Hyperhomocysteinemia (HHCY) Increases the Risk for Lower Extremity Ulcers (LEUs).
Authors: Mavromatis Blanche H. , Gaughan Elizabeth M. , Cheson Bruce D. , Attinger Christopher , Cupps Thomas , Couch Kara , Picken Katherine , Kessler Craig 
Published: April 2020

Abstract
Introduction: LUEs affect 6 million individuals annually in the US, with high morbidity and cost. Normal wound healing requires coagulation, inflammatory responses, angiogenesis, scar formation, and epithelialization. LUEs arise when any of these pathways fail. Aberrant thrombus formation, exacerbated and/or precipitated by inflammation, results in microvascular ischemia and subsequent skin ulceration. HHcy is associated with either inherited (MTHFR C677T and A1298C polymorphisms) or acquired thrombophilia. HHcy accelerates atherosclerosis, but its role in venous hypercoagulability has not been as well established. We conducted a retrospective analysis of 20 consecutive patients (pts) with refractory LEUs and HHcy identified after comprehensive hypercoagulable evaluations. Therapeutic normalization of HHcy was based on supplemental folic acid 1 mg/d, vitamin B6 150 mg/d. The target Hcy level was &lt; 8 μmole/L. Local wound care included frequent dressing changes, silvadene, debridement, whirlpool treatment, skin grafting, compression stockings, and unna boots, and had already been initiated in these pts months previously with little benefit to wound healing of LUEs.
Results: The median age of this cohort was 58 y with 12 females and 8 males. There was predominant Caucasian ethnicity with 17 whites, 2 African Americans, and 1 Asian. Forty per cent (8/20) were heterozygous for the C677T MTHFR gene polymorphism, and 70% (14/20) had at least one other additional hypercoagulable risk factor, including circulating antiphospholipid antibodies, lupus anticoagulant, anti-β-2 glycoprotein-1 antibodies, or anti-cardiolipin antibodies. 2 pts developed their LEUs while on coumadin for their hypercoagulable state. Relevant past medical history included hypertension (10 pts), DM (6), peripheral vascular disease (8), dyslipedemia (5), venous insufficiency (9), obesity (3), prior DVT or PE (3), current DVT (1); sickle cell trait (1) and Ehlers-Danlos syndrome (1). Median number of ulcers/pt was 1 (range 1–8). Median plasma/serum Hcy level was 15.6 μmole/L (range 11.2–42.3). Forty per cent (13/33) LEUs healed completely. 7 pts whose LEUs were unchanged after 1–2 months of vitamin supplementation received prophylactic doses of low molecular weight heparin (LMWH) (Lovenox 40 mg/kg sq/d); 3 of those 7 (43%) experienced complete resolution of their LEUs within weeks. For the overall cohort, reduced LEU dimensions were observed as early as 6 weeks after vitamin intervention. In the remaining 20 a 63.3% reduction in ulcer size (by bi-dimentional measurement) was observed. 4 LEUs healed completely with only folic acid and vitamin B6. Failure was associated with documented vasculitis (1) and elevated lipoprotein a (1). In 15 pts reduced Hcy levels correlated with LUE improvement or complete resolution.
Conclusion: HHcy increases the risk of LUEs. Other associated hypercoagulable risk factors may contribute to refractory or poor healing responses. Normalizing HHcy may contribute to improved stasis ulcer healing. LMWH may provide additional beneficial effects. Individuals with refractory LUEs should be evaluated for HHcy and hypercoagulability, and should be considered for long term folate and vitamin B6 supplementation to lower the Hcy levels, perhaps with adjunctive LMWH. Prospective studies are necessary to elucidate the relative importance of each of these therapies.