Thrombocytopenia is associated with severe retinopathy of prematurity
Bertan Cakir, Raffael Liegl, Gunnel Hellgren, Pia Lundgren, Ye Sun, Susanna Klevebro, Chatarina Löfqvist, Clara Mannheimer, Steve Cho, Alexander Poblete, Rubi Duran, Boubou Hallberg, Jorge Canas, Viola Lorenz, Zhi-Jian Liu, Martha C. Sola-Visner, Lois E.H. Smith, Ann Hellström
Bertan Cakir, Raffael Liegl, Gunnel Hellgren, Pia Lundgren, Ye Sun, Susanna Klevebro, Chatarina Löfqvist, Clara Mannheimer, Steve Cho, Alexander Poblete, Rubi Duran, Boubou Hallberg, Jorge Canas, Viola Lorenz, Zhi-Jian Liu, Martha C. Sola-Visner, Lois E.H. Smith, Ann Hellström
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Research Article Angiogenesis Vascular biology

Thrombocytopenia is associated with severe retinopathy of prematurity

Abstract

Retinopathy of prematurity (ROP) is characterized by abnormal retinal neovascularization in response to vessel loss. Platelets regulate angiogenesis and may influence ROP progression. In preterm infants, we assessed ROP and correlated with longitudinal postnatal platelet counts (n = 202). Any episode of thrombocytopenia (<100 × 109/l) at ≥30 weeks postmenstrual age (at onset of ROP) was independently associated with severe ROP, requiring treatment. Infants with severe ROP also had a lower weekly median platelet count compared with infants with less severe ROP. In a mouse oxygen-induced retinopathy model of ROP, platelet counts were lower at P17 (peak neovascularization) versus controls. Platelet transfusions at P15 and P16 suppressed neovascularization, and platelet depletion increased neovascularization. Platelet transfusion decreased retinal of vascular endothelial growth factor A (VEGFA) mRNA and protein expression; platelet depletion increased retinal VEGFA mRNA and protein expression. Resting platelets with intact granules reduced neovascularization, while thrombin-activated degranulated platelets did not. These data suggest that platelet releasate has a local antiangiogenic effect on endothelial cells to exert a downstream suppression of VEGFA in neural retina. Low platelet counts during the neovascularization phase in ROP is significantly associated with the development of severe ROP in preterm infants. In a murine model of retinopathy, platelet transfusion during the period of neovascularization suppressed retinopathy.

Authors

Bertan Cakir, Raffael Liegl, Gunnel Hellgren, Pia Lundgren, Ye Sun, Susanna Klevebro, Chatarina Löfqvist, Clara Mannheimer, Steve Cho, Alexander Poblete, Rubi Duran, Boubou Hallberg, Jorge Canas, Viola Lorenz, Zhi-Jian Liu, Martha C. Sola-Visner, Lois E.H. Smith, Ann Hellström

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Figure 5

Comparison of neovascularization and vaso-obliteration in OIR using degranulated versus resting platelets.

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Comparison of neovascularization and vaso-obliteration in OIR using degr...
Platelet degranulation was achieved by stimulating platelet suspensions for 10 minutes with 1 U/ml thrombin. Control resting platelets were treated exactly the same except thrombin activation. (A) Representative FACS dot plot images of P-selectin and CD41 expression on degranulated (right) and resting platelets (left). (B) P-selectin expression on degranulated platelets was significantly increased compared with resting platelets, demonstrating that platelets were effectively degranulated through thrombin stimulation (93% vs. 0.737%; P < 0.0001). (C) Comparison of degranulated and resting platelet clearance over time was determined by measuring GFP+ fluorescence in platelets from GFP+ donor mice through FACS analysis. Time 0 was defined as 24 hours after platelet transfusion. In vivo clearance of GFP+ degranulated and resting platelets was unchanged. (D) Neovascularization was significantly decreased in the resting platelet transfusion group (n = 21 eyes) compared with the degranulated platelet transfusion group (n = 18 eyes; P = 0.039). Vaso-obliteration was unchanged (P = 0.87). Unpaired t test was used for statistical analysis. Data represent mean ± SD.