unspecified (n = 78), glomuvenous malformation (n = 2), or blue rubber bleb naevus syndrome (n = 4). Four others had a lymphovenous malformation or generalised lymphatic anomaly, whichwe collated separately (Supplemental Figure S1A–C). Datawere collected on baseline coagulation profile at diagnosis, or when coagulation was first assessed with the following together: prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), functional (Clauss) fibrinogen and D-dimers, as well as platelet count, factor XIII levels and extended factor assays, where available. As described previously, there were no consistent abnormalities in the PT and APTT (Figure 1A) or, where assessed, the associated coagulation factors (Table 1). Two patients had amild decrease in factor V (Table 1), which is known to occur in DIC.9 D-dimers were elevated in themajority of patients (48/77) and were the first and only test noted to be abnormal in somepatientswithdevelopingDIC (Figure1B, data forVM subgroups inSupplemental FigureS1A). This is in keepingwithprevious data,5 but in the small number of patients with a progressive consumptive coagulopathy we also noted a platelet count drop (Figure 1C). Importantly, around 25% of patients (20/84) had a fibrinogen level below our laboratory normal range of 1.7 g/L (Figure 1D, data for VM subgroups in Supplemental Figure S1B). Patients with a low fibrinogen also had significantly elevated D-dimers (Figure 1E), suggestive of an underlying severe coagulopathy. Further, a fibrinogen below 1.5 g/L was predictive of a low factor XIII (Figure 1F, data for VM subgroups in Supplemental Figure S1C). Only 1/16 patients with a low fibrinogen had a normal factor XIII: this patient had a very small VM, and on analysis of further data the fibrinogen level spontaneously returned to normal and remained robustly normal with no intervention, suggesting an alternative cause for the low fibrinogen or inter-current illness of the patient at first testing. In contrast, all patients with a normal fibrinogen concentration had a normal factor XIII (Figure 1F). In patients with more pronounced DIC, indicated by elevated D-dimers, factor XIII levels were also significantly depleted (Supplemental Figure S1D), suggesting a role of DIC in the depletion of FXIII. Taken together, this suggests that any VM patient with a low fibrinogen should be assessed for factor XIII which may help guide supplementation around procedures, or in the case of major haemorrhage. However, the role of supplementation should be evaluated in trials. Patients with a lymphovenous malformation showed a similar pattern, but with little data to extrapolate further (Supplemental Figure S1A–C). Overall, our data demonstrates that in patients with slow-flow vascular malformations, a low fibrinogen level correlates closely with a reduction in factor XIII levels. There are no other clinically significant coagulation defects, and platelet counts are maintained in all but the most severe cases. Whilst our study is retrospective, all patients coming to our VM service have a baseline coagulation screen with factor XIII assessed where indicated. FactorXIII ismore significantly depleted in our cohort than in the literature, suggesting that the acquired factor XIII deficiency can be more profound than previously described.8 Our centre is a major paediatric referral centres for children’s VMs, and therefore the data may be reflective of more severe and significant defects. This is also supported by lower fibrinogen levels than are seen in other studies.3,7 Our laboratory uses an automated functional chromogenic