Platelets and Thrombin Generation

Monroe, Dougald M.; Hoffman, Maureane; Roberts, Harold R.

doi:10.1161/01.atv.0000031340.68494.34

Cited by 604 publications

(520 citation statements)

References 116 publications

Supporting

Mentioning

482

Contrasting

Unclassified

Order By: Relevance

“…Although the statistical power of this finding has been questioned, it is known that platelet-dependent mechanisms and coagulation interdigitate. The platelet surface has a pivotal role in the promotion and regulation of thrombin generation (Monroe et al, 2002). After P2Y12 blockage in rabbits, thrombin generation and thrombus size is decreased in experimental vessel wall injury of mesenteric arterioles (van Gestel et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Antiplatelet Pretreatment does not Increase Hematoma Volume in Experimental Intracerebral Hemorrhage

Lauer

Schlunk

Cott

et al. 2011

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

While oral anticoagulants are associated with greater hematoma expansion and higher mortality rates in patients with intracerebral hemorrhage (ICH), there is ongoing discussion whether pretreatment with antiplatelet drugs also worsens prognosis. Using an experimental model of ICH, we investigated the effects of antiplatelet pretreatment on hematoma volume and functional outcome. CD-1 mice were treated with acetyl-salicylic acid (ASA, 60 mg/kg per 24 hours), clopidogrel (22.5 mg/kg per 24 hours), or both (ASA + clopidogrel) through drinking water for 3 days (n = 20 per group). Thereafter, platelet aggregation was found to be significantly reduced. Untreated mice and mice pretreated with warfarin served as controls. A stereotactic injection of collagenase into the right striatum was used to induce ICH. Twenty-four hours after ICH induction, hematoma volume was measured to be 15.0±4.4 lL in controls, 14.1±5.3 lL in ASA mice, 16.8±5.1 lL in clopidogrel mice, and 16.4 ± 5.1 lL in ASA + clopidogrel animals. These differences were not statistically significant. However, mice pretreated with warfarin revealed largely increased hematoma volumes (25.0 ± 7.4 lL versus controls, P = 0.001). Neurologic outcome was not different between antiplateletpretreated animals and untreated controls. Our results suggest that plasmatic coagulation rather than platelet function is the most critical element for preventing hematoma expansion in acute ICH. Future therapeutic strategies may take these findings into account.

show abstract

Section: Discussionmentioning

confidence: 99%

Antiplatelet Pretreatment does not Increase Hematoma Volume in Experimental Intracerebral Hemorrhage

Lauer

Schlunk

Cott

et al. 2011

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…The TFM proposes that sequestered pRBC and activated platelets play an active role in amplifying, propagating, and consolidating the coagulation cascade initiated by endothelium TF. It is well known that amplification of coagulation cascade is supported by activated platelets that display phosphatidylserine (PS), a negatively charged phospholipid that assembles the prothrombinase and Xnase complexes 37 . In fact, pRBC obtained from P. falciparum-infected patients are procoagulant ex vivo 38 .…”

Section: The Tissue Factor Model For Malaria Pathogenesismentioning

confidence: 99%

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Francischetti

2008

Trends in Parasitology

View full text Add to dashboard Cite

Plasmodium falciparum infection is often associated with a procoagulant state. Recent identification of tissue factor (TF) in the brain endothelium of patients who died from cerebral malaria casts new light in our understanding of the coagulation disorder found in P. falciparum infection. It has also been revealed that parasitized red blood cells (pRBC) support assembly of multimolecular coagulation complexes. In this article, the role of TF expression by the endothelium and amplification of the coagulation cascade by pRBC and/or activated platelets-particularly at sequestration sitesis discussed as crucial events in mounting and sustaining a coagulation-inflammation cycle that contributes to organ dysfunction and coma in P. falciparum malaria. Blood coagulation and malariaMalaria caused by P. falciparum remains a highly endemic disease; it has been estimated that at least one million deaths occur every year. Children are at high risk, and often severe malaria (severe anemia or cerebral malaria [CM]) is the cause of death in this population 1-4. P. falciparum infection is associated with sequestration 5 -8 , endothelial cell (EC) activation 8-10, increase in inflammatory cytokines 3 , 11, and activation of the coagulation cascade 12 -20. Despite several papers devoted to the coagulation disorder in malaria-many of them published during the 1970s and 1980s (reviewed in Ref. 20)-the mechanism that triggers and propagates the coagulation activation in P. falciparum infection has remained elusive. These studies, however, demonstrated that bleeding and/or hemorrhage are typically not present, although laboratory tests indicate a certain degree of in vivo blood coagulation activation 12 -20 . Accordingly, prothrombin time (PT) and partial thromboplastin time (PTT) are close to normal values or prolonged, whereas thrombin-antithrombin complex (TAT) (which indicates in vivo thrombin formation) and D-dimers (which are a marker of in vivo fibrinolysis) are often elevated, and thrombocytopenia is a usual finding 12 -21 . This laboratory profile is compatible with disseminated intravascular coagulation (DIC), which is diagnosed according to a score defined by the International Society of Thrombosis and Haemostasis (ISTH) 22 . The scoring system takes into account i) platelet count, ii) elevated fibrin related markers, iii) prolonged prothrombin time, and iv) fibrinogen level 22 23 . Depending on the score punctuation, levels < 5 are suggestive of non-overt (compensated) DIC while scores > or = 5 are compatible with overt (decompensated) DIC. Bleeding is more common in overt DIC, but it is not needed for the formal diagnosis 22 23. In other words, absence of bleeding in P. falciparum-infected patients does not exclude the presence of DIC in this same population; actually, most of these patients meet the criteria for DIC as defined above 22 . Unfortunately, absence of bleeding is often mistakenly regarded as the reason why DIC is supposedly not present in malaria. Further, some reports do not support the view that coa...

show abstract

“…This platelet P-selectin/␣ IIb ␤ 3 integrin-mediated phenomenon may be physiologically relevant because it can take place in the presence of erythrocytes. Moreover, several reports indicate that platelet activation could be triggered in vivo by tissue factor constitutively expressed on the surface of many tumor cells, including colon carcinomas, by inducing thrombin production in the coagulation cascade (20,31). Overall, these findings promote our understanding of the role of platelets in hematogenous spread of cancer, which could potentially lead to new strategies to combat metastasis.…”

Section: Discussionmentioning

confidence: 87%

Platelet-induced enhancement of LS174T colon carcinoma and THP-1 monocytoid cell adhesion to vascular endothelium under flow

Burdick¹,

Κωνσταντόπουλος²

2004

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Burdick, Monica M., and Konstantinos Konstantopoulos. Platelet-induced enhancement of LS174T colon carcinoma and THP-1 monocytoid cell adhesion to vascular endothelium under flow. Am J Physiol Cell Physiol 287: C539 -C547, 2004. First published April 14, 2004 10.1152/ajpcell.00450.2003.-This study was undertaken to characterize the adhesion of LS174T colon adenocarcinoma cells to 4-h TNF-␣-stimulated human umbilical vein endothelial cells (HUVECs) under flow in the presence and absence of platelets and erythrocytes. Cell binding to HUVECs was significantly enhanced by simultaneous perfusion of thrombin-activated, but not resting, platelets. This increase was achieved via a platelet bridging mechanism whereby a previously tethered LS174T cell (primary tether) captures a free-flowing cell (secondary tether) that subsequently attaches to the endothelium downstream of the already adherent cell. The total number of tumor cells tethering to HUVECs and the percentage of secondary tethers relative to the total amount of cell tethering depended on platelet concentration and wall shear stress. At 0.8 dyn/cm 2 and a platelet-to-LS174T cell ratio of 25:1, the total amount of cell tethering nearly doubled as a result of platelet-induced enhancement compared with the amount without platelet perfusion. Moreover, the percentage of secondary tethers increased from background levels (Ͻ5%) in the absence of platelets to ϳ60% at a platelet-to-LS174T cell ratio of 25:1. Platelet-mediated secondary tethering is not limited to LS174T colon carcinoma cells, as THP-1 monocytoid cells also displayed this pattern of interaction. Secondary tethering was dependent on both platelet P-selectin and ␣IIb␤3-integrin for LS174T cells and P-selectin alone for THP-1 cells. Furthermore, platelet-mediated secondary tethering of both cell types occurred in the presence of red blood cells. Altogether, these results reveal a novel role for platelets in promoting cell binding to endothelium through a secondary tethering mechanism. P-selectin; ␣ IIb␤3-integrins; shear stress HEMATOGENOUS METASTASIS is a highly regulated, multistep process in which cancerous cells separate from a primary tumor, migrate across blood vessel walls into the vasculature, and then disperse to establish secondary colonies throughout the body. It has been proposed that tumor cells follow an adhesion cascade similar to that of leukocytes during the inflammatory response to immunologic insults. In this model, leukocytes first tether and roll on activated endothelium lining the blood vessel before they firmly adhere and ultimately extravasate into the tissue space. The occurrence of homotypic leukocyte-leukocyte interactions may provide a potential mechanism to augment recruitment to sites of inflammation, thereby enhancing attachment above direct leukocyte-endothelial cell interactions (primary tethers) (2, 36). In this phenomenon known as secondary tethering, a previously tethered leukocyte forms a brief adhesive interaction with a free-flowing leukocyte before subsequently attach...

show abstract

Platelets and Thrombin Generation

Cited by 604 publications

References 116 publications

Antiplatelet Pretreatment does not Increase Hematoma Volume in Experimental Intracerebral Hemorrhage

Antiplatelet Pretreatment does not Increase Hematoma Volume in Experimental Intracerebral Hemorrhage

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Platelet-induced enhancement of LS174T colon carcinoma and THP-1 monocytoid cell adhesion to vascular endothelium under flow

Contact Info

Product

Resources

About