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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus responsible for the pandemic coronavirus disease 19 (COVID-19). It has significant impact on human health and public safety along with negative social and economic consequences. Vaccination against SARS-CoV-2 is likely the most effective approach to sustainably control the global COVID-19 pandemic. Vaccination is highly effective in reducing the risk of severe COVID-19 disease. Mass-scale vaccination will help us in attaining herd immunity and will lessen the negative impact of the disease on public health, social and economic conditions. The present pandemic stimulated the development of several effective vaccines based on different platforms. Although the vaccine is safe and efficacious, rare cases of thrombosis and thrombocytopenia following the use of vaccination with the ChAdOx1 CoV-19 vaccine (AstraZeneca, University of Oxford, and Serum Institute of India) or the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) have been reported globally. This review focussed on the definition, epidemiology, pathogenesis, clinical features, diagnosis, and management of vaccine associated thrombosis.

Since March 2021, cases with unusual clots, particularly cerebral venous sinus thrombosis and splanchnic vein thrombosis, have been reported worldwide following adenoviral vector-based coronavirus disease 2019 (COVID-19) vaccination. This entity has been termed vaccine-induced thrombotic thrombocytopenia (VITT). We report a 23-year-old healthy female who developed seizures, altered sensorium, and left hemiparesis, 20 days after receiving the first dose of adenoviral vector-based COVID-19 vaccine “Covishield™.” The patient had transient thrombocytopenia. The D-dimer level was 2460 ng/mL. Magnetic resonance imaging (MRI) demonstrated occlusion of M2 segment of the middle cerebral artery and cerebral infarction. Platelet factor-4 antibodies level was normal. Treatment with aspirin and antiepileptic drugs resulted in a remarkable recovery. This is the first Indian case report of ischemic stroke and transient thrombocytopenia following SARS-CoV-2 ChAdOx1 nCoV-19 vaccination. Our case had clinical features consistent with the diagnosis of probable VITT. Familiarity with VITT is crucial because timely treatment with non-heparin anticoagulants and intravenous immunoglobulin improves the outcome.

Objectives: The goal of this exploratory study is to determine if urine:serum fractional excretion ratios can outperform the corresponding urinary biomarker proteins in identifying active renal disease in systemic lupus erythematosus (SLE). Methods: Thirty-six adult SLE patients and twelve healthy controls were examined for serum and urine levels of 8 protein markers, namely ALCAM, calpastatin, hemopexin, peroxiredoxin 6 (PRDX6), platelet factor 4 (PF4), properdin, TFPI and VCAM-1, by ELISA. Fractional excretion of analyzed biomarkers was calculated after normalizing both the urine and serum biomarker levels against creatinine. A further validation cohort of fifty SLE patients was included to validate the initial findings. Results: The FE ratios of all 8 proteins interrogated outperformed conventional disease activity markers such as anti-dsDNA, C3 and C4 in identifying renal disease activity. All but VCAM-1FE were superior to the corresponding urine biomarkers levels in differentiating LN activity, exhibiting positive correlation with renal SLEDAI. ALCAMFE, PF4FE and properdinFE ratios exhibited the highest accuracy (AUC>0.9) in distinguishing active LN from inactive SLE. Four of the FE ratios exhibited perfect sensitivity (calpastatin, PRDX6, PF4 and properdin), while ALCAMFE, PF4FE and properdinFE exhibited the highest specificity values for active LN. In addition, several of these novel biomarkers were associated with higher renal pathology activity indices. In the validation cohort ALCAMFE, PF4FE and properdinFE once again exhibited higher accuracy metrics, surpassing corresponding urine and serum biomarkers levels, with ALCAMFE exhibiting 95% accuracy in distinguishing active LN from inactive SLE. Conclusions: With most of the tested proteins, urine:serum fractional excretion ratios outperformed corresponding urine and serum protein measurements in identifying active renal involvement in SLE. Hence, this novel class of biomarkers in SLE ought to be systemically evaluated in larger independent cohorts for their diagnostic utility in LN assessment. [ABSTRACT FROM AUTHOR]

ObjectivesThe goal of this exploratory study is to determine if urine:serum fractional excretion ratios can outperform the corresponding urinary biomarker proteins in identifying active renal disease in systemic lupus erythematosus (SLE).MethodsThirty-six adult SLE patients and twelve healthy controls were examined for serum and urine levels of 8 protein markers, namely ALCAM, calpastatin, hemopexin, peroxiredoxin 6 (PRDX6), platelet factor 4 (PF4), properdin, TFPI and VCAM-1, by ELISA. Fractional excretion of analyzed biomarkers was calculated after normalizing both the urine and serum biomarker levels against creatinine. A further validation cohort of fifty SLE patients was included to validate the initial findings.ResultsThe FE ratios of all 8 proteins interrogated outperformed conventional disease activity markers such as anti-dsDNA, C3 and C4 in identifying renal disease activity. All but VCAM-1FE were superior to the corresponding urine biomarkers levels in differentiating LN activity, exhibiting positive correlation with renal SLEDAI. ALCAMFE, PF4FE and properdinFE ratios exhibited the highest accuracy (AUC>0.9) in distinguishing active LN from inactive SLE. Four of the FE ratios exhibited perfect sensitivity (calpastatin, PRDX6, PF4 and properdin), while ALCAMFE, PF4FE and properdinFE exhibited the highest specificity values for active LN. In addition, several of these novel biomarkers were associated with higher renal pathology activity indices. In the validation cohort ALCAMFE, PF4FE and properdinFE once again exhibited higher accuracy metrics, surpassing corresponding urine and serum biomarkers levels, with ALCAMFE exhibiting 95% accuracy in distinguishing active LN from inactive SLE.ConclusionsWith most of the tested proteins, urine:serum fractional excretion ratios outperformed corresponding urine and serum protein measurements in identifying active renal involvement in SLE. Hence, this novel class of biomarkers in SLE ought to be systemically evaluated in larger independent cohorts for their diagnostic utility in LN assessment.

In the new science emanating from the COVID-19 pandemic, effective vaccine development has made a huge difference and saved countless lives. Vaccine roll-out led to the identification of rare cases of severe thrombotic and thrombocytopenic problems in some recipients. This apparent coupling of thrombosis with haemorrhagic potentiation might seem baffling but the ensuing clinical investigation rapidly shed important light on its molecular mechanism. This review outlines the current understanding on the role of adenovirus-based platforms, the immunogenic triggers and the immunothrombotic response underlying vaccine-induced immune thrombotic thrombocytopenia. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus responsible for the pandemic coronavirus disease 19 (COVID-19). It has significant impact on human health and public safety along with negative social and economic consequences. Vaccination against SARS-CoV-2 is likely the most effective approach to sustainably control the global COVID-19 pandemic. Vaccination is highly effective in reducing the risk of severe COVID-19 disease. Mass-scale vaccination will help us in attaining herd immunity and will lessen the negative impact of the disease on public health, social and economic conditions. The present pandemic stimulated the development of several effective vaccines based on different platforms. Although the vaccine is safe and efficacious, rare cases of thrombosis and thrombocytopenia following the use of vaccination with the ChAdOx1 CoV-19 vaccine (AstraZeneca, University of Oxford, and Serum Institute of India) or the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) have been reported globally. This review focussed on the definition, epidemiology, pathogenesis, clinical features, diagnosis, and management of vaccine associated thrombosis. [ABSTRACT FROM AUTHOR]

Background: Heparin induced thrombocytopenia (HIT) is reported at a variable rate in extracorporeal membrane oxygenation (ECMO) patients. A critical factor impacting platelet factor-4 (PF4)-heparin antibody formation is plasma PF4 concentration. We hypothesized that PF4 concentration would be increased during veno-arterial (VA) ECMO. Methods: Plasma PF4 concentration was measured during the first 5 ECMO days in 20 VA ECMO patients and 10 control plasma samples. PF4-heparin ratios were estimated using an assumed heparin concentration of 0.4 IU/mL. This correlates with an activated partial thromboplastin time of 60 to 80 seconds, which is the anticoagulation target in our center. Results: Twenty VA ECMO patients were enrolled, 10 of which had pulmonary embolism. Median PF4 concentration was 0.03 µg/mL [0.01, 0.13] in control plasma. Median PF4 concentration was 0.21 µg/mL [0.12, 0.34] on ECMO day 1 or 2, 0.16 µg/mL [0.09, 0.25] on ECMO day 3, and 0.12 µg/mL [0.09, 0.22] on ECMO day 5. Estimated median PF4-heparin ratios were 0.04, 0.03, and 0.02 respectively. Two patients (10%) developed HIT that was confirmed by serotonin release assay. PF4 concentration did not differ significantly in these patients compared to non-HIT patients (p = 0.37). No patient had an estimated PF4-heparin ratio between 0.7 and 1.4, which is the reported optimal range for PF4-heparin antibody formation. Conclusion: Our data suggest that PF4 concentration is mildly elevated during VA ECMO compared to control plasma. Estimated PF4-heparin ratios were not optimal for HIT antibody formation. These data support epidemiologic studies where HIT incidence is low during VA ECMO. [ABSTRACT FROM AUTHOR]

Abstract: Platelet factor-4 (CXCL4/PF-4) is the first chemokine identified to have several biological functions. Notably, CXCL4/PF-4 inhibits endothelial cell proliferation and migration, leading to suppression of angiogenesis. Since angiogenesis is essential for the growth of most primary tumors and their subsequent metastases, it is a target for cancer therapy; due to its multiple functions, CXCL4/PF-4 is a potential clinical anti-tumor agent. This report reviews the mechanisms of CXCL4/PF-4 angiostatic activity, including interference with angiogenic growth factors bFGF-2 and VEGF165, activation of CXCR3B, interactions with integrins, interference with cell cycle, interactions with factors such as VEGF121 and CXCL8/IL-8, and derived molecules of CXCL4/PF-4 with angiostatic and anti-tumoral activities in different models in vivo or in vitro. [Copyright &y& Elsevier]

Abstract: This study aimed at examining the presence and role of chemokines (angiogenic CCL2/MCP-1 and angiostatic CXCL4/PF-4, CXCL9/Mig, CXCL10/IP-10) in proliferative diabetic retinopathy (PDR). Regulated chemokine production in human retinal microvascular cells (HRMEC) and chemokine levels in vitreous samples from 40 PDR and 29 non-diabetic patients were analyzed. MCP-1, PF-4, Mig, IP-10 and VEGF levels in vitreous fluid from PDR patients were significantly higher than in controls. Except for IP-10, cytokine levels were significantly higher in PDR with active neovascularization and PDR without traction retinal detachment (TRD) than those in inactive PDR, PDR with TRD and control subjects. Exploratory regression analysis identified associations between higher levels of IP-10 and inactive PDR and PDR with TRD. VEGF levels correlated positively with MCP-1 and IP-10. Significant positive correlations were observed between MCP-1 and IP-10 levels. In line with these clinical findings Western blot analysis revealed increased PF-4 expression in diabetic rat retinas. HRMEC produced MCP-1, Mig and IP-10 after stimulation with IFN-γ, IL-1β or lipopolysaccharide. IFN-γ synergistically enhanced Mig and IP-10 production in response to IL-1β or lipopolysaccharide. MCP-1 was produced by HRMEC in response to VEGF treatment and activated HRMEC via the ERK and Akt/PKB pathway. On the other hand, phosphorylation of ERK induced by VEGF and MCP-1 was inhibited by PF-4, Mig and IP-10. In accordance with inhibition of angiogenic signal transduction pathways, PF-4 inhibited in vitro migration of HRMEC. Thus, regulatory roles for chemokines in PDR were demonstrated. In particular, IP-10 might be associated with the resolution of active PDR and the development of TRD. [Copyright &y& Elsevier]

Paraneoplastic thrombocytosis has been reported in different types of solid tumors, including ovarian epithelial cancer, and found to be associated with a worse outcome. Although the effect of cancer on increasing platelet counts is well documented, the effect of cancer on platelet functions is not well known. We comparedin vitroaggregation response of platelets isolated from 34 patients with ovarian cancer to those of platelets from 19 patients with benign ovarian tumors. Aggregation studies were conducted in a light transmission aggregometer, using both a high and a low dose of ADP and collagen. We evaluated platelet preactivation by measuring the plasma concentration of β-thromboglobulin (β-TG) and platelet factor-4 (PF-4) as markers of platelet α granule secretion, using ELISA. We found that ovarian cancer is not associated with an enhanced aggregation response of platelets to ADP or collagen, and plasma concentration of β-TG and PF-4 is not higher in patients with ovarian cancer compared to those in patients with benign ovarian tumors. [ABSTRACT FROM PUBLISHER]

Abstract: Inhibition of angiogenesis provides a potential anti-cancer therapy. Here we describe a novel recombinant peptide composed of active fragments of two distinct angiogenesis inhibitors, platelet factor-4 (C-13 fragment) and vasostatin (N-terminal amino acids 135–164) with a nonpolar peptide bridge of Gly-Pro-Gly. This fusion peptide showed significantly enhanced efficacy compared with its parent peptides in inhibiting human endothelial cell proliferation and neovasculerization in chick embryo chorioallantoic membrane. The data suggest that making a single recombinant peptide containing the active fragments of multiple angiogenesis inhibitors is a promising approach to developing a better anti-angiogenetic therapy. [Copyright &y& Elsevier]

Summary: The aim of this study was to determine the serum adenosine deaminase (ADA) and plasma platelet factor (PF-4) activities in patients with active pulmonary tuberculosis, HIV seropositive subjects, cancer patients (acute and chronic type lymphoblastic leukaemia) and to compare them with the results of healthy individuals. Eighty-eight subjects were enrolled in this study, 24 patients with active pulmonary tuberculosis, 20 patients with HIV seropositive subjects, 24 patients with cancer, 12 patients with acute type lymphoblastic leukaemia, 12 patients with chronic type lymphoblastic leukaemia) patients and 20 healthy individuals. ADA activity was determined in serum samples using colorimetric method and plasma PF4 activity was measured by using a sandwich-type enzyme immunoassay. When all study groups were compared with the control group, mean serum ADA activities were found to be significantly (p<0.01) higher in the sera of patients with active pulmonary tuberculosis (median, range: 39IU/l), HIV seropositive subjects (median, range: 31IU/l) than in the sera of cancer patients (median, range: 15) and healthy controls (median, range: 32IU/l). Plasma PF-4 activities in active pulmonary tuberculosis patients (median, range: 84IU/ml) were found to be significantly elevated when compared to HIV seropositive subjects (median, range: 59IU/ml), cancer patients (median, range 55IU/ml) and healthy individuals (median, range: 56IU/ml) (p<0.01). Serum ADA and plasma PF-4 activities showed significant alteration in patients with active pulmonary tuberculosis compared to patients with HIV seropositive subjects, cancer patients and healthy individuals. In conclusion, we suggest that serum ADA and PF-4 activities can be used in the diagnosis of tuberculosis as an supplementary laboratory test in combination with clinical and laboratory findings. Further controlled studies are necessary to determine the importance of the PF-4 and ADA activities in patients with active pulmonary tuberculosis, HIV seropositive subjects and cancer patients. [Copyright &y& Elsevier]

Summary: We investigated the plasma levels of D-dimer, fibrinogen, β-thromboglobulin (BTG) and platelet factor-4 (PF-4), indices of the occurrence of platelet activation in vivo, to find out their role in pathophysiology of ischemic stroke and whether or not such a role has any effect on the disability and the prognosis of stroke patients. A total of 76 patients with AIS aged from 26 to 85 (32 men, 44 women) and 30 cases as controls with similar age (18 men, 12 women) were included in the study. The plasma levels of D-dimer, BTG and PF-4 were measured by ELISA method using a special commercial kit. The cases were allocated into two groups as non-embolic (NEI) and cardioembolic stroke (CEI). The D-dimer levels in 76% of 42 patients in NEI group (p <0.05) and 85.2% of 34 patients in CEI group (p <0.05) were outside the confidence interval (CI) defined for the control group. The levels of BTG were elevated in 81% of 42 cases with NEI (p <0.05) and in 76% of 34 cases with CEI, with reference to CI of control group. The levels of PF-4 were significantly increased in 86% of cases with NEI (p <0.05) and in 88% of cases with CEI than controls (p <0.05). It was observed that the cases with high Rankin scores had higher levels of D-dimer (p <0.005), BTG (p <0.01) and PF-4 (p <0.01) than those with lower scores. There was a correlation between hemostatic markers, platelet activation and functional disability. D-dimer levels were an important marker that determined to degree of the activation of hemostatic system, especially in CEI subtype. The platelet aggregation had an important role in pathophysiology of ischemic stroke and this condition is significant in NEI subgroup and subjects with large infarcts and high disability scores. [Copyright &y& Elsevier]

The coronavirus disease 2019 (COVID-19), a deadly pandemic that has affected millions of people worldwide, is associated with cardiovascular complications, including venous and arterial thromboembolic events. Viral spike proteins, in fact, may promote the release of prothrombotic and inflammatory mediators. Vaccines, coding for the spike protein, are the primary means for preventing COVID-19. However, some unexpected thrombotic events at unusual sites, most frequently located in the cerebral venous sinus but also splanchnic, with associated thrombocytopenia, have emerged in subjects who received adenovirus-based vaccines, especially in fertile women. This clinical entity was soon recognized as a new syndrome, named vaccine-induced immune thrombotic thrombocytopenia, probably caused by cross-reacting anti-platelet factor-4 antibodies activating platelets. For this reason, the regulatory agencies of various countries restricted the use of adenovirus-based vaccines to some age groups. The prevailing opinion of most experts, however, is that the risk of developing COVID-19, including thrombotic complications, clearly outweighs this potential risk. This point-of-view aims at providing a narrative review of epidemiological issues, clinical data, and pathogenetic hypotheses of thrombosis linked to both COVID-19 and its vaccines, helping medical practitioners to offer up-to-date and evidence-based counseling to their often-alarmed patients with acute or chronic cardiovascular thrombotic events. [ABSTRACT FROM AUTHOR]

Angiogenesis is the process of new vascular formation, which is derived from various factors. For suppressing cancer cell growth, targeting angiogenesis is one of the therapeutic approaches. Vascular endothelial growth factor family receptors, including Flt-1, Flk-1 and Flt-4, have been found to play an essential role in regulating angiogenesis. Rapamycin is a macrolide compound with anti-proliferative properties, while platelet factor-4 (PF-4) is an antiangiogenic ELR-negative chemokine. Rapamycin inhibits mTOR ligands activation, thus suppressing cell proliferation, while PF-4 inhibits cell proliferation through several mechanisms. In the present study, we evaluated the effects of rapamycin and platelet factor-4 toward breast carcinoma at the proteomic and genomic levels. A total of 60 N-Methyl-N-Nitrosourea-induced rat breast carcinomas were treated with rapamycin, platelet factor-4 and rapamycin+platelet factor-4. The tumours were subsequently subjected to immunohistochemical protein analysis and polymerase chain reaction gene analysis. Protein analysis was performed using a semiquantitative scoring method, while the mRNA expression levels were analysed based on the relative expression ratio. There was a significant difference in the protein and mRNA expression levels for the selected markers. In the rapamycin+platelet factor-4-treated group, the Flt-4 marker was downregulated, whereas there were no differences in the expression levels of other markers, such as Flt-1 and Flk-1. On the other hand, platelet factor-4 did not exhibit a superior angiogenic inhibiting ability in this study. Rapamycin is a potent antiangiogenic drug; however, platelet factor-4 proved to be a less effective drug of anti-angiogenesis on rat breast carcinoma model.

The article examines herapin-induced thrombocytopenia (HIT) as a severe immune-mediated drug disorder caused by antibodies of platelet factor-4 (PF4) and herapin. The importance of antigen for cellular recognition and uptake by antigen-presenting cells (APCs) were studied. Accordingly, myeloid differentiation primary response gene 88 or MyD88 were used as a common adaptor protein to investigate the mechanisms by which APCs recognize the multimolecular PF4/herapin complexes.

To evaluate the platelet function in sickle cell syndromes we measured the β-thromboglobulin (β-TG) and platelet factor 4 (PF-4) plasma values of 45 patients suffering from homozygous sickle cell anaemia (10) and sickle cell β-thalassaemia (35) in steady state. The results were compared to those of 32 normal controls. Both the β-TG and PF-4 levels were found to be significantly higher in patients than in controls but the β-TG: PF-4 ratio was significantly lower in the patients group. This finding and the absence of any statistical correlation between platelet number and β-TG or PF-4 indicate that platelets seem to be somehow activated in sickle cell syndromes, both in homozygotes and sickle cell/β-thalassaemia heterozygotes. This platelet activation seems to exist even in steady state sickle cell disease patients, regardless of the functional status of the spleen. [ABSTRACT FROM AUTHOR]

Introduction: The role of platelet activation in allergic inflammation is receiving increasing attention. Sublingual immunotherapy for allergic rhinitis can modify the immunological process to an allergen, rather than simply treating symptoms., Objective: The aim of this study was to explore the role of platelet activation during sublingual immunotherapy in children with allergic rhinitis., Methods: Forty-two House Dust Mite - sensitized children with allergic rhinitis were enrolled and received House Dust Mite allergen extract for sublingual immunotherapy or placebo. Serum of different time points during treatment was collected and used for detection of Platelet Factor-4 and Beta-Thromboglobulin concentration by Enzyme-Linked Immuno Sorbent Assay., Results: Our data showed decreased expression of Platelet Factor-4 and Beta-Thromboglobulin protein after one year's sublingual immunotherapy. In addition, the decrease of symptom scores and serum Platelet Factor-4 and Beta-Thromboglobulin protein concentrations was positively related., Conclusion: During sublingual immunotherapy, platelet activation was inhibited significantly. Our results might indicate that inhibition of platelet activation within the systemic circulation is an important mechanism during sublingual immunotherapy., (Copyright © 2016. Published by Elsevier Editora Ltda.)

Platelet activation and thrombin generation are crucial steps in primary and secondary haemostasis. However, both also play major roles in intravascular thrombus formation and therefore in the development of adverse cardiovascular events. In the current study, we first sought to investigate the associations of the platelet biomarkers platelet factor (PF)-4, thrombospondin (TSP)-1, soluble CD40 ligand (sCD40L), and soluble P-selectin (sP-selectin) with each other and with monocyte-platelet aggregate (MPA) formation in 316 patients undergoing angioplasty and stenting. To better understand the interplay between platelet activation and thrombin generation, we subsequently investigated the associations of the platelet biomarkers with thrombin generation potential. The mostly platelet-specific markers PF-4, TSP-1 and sCD40L correlated strongly with each other (all p < 0.001), and the best correlation was observed between PF-4 and TSP-1 (r=0.91). In contrast, sP-selectin, which derives from platelets and endothelial cells, correlated rather poorly with TSP-1 (r=0.12, p=0.04), and did not correlate with PF-4 and sCD40L. While PF-4, TSP-1 and sP-selectin correlated significantly with in vivo MPA formation (all p< 0.001), no such association was found between sCD40L and MPA formation. PF-4, TSP-1 and sCD40L correlated strongly with peak thrombin generation (all p< 0.001) with the best correlation between PF-4 and peak thrombin generation (r=0.55), whereas sP-selectin did not correlate with peak thrombin generation. Likewise, PF-4, TSP-1 and sCD40L correlated significantly with the area under the thrombin generation curve (AUC; all p< 0.01), whereas sP-selectin did not correlate with the AUC. In conclusion, platelet-specific markers are associated with MPA formation and thrombin generation potential in patients with advanced atherosclerosis.