A Potential Role of Vitamin D on Platelet Leukocyte Aggregation and Pathological Events in Sepsis: An Updated Review

Figures & data

Table 1 Randomized Clinical Trial of Vitamin D Reinforcement in Critical Ill and Sepsis

Study	Participant’s Conditions	Number	Age	Intervention	Changes in Vitamin D Level After Intervention	Changes in Markers of Immune Function	Clinical Outcomes
Amrein et al, 2011.^Citation36 Double-blind	Critical ill patients	Placebo 12 VD group 13	Both placebo and VD group 62± 16 year	Single dose of 540,000 IU Cholecalciferol or matched placebo Orally	25(OH)D3 (nmol/L) Baseline Placebo group 35.25 ± 9.25 VD group 32.75 ± 5 At 7th day Placebo group 34.25 ± 10.5 VD group 95.5 ± 41.25	Not measured	No significant effect in 28 mortality, Hospital stays and ICU stays.
Leaf et al, 2014^Citation31 Double-blind	Severe sepsis	Placebo group 31 VD group 36	Placebo group 58 (49–69) year VD group 68 (54–70) year	Single dose of 2 μg of (calcitriol) 1,25-dihydroxyvitamin D or matched placebo intravenous	Significant increase in 1.25 D concentration after 6 hours in VD group- versus placebo- (75.7 [52.1–115.5] and 16.9 [9.0–26.9] pg/mL)	Significant increase in Leukocyte mRNA Expression of cathelicidin at 24 h of calcitriol administration No difference between groups inTNF-α, IL-1β, IL-2, IL-10, IL-6, And Cathelicidin (LL-37)	No significant effects in extent of respiratory support with mechanical ventilator, length of hospitalization and 28-day mortality.
Amrein et al, 2014^Citation33 Double blind	Critical ill patients	Placebo group 238 VD group 237	Placebo group 63.9 VD group 65.3	Initial dose of 540 000 IU, following that, 5 doses of 90,000 IU each month or matched placebo Orally	25(OH)D3 (nmol/L) Baseline Placebo group 32.75 VD group 32.5 At day 7th Placebo group 36.25 VD group 88.75	No significant effect in CRP	No significant effect in duration of hospital stays, hospital death rate 6-month deaths Lower hospital death rate among subgroup of sever vitamin deficiency (25(OH)D3 ≤12 ng/mL)
Quraishi et al, 2015^Citation32 Double blind	Sepsis	Placebo group 10 VD group (200,000 IU) 10 VD group (400,000 IU) 10	Placebo group 65 (58–70) VD group (200,000 IU) 64 (55–66) VD group (400,000 IU) 62 (59–67)	Single dose of 200.000 IU or 400.000 IU of cholecalciferol or matched placebo Orally	25(OH)D3 (nmol/L) Baseline placebo group 47.5 (32.5–55) VD group (200,000 IU) 37.5 (30–50) VD group (400.000 IU) 42.5 (32.5–62.5) At 5th day Placebo group 47.5 (27.5–57.5) VD group (200.000 IU) 55 (40–62.5) VD group (400.000 IU) 72.5 (80–102.5)	Significant increase in cathelicidin LL-37 in VD group Significant reduction in IL-1β 1L-6 increase in Il-10 in VD group No differences in hsCRP levels between groups	30-day ICU readmission rate is 20% in placebo group And 0% In both vitamin D group No difference ICU length of stay.
Han et al, 2016^Citation34 Double blind	Intensive care unit patients	Placebo group 10 VD group (50,000 IU) 10 VD group (100,000 IU) 11	Placebo group 64.8 VD group (50,000 IU) 56.4 VD group (100,000 IU) 68.1	50,000 IU VD3 or 100,000 IU VD3 every day for 5 days consecutively or matched placebo orally	25(OH)D3 (nmol/L) Baseline Placebo group 53.75 VD group (50,000 IU) 58 VD group (100,000 IU) 50 At day 7th Placebo group no change VD group (50,000 IU) 112.5 ± 50  VD group (100,000 IU) 137.5 ±35	No significant effect in antimicrobial peptide cathelicidin (LL-37)	Significant reduction in duration of hospital stay in both vitamin D group
National Heart and Network, 2019^Citation37 Double blind	Critical ill	Placebo group 540 VD group 530	Placebo group 56±15.9 VD group 54.6±16.7	Single dose of 540,000 IU vitamin D3 or matched placebo Orally	25(OH)D3 (nmol/L) Baseline Placebo group 27.5±11.75 VD group 28 ± 12 At 3rd Day Placebo group 28.5 ±14 VD group 117.25±58	Not measured	No significant effect in 28 day death rate, 90 day hospital death rate, duration of stay at hospital and other health care facility and duration respiratory support free time
Miri et al, 2019^Citation35 Double blind	Critical ill	Placebo group 18 VD group 22	Placebo group 56 ± 22.1 VD group 52 ± 22.1	Single dose of 300,000 IU vitamin D or matched placebo Intramuscular	25(OH)D3 (ng/dl) Baseline placebo group 28.38 ± 18.23 VD group 8.43 ± 6.8 At 7th day Placebo group 11.16 ± 18.22 VD group 10.48 ± 9.80	Not measured	Reduction in the duration of respiratory support with mechanical ventilators, the duration of hospitalization, and mortality rate in the ICU

Abbreviations: VD, vitamin D; ICU, intensive care unit; TNF, tumor necrosis factor; CRP, C reactive protein; hsCRP, high sensitivity C reactive protein.

Figure 1 Vitamin D effects on the cellular interaction of platelets, leukocytes and endothelium. Stimulation of platelets, leukocytes and endothelium by PAMPs, DAMPs and the released mediators in response to such stimulation results in the attachment of platelets to leukocytes and generating platelet leukocyte aggregates moving freely in the circulatory system or fixed to the stimulated endothelium. Several molecular interactions, which could be interfered by the action of VD, mediate this pathological phenomenon including P-Selectin with PSGL-1 and αMβ2 integrin with GPIbα, (TREM-1) with its ligand on neutrophil, platelet JAM-3 with neutrophil αMβ2 integrin, and LFA-1 to its legend on platelet. These interactions induce further cell activation resulting in increased surface expression of adhesion receptors, degranulation, release of CD40L, Angiopoietin 2 (Ang2), inflammatory mediators, reactive oxygen species, tissue factor expression, microparticles release, thrombus and neutrophil extracellular trap formation (NET). Sites of Vitamin D (VD) effects are indicated in green. The figure was created using Biorender.com.

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