Heparin–protamine balance after neonatal cardiopulmonary bypass surgery

Peterson, Julie A.; Maroney, Susan A.; Zwifelhofer, Wes; Wood, Jeremy P.; Yan, Ke; Bercovitz, Rachel S.; Woods, Ronald K.; Mast, Alan E.

doi:10.1111/jth.14245

Cited by 12 publications

(12 citation statements)

References 39 publications

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“…These included measures of coagulation function such as hematocrit, fibrinogen level, prothrombin time, or partial thromboplastin time, as was also reported previously. 52 Unique to this study is the report that platelet count and platelet responses to stimulation with agonists that activate platelets through the thromboxane A2, thrombin, collagen, or P2Y 1 and P2Y 12 receptors also did not differ significantly between patients who bled excessively and those who did not. Platelet responses to epinephrine and ristocetin, which activate platelets through the α 2 -adrenergic and GPIb/IX/V receptors, respectively, were also tested in this study but found to be too low to allow for meaningful comparisons (data not shown).…”

Section: Discussionmentioning

confidence: 88%

Platelet Function Changes during Neonatal Cardiopulmonary Bypass Surgery: Mechanistic Basis and Lack of Correlation with Excessive Bleeding

et al. 2019

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Thrombocytopenia and platelet dysfunction induced by extracorporeal blood circulation are thought to contribute to postsurgical bleeding complications in neonates undergoing cardiac surgery with cardiopulmonary bypass (CPB). In this study, we examined how changes in platelet function relate to changes in platelet count and to excessive bleeding in neonatal CPB surgery. Platelet counts and platelet P-selectin exposure in response to agonist stimulation were measured at four times before, during, and after CPB surgery in neonates with normal versus excessive levels of postsurgical bleeding. Relative to baseline, platelet counts were reduced in patients while on CPB, as was platelet activation by the thromboxane A2 analog U46619, thrombin receptor activating peptide (TRAP), and collagen-related peptide (CRP). Platelet activation by adenosine diphosphate (ADP) was instead reduced after platelet transfusion. We provide evidence that thrombocytopenia is a likely contributor to CPB-associated defects in platelet responsiveness to U46619 and TRAP, CPB-induced collagen receptor downregulation likely contributes to defective platelet responsiveness to CRP, and platelet transfusion may contribute to defective platelet responses to ADP. Platelet transfusion restored to baseline levels platelet counts and responsiveness to all agonists except ADP but did not prevent excessive bleeding in all patients. We conclude that platelet count and function defects are characteristic of neonatal CPB surgery and that platelet transfusion corrects these defects. However, since CPB-associated coagulopathy is multifactorial, platelet transfusion alone is insufficient to treat bleeding events in all patients. Therefore, platelet transfusion must be combined with treatment of other factors that contribute to the coagulopathy to prevent excessive bleeding.

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Section: Discussionmentioning

confidence: 88%

Platelet Function Changes during Neonatal Cardiopulmonary Bypass Surgery: Mechanistic Basis and Lack of Correlation with Excessive Bleeding

et al. 2019

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“…Numerous studies have evaluated CAT as a predictor of bleeding in adults [54,55], but few have in neonates. Peterson et al found that CAT did not predict post-operative bleeding after cardiopulmonary bypass (CPB) [40]. Tripodi et al found no difference in ETP measurements at birth, between VLBW infants that developed an IVH and those that did not [9].…”

Section: Cat As a Predictor Of Clinical Bleeding In Neonatesmentioning

confidence: 99%

“…Haidl et al centrifuged whole blood at 200 × g for 10 min and diluted this with PPP to produce a specific platelet count (10, 50, 75 and 100 × 10^9/L) [ 25 ]. Peterson et al centrifuged whole blood at 100 × g for 10 min, before diluting with PPP to achieve a standard platelet count of 50 × 10^9/L [ 40 ]. Bernhard et al pelleted and washed platelets, before re-suspending them in PPP and adjusting “to similar counts” [ 38 ].…”

Section: Evaluating the Effect Of Neonatal Plateletsmentioning

confidence: 99%

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The role of the calibrated automated thrombogram in neonates: describing mechanisms of neonatal haemostasis and evaluating haemostatic drugs

et al. 2021

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Premature infants are at high risk of haemorrhage and thrombosis. Our understanding of the differences between the neonatal and adult haemostatic system is evolving. There are several limitations to the standard coagulation tests used in clinical practice, and there is currently a lack of evidence to support many of the transfusion practices in neonatal medicine. The evaluation of haemostasis is particularly challenging in neonates due to their limited blood volume. The calibrated automated thrombogram (CAT) is a global coagulation assay, first described in 2002, which evaluates both pro- and anti-coagulant pathways in platelet-rich or platelet-poor plasma. In this review, the current applications and limitations of CAT in the neonatal population are discussed.Conclusion: CAT has successfully elucidated several differences between haemostatic mechanisms in premature and term neonates compared with adults. Moreover, it has been used to evaluate the effect of a number of haemostatic drugs in a pre-clinical model. However, the lack of evidence of CAT as an accurate predictor of neonatal bleeding, blood volume required and the absence of an evidence-based treatment algorithm for abnormal CAT results limit its current application as a bedside clinical tool for the evaluation of sick neonates. What is Known:• The Calibrated automated thrombogram (CAT) is a global coagulation assay which evaluates pro- and anti-coagulant pathways.• CAT provides greater information than standard clotting tests and has been used in adults to evaluate bleeding risk. What is New:• This review summarises the physiological differences in haemostasis between neonates and adults described using CAT.• The haemostatic effect of several drugs has been evaluated in neonatal plasma using CAT.

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“…Plasma TFPIα levels promptly increase ≈2-to 4-fold following infusion of unfractionated or low-molecular-weight heparin into adults 26,27 or neonates. 28 Heparin-releasable TFPIα is also present in cultured human endothelial cells. 29,30 Heparin-releasable TFPIα and endothelial bound TFPIβ maintain anticoagulant properties of the vasculature.…”

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confidence: 99%

Major Reservoir for Heparin-Releasable TFPIα (Tissue Factor Pathway Inhibitor α) Is Extracellular Matrix

Peterson

Maroney

Martinez

et al. 2021

ATVB

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Objective: Human endothelial cells produce 2 alternatively spliced TFPI (tissue factor pathway inhibitor) isoforms that maintain anticoagulant properties of the vasculature. TFPIβ is glycosylphosphatidylinositol anchored on the cell surface. TFPIα has a basic C terminus sharing homology with VEGF (vascular endothelial growth factor) and is a heparin-releasable protein, suggesting it binds glycosaminoglycans on the endothelium surface. However, this is unclear because TFPIα is not on the surface of cultured endothelial cells. This study identifies the source of heparin-releasable TFPIα. Approach and Results: ELISA assays localized heparin-releasable TFPIα to the extracellular matrix (ECM) of Ea.hy926 cells and human umbilical vein endothelial cells. Immunofluorescence microscopy for TFPIα showed punctate intracytoplasmic staining and ECM staining beneath individual cells. Flow cytometry identified TFPIβ but not TFPIα on the cell surface. TFPIα localization to ECM was confirmed with ELISA and immunohistochemistry studies of umbilical cord veins. The TFPIα C terminus interacted with Ea.hy926 ECM glycosaminoglycans, and a homologous VEGF peptide competed for this binding, suggesting these interactions modulate VEGF responses. Immobilized TFPIα C-terminal peptide bound to several ECM proteoglycans in Ea.hy926 conditioned media. Immunofluorescence studies of human kidney colocalized TFPIα with 4 of these proteoglycans surrounding the microvasculature: glypican-1, syndecan-4, thrombospondin, and laminin-5. The absence of TFPIα on the surface of endothelial cells and its co-localization with specific ECM proteins suggests TFPIα binds to unique proteoglycan structures. Conclusions: ECM contained the primary vascular pool of heparin-releasable TFPIα. By localizing to ECM, TFPIα is positioned to inhibit the procoagulant activity of tissue factor surrounding the vasculature.

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Heparin–protamine balance after neonatal cardiopulmonary bypass surgery

Cited by 12 publications

References 39 publications

Platelet Function Changes during Neonatal Cardiopulmonary Bypass Surgery: Mechanistic Basis and Lack of Correlation with Excessive Bleeding

Platelet Function Changes during Neonatal Cardiopulmonary Bypass Surgery: Mechanistic Basis and Lack of Correlation with Excessive Bleeding

The role of the calibrated automated thrombogram in neonates: describing mechanisms of neonatal haemostasis and evaluating haemostatic drugs

Major Reservoir for Heparin-Releasable TFPIα (Tissue Factor Pathway Inhibitor α) Is Extracellular Matrix

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