Indirect Thrombin Inhibitors Research Articles

Evidence-based research and prognosis of novel coagulation factor Ⅺ inhibitors in venous thromboembolism

Thrombosis is the main cause of the development and progression of venous thromboembolism(VTE). Anticoagulant therapy is the cornerstone for the prophylaxis and treatment of VTE, and it has evolved mainly through indirect thrombin inhibitors, direct thrombin inhibitors, vitamin K antagonists and new oral anticoagulants. Although safety is improving, the risk of bleeding remains a non-negligible side effect of current anticoagulation therapy, especially in patients with higher bleeding risk. Studies of the coagulation pathway have found that FXI is not involved in the initiation of hemostasis, but promotes thrombus growth and stabilization primarily through feedback activation of FⅪ by thrombin. Further studies have found that inhibition of FⅪ significantly inhibits thrombus formation and only affects hemostasis slightly. Recent studies have confirmed the efficacy and safety of FⅪ inhibitors in the prevention of VTE in patients after knee replacement. In addition, the safety of FⅪ inhibitors has been further confirmed by the studies of FⅪ inhibitors in people with higher bleeding risk. FⅪ inhibitors may be the most promising anticoagulant drugs in the next decade.

A systematic review of the evidence supporting post-operative antithrombotic use following cardiopulmonary bypass in children with CHD.

To determine the optimal antithrombotic agent choice, timing of initiation, dosing and duration of therapy for paediatric patients undergoing cardiac surgery with cardiopulmonary bypass. We used PubMed and EMBASE to systematically review the existing literature of clinical trials involving antithrombotics following cardiac surgery from 2000 to 2020 in children 0-18 years. Studies were assessed by two reviewers to ensure they met eligibility criteria. We identified 10 studies in 1929 children across three medications classes: vitamin K antagonists, cyclooxygenase inhibitors and indirect thrombin inhibitors. Four studies were retrospective, five were prospective observational cohorts (one of which used historical controls) and one was a prospective, randomised, placebo-controlled, double-blind trial. All included were single-centre studies. Eight studies used surrogate biomarkers and two used clinical endpoints as the primary endpoint. There was substantive variability in response to antithrombotics in the immediate post-operative period. Studies of warfarin and aspirin showed that laboratory monitoring levels were frequently out of therapeutic range (variably defined), and findings were mixed on the association of these derangements with bleeding or thrombotic events. Heparin was found to be safe at low doses, but breakthrough thromboembolic events were common. There are few paediatric prospective randomised clinical trials evaluating antithrombotic therapeutics post-cardiac surgery; most studies have been observational and seldom employed clinical endpoints. Standardised, validated endpoints and pragmatic trial designs may allow investigators to determine the optimal drug, timing of initiation, dosing and duration to improve outcomes by limiting post-operative morbidity and mortality related to bleeding or thrombotic events.

Bivalirudin in Primary PCI: Can Its Glory Being Restored?

Abstract Intravenous anticoagulant therapy is critical to prevent ischemic recurrences and complications without increasing the risk of bleeding in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). It includes the indirect thrombin inhibitor heparins and the direct thrombin inhibitor bivalirudin. However, the ideal anticoagulant for patients undergoing PPCI remains controversial. In this review, we provide an overview of currently available anticoagulant therapies used in STEMI patients undergoing PPCI, including describing the rationale for their use, pivotal clinical trial data, and treatment recommendations of guidelines, providing much-needed clarity to guide the selection of the safest and most effective anticoagulant regimens for PPCI.

Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model

Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (>95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs.

The polyphenolic-polysaccharide complex of Agrimonia eupatoria L. as an indirect thrombin inhibitor - isolation and chemical characterization

The polyphenolic-polysaccharide complex was isolated from the dried aerial parts of the medicinal plant Agrimonia eupatoria L. using a multi-step process involving the degreasing of the plant material by extraction with organic solvents, followed by extraction with hot alkali, neutralization, further separation with organic solvents and dialysis. The complex was homogeneous with a molecular weight of about 55 × 103 g/mol and consisted mainly of carbohydrates and polyphenols matrix, composed of lignin-related units, with the dominance of dimethoxyphenyl structures. The carbohydrate moiety consists mostly of arabinogalactan associated with highly esterified rhamnogalacturonan. In vitro anticoagulant studies revealed the ability of the A. eupatoria complex to inhibit plasma clot formation, mainly in the intrinsic pathway of the blood coagulation cascade. Further studies on the mechanisms of this anticoagulant activity revealed that the isolate was primarily an indirect inhibitor of thrombin, mediated by antithrombin or by heparin cofactor II. Such mechanism of action is characteristic for highly sulfated glycosaminoglycans.

Does VALIDATE-SWEDEHEART invalidate the use of bivalirudin in myocardial infarction?

Over the past two decades, technological advances in percutaneous coronary intervention (PCI) [such as 2 nd generation drug eluting stents (DES), use of transradial access] and antithrombotic therapy (more potent P2Y 12 agents) have made PCI safer and more effective in treating patients with acute coronary syndrome (ACS). The use of direct and indirect thrombin inhibitors along with glycoprotein IIb/IIIa inhibitors (GPI) during PCI have contributed to improved angiographic and clinical outcomes, but at the cost of increased bleeding complications and its attendant risks of morbidity and death (1).

Thrombocytopenia induced by dabigatran: two case reports

BackgroundVitamin K inhibitors (e.g. warfarin) and indirect thrombin inhibitors (e.g. heparin) are widely used to prevent thromboembolic disorders (e.g. myocardial infarction, venous thromboembolism, and stroke). These agents have been mainstays of anticoagulation for people older than 60 years. However, their administration is associated with a risk of bleeding and requires careful monitoring of patients. Novel oral anticoagulants (NOACs), such as dabigatran, are significantly safer in preventing thromboembolism than warfarin and heparin (sporadically causes thrombocytopenia) and are more specific for their target protein, thrombin. The major advantage of dabigatran, a direct thrombin inhibitor, is that it reversibly inhibits both free and clot-bound thrombin by tight binding affinity and the predictable pharmacodynamic effect. A few studies, however, reported that dabigatran can cause thrombocytopenia, although the underlying mechanism remains unclear. Thus, an antidote for dabigatran was developed to prevent thrombocytopenia.Case presentationIn this report, we discuss two cases of thrombocytopenia and purpura after dabigatran treatment. A 73-year-old man showed hemorrhagic necrotic skin lesions on his neck and right hand. He was administered dabigatran (220 mg/day) for cerebral infarction for three days and his platelet count decreased abruptly (6000/μL). This suggested that dabigatran had caused thrombocytopenia and purpura; therefore, dabigatran administration was discontinued. The results of a blood test, performed 14 days after stopping dabigatran treatment, showed that the platelet count had recovered to the normal range of more than 150,000/μL. A 75-year-old woman had taken warfarin continuously for 8 years. However, she had a new cerebral infarction. Therefore, warfarin treatment was replaced with dabigatran (300 mg/day). Her platelet count decreased (41,000/μL) significantly and dabigatran treatment was discontinued. The blood test results show that platelet counts gradually recovered to the normal range.ConclusionsDabigatran application may cause bleeding; therefore, careful monitoring during dabigatran treatment is required to prevent thrombocytopenia. An explanation is that the interaction of dabigatran with thrombin, because of its strong binding affinity, may cause the observed thrombocytopenia.

A STUDY ON THE EFFECT OF LOW MOLECULAR WEIGHT ON POTASSIUM HOMEOSTASIS IN PATIENTS ADMINISTERED HEPARIN FOR THROMBOPROPHYLAXIS IN A TERTIARY CARE HOSPITAL

Objective: Low molecular weight heparin (LMWH) is an indirect thrombin inhibitor used clinically as an anticoagulant for thromboprophylaxis of patients at risk of deep vein thrombosis. The study was done to assess the magnitude of rise in serum potassium after administration of low molecular weight heparin comparing enoxaparin with dalteparin and to evaluate the frequency of clinically significant hyperkalemia in the population studied.Methods: The study was done as a prospective non-randomized observational study in a population of 32 patients started on heparin for thromboprophylaxis for deep venous thrombosis, pulmonary thromboembolism or stroke.Results: A statistically significant elevation in serum potassium was seen in patients treated with LMWH (p = 0.007). The magnitude of rise in potassium was significantly higher in enoxaparin (p = 0.008) than the dalteparin group (p = 0.447). A clinically relevant hyperkalemia of>5 mEq/l was seen in 25% of the population studied. Other important associations detected from the study were that the advancing age and increasing dose could be potential risk factors contributory to an accentuated rise in serum potassium which may culminate in clinically significant hyperkalemia.Conclusion: The study has highlighted that the likelihood of rise in potassium levels during LMWH therapy necessitates monitoring of serum potassium.

Antithrombotic therapy for patients with STEMI undergoing primary PCI.

Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the cornerstone of pharmacological treatment to optimize clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Intravenous anticoagulant drugs available for PPCI include the indirect thrombin inhibitors unfractionated heparin and low-molecular-weight heparin, and the direct thrombin inhibitor bivalirudin. Intravenous antiplatelet drugs mainly include glycoprotein IIb/IIIa inhibitors and the P2Y12-receptor inhibitor cangrelor. Dual antiplatelet therapy with aspirin and an oral P2Y12-receptor inhibitor is pivotal for the acute and long-term treatment of patients with STEMI undergoing PPCI. Prasugrel and ticagrelor provide a more prompt, potent, and predictable antiplatelet effect compared with clopidogrel, which translates into better clinical outcomes. Therefore, these agents are the first-line treatment in PPCI. However, patients can still experience adverse ischaemic events, which might be in part attributed to alternative pathways triggering thrombosis. Thrombin has an important role, suggesting the need for strategies directly targeting circulating thrombin or other factors of the coagulation cascade, such as oral anticoagulants (rivaroxaban), and the thrombin receptor on the platelet membrane (vorapaxar). In this Review, we provide an overview of currently available antithrombotic therapies used in patients with STEMI undergoing PPCI, results from pivotal clinical trials and their implications for guidelines, as well as recommendations for clinical practice.

Differential effects on glial activation by a direct versus an indirect thrombin inhibitor

Thrombin is a potent regulator of brain function in health and disease, modulating glial activation and brain inflammation. Thrombin inhibitors, several of which are in clinical use as anti-coagulants, can reduce thrombin-dependent neuroinflammation in pathological conditions. However, their effects in a healthy CNS are largely unknown. In adult healthy mice, we compared the effects of treatment by the direct thrombin inhibitor dabigatran etexilate (DE), to those of warfarin, which acts by preventing vitamin K recycling essential for coagulation. After 4weeks, warfarin increased both astrocyte GFAP and microglia Iba-1 staining throughout the CNS; whereas DE reduced expression of both markers. Warfarin, but not DE, reduced sulfatide levels; and warfarin showed longer lasting changes in cerebellar gene expression. DE also reduced glial activation in a mouse model of Alzheimer's disease, although no changes in amyloid plaque burden were observed. These results suggest that treatment with direct thrombin inhibitors may be preferable to those agents which reduce vitamin K levels and have the potential to increase glial activation.

Effects of blood flow properties on ocular hemodynamics

to study the effects of blood rheology on ocular blood flow (OBF) parameters and estimated individual normal range of intraocular pressure (IOP). A total of 15 patients (15 eyes) taking warfarin were enrolled. Volumetric parameters and linear velocity of OBF under warfarin treatment and after its cessation were obtained by means of flowmetry (Paradigm's Blood Flow Analyzer) and color Doppler flow mapping (Voluson 730), respectively. On the basis of flowmetry results an individual normal range of IOP was calculated in all patients. Pulsatile OBF does not appear to correlate with warfarin-induced changes in blood rheology (p = 0.09), however, depends on IOP fluctuations (p = 0.02). Resistance index of retinal vessels is found to rise significantly with increasing blood viscosity (p < 0.05). The use of warfarin, an indirect thrombin inhibitor, has no effect on estimated individual normal range of IOP, which is crucial for glaucoma diagnosis and monitoring.

Different Classes of Anticoagulant Drugs in Clinical Use. Is there a Class Effect?

Hippocrates first proposed ‘Blood thinners’ in ancient Greek medicine. Historically, extracts from many plants, bloodletting, leech bleeding, acid fruits and clear wines were considered as anticoagulants. Although, Haycraft in 1884 identified the anticoagulant in the saliva of European medicinal leech, later named hirudin, the extract was found to be too toxic. Following Jay McLean’s discovery of an anticoagulant in 1916, and naming of this anticoagulant as ‘heparin’ by Howel and Holt in 1918 and Howel’s purification of this compound in 1925, it was only in 1930s that the effective anticoagulant treatment started. Soon after the discovery of the first oral anticoagulant, dicoumarin in 1935, the purified injectable preparations of heparin were used. Later, other types of antithrombotic and anticoagulant treatment, including antiplatelet drugs, snake venoms, direct and indirect thrombin inhibitors, activated protein C, direct Factor Xa inhibitors and recombinant hirudins have since been introduced [1]. Warfarin, a conventionally used oral anticoagulant, despite its limitations of drugfood, drug-drug interactions, need for frequent PT/INR monitoring, adverse drug reactions, bleeding, warfarin-induced skin necrosis, frequent need for dosage adjustments because of changes in the dietary patterns, effects due to VKORC polymorphism, has stood the test of time and still continues to be used in clinical practice. Recently the New Oral Anticoagulant drugs, direct Factor Xa such as Rivaroxaban, Apixaban and Edoxaban and direct thrombin inhibitors such as Dabigatran were approved by the USFDA. There are several limitations in the use of NOACs such as the lack of an effective test to monitor their anticoagulant activities, the lack of an effective antidote, and dose adjustments in patients with renal impairment [2]. Thus, a bewildering wide array of anticoagulant drugs are now available for use and it is interesting to see whether or not these drugs representing different classes of anticoagulant drugs, especially direct thrombin and direct Factor Xa inhibitors have any class effects in terms of differences in their clinical outcomes.

Direct thrombin inhibitors: Patents 2002–2012 (Review)

Acute vascular diseases and other thromboses of the blood system constitute major health risks in developing countries. Thrombin plays a central role in blood coagulation, which is a crucial process involved in thrombosis. Direct thrombin inhibitors (DTIs) such as argatroban, dabigatran, dabigatran etexilate, lepirudin, desirudin and bivalirudin, which bind to thrombin and block its enzymatic activity, are widely and effectively used in the treatment of thromboembolic diseases. DTIs appear to overcome the disadvantages of indirect thrombin inhibitors such as unfractionated heparins (UFH). Although these DTIs show specific advantages over indirect inhibitors, they still present limitations, such as a narrow therapeutic window, and bleeding and anaphylaxis as side-effects. Novel anticoagulant drugs need thus to be developed to overcome these limitations. In the search for additional candidate agents with improved efficacy, safety and high bioavailability in oral administration, a high number of compounds has been identified, such as those derived from the tripeptide template D-Phe-Pro-Arg, aptamers and peptides isolated from blood-sucking animals. These candidates may prove the new agents of choice for the treatment of cardiovascular diseases.

New Oral Anticoagulants: Comparative Pharmacology with Vitamin K Antagonists

New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. FXa inhibitors, e.g. rivaroxaban and apixaban, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free FXa. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of rivaroxaban and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists. Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. Dabigatran has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound thrombin. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin. Dabigatran shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > apixaban > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs.

The discovery of dabigatran etexilate.

Thromboembolic disease is a major cause of mortality and morbidity in the developed world and is caused by an excessive stimulation of coagulation. Thrombin is a key serine protease in the coagulation cascade and numerous efforts have been made to develop safe and effective orally active direct thrombin inhibitors (DTIs). Current anticoagulant therapy includes the use of indirect thrombin inhibitors (e.g., heparins, low-molecular-weight-heparins) and vitamin K antagonists such as warfarin. However there are several caveats in the clinical use of these agents including narrow therapeutic window, parenteral delivery, and food- and drug–drug interactions. Dabigatran is a synthetic, reversible DTI with high affinity and specificity for its target binding both free and clot-bound thrombin, and offers a favorable pharmacokinetic profile. Large randomized clinical trials have demonstrated that dabigatran provides comparable or superior thromboprophylaxis in multiple thromboembolic disease indications compared to standard of care. This minireview will highlight the discovery and development of dabigatran, the first in a class of new oral anticoagulant agents to be licensed worldwide for the prevention of thromboembolism in the setting of orthopedic surgery and stroke prevent in atrial fibrillation.

Abstract 264: Differential Profiles of Thrombin Inhibitors (Dabigatran, Hirudin, Bivalirudin and Heparin) in the Thrombin Generation Assay (TGA) and Thromboelastography (TEG) in Vitro

Thrombin is a central enzyme in haemostasis and thrombosis, and a proven target for anticoagulant therapies. Different classes of thrombin inhibitors, while exerting therapeutic benefits in most clinical trials, have different indications, dosing regimens, and bleeding complications. To gain more insight into the underlying mechanisms for their differential clinical profiles, we compared four marketed and representative agents, including dabigatran, hirudin, bivalirudin (direct thrombin inhibitors, DTIs), and heparin (an indirect thrombin inhibitor), in two in vitro spike-in assays with concentration titrations covering their therapeutic ranges. The two assays were the Thrombinoscope TGA with plasma, triggered by low tissue factor (1 nM TF), and TEG with whole blood, triggered by 1:8000 Recombiplastin (equivalent to low TF), with or without a threshold level of tPA to induce fibrinolysis. In TGA, the largest effect was prolongation of lag time, with the potency of the three DTIs rank-ordered as hirudin&gt;dabigatran&gt;bivalirudin; regarding peak, slope, and ETP, while complete inhibition was achieved with 1-2 μM dabigatran or hirudin, bivalirudin had no effect even at 4 μM, possibly due to its short half life in plasma. In TEG, the three DTIs prolonged clotting time (R) in the same rank order as TGA; for clot strength (MA), while all four agents reduced MA in synergy with tPA, only hirudin reduced MA without tPA, likely due to its highest potency. With tPA-induced fibrinolytic activity (Ly30), dabigatran and bivalirudin enhanced Ly30 (dabigatran&gt;bivalirudin), but hirudin and heparin did not. This contrast might involve differential access to clot-bound thrombin. Heparin had a steep dose-response curve for both lag time in TGA and R in TEG, which is in line with its very narrow therapeutic index. All three DTIs, but not heparin, displayed the previously reported paradoxical increase in peak and slope in TGA in the low concentration range, suggesting this is indeed a class effect of DTI. In summary, our observations highlight the distinct features of each agent in thrombin generation, coagulation, and fibrinolysis. These results in combination with known clinical properties are informative on efforts to define the optimal profiles of new anticoagulants.

P-717 - Thrombin inhibitors in alzheimer's disease

Alzheimer's disease (AD) is a disorder characterized by progressive cognitive decline and dementia. Actually, no disease-modifying drug exists. Based on some evidence, it has been postulated that neurovascular damage is one important inaugurating event of a subsequent cascade and that secondary injuries including β-amyloid deposition may exacerbate vascular damage leading to neurodegeneration and ultimately cognitive decline. Neurovascular damage is the result of the presence of cardio-vascular risk factors activating the endothelial cells of the brain microvasculature. This endothelial activation could lead to a secretion of many pro-inflammatory cytokines and growth factors such as thrombin. The latter seems to play a major role in the initiation and perpetuation of neurovascular damage via its pro-inflammatory and pro-coagulant effect. Indirect thrombin inhibitors such as heparin and related oligosaccharides have been shown to be efficient in the improvement of symptoms of AD. Their efficacy may be limited by their non-selective inhibitory effect of thrombin activity. Many direct thrombin inhibitors are commercialized. Of those dabigatran is the only one that exists in an oral form of administration. Dabigatran's safe side effect profile and high selectivity for thrombin's activity inhibition render it an eligible, though yet unexplored, efficient treatment for patients suffering from AD.

Exploring the Impact of Clinical Anticoagulants on Venous Thrombosis Stability Using a Novel Intravital Murine Model

Abstract 1246 Background:Thrombus stability influences the progression of deep vein thrombosis to a potentially fatal pulmonary embolism (PE) event. Anticoagulants are clinically administered to treat venous thrombosis. However, the effect of anticoagulants on thrombus stability remains unknown. Objective:We developed a novel intravital mouse model to explore the hypothesis that administration of clinical anticoagulants would decrease early thrombus stability, thereby potentially increasing PE risk. Methods:The trachea and jugular vein were cannulated, and the femoral vein isolated, in wild type C57/Bl6 female mice. Platelets were labeled in vivo using anti-mouse CD41 Fab fragments conjugated to Alexa Fluor-488. A 1 × 2 mm filter paper strip, saturated in 4% ferric chloride, was applied to the femoral vein for 5 minutes to induce thrombus formation. Wide-field fluorescent microscopy was used to quantify thrombus stability. Stability was related to the number of embolic events and loss of platelet intensity captured downstream of the thrombus at 5, 15, 30, 45, and 60 minutes post thrombus formation. Results:The mean number of embolic events and loss of platelet intensity decreased over time in wild type mice (n = 12). This suggested that thrombus stability increases over time. Anticoagulants were administered via a jugular vein catheter, at 12 minutes post thrombus formation, to assess impact on embolization. The anticoagulants examined were hirudin (8U/g mouse body weight), unfractionated heparin (UFH) (0.1U/g), a covalent antithrombin-heparin complex (ATH) (0.08U/g), and fondaparinux (0.1μg/g). We observed an overall a) increase in the number of embolic events and b) increase in platelet intensity lost over time in mice injected with hirudin (n = 12) and UFH (n = 12) when compared to untreated wild type control mice. The total number of embolic events occurring over one hour substantially increased in the hirudin-treated group (p = 0.09), which was also associated with an overall increase in total platelet intensity (p = 0.08), compared to untreated control mice. In addition, there was an increase in the total number of embolic events compared to the UFH-treated group (p = 0.09). Administration of hirudin, a direct thrombin inhibitor (DTI), and UFH, an indirect thrombin inhibitor, could result in decreased venous thrombus stability. However, it appears that the DTI is associated with greater thrombus instability. In the ATH-treated group (n = 12), an increase in embolic events at 15 minutes was observed, followed by a decrease in embolization. ATH could initially disrupt thrombus stability through inhibition of fibrin-bound thrombin, before acting in a stabilizing manner. Administration of fondaparinux (n = 6), an indirect factor-Xa inhibitor, demonstrated an overall decrease in embolic events and platelet intensity lost over time. When compared to control groups, there was a significant decrease in total number of embolic events and total amount of platelet intensity lost in the fondaparinux group (p < 0.05). Use of a factor-Xa inhibitor appears to enhance thrombus stability more effectively in comparison to direct and indirect thrombin inhibitors. Conclusion:Use of anticoagulants that inhibit thrombin predominantly could decrease early thrombus stability and potentially increase the likelihood of a PE event. Disclosures:No relevant conflicts of interest to declare.

Hematology Pharmacology

Alterations in hemostasis and coagulation are common problems during critical illness. For that reason, it is essential that advanced practice and critical care nurses have an understanding of the medications used to treat these potentially deadly disorders. The antithrombotic drugs, including anticoagulants, antiplatelet agents, and fibrinolytics, are among the most frequently used drug therapies in the United States. These agents prevent and treat the thrombotic diseases, a leading cause of morbidity and mortality. Anticoagulants, the indirect and direct thrombin inhibitors as well as the vitamin K antagonists, are critical in treating venous thrombosis and preventing serious thrombotic complications with atrial fibrillation. The antiplatelet drugs work to decrease platelet aggregation and are especially effective in preventing and managing arterial thrombus. On the other end of the spectrum, the procoagulants are used to help prevent and control blood loss. These agents include human blood stimulators, human factor concentrates, including recombinant activated factor VIIa, and desmopressin.

Hematology Pharmacology

Alterations in hemostasis and coagulation are common problems during critical illness. For that reason, it is essential that advanced practice and critical care nurses have an understanding of the medications used to treat these potentially deadly disorders. The antithrombotic drugs, including anticoagulants, antiplatelet agents, and fibrinolytics, are among the most frequently used drug therapies in the United States. These agents prevent and treat the thrombotic diseases, a leading cause of morbidity and mortality. Anticoagulants, the indirect and direct thrombin inhibitors as well as the vitamin K antagonists, are critical in treating venous thrombosis and preventing serious thrombotic complications with atrial fibrillation. The antiplatelet drugs work to decrease platelet aggregation and are especially effective in preventing and managing arterial thrombus. On the other end of the spectrum, the procoagulants are used to help prevent and control blood loss. These agents include human blood stimulators, human factor concentrates, including recombinant activated factor VIIa, and desmopressin.