Filgrastim, fibrinolysis, and neovascularization

Darwin Eton, Guolin Zhou, Tong-Chuan He, Amelia Bartholomew, Rachana Patil, Darwin Eton, Guolin Zhou, Tong-Chuan He, Amelia Bartholomew, Rachana Patil

Abstract

Segmental recanalization of chronically occluded arteries was observed in patients with chronic limb-threatening ischemia (CLTI) treated with Filgrastim, a granulocyte colony stimulating factor, every 72 h for up to a month, and an infra-geniculate programmed compression pump (PCP) for 3 h daily. Molecular evidence for fibrinolysis and neovascularization was sought. CLTI patients were treated with PCP alone (N = 19), or with Filgrastim and PCP (N = 8 and N = 6, at two institutions). Enzyme-Linked Immunosorbent Assay was used to measure the plasma concentration of plasmin and of fibrin degradation products (FDP), and the serum concentration of proteins associated with neovascularization. In the PCP-alone group, blood was sampled on Day 1 (baseline) and after 30 days of daily PCP. In the Filgrastim and PCP group, blood was drawn on Day 1, and 1 day after the 5th and the 10th Filgrastim doses. Each blood draw occurred before and after 2 h of supervised PCP. Significant (p < 0.01) PCP independent increases in the plasma concentration of plasmin (>10-fold) and FDP (>5-fold) were observed 1 day after both the 5th and the 10th Filgrastim doses, compared to Day 1. Significant (p < 0.05) increases in the concentration of pro-angiogenic proteins (e.g., HGF, MMP-9, VEGF A) were also observed. Filgrastim at this novel dosimetry induced fibrinolysis without causing acute hemorrhage, in addition to inducing a pro-angiogenic milieu conducive to NV. Further clinical testing is warranted at this novel dosimetry in CLTI, as well as in other chronically ischemic tissue beds. Trial registration. https://ichgcp.net/clinical-trials-registry/NCT02802852.

Keywords: Filgrastim; angiogenesis; arteriogenesis; chronic limb ischemia; fibrinolysis; neovascularization.

Conflict of interest statement

Authors report no specific financial conflict of interest. ACI Medical, LLC Inc (Ed Arkans CEO) provided funding for some of the UC assays and provided the ArtAssist devices for patients. Darwin Eton: Science and clinical advisor at Vasogenesis Inc (Brookline, MA). [Correction added on 21 March 2021, after first online publication: Conflict of Interest have been updated to reflect full company name and correct spelling of CEO in the second sentence and correct company name in the third sentence.]

© 2022 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
(a) CT angiogram of an ischemic left leg in a diabetic lady after two failed bypasses and 5‐cm ulcers on anterior and posterior ankle. The bright signals in the left leg are surgical hemoclips. (b) The pre‐treatment catheter angiogram showing attenuated left infrageniculate flow. (c) An angiogram 1 year after treatment showing recanalization of tibial arteries and cork‐screw collaterals expected with neovascularization. Her foot wounds healed. She still has her limb 12 years later
FIGURE 2
FIGURE 2
75‐year‐old insulin‐dependent diabetic male (Patient 1403) was initially treated with an infrageniculate bypass for dry gangrene. When this failed, he was treated with atherectomy and laser angioplasty of the anterior tibial and dorsalis pedis artery. When this failed, he presented with wet gangrene of toes 1, 2, and 3. Following open amputation, he was treated with G‐CSF and PCP in lieu of below knee amputation. (a,b) Pre‐treatment distal calf and foot angiogram. (c,d) Operative angiogram with hand injection of contrast through 4F catheter in femoral artery showing recanalization and neovascularization at 9 months after onset of therapy. Patient healed his open toe amputations
FIGURE 3
FIGURE 3
Filgrastim effect on the concentration of plasmin (“[Plasmin]”) for each patient on the day after the 5th and 10th doses, relative to Day 1 (at T = 0). The [Plasmin] was higher in plasma (a) than in serum (b). Patients P008, 1403, and 1406 had recent post intervention thromboses; their elevated [plasmin] and [FDP] on Day 1 (blue*) likely reflect endogenous fibrinolysis following thrombosis. ^Patient 1406 only had 7 doses of filgrastim: [plasmin] after the 7th dose is substituted for the 10th dose
FIGURE 4
FIGURE 4
Filgrastim effect on the concentration of FDP (“[FDP]”) for each patient on the day after the 5th and 10th doses, relative to Day 1. The [FDP] was higher in plasma (a) than in serum (b). Patients P008, 1403, and 1406 had recent post‐intervention thromboses; their elevated [plasmin] and [FDP] on Day 1 (blue*) likely reflect endogenous fibrinolysis following thrombosis. ^Patient 1406 only had 7 doses of filgrastim: [FDP] after the 7th dose is substituted for the 10th dose

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