scholarly journals Uncomplicated Plasmodium vivax malaria: mapping the proteome from circulating platelets

2022 ◽  
Vol 19 (1) ◽  
Author(s):  
Diana Fernández ◽  
Cesar Segura ◽  
Mònica Arman ◽  
Suzanne McGill ◽  
Richard Burchmore ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Plasma Levels ◽  
Acute Phase Proteins ◽  
Intracellular Localization ◽  
Endothelial Activation ◽  
Parasite Development ◽  
Molecular Pathways ◽  
Healthy Controls ◽  
Platelet Factor

Abstract Background Thrombocytopenia is frequent in Plasmodium vivax malaria but the role of platelets in pathogenesis is unknown. Our study explores the platelet (PLT) proteome from uncomplicated P. vivax patients, to fingerprint molecular pathways related to platelet function. Plasma levels of Platelet factor 4 (PF4/CXCL4) and Von Willebrand factor (VWf), as well as in vitro PLTs—P. vivax infected erythrocytes (Pv-IEs) interactions were also evaluated to explore the PLT response and effect on parasite development. Methods A cohort of 48 patients and 25 healthy controls were enrolled. PLTs were purified from 5 patients and 5 healthy controls for Liquid Chromatography–Mass spectrometry (LC–MS/MS) analysis. Plasma levels of PF4/CXCL4 and VWf were measured in all participants. Additionally, P. vivax isolates (n = 10) were co-cultured with PLTs to measure PLT activation by PF4/CXCL4 and Pv-IE schizonts formation by light microscopy. Results The proteome from uncomplicated P. vivax patients showed 26 out of 215 proteins significantly decreased. PF4/CXCL4 was significantly decreased followed by other proteins involved in platelet activation, cytoskeletal remodeling, and endothelial adhesion, including glycoprotein V that was significantly decreased in thrombocytopenic patients. In contrast, acute phase proteins, including SERPINs and Amyloid Serum A1 were increased. High levels of VWf in plasma from patients suggested endothelial activation while PF4/CXCL4 plasma levels were similar between patients and controls. Interestingly, high levels of PF4/CXCL4 were released from PLTs—Pv-IEs co-cultures while Pv-IEs schizont formation was inhibited. Conclusions The PLT proteome analyzed in this study suggests that PLTs actively respond to P. vivax infection. Altogether, our findings suggest important roles of PF4/CXCL4 during uncomplicated P. vivax infection through a possible intracellular localization. Our study shows that platelets are active responders to P. vivax infection, inhibiting intraerythrocytic parasite development. Future studies are needed to further investigate the molecular pathways of interaction between platelet proteins found in this study and host response, which could affect parasite control as well as disease progression.

scholarly journals Uncomplicated Plasmodium vivax malaria: Mapping the proteome from circulating platelets

2021 ◽  
Author(s):  
Diana Fernández ◽  
Cesar Segura ◽  
Mònica Arman ◽  
Suzzane McGill ◽  
Richard Burchmore ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Platelet Activation ◽  
Plasma Levels ◽  
Vivax Malaria ◽  
Endothelial Activation ◽  
Molecular Pathways ◽  
Healthy Controls ◽  
Cytoskeletal Remodeling ◽  
Plasmodium Vivax Malaria ◽  
Platelet Proteome

Abstract Background: Thrombocytopenia is frequent in uncomplicated Plasmodium vivax malaria. Contribution of platelets to pathogenesis is unknown and poorly understood. Our study explores the platelet proteome from uncomplicated P. vivax malaria patients to fingerprint molecular pathways in relation to platelet function. Also, plasma levels of platelet activation (Platelet factor 4 – PF4/CXCL4) and endothelial activation (Von Willebrand factor – VWf) markers, in conjunction with some in vitro interactions between platelets and P. vivax infected erythrocytes ( Pv -IEs) were measured to explore platelet responses during infection and their effect on parasite development. Methods: This study was performed in a cohort of 48 patients and 25 healthy controls. Platelets were purified from a subgroup of 5 patients and 5 healthy controls to be analyzed by LC-MS/MS. In all participants enrolled in this study, PF4/CXCL4 and VWf plasma levels were measured. Finally, a subsample of 10 P. vivax isolates were co-cultured with platelets to measure P v- IE schizonts inhibition as well as platelet activation due to their interaction. Results: In total 28 out of 215 proteins were significantly abundant in the proteomes from patients. The most significantly decreased protein was PF4/CXCL4 followed by other proteins related to platelet activation, cytoskeletal remodeling, and adhesion to endothelial cells. In contrast, acute phase proteins including SERPINs and Amyloid Serum A 1 (SAA1) were increased. High VWf plasma levels in patients suggested endothelial activation. Interestingly, PF4/CXCL4 plasma levels were similar between patients and controls, but high levels of this protein were found in co-cultures, and platelets inhibited Pv -IEs development to schizonts. Conclusions: Platelet proteome from patients with uncomplicated P. vivax malaria suggests platelet degranulation, platelet activation, cytoskeletal remodeling, and adhesion to endothelial cells. According to the evidenced endothelial activation our study plus the suggested specific localization of PF4/CXCL4 during P. vivax infection due to the normal levels in plasma, and the inhibition of Pv -IE schizonts development; our study suggest that platelets are active players during the response to P . vi vax infection. Future studies are needed to further investigate the molecular pathways of interaction between altered platelet proteins and host response; which could affect parasite control as well as disease progression.

Effects of Ticlopidine of Platelet Function in Men with Stable Angina Pectoris

1985 ◽  
Vol 54 (04) ◽  
pp. 808-812 ◽  
Author(s):  
Ulf Berglund ◽  
Henning von Schenck ◽  
Lars Wallentin
Keyword(s):  
Platelet Aggregation ◽  
Angina Pectoris ◽  
Platelet Function ◽  
Plasma Levels ◽  
Platelet Reactivity ◽  
Inhibitory Effect ◽  
Controlled Study ◽  
Double Blind ◽  
Platelet Factor

SummaryThe effects of ticlopidine (T) (500 mg daily) on platelet function were investigated in a double-blind placebo-controlled study in 38 middle-aged men with stable incapacitating angina pectoris. The in vitro platelet reactivity to aggregating agents, the platelet sensitivity to prostacyclin and the plasma levels of platelet specific proteins and fibrinogen were determined before and after 4 and 8 weeks of treatment. T exerted a potent inhibitory effect on ADP- and collagen-induced platelet aggregation. The effect of T was proportional to the pretreatment reactivity to ADP and collagen. The inhibitory effect of T on the epinephrine response was less pronounced. The plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen were not influenced by T. The platelet inhibition of prostacyclin was potentiated by T, and it was demonstrated that T and prostacyclin had synergistic inhibitory effects on platelet aggregation.

scholarly journals Shortened platelet half-life in multiple myeloma

Blood ◽  
1986 ◽  
Vol 68 (2) ◽  
pp. 514-520
Author(s):  
E Fritz ◽  
H Ludwig ◽  
W Scheithauer ◽  
H Sinzinger
Keyword(s):  
Multiple Myeloma ◽  
Half Life ◽  
Serum Levels ◽  
Statistical Correlation ◽  
Control Group ◽  
Healthy Controls ◽  
Platelet Factor ◽  
Healthy Control

Various defects in platelet function have been reported as being associated with multiple myeloma. In 30 myeloma patients and 15 healthy controls, we investigated platelet survival using in vitro labeling of autologous platelets with 111indium-oxine and measuring the in vivo kinetics of the radioisotope. Significantly shortened platelet half- life in patients averaged 73 hours, while platelet half-life in the healthy controls averaged 107 hours. In myeloma patients, serum levels of thromboxane B2, beta-thromboglobulin, and platelet factor 4 were significantly elevated; aggregation indices were within the pathological range; platelet counts and spleen-liver indices, however, were comparable to those of the healthy control group. No statistical correlation was found between platelet half-life and paraprotein concentrations. Our findings suggest an initial--so far unexplained-- intravascular process of platelet activation and consumption that finally manifests in shortened platelet half-life. It seems that overt thrombocytopenia develops only when the compensatory capacity of the bone marrow finally becomes exhausted. Further studies should be able to elucidate the pathophysiologic processes involved.

scholarly journals Analysis of Plasmodium vivax schizont transcriptomes from field isolates reveals heterogeneity of expression of genes involved in host-parasite interactions

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sasha V. Siegel ◽  
Lia Chappell ◽  
Jessica B. Hostetler ◽  
Chanaki Amaratunga ◽  
Seila Suon ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Ex Vivo ◽  
Culture Method ◽  
Surface Proteins ◽  
Parasite Development ◽  
Field Isolates ◽  
Host Parasite Interactions ◽  
Short Period ◽  
Host Parasite

Abstract Plasmodium vivax gene regulation remains difficult to study due to the lack of a robust in vitro culture method, low parasite densities in peripheral circulation and asynchronous parasite development. We adapted an RNA-seq protocol “DAFT-seq” to sequence the transcriptome of four P. vivax field isolates that were cultured for a short period ex vivo before using a density gradient for schizont enrichment. Transcription was detected from 78% of the PvP01 reference genome, despite being schizont-enriched samples. This extensive data was used to define thousands of 5′ and 3′ untranslated regions, some of which overlapped with neighbouring transcripts, and to improve the gene models of 352 genes, including identifying 20 novel gene transcripts. This dataset has also significantly increased the known amount of heterogeneity between P. vivax schizont transcriptomes from individual patients. The majority of genes found to be differentially expressed between the isolates lack Plasmodium falciparum homologs and are predicted to be involved in host-parasite interactions, with an enrichment in reticulocyte binding proteins, merozoite surface proteins and exported proteins with unknown function. An improved understanding of the diversity within P. vivax transcriptomes will be essential for the prioritisation of novel vaccine targets.

scholarly journals Association of Endothelial Biomarkers with Cerebral MRI Perfusion Analysis in Patients with Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1000-1000
Author(s):  
Liza Afzali-Hashemi ◽  
Lena Vaclavu ◽  
Erfan Nur ◽  
Aart J Nederveen ◽  
Bart J. Biemond
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Adhesion Molecule ◽  
Plasma Levels ◽  
Cerebral Perfusion ◽  
Endothelial Activation ◽  
Healthy Controls ◽  
Standard Laboratory ◽  
Cell Disease ◽  
Laboratory Parameters

Introduction Sickle cell disease (SCD) is associated with silent cerebral infarcts (SCI) which are related to neurocognitive damage. One of the major causes of SCI is the impaired cerebral oxygenation, which makes cerebral blood flow (CBF) an essential parameter to measure. Previous hemodynamic studies have shown elevated CBF and reduced cerebrovascular reserve (CVR) in patients with SCD (Helton 2015; Václavů 2018). CVR is known as the increase of CBF in response to vasoactive stimulus, relative to the baseline. The reduced CVR renders SCD patients susceptible to cerebral ischemia, especially under hypotensive or hypoxic conditions. Possible factors contributing to microvascular damage and thus reduced CVR include hemoglobin S polymerization, neutrophil activation and endothelial activation and adhesion. Previous studies examined the role of these factors in patients with SCD (Sins 2017; Al Najjar 2017). However, the association between the endothelial biomarkers and hemodynamic parameters is unknown in adult patients with SCD. In this study, we investigated the correlation between CBF and CVR and the adhesion molecules including sVCAM-1, sP-selectin, VWF-Ag and ADAMTS13. Additionally, we studied the association of these endothelial biomarkers with standard laboratory parameters. Methods This study was performed in accordance with the Declaration of Helsinki and was approved by the Review Board of Amsterdam UMC. For this study, 33 steady state patients with SCD (mean age 32.1 ± 10.7, 64% male, 29 HbSS, 4 HbSß) and 10 healthy volunteers (mean age 36,4 ± 15.9, 60% male, 2 HbAS, 8 HbAA) were included. Hematologic laboratory parameters were assessed using standard laboratory procedures. Plasma levels of sVCAM-1 and sP-selectin were determined using ELISA (R&D Systems, USA) and ADAMTS13 and VWF-Ag were measured with the INNOVANCE assay (Siemens Healthcare Diagnostics). For the CBF measurements, pseudo-continuous arterial spin labelling (pCASL) was acquired at 3T MRI (Philips Healthcare, The Netherlands). CBF was measured before and after acetazolamide (vasoactive stimulus) administration and subsequently CVR was calculated using the following equation: CVR = (CBFafter - CBFbefore) / CBFbefore x 100% Plasma levels of endothelial biomarkers were compared between groups using ANOVA test. Correlation between the parameters were measured using single regression model where p<0.05 was considered as statistically significant. Results sVCAM-1 levels and VWF-Ag were significantly higher in SCD patients compared to healthy controls (p < 0.01 and p = 0.01). ADAMTS13 and sP-selectin were not significantly different between the two groups (p = 0.06 and p = 0.33). sVCAM-1 was significantly associated with CBF, and parameters of hemolysis LDH and bilirubin in SCD patients (Fig. 1A and 2C). Negative correlation was observed between sVCAM-1 and hemoglobin (Fig. 1B). The relationship between sVCAM-1 and hemodynamic and laboratory parameters are shown in Table 1. No significant correlation was found between sVCAM-1, hemodynamic and standard laboratory parameters in healthy controls. VWF-Ag, ADAMTS13 and sP-selectin were not significantly associated with hemodynamic MRI parameters. Discussion Our results show elevated sVCAM-1 levels in sickle cell patients, strongly related to CBF. sVCAM-1 is an adhesion molecule and elevated plasma levels are found in patients with endothelial activation due to inflammation or atherosclerosis (Cook-Mills 2013; Cybulsky 2001). Previous studies showed elevated levels in sickle cell disease but no correlation with parameters of cerebral perfusion have been demonstrated yet (Antwi-Boasiako 2018; Kato 2005). The strong correlation with CBF is mostly related to the chronic hemolysis given the association found with hemoglobin levels and markers of hemolysis like LDH and bilirubin. In contrast to sVCAM-1, no such relation was found with other markers of endothelial activation such as VWF activity and sP-selectin levels. No correlation between endothelial markers and the CVR was demonstrated, suggesting that endothelial damage itself may not related to the impaired cerebral vasodilatation in response to a vasoactive stimulus. Conclusion Endothelial adhesion molecule sVCAM-1 showed a strong correlation with CBF and parameters of hemolysis, suggesting a relation between the hemolytic damage of endothelial cells and impaired cerebral perfusion. Disclosures Nur: Novartis Pharmaceuticals: Consultancy.

Multiplex Assay for Profiling Plasma Protein Biomarkers for Improved Diagnosis and Prognosis of Heparin Induced Thrombocytopenia (HIT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4106-4106
Author(s):  
Resmi Ravindran ◽  
Imran Khan ◽  
Robert C. Gosselin ◽  
Ted Wun ◽  
Krish Krishnan ◽  
...  
Keyword(s):  
Growth Factors ◽  
Plasma Protein ◽  
Plasma Levels ◽  
Simultaneous Detection ◽  
Soluble Form ◽  
Healthy Controls ◽  
Plasma Samples ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Diagnosis And Prognosis

Abstract Background: Laboratory diagnosis of heparin-induced thrombocytopenia (HIT) is currently done by using immunologic, platelet aggregation, and serotonin-release assays; however, the diagnostic efficacy of these tests is variable. Although, various clinical scoring systems are currently used to attempt to differentiate patients with HIT from those with other causes of thrombocytopenia, a definite predictive test for HIT is still not available. The pathogenesis of HIT could involve dysregulation of inflammatory mediators (and other immunomodulators) and growth factors from platelets and endothelial cells. Accordingly, with the goal of identifying potential biomarkers of disease, the present study examined the profiles of cytokines, chemokines, and selected growth factors in HIT patients. We are testing a novel multiplex microbead immunoassay approach, developed by Luminex (Austin, TX), for simultaneous detection of multiple plasma protein analytes. Methods: Plasma samples were obtained from 20 patients diagnosed with HIT and from 15 healthy controls. Patient plasma samples in this study were positive for heparin-platelet factor 4 (PF4) antibodies by ELISA (GTI, Mulwaukee WI). Using the multiplex microbead immunoassay, measurements were made on plasma levels of thirty four cytokines/chemokines, which included tumor necrosis factor (TNF) alpha, interferon (IFN) gamma, IL-1 beta, IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p40), IL12(p70), IL-16, Eotaxin, RANTES, MCP-1, MIP-1alpha, MIP-1beta (CCL4), IP-10, MCP-3 (CCL7), GM-CSF, TNF-beta, IL-1RA, soluble form of interleukin (IL) 2 receptor (sIL-2R)alpha, IFNalpha2a, sFAS ligand, GRO, MDC(CCL22), G-CGF in HIT patients and healthy controls; commercial multiplex detection panels were used (Upstate, Lake Placid, NY). In addition, the levels of six growth factors were measured, including FGF-2, VEGF, EGF, Flt-3 Ligand, PDGF-AA and PDGF-AB/BB by the multiplex method (by detection panels also from Upstate). Results: Multiplex data were analyzed by methods of computational biology to establish hierarchical clustering. In these surveys, the level of sIL-2R, an in vivo marker of T-cell activation was higher in patient plasma than in healthy control subjects (p≤0.002). Plasma levels of the chemokines, MCP-1, MIP-1alpha and IP-10, were significantly reduced in patients compared to controls. Among the growth factors tested, EGF appeared to be significantly decreased in HIT patients compared to the control group. In addition, patients showed lower PDGF-AA and PDGF-AB/BB levels. Conclusions: Various immunomodulators and growth factors were either increased or decreased in HIT patient plasma. Accordingly, our studies are providing leads for further characterization of plasma biomarkers of HIT in a larger number of patients, including longitudinal samples. In combination with the detection of anti-PF4-heparin antibodies, and other criteria, multiple microbead immunoassays of plasma protein profiles may enhance the accuracy of HIT diagnosis and prognosis. Additionally, the multiplex method, enabling simultaneous detection of multiple protein factors, is also providing novel leads for further studies on the molecular and cellular mechanisms of HIT.

scholarly journals LncRNA GAS8-AS1 is a Novel Prognostic and Diagnostic Biomarker for Pancreatic Cancer

2021 ◽  
Author(s):  
Ling Zhang ◽  
Miao Li ◽  
Lihong Deng ◽  
Dujiang Yang ◽  
Chao Yue ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Plasma Levels ◽  
Early Stage ◽  
Migration And Invasion ◽  
Cell Transfection ◽  
Healthy Controls ◽  
Overall Survival Rate ◽  
Diagnostic Biomarker ◽  
Real Time Quantitative Pcr

Abstract Background: LncRNA GAS8-AS1 inhibits thyroid carcinoma, but its function in other malignancies is unknown. The present study aimed to investigate the involvement of GAS8-AS1 in pancreatic cancer (PC). Methods: The present study included 68 PC patients (38 males and 30 females, 42- 66 years, 52.1±4.5) and 62 healthy volunteers (28 males and 24 females, 43- 67 years, 52.3 ±4.9). Real-time quantitative PCR, transient cell transfection and in vitro cell migration and invasion assay were applied for the research. In the present study we found that plasma GAS8-AS1 was lower in PC patients than in healthy controls. Downregulation of plasma GAS8-AS1 distinguished early stage PC patients from healthy controls. Results: Patients with low plasma levels of GAS8-AS1 showed significantly lower 5-year overall survival rate. Plasma levels of miR-1179 were also significantly lower in PC patients than in healthy controls, and were positively correlated with plasma levels of GAS8-AS1 only in PC patients. GAS8-AS1 overexpression resulted in the upregulation of miR-1179. MiR-1179 overexpression also led to the overexpression of GAS8-AS1. Overexpression of both GAS8-AS1 and miR-1179 led to inhibited migration and invasion of PC cells. Conclusions: Therefore, GAS8-AS1 may promote PC by positively interacting with miR-1179.

Increased Platelet Serotonin Content and Hypersecretion from Dense and A-Granules In Vitro In Tension-Type Headache

Cephalalgia ◽  
1993 ◽  
Vol 13 (5) ◽  
pp. 349-353 ◽  
Author(s):  
Giovanni D'Andrea ◽  
Lena Hasselmark ◽  
Michela Alecci ◽  
Francesco Perini ◽  
KMA Welch
Keyword(s):  
Platelet Aggregation ◽  
Tension Type Headache ◽  
Platelet Factor 4 ◽  
Healthy Controls ◽  
Platelet Factor ◽  
Serotonin Content ◽  
Platelet Serotonin ◽  
Serotonin Turnover ◽  
Type Headache

We investigated platelet aggregation and secretion from dense and a-granules in vitro in 28 tension-type headache (TH) patients and 26 healthy controls. We also measured basal platelet serotonin levels, Platelet aggregation was normal in TH, but the secretion of serotonin and platelet factor 4 (PF4) was significantly increased in response to 0.5 and 2.0 mg/ml collagen and to 1.0 mmol/l PAF. The basal platelet serotonin levels were also higher in patients than in controls. The mechanisms of platelet hypersecretion remain to be determined, but the increased secretion of serotonin is probably in part related to the increased basal levels. The increased platelet serotonin in TH patients may reflect an enhanced serotonin turnover.

Soluble P-Selectin During a Single Hemodialysis Session in Patients With Chronic Renal Failure and Erythropoietin Treatment

2007 ◽  
Vol 13 (4) ◽  
pp. 410-415 ◽  
Author(s):  
Ján Staško ◽  
Peter Galajda ◽  
Jela Ivanková ◽  
Pavol Hollý ◽  
Eva Rozborilová ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Plasma Levels ◽  
Platelet Factor 4 ◽  
Control Group ◽  
Healthy Controls ◽  
Soluble Adhesion Molecules ◽  
Platelet Factor ◽  
Soluble P

In several studies, hemodialysis (HD) patients treated with recombinant human erythropoietin (rHuEPO) because of renal anemia showed increased levels of soluble adhesion molecules. The purpose of the study was to investigate the changes of soluble P-selectin (sSELP) and its relationship to platelet activation during a single HD session in patients with long-term rHuEPO treatment. Fifty-two HD patients with chronic renal failure were involved—26 with rHuEPO treatment (EPO group) and 26 without (non-EPO group). Thirty healthy subjects served as the control group. The sSELP, β-thromboglobulin, and platelet factor 4 plasma levels were measured before and after a single 4-hour HD session on a cuprophane dialyzer. The basal β-thromboglobulin and platelet factor 4 plasma levels were significantly increased in both HD groups compared with healthy controls but did not change after a single HD session, except for a significant decrease of platelet factor 4 in the non-EPO group. The predialysis sSELP plasma levels did not differ significantly compared with those of the healthy controls, but there was a significant increase of sSELP levels after a single HD session in both groups (EPO, P < .005; non-EPO, P < .05, respectively). These results suppose that the increased sSELP level was released from platelets during the course of a single HD session. The more significant increase of the sSELP plasma levels in EPO group during HD indicates that platelets are more activated in patients with long-term rHuEPO treatment, and this fact could partially explain the suspected tendency for thrombosis in these patients.

scholarly journals Plasma levels of beta-thromboglobulin and platelet factor 4 as indices of platelet activation in vivo

Blood ◽  
1981 ◽  
Vol 57 (2) ◽  
pp. 199-202 ◽  
Author(s):  
KL Kaplan ◽  
J Owen
Keyword(s):  
Plasma Level ◽  
Platelet Activation ◽  
Plasma Levels ◽  
In Vitro Release ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Rapid Removal ◽  
Vitro Release

Abstract Measurement of plasma levels of two secreted platelet proteins (beta- thromboglobulin and platelet factor 4) has been suggested as a means for detecting increased platelet activation in vivo. A crucial question in the measurement is the distinction between in vivo and in vitro secretion of the proteins. One approach to this distinction is the measurement of both proteins in each sample. These proteins are present in platelets in similar amounts and are released in similar quantities, but the plasma levels of beta-thromboglobulin exceed the plasma levels of platelet factor 4. This difference in plasma level is presumably due to more rapid removal of platelet factor 4 from the plasma level, and there is suggestive evidence that the rapid removal of released platelet factor 4 is due to its binding to endothelial cells. It appears that when there is increased release of beta-thromboglobulin and platelet factor 4 in vivo, there is an increase in the ratio of plasma beta-thromboglobulin to plasma platelet factor 4 compared to that found in normal individuals, whereas when in vitro release is responsible for elevated levels, the ratio decreases. Thus measurements of both proteins in each blood sample will allow distinction between in vivo release and artefactual in vitro release.

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