Introduction: The challenges in the treatment of sepsis are due to the major dysregulation of multiple physiologic processes. In particular, a dynamic interplay exists between inflammation and thrombosis. Emerging data highlight critical cross-talk between thrombotic and inflammatory pathways mediated by specific platelet receptors. Here, we focus on a platelet membrane collagen receptor, glycoprotein (GP) VI, that is central in the release of platelet microparticles (pMPs) following platelet activation. These pMPs are membrane-bound vesicles and are associated with both pro-thrombotic and pro-inflammatory responses. There are, two GPVI haplotypes, GP6a and GP6b, that differ in their ability to release pMPs. Individuals with homozygous GP6a alleles (T/T) have 2-fold higher levels of circulating pMPs in their blood compared to heterozygous individuals with GP6a/GP6b alleles (T/C). Prior studies have shown that the relative gene frequencies of GP6a and GP6b in the general population are 85% and 15%, respectively. Here, we examine the relevance of platelet GPVI haplotypes to patient illness and the progression of sepsis. Method: Our study is an observational prospective. The patients (0-17 years old) were admitted to the pediatric intensive care unit at Arkansas Children's Hospital in 2016, with an initial diagnosis of sepsis or septic shock. GPVI haplotypes were determined through blood sampling and PCR. Clinical data was collected for patient demographics, baseline characteristics, ICU and hospital length of stay, type of infection, and inotropes use. Outcomes evaluated included the spectrum of sepsis, GPVI haplotype, PELOD-2, and PRISM III scores during the initial 24 hours. P-values were calculated for categorical variables using Fisher’s exact test; and for continuous variables the Mann Whitney U-test. Results: Overall, 73 patients were included in the final analysis. Enrolled patients were divided into two groups GP6a vs GP6b. Fifty-nine (80%) participants were found to have the GP6a haplotype and 14 (19%) with GP6b. There was no statistical difference between the two groups in regards to demographic characteristics. Patients in both groups had the same likelihood of having bacterial or viral infection. However, patients with the GP6a haplotype were more likely to have higher PELOD-2 and PRISM III scores (GP6a vs GP6b: 7,13 vs 4,4, P < 0.0001) as well as meeting criteria for severe sepsis or septic shock [Gp6a 91% vs GP6b 57%, P: 0.005). There was no statistical difference in length of hospital or ICU stay. Discussion: Septic patients with the GP6a haplotype are more likely to present with severe sepsis or shock as compared to patients with the GP6b haplotype. This worsening of the septic condition for GP6a patients was confirmed with higher PELOD-2 and PRISM III scores. The idea of platelet-dependent contributions to the progression of sepsis removes a barrier to further innovation in understanding the complex disease process that is sepsis.