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Edited by
Nevena V. Radonjić, State University of New York Upstate Medical University,Thomas L. Schwartz, State University of New York Upstate Medical University,Stephen M. Stahl, University of California, San Diego
Lipid emulsions are essential components of parenteral nutrition solutions that provide energy and essential fatty acids. The complexity of the formulations of lipid emulsions may lead to adverse outcomes such as platelet reactivity and changes in platelet aggregation and related coagulation. Platelets are responsible for haemostasis; they activate and demonstrate morphological changes upon extracellular factors to maintain blood fluidity and vascular integrity. Although parenteral nutrition lipid emulsions are generally found safe with regard to modulation of platelet activity, studies are still accumulating. Thus, this review aims to investigate platelet-related changes by parenteral nutrition lipid emulsions in human studies. Studies have pointed out patients at risk of bleeding and increased platelet aggregation responses due to the administration of lipid emulsions. Lipid emulsions may further benefit patients at high risk of thrombosis due to anti-thrombotic effects and should be cautiously used in patients with thrombocytopenia. The reported platelet-related changes might be associated with the fatty acid change in the plasma membranes of platelets following changes in platelet synthesis and plasma levels of eicosanoids. In conclusion, studies investigating platelets and parenteral nutrition should be supported to minimize the adverse effects and to benefit from the potential protective effects of parenteral nutrition lipid emulsions.
Thrombotic microangiopathies (TMA) are a group of conditions characterized by excessive platelet activation, resulting in microvascular thrombi and platelet consumption (thrombocytopenia). The thrombosed microvasculature shears red blood cells (RBCs), causing microangiopathic hemolytic anemia. Primary TMAs include thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), while secondary TMAs result from infection, pregnancy, malignancy, drugs and toxins, among other causes.
TMAs do not directly involve the coagulation cascade, and therefore do not prolong coagulation studies. Microthrombi may result in ischemic complications in any organ system.
1. Abnormal coagulation results are not uncommon in critically unwell patients.
2. In vitro tests do not always fully correlate with events in vivo, and so all results should be interpreted with reference to the clinical history, particularly any bleeding or thrombosis history.
3. The clinical severity of disseminated intravascular coagulation may not necessarily correlate with abnormalities seen in the laboratory tests, and an individualised plan should be made depending on the clinical scenario.
4. Patients with cirrhosis are at risk of thrombosis, as well as bleeding.
5. In a stable, non-bleeding patient with liver disease, there is no need for ‘prophylactic’ blood components unless procedures are required.
Acute stent thrombosis may complicate neonatal arterial duct stenting for reduced pulmonary blood flow. Thrombolytic agents recanalise the clot but may cause bleeding around the vascular sheaths and other sites. Since early thrombus is platelet mediated, intravenous platelet glycoprotein inhibitor like eptifibatide is likely to be effective, but rarely utilised in neonates. Ductal stent thrombosis treated with eptifibatide is reported.
This study revealed that the mass ratio of large anisometric particles (platelets) to ultrafine, equiaxed particles strongly influences dynamic and quasistatic compressive response and the process of damage evolution in ice-templated alumina materials. The improved sinterability between particles of significantly dissimilar size and morphology enabled the utilization of a high mass ratio of the particles in harnessing a markedly enhanced level of strength in highly porous ice-templated ceramics. The high volume fraction of platelets increased lamellar bridge density and resulted in dendritic morphology as opposed to lamellar morphology without platelets. All the materials showed strain rate-sensitivity, where strength increased with strain rate. Materials with highly dendritic morphology exhibited the best performance in terms of maximum strength and energy absorption capacity, and the performance improved from quasistatic to dynamic regime. Direct observation of the process of damage evolution revealed the effects of both strain rate and ratio of platelets to ultrafine particles.
Thrombocytopenia is a risk factor for patent ductus arteriosus. Immature and mature platelets exhibit distinct haemostatic properties; however, whether platelet maturity plays a role in postnatal, ductus arteriosus closure is unknown.
Methods:
In this observational study, counts of immature and mature platelets (=total platelet count − immature platelet count) were assessed on days 1, 3, and 7 of life in very low birth weight infants (<1500 g birth weight). We performed echocardiographic screening for haemodynamically significant patent ductus arteriosus on day 7.
Results:
Counts of mature platelets did not differ on day 1 in infants with (n = 24) and without (n = 45) haemodynamically significant patent ductus arteriosus, while infants with significant patent ductus arteriosus exhibited lower counts of mature platelet on postnatal days 3 and 7. Relative counts of immature platelets (fraction, in %) were higher in infants with patent ductus arteriosus on day 7 but not on days 1 and 3. Receiver operating characteristic curve analysis unraveled associations between both lower mature platelet counts and higher immature platelet fraction (percentage) values on days 3 and 7, with haemodynamically significant ductus arteriosus. Logistic regression analysis revealed that mature platelet counts, but not immature platelet fraction values, were independent predictors of haemodynamically significant patent ductus arteriosus.
Conclusion:
During the first week of postnatal life, lower counts of mature platelets and higher immature platelet fraction values are associated with haemodynamically significant patent ductus arteriosus. Lower counts of mature platelet were found to be independent predictors of haemodynamically significant patent ductus arteriosus.
In this chapter on hematology and transfusion, the author reviews commonly encountered perioperative disorders such as hemoglobinopathies, G6PD, Sickle Cell Disease, von Willebrand Disease and Hemophilia. Pediatric transfusion of blood components is discussed as well as use of thromboelastography to guide treatment.
We are developing the novel αIIbβ3 antagonist, RUC-4, for subcutaneously (SC)-administered first-point-of-medical-contact treatment for ST segment elevation myocardial infarction (STEMI).
Methods:
We studied the (1) pharmacokinetics (PK) of RUC-4 at 1.0, 1.93, and 3.86 mg/kg intravenous (IV), intramuscular (IM), and SC in non-human primates (NHPs); (2) impact of aspirin on RUC-4 IC50 in human platelet-rich plasma (PRP); (3) effect of different anticoagulants on the RUC-4 IC50 in human PRP; and (4) relationship between αIIbβ3 receptor blockade by RUC-4 and inhibition of ADP-induced platelet aggregation.
Results:
(1) All doses of RUC-4 were well tolerated, but animals demonstrated variable temporary bruising. IM and SC RUC-4 reached dose-dependent peak levels within 5–15 minutes, with T1/2 s between 0.28 and 0.56 hours. Platelet aggregation studies in NHPs receiving IM RUC-4 demonstrated >80% inhibition of the initial slope of ADP-induced aggregation with all three doses 30 minutes post-dosing, with subsequent dose-dependent loss of inhibition over 4–5 hours. (2) The RUC-4 IC50 for ADP-induced platelet aggregation was unaffected by aspirin treatment (40±9 nM vs 37±5 nM; p = 0.39). (3) The RUC-4 IC50 was significantly higher in PRP prepared from D-phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK)-anticoagulated blood compared to citrate-anticoagulated blood using either thrombin receptor activating peptide (TRAP) (122±17 vs 66±25 nM; p = 0.05; n = 4) or ADP (102±22 vs 54±13; p<0.001; n = 5). (4) There was a close correspondence between receptor blockade and inhibition of ADP-induced platelet aggregation, with aggregation inhibition beginning with ~40% receptor blockade and becoming nearly complete at >80% receptor blockade.
Discussion:
Based on these results and others, RUC-4 has now progressed to formal preclinical toxicology studies.
The relationship between serum Mg and blood cell counts in Chinese adult diabetes or central obesity was assessed by investigating 8163 subjects with China Health and Nutrition Survey (mean age 59⋅6 years, 54⋅9 % men). Participants were classified according to blood Mg (below 0⋅65 mmol/l, or 0⋅66–0⋅94 mmol/l or above 0⋅95 mmol/l), type 2 diabetes (yes/no) and central obesity (yes/no). Leucocytes, erythrocytes, platelets (PLT), Hb and glycated Hb (HbA1c) were determined using standardised methods and conditions. HbAc1, leucocytes and PLT were significantly higher among subjects with central obesity than without central obesity (P < 0⋅05). A significant increase for Hb, erythrocytes, PLT, but not leucocytes, across progressive Mg groups was observed in subjects without diabetes (P < 0⋅05). Hb, erythrocytes and HbAc1 were significantly higher among subjects with higher Mg than in subjects with lower Mg with diabetes (P < 0⋅05). Central obesity disturbed the positive association between PLT count and serum Mg. Type 2 diabetes caused metabolism disorder in serum Mg, blood sugar and blood cell count. Hb, erythrocytes and PLT, but not leucocytes, are positively correlated with serum Mg, but this association is somehow disturbed by type 2 diabetes or central obesity.
To assess the diagnostic role of mean platelet volume in tonsillitis with and without peritonsillar abscess.
Methods
Mean platelet volume and other laboratory data were retrospectively investigated.
Results
Mean platelet volume was significantly lower in the tonsillitis group (7.8 per cent ± 0.7 per cent) than in the control group (8.7 per cent ± 0.6 per cent; p < 0.0001), and it was significantly lower in the abscess group (7.5 per cent ± 0.6 per cent) than in the no abscess group (8.0 per cent ± 0.7 per cent; p = 0.0277). White blood cell counts and C-reactive protein levels were not significantly different between patients with an abscess and those without. The mean platelet volume cut-off values for the diagnosis of tonsillitis and peritonsillar abscess were 7.95 fl and 7.75 fl, respectively.
Conclusion
Our results suggest that a decreased mean platelet volume is associated with the development and severity of tonsillitis. This finding provides useful diagnostic information for physicians treating patients with tonsillitis.
Platelet ultrastructural alterations representing spurious activation have been identified in pathological conditions. A limitation of platelet studies is that sample preparation may lead to artifactual activation processes which may confound results, impacting the use of scanning electron microscopy as a supplemental diagnostic tool. We used scanning electron microscopy and flow cytometry to analyze platelet activation in platelet-rich plasma (PRP) and whole blood (WB) samples. PRP generated using a single high g force centrifugation, and WB samples treated with a red blood cell lysis buffer, were exposed to increasing concentrations of the agonist thrombin. Platelets in lysed WB samples responded to thrombin by elevating the activation marker CD62p definitively, with corresponding ultrastructural changes indicating activation. Conversely, CD62p expression in PRP preparations remained static. Ultrastructural analysis revealed fully activated platelets even under low concentration thrombin stimulation, with considerable fibrin deposition. It is proposed that the method for PRP production induced premature platelet activation, preventable by using an inhibitor of platelet aggregation and fibrin polymerization. Nevertheless, our results show a definitive correspondence between flow cytometry and scanning electron microscopy in platelet activation studies, highlighting the potential of the latter technique as a supplemental diagnostic tool.
Angiogenesis is a closely controlled biological process that takes place during fetal development of blood vessels and wound healing, and includes the development of new blood vessels from preexisting blood vessels. Tumor angiogenesis is a means by which tumors obtain oxygen, nutrition and promote tumor growth. Angiogenesis-regulating proteins are therefore ideal biomarkers in the study of tumor pathophysiology. In our laboratory, a new in silico-designed analogue of 2-methoxyestradiol has been synthesized with angiogenic properties, namely 2-ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16). The ex vivo influence of ESE-16 on angiogenesis and morphology in platelets of healthy participants was investigated. Scanning electron microscopy revealed no morphological changes in ESE-16-treated platelets. The possible antiangiogenic effect of ESE-16-exposed platelets was determined by means of flow cytometry measurement of angiogenic protein levels, which were significantly increased after platelets were added to tumorigenic breast epithelial cells. This indicates that binding of platelets to cancer cells causes differential release of platelet constituents. Vascular endothelial growth factor levels were decreased in platelets, whereas platelet-derived growth factor and matrix metallopeptidase-9 levels were not significantly affected in platelets. In light of the above-mentioned data, further investigation of ESE-16’s influence on morphology and angiogenic markers in platelets of cancer patients is warranted.
Maternal and fetal requirements during uncomplicated pregnancy are associated with changes in the hematopoietic system. Platelets and erythrocytes [red blood cells (RBCs)], and especially their membranes, are involved in coagulation, and their interactions may provide reasons for the changed hematopoietic system during uncomplicated pregnancy. We review literature regarding RBC and platelet membrane structure and interactions during hypercoagulability and hormonal changes. We then study interactions between RBCs and platelets in uncomplicated pregnancy, as their interactions may be one of the reasons for increased hypercoagulability during uncomplicated pregnancy. Scanning electron microscopy was used to study whole blood smears from 90 pregnant females in different phases of pregnancy. Pregnancy-specific interaction was seen between RBCs and platelets. Typically, one or more platelets interacted through platelet spreading and pseudopodia formation with a single RBC. However, multiple interactions with RBCs were also shown for a single platelet. Specific RBC–platelet interaction seen during uncomplicated pregnancy may be caused by increased estrogen and/or increased fibrinogen concentrations. This interaction may contribute to the hypercoagulable state associated with healthy and uncomplicated pregnancy and may also play a fundamental role in gestational thrombocytopenia.
Thrombus formation in flowing blood is a complex time- and space-dependent process ofcell adhesion and fibrin gel formation controlled by huge intricate networks ofbiochemical reactions. This combination of complex biochemistry, non-Newtonianhydrodynamics, and transport processes makes thrombosis difficult to understand. That iswhy numerous attempts to use mathematical modeling for this purpose were undertaken duringthe last decade. In particular, recent years witnessed something of a transition from the“systems biology” to the “systems pharmacology/systems medicine” stage: computationalmodeling is being increasingly applied to practical problems such as drug development,investigation of particular events underlying disease, analysis of the mechanism(s) ofdrug’s action, determining an optimal dosing protocols, etc. Here we review recentadvances and challenges in our understanding of thrombus formation.
The cumulative effect of co-infections between pathogen pairs on the haematological response of East African Short-horn Zebu calves is described. Using a longitudinal study design a stratified clustered random sample of newborn calves were recruited into the Infectious Diseases of East African Livestock (IDEAL) study and monitored at 5-weekly intervals until 51 weeks of age. At each visit samples were collected and analysed to determine the infection status of each calf as well as their haematological response. The haematological parameters investigated included packed cell volume (PCV), white blood cell count (WBC) and platelet count (Plt). The pathogens of interest included tick-borne protozoa and rickettsias, trypanosomes and intestinal parasites. Generalized additive mixed-effect models were used to model the infectious status of pathogens against each haematological parameter, including significant interactions between pathogens. These models were further used to predict the cumulative effect of co-infecting pathogen pairs on each haematological parameter. The most significant decrease in PCV was found with co-infections of trypanosomes and strongyles. Strongyle infections also resulted in a significant decrease in WBC at a high infectious load. Trypanosomes were the major cause of thrombocytopenia. Platelet counts were also affected by interactions between tick-borne pathogens. Interactions between concomitant pathogens were found to complicate the prognosis and clinical presentation of infected calves and should be taken into consideration in any study that investigates disease under field conditions.
We aimed to determine: (1) whether mean platelet volume was elevated in patients with sudden sensorineural hearing loss, compared with healthy controls; and (2) whether mean platelet volume level was related to hearing loss severity.
Materials and methods:
The study included 31 patients with sudden sensorineural hearing loss and 31 age- and sex-matched, healthy controls. Peripheral venous blood samples were taken from subjects and mean platelet volume and levels of glucose, total cholesterol, high-density lipoprotein, low-density lipoprotein and triglyceride were measured.
Results:
Mean platelet volume was significantly greater in the sudden sensorineural hearing loss group compared with the control group. However, there was no significant correlation between mean platelet volume level and hearing loss severity.
Conclusion:
Mean platelet volume, a determinant of platelet activation, is elevated in patients with sudden sensorineural hearing loss. To our knowledge, this is the first report investigating mean platelet volume levels in such patients. Our findings indirectly support the hypothesis of vascular impairment as a pathogenetic factor in sudden sensorineural hearing loss.
Nanoparticles composed of a magnetic iron oxide core surrounded by a metal shell have utility in a broad range of biomedical applications. However, the presence of surface energy differences between the two components makes wetting of oxide with metal unfavorable, precluding a “core–shell” structure of an oxide core completely surrounded by a thin metal shell. Three-dimensional island growth followed by island coalescence into thick shells is favored over the two-dimensional layer-by-layer growth of a thin, continuous metal coating of a true core–shell. Aqueous synthesis of gold-coated magnetite nanoparticles with analysis by infrared, energy-dispersive X-ray, and electron energy loss spectroscopies; high-resolution transmission electron microscopy; selected area electron diffraction; and high-angle annular dark-field scanning transmission electron microscopy showed two distinct morphologies that are inconsistent with an idealized core–shell. The majority were isolated ~16–22-nm-diameter nanoparticles consisting of ~7-nm-diameter magnetite and a thick deposition of gold, most often discontinuous, with some potentially “sandwiched” morphologies. A minority were aggregates of agglomerated magnetite decorated with gold but displaying significant bare magnetite. Both populations were successfully conjugated to fibrinogen and targeted to surface-activated platelets, demonstrating that iron oxide–gold nanoparticles produced by aqueous synthesis do not require an ideal core–shell structure for biological activity in cell labeling and targeting applications.
Shunt thrombosis after implantation of systemic-to-pulmonary shunts in paediatric patients is common. Acetyl salicylic acid is used for anti-thrombotic treatment; however, the effect is rarely monitored, although it is known that the response varies. The aim was to determine the effects of acetyl salicylic acid medication on platelet aggregation in children with systemic-to-pulmonary shunts.
Methods
A total of 14 children – median age 12 days; ranging from 3 to 100 days – were included in a prospective observational longitudinal study. All children were treated with oral acetyl salicylic acid (3–5 milligrams per kilogram once daily) after shunt implantation. Acetyl salicylic acid-dependent platelet aggregation in whole blood was analysed with impedance aggregometry (Multiplate®) after addition of arachidonic acid. Analyses were carried out before the primary operation, before and 5 and 24 hours after the first acetyl salicylic acid dose, and after 3–6 months of treatment. The therapeutic range for acetyl salicylic acid was defined as a test result less than 60 units.
Results
Acetyl salicylic acid reduced the arachidonic acid-induced platelet aggregation in all but one patient. Of the patients, 93% were in the therapeutic range 5 hours after acetyl salicylic acid intake, 86% were in the range after 24 hours, and 64% after 3–6 months.
Conclusions
Acetyl salicylic acid reduces platelet aggregation after shunt implantation in paediatric patients, but a considerable percentage of the children are outside the therapeutic range. Monitoring of platelet aggregation has the potential to improve anti-platelet treatment after shunt implantation by identifying children with impaired acetyl salicylic acid response.
Blood rheology is completely determined by its major corpuscles which are erythrocytes,or red blood cells (RBCs). That is why understanding and correct mathematical descriptionof RBCs behavior in blood is a critical step in modelling the blood dynamics. Variousphenomena provided by RBCs such as aggregation, deformation, shear-induced diffusion andnon-uniform radial distribution affect the passage of blood through the vessels. Hence,they have to be taken into account while modelling the blood dynamics. Other importantblood corpuscles are platelets, which are crucial for blood clotting. RBCs strongly affectthe platelet transport in blood expelling them to the vessel walls and increasing theirdispersion, which has to be considered in models of clotting. In this article we give abrief review of basic modern approaches in mathematical description of these phenomena,discuss their applicability to real flow conditions and propose further pathways fordeveloping the theory of blood flow.