What Are Anticoagulants Used For
West J Emerg Med. 2015 January; 16(ane): eleven–17.
Anticoagulation Drug Therapy: A Review
Received 2014 Jun 23; Revised 2014 Dec 23; Accepted 2014 December 23.
Abstruse
Historically, well-nigh patients who required parenteral anticoagulation received heparin, whereas those patients requiring oral anticoagulation received warfarin. Due to the narrow therapeutic index and need for frequent laboratory monitoring associated with warfarin, there has been a desire to develop newer, more than effective anticoagulants. Consequently, in contempo years many novel anticoagulants have been developed.
The emergency doc may institute anticoagulation therapy in the brusk term (e.g. heparin) for a patient being admitted, or may start a novel anticoagulation for a patient existence discharged. Similarly, a patient on a novel anticoagulant may present to the emergency section due to a hemorrhagic complication. Consequently, the emergency physician should be familiar with the newer and older anticoagulants. This review emphasizes the indication, machinery of action, adverse effects, and potential reversal strategies for various anticoagulants that the emergency medico will probable run across.
INTRODUCTION
During routine homeostatic weather, the human trunk maintains a constant balance between thrombus formation and devastation. This equilibrium is maintained by a complex interaction between platelets and the vascular endothelium, the coagulation cascade, and the fibrinolytic organisation. The coagulation cascade (Figure ane) involves an interaction betwixt the contact activation pathway (previously called the intrinsic system), and the tissue gene pathway (previously the extrinsic organisation). These two seemingly independent pathways lead to the conversion of factor X to Xa, which is the commencement of the common pathway. This common pathway converts prothrombin to thrombin, which subsequently catalyzes the germination of fibrin and ultimately leads to the stabilization of aggregated platelets to form a stable clot.1 , ii
Historically, vitamin Yard antagonists, such as warfarin, were the merely anticoagulants widely available for homo use. It has been estimated that more than 65,000 patients are treated in U.S. emergency departments (ED) annually for warfarin-related hemorrhage.iii Because of this loftier rate of bleeding, along with the drug'due south narrow therapeutic index and the need for frequent monitoring, there has been a desire to create safer anticoagulants without such strict drug monitoring. Consequently, in that location have been several novel anticoagulants (NACs) developed, including directly thrombin inhibitors (eastward.yard. dabigatran), and factor Xa inhibitors (e.g. rivaroxaban, apixaban), designed to target different points of the coagulation cascade (Figure two).4 , 5
Site of action of drugs. Modified, with permission, Gresham C, Levine M, Ruha AM.17
Equally NACs become more pervasive in the clinical setting, used for both therapeutic and prophylactic purposes, it volition become essential for the emergency doctor to become aware of the indications to offset specific drugs, also equally unique complications and recommended reversal methods for such agents. An intimate knowledge of these drugs will exist required for the ideal management. Unfortunately, while the clinical efficacy of NACs has been established, much less is known well-nigh the risks of adverse reactions as well as the ability to contrary these agents.6 Figure 3 beneath summarizes the most widely-used anticoagulants; they will exist discussed in this article. This article provides a review of the literature as it focuses on both the risks associated with anticoagulants, as well as reversal agents of the most usually used NACs to help guide direction in the emergency setting.
Comparison table for anticoagulants.nine , 19 , 25 , 38
PT, pro-thrombin time; INR, international normalized ratio; HIT, heparin-induced thrombocytopenia; PO, oral administration; IV, intravenous; FFP, fresh frozen plasma; aPTT, activated partial thromboplastin time; UFH, unfractionated heparin; PCC, prothrombin complex concentrates
Vitamin 1000 antagonists
Vitamin K antagonists (VKAs) such as warfarin function by blocking the vitamin Thou-epoxide reductase, thereby preventing formation of the agile form of the vitamin K-dependent clotting factors.seven The VKAs have an initial pro-thrombotic effect, by initially blocking proteins C and S, followed by a delayed antithrombotic effect, through the inhibition of coagulation factors II, VII, IX, and X.7
Warfarin
Federal Drug Administration indications for use include long-term anticoagulation following a thrombotic result or prevention of thrombotic events in patients at high risk, including postal service-operative states, atrial fibrillation, and those with artificial valves.8 Because of the initial pro-coagulant upshot, if rapid anticoagulation is required, warfarin is paired with a rapid-acting parenteral anticoagulant, which can be discontinued after therapeutic levels are achieved and stable over the course of 24 hours.
Warfarin is taken orally, at doses typically ranging from 5–10mg daily, tailored based on the international normalized ratio (INR), the universal monitoring index based on pro-thrombin time (PT). Warfarin is primarily metabolized through the P450 organization.9 Induction or inhibition of the isoenzymes involved with warfarin'south metabolism can potentially increase the INR significantly.7 Furthermore, alterations in oral vitamin 1000 consumption can create significant fluctuations in the INR.10
Side Effects and Reversal Agents
Hemorrhage is the most significant agin effect associated with warfarin and is directly related to the level of INR; the risk of hemorrhage is increased if the INR is greater than five.7 Risk factors for warfarin-related hemorrhage include advanced age, serious co-morbid conditions including cancer, chronic kidney disease (CKD), liver dysfunction, arterial hypertension, prior stroke, alcohol abuse, and the concomitant utilize of antiplatelet or other drugs.seven In the event of hemorrhage, the anticoagulant furnishings of warfarin can exist reversed with the administration of vitamin K (phytonadione), fresh frozen plasma (FFP) or prothrombin complex concentrates (PCCs).12 , 13 In addition, recombinant cistron VIIa (rfVIIa) has been suggested as a possible reversal agent. While the use of rfVIIa has been demonstrated to provide a rapid reduction in the INR, its apply is not associated with improved clinical outcomes.14 , fifteen
Heparins
Antithrombin III (AT3) is a peptide that inhibits several of the activated clotting factors. Drugs that augment the function of AT3 serve equally anticoagulants. Unfractionated heparin (UFH) binds to and increases the activity of antithrombin III by inducing a conformational alter to Factor Xa, which ultimately leads to inhibition at Xa and IIa in a 1:one ratio.xvi Unfractionated heparin besides has some inhibition on factors IXa, XIa, XIIa.17 Depression molecular weight heparins (LMWH), which also bind AT3, are smaller and take a higher proportional impact on Xa, versus IIa, in a iii:1 or two:1 ratio.xvi , 17 As a result of this inhibition, both the UFH and LMWH ultimately inhibit thrombin activation.
Unfractionated Heparin (UFH)
UFH is indicated for numerous conditions including the treatment and prophylaxis of venous thromboembolisms (VTE), thrombus prophylaxis in atrial fibrillation, and handling of disseminated intravascular coagulation.18 Unlike warfarin, UFH is administered parenterally, both subcutaneous for its prophylaxis use and as a continuous intravenous infusion when used therapeutically. UFH has much faster onset of action as compared to warfarin; when used intravenously, therapeutic efficacy occurs almost immediately, while therapeutic efficacy is reached within 20–hr when administered subcutaneously.nine UFH has a shorter one-half- life than warfarin, and does not crave dosage adjustment in renal failure.9
Side Effects and Reversal Agents
Hemorrhage is a main adverse outcome in those receiving UFH. The incidence of major bleeding varies based on the indication of its use, dosage and route of assistants. Notwithstanding, on average, UFH is associated with a 2.0% incidence of major bleeding when used therapeutically for VTE.xix While major haemorrhage can be potentially fatal, UFH tin can be reversed with the administration of protamine sulfate. Typically, protamine is dosed based on the amount of UFH administered, non based on laboratory abnormalities. A dose of 1mg will reverse 100 units of UFH.
Another significant and well-documented agin outcome of UFH use is the evolution of heparin-induced thrombocytopenia (HIT). A detailed discussion of HIT, withal, is beyond the scope of this review. Nonetheless, treatment options for HIT include discontinuation of UFH, and the subsequent use of a different class of NAC, either a direct thrombin inhibitor (e.thousand. argatroban) or a factor Xa inhibitor (e.g. fondaparinux).
Low Molecular Weight Heparin (LMWH)
The LMWH are parenterally-administered drugs, and include dalteparin, enoxaparin, and tinzaparin. Compared with UFH, the LMWH accept the advantage of a more predictable dose-response bend.17 Consequently, the LMWHs are administered at a stock-still dose, based on total body weight, and do non require tight regulation and monitoring equally is indicated with warfarin and UFH.17 These drugs accept virtually 100% bioavailability and reach peak levels 2–four hours after subcutaneous assistants.9 , 17 They have a half-life of 3–iv hours and are eliminated primarily (80%) via renal clearance, thus necessitating dose reduction considerations in patients with renal insufficiency.ix Additionally, since dosing is based on full body weight, rather than ideal torso weight, dosing complications ascend in obese patients.17 While therapeutic monitoring is non routinely indicated, in cases of renal insufficiency, obesity, or when iatrogenic overdose is a concern, antifactor Xa levels can be used to monitor LMWH.ix , 17 Ideally, the antifactor Xa level should be obtained iv hours afterward the administration of the LMWH.
Side Furnishings and Reversal Agents
Acute bleed is the major risk associated with LMWH. When used prophylactically the incidence of major bleeding associated with the LMWH is approximately 1.5–ane.seven%.19 , 20 The incidence of major bleeding associated with therapeutic dosage of the LMWH is slightly higher at approximately 2%, with even college incidences observed when used to treat acute coronary syndrome (ACS).19 In the upshot of a major bleed, protamine sulfate tin be used every bit a fractional reversal agent and tin reverse at near lx% of the anticoagulation issue of LMWH.19 Initial doses of 1mg per 100 units of antifactor Xa should exist administered within 8 hours of LMWH administration. A 2d dose of 0.5mg per 100 units antifactor Xa can be repeated.17 For significant bleeding associated with LMWH, cryoprecipitate and fresh frozen plasma is also recommended.17 , 19
Factor Xa inhibitors
Factor Xa inhibitors are used for prophylaxis and treatment of VTE, as well as for prophylaxis of embolic illness in non-valvular atrial fibrillation, and every bit an culling anticoagulant in the setting of HIT. These drugs inhibit cistron Xa, the starting time stride in the mutual pathway, either directly or indirectly. The inhibition occurs in a dose-dependent manner.21 Apixaban and rivaroxiban, directly bind to the active site of cistron Xa, thereby inhibiting both free and clot-associated factor Xa. These drugs also inhibit prothrombinase activeness.5 Indirect Xa inhibitors, such as fondaparinux, demark to AT3, resulting in a conformational alter, thereby inhibiting cistron Xa without having any effect on IIa.17 Fondaparinux is primarily eliminated unchanged in the urine. Thus, its use in patients with renal insufficiency is contraindicated as its use in this patient population may increase the risk of hemorrhage.
There are no specific laboratory parameters available to monitor the anticoagulant impact of factor Xa inhibitors. A dose-dependent prolongation of aPTT and PT may exist seen 1–four hours after assistants of direct Xa inhibitors such as rivaroxiban, matching the pinnacle plasma level; however, this increase is short lived and in general PT, aPTT and bleeding time should non be affected at therapeutic levels of these drugs.9 Supratherapeutic concentrations of Xa inhibitors, nevertheless, accept been associated with a dose-dependent increase in PT.9 This increase in PT does non direct correlate with the increase in PT secondary to VKAs, and there is not a consequent conversion between the PT and the INR with these drugs.22 Antifactor Xa levels were originally designed and calibrated for LMWH; however, they tin can also be used to monitor or confirm overdose of factor Xa inhibitors.9 This test must be specifically calibrated for Cistron Xa inhibitors, equally the results of the antifactor Xa level is assay specific.17 , 23
Side Effects and Reversal Agents
Adverse events related to Xa inhibitors include hemorrhage, as is the case with all anticoagulants. Thrombocytopenia has also been reported following the use of Xa inhibitors; nonetheless, the machinery is unclear.17 While no specific reversal agent exists, both rVIIa and PCC have been proposed.nine , 19 The Thrombosis and Hemostasis Order of North America suggests that iv-factor PCC may be the best pick currently available.24 The German Society of Neurology recommends PCC for reversal of gene Xa inhibitor-induced coagulopathy. However, now, there is insufficient data to clearly back up any reversal agent or to develop a standard of intendance.25
Direct thrombin inhibitors (DTIs)
As their name implies, the direct thrombin inhibitors (DTIs) inhibit the intrinsic action of the thrombin. Unlike heparin, which as well inhibits thrombin, the DTIs practice not require a gene, and can inhibit thrombin directly.7 , 26 Nigh direct thrombin inhibitors are administered parenterally, including argatroban, bivalirudin; however, dabigatran is orally administered. These drugs are used for prophylaxis and handling of VTE and ACS, and for prophylaxis of thrombus formation in non-valvular atrial fibrillation. They are also used as anticoagulation alternatives in the setting of HIT. Dabigatran, the only orally available DTI, is approved for treatment of VTE in patients treated with concomitant parenteral anticoagulation for at least v days, and for the treatment of thrombus secondary to not-valvular atrial fibrillation.
Laboratory evaluation of the DTIs includes measurement of a thrombin time (TT) or ecarin clotting time (ECT).29 Even so, these tests are not widely available, thereby limiting their applicability, particularly in the emergency setting. The Hemoclot test is a diluted thrombin time analysis designed specifically equally an assay for the DTIs; however, like the TT and ECT, this test is non routinely available.30 , 31 In the clinical setting, activated partial thromboplastin time (aPTT) can be used as a surrogate to monitor the upshot of the DTIs; aPTT increases following a non-linear dose response curve and plateaus at higher concentrations of DTIs. Thus, a normal aPTT excludes the presence of significant amounts of a DTI, but the degree of elevation of the aPTT does not necessarily correlate with the caste of DTI-induced coagulopathy.29
Side Effects and Reversal Agents
The primary toxicity of patients on DTIs is hemorrhage, including gastrointestinal bleeding and intracranial hemorrhage. The charge per unit of bleeding is dose dependent, and is more common in those over 75 years of age.27 , 28 Like many other NACs, no specific antidotes exist. The American College of Cardiology Foundation and the American Middle Association recommend transfusion of packed red claret cells and FFP, in addition to surgical intervention, if feasible, to control bleeding.32 Still, given that FFP contains factor 2, which is inhibited from activation by DTIs, the apply of FFP is unlikely to be beneficial.25 For patients with impaired renal function who have life-threatening bleeding following dabigatran-induced coagulopathy, hemodialysis has been recommended by some experts.29 Others have suggested that in the issue of meaning haemorrhage, the use of a four-circuitous PCC may be the most constructive option; however, there is limited evidence-based data.25
Fibrinolytics
The antithrombotic effect of fibrinolytics, which include tissue plasminogen activator (tPA) and urokinase, is achieved by inducing the conversion of inactive plasminogen into the active enzyme plasmin, which degrades the fibrin matrix responsible for stabilizing a thrombus.33 Recombinant forms of tPA and urokinase have been manufactured as fibrinolytics. Alteplase, an unmodified form of human tPA, along with reteplase and tenecteplase, a modified grade of human tPA, are the well-nigh ordinarily used drugs in this class.34 Mutual uses of these drugs include the treatment of acute cerebrovascular accidents (CVA), myocardial infarction, pulmonary emboli, equally well equally to dissolve thrombi in indwelling catheters. Following administration of fibrinolytics, an increase in the PT/INR and aPTT tin can be observed, along with a corresponding subtract in the fibrinogen; even so, at that place are no specific laboratory indices to precisely measure the anticoagulant effect of fibrinolytics.
Side Furnishings and Reversal Agents
The incidence of hemorrhage varies depending on the indication for the fibrinolytic. When used for acute CVA, tPA is associated with symptomatic intracranial hemorrhage at a rate of approximately vi%.35 , 36 All the same, when tPA is given to those with healthy brains, the rate of such hemorrhage is much lower.37
In the event of acute hemorrhage the administration of blood products, including FFP, PCC, and platelets, take been found to accept poor efficacy, and other agents, including tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA), have been considered.38 TXA and EACA are both structurally similar to the amino acid lysine and inhibit fibrinolysis past competitively inhibiting plasminogen activation.38
CONCLUSION
Acute hemorrhage is the almost feared agin result associated with all anticoagulants. While it is relatively uncommon that patients present with a life-threatening hemorrhage while on systemic anticoaguation, prompt recognition and direction is vital. As the NAC become more oft used in clinical settings, information technology will be imperative that the emergency medico has a thorough understanding of these agents, and is knowledgeable nigh potential reversal strategies, when available.
Footnotes
Supervising Section Editor: Michael Abraham, Dr.
Full text available through open admission at http://escholarship.org/uc/uciem_westjem
Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disembalm all affiliations, funding sources and financial or management relationships that could exist perceived as potential sources of bias. The authors disclosed none.
REFERENCES
1. Wheeler AP, Rice TW. Coagulopathy in critically ill patients: Part 2 - soluble clotting factors and hemostatic testing. Breast. 2010;137:185–94. [PubMed] [Google Scholar]
2. Dahlback B. Blood coagulation. Lancet. 2000;355:1627–32. [PubMed] [Google Scholar]
3. Shehab N, Sperling LS, Kegler SR, et al. National estimates of emergency section visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med. 2010;170:1926–33. [PubMed] [Google Scholar]
4. Hirsh J, O'Donnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin current and future advances. Circulation. 2007;116:552–560. [PubMed] [Google Scholar]
5. Weitz JI, Eikelboom JW, Samama MM. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians bear witness-based clinical exercise guidelines. Breast. 2012;141(suppl):e102s–51s. [PMC costless commodity] [PubMed] [Google Scholar]
half-dozen. Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood. 2010;115:fifteen–20. [PubMed] [Google Scholar]
7. Ageno W, Gallus AS, Wittkowsky A, et al. Antithrombotic therapy and prevention of thrombosis, ninth ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(suppl):e44S–e88S. [PMC complimentary article] [PubMed] [Google Scholar]
nine. Douketis JD. Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. Curr Pharm Des. 2010;xvi:3436–3441. [PubMed] [Google Scholar]
10. Couris R, Tataronis G, McCloskey West, et al. Dietary vitamin G variability affects international normalized ratio (INR) coagulation indices. Int J Vitam Nutr Res. 2006;76:65–74. [PubMed] [Google Scholar]
11. Levine Yard, Pizon AF, Padilla-Jones A, et al. Warfarin overdose: a 25 twelvemonth feel. J Med Toxicol. 2014 [PMC complimentary article] [PubMed] [Google Scholar]
12. Guyatt GH, Akl EA, Crowther Yard, et al. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Show-Based clinical practice guidelines. Chest. 2012;141(suppl):7S–47S. [PMC costless article] [PubMed] [Google Scholar]
xiii. Tran HA, Chunilal SD, Harper PL. An update of consensus guidelines for warfarin reversal. Med J Aust. 2013;198:198–ix. [PubMed] [Google Scholar]
fourteen. DeLoughery EP, Lenfesty B, DeLoughery TG. The use of recombinant cistron VIIa in warfarin patients with traumatic brain injury: a retrospective case. Blood Coagul Fibrinolysis. 2013;24:317–20. [PubMed] [Google Scholar]
15. Nishijima DK, Dager We, Schrot RJ, et al. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med. 2010;17:244–51. [PubMed] [Google Scholar]
sixteen. Weitz JI. Blood coagulation and anticoagulant, fibrinolytic, and antiplatelet drugs. In: Brunton LL, editor. Goodman & Gilman'due south The pharmacological footing of therapeutics. 12th edition. Vol. 211. McGraw Hill Medical; New York: pp. 848–76. [Google Scholar]
17. Gresham C, Levine Yard, Ruha AM. Case files of the medical toxicology fellowship at Banner Good Samaritan Medical Center in Phoenix, AZ: a non-warfarin anticoagulant overdose. J Med Toxicol. 2009;5:242–49. [PMC gratuitous article] [PubMed] [Google Scholar]
19. Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood. 2008;111:4871–4879. [PubMed] [Google Scholar]
twenty. Turpie AG, Mason JA. Review of enoxaparin and its clinical application in venous and arterial thromboembolism. Expert Opin Pharmacother. 2002;three:575–98. [PubMed] [Google Scholar]
21. Kubitza D, Becka One thousand, Roth A, et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008;24:2757–65. [PubMed] [Google Scholar]
22. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet. 2009;48:1–22. [PubMed] [Google Scholar]
23. Hillarp A, Baghaei F, Fagerberg Blixter I, et al. The effects of the oral, directly cistron Xa inhibitor rivaroxaban on unremarkably used coagulation assays. J Thromb Haemost. 2011;ix:133–9. [PubMed] [Google Scholar]
24. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Haematol. 2012;87(suppl1):S141–5. [PubMed] [Google Scholar]
25. Levine G, Goldstein JN. Emergency reversal of anticoagulation: novel agents. Curr Neurol Neurosci Rep. 2014 in press. [PubMed] [Google Scholar]
26. Yee DL, O'Brien SH, Young Thousand. The pharmacokinetics and pharmacodynamics of anticoagulants in paediatric patients. Clin Pharmacokinet. 2013;52:967–lxxx. [PubMed] [Google Scholar]
27. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: An analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Apportionment. 2011;123:2363–72. [PubMed] [Google Scholar]
28. Connolly SJ, Ezekowitz Doc, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51. [PubMed] [Google Scholar]
29. Ganetsky M, Babu KM, Salhanick SD, et al. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol. 2011;7:281–seven. [PMC complimentary article] [PubMed] [Google Scholar]
thirty. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to make up one's mind plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012;23:138–43. [PubMed] [Google Scholar]
31. Van Ryn J, Stangier J, Haertter South, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116–27. [PubMed] [Google Scholar]
32. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): A report of the American Higher of Cardiology Foundation/American Heart Clan Chore Force on exercise guidelines. J Am Col Cardiol. 2011;57:1330–7. [PubMed] [Google Scholar]
33. Simpson D, Siddiqui MA, Scott LJ, et al. Reteplase: a review of its utilize in the direction of thrombotic occlusive disorders. Am J Cardiovasc Drugs. 2006;vi:265–85. [PubMed] [Google Scholar]
34. Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medicine. Eye. 2003;89:1358–62. [PMC free commodity] [PubMed] [Google Scholar]
35. Miller DJ, Simpson JR, Silver B. Safety of thrombolysis in acute ischemic stroke: A review of complications, adventure factors, and newer technologies. Neurohospitalist. 2011;1:138–47. [PMC gratuitous commodity] [PubMed] [Google Scholar]
36. Whiteley WN, Slot KB, Fernandez P, et al. Risk factors for intracranial hemorrhage in astute ischemic stroke patients treated with recombinant tissue plasminogen activator: A systematic review and meta-analysis of 55 studies. Stroke. 2012;43:2904–nine. [PubMed] [Google Scholar]
37. Marder VJ, Stewart D. Towards safer thrombolytic therapy. Semin Hematol. 2002;39:206–xvi. [PubMed] [Google Scholar]
38. French KF, White J, Hoesch RE. Treatment of Intracerebral Hemorrhage with Tranexamic Acid Later Thrombolysis with Tissue Plasminogen Activator. Neurocrit Intendance. 2012;17:107–111. [PubMed] [Google Scholar]
Articles from Western Journal of Emergency Medicine are provided here courtesy of The University of California, Irvine
What Are Anticoagulants Used For,
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307693/
Posted by: bakerboser1959.blogspot.com
0 Response to "What Are Anticoagulants Used For"
Post a Comment