Anestezjologia. Intensywna Terapia 4/2015-Tranexamic acid: a clinical review

Tranexamic acid: a clinical review

William Ng1, Angela Jerath1,2, Marcin Wąsowicz1,2

1Department of Anesthesia and Pain Management, Toronto General Hospital/University Health Network, Canada

2Department of Anesthesia, University of Toronto, Canada

Blood loss and subsequent transfusions are associated with major morbidity and mortality. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, liver surgery and solid organ transplantation, obstetrics and gynecology, neurosurgery and non-surgical diseases. The evidence of their efficacy has been mounting for years. Tranexamic acid (TXA), a synthetic lysine-analogue antifibrinolytic, was first patented in 1957 and its use has been increasing in contrast to aprotinin, a serine protease inhibitor antifibrinolytic. This review aims to help acute care physicians navigate through the clinical evidence available for TXA therapy, develop appropriate dose regimens whilst minimizing harm, as well as understand its broadening scope of applications. Many questions remain unanswered regarding other clinical effects of TXA such as anti-inflammatory response to cardiopulmonary bypass, the risk of thromboembolic events, adverse neurological effects such as seizures, and its morbidity and mortality, all of which necessitate further clinical trials on its usage and safety in various clinical settings.

Keywords: anesthesia, tranexamic acid, antifibrinolytic, blood conservation

Anestezjologia Intensywna Terapia 2015, tom XLVII, nr 4, 353–364

Należy cytować wersję:

Ng W, Jerath A, Wąsowicz M: Tranexamic acid: a clinical review. Anaesthesiol Intensive Ther 2015; 47: 339–350. 10.5603/AIT.a2015.0011.

Blood loss and subsequent transfusions are associated with major morbidity and mortality [1, 2]. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, liver surgery and solid organ transplantation and non-surgical diseases. The evidence of their efficacy has been mounting for years [3, 4]. Synthetic lysine-analogue tranexamic acid (TXA, trans-4-aminomethylcyclohexane-1-carboxylic acid), along with ε-aminocaproic acid (ε-ACA), were first patented by S. Okamotoin 1957 [5]. Many questions remain unanswered regarding other clinical effects of TXA such as anti-inflammatory response to cardiopulmonary bypass (CPB), the risk of thromboembolic events and adverse neurologic effects (seizures), as well as the morbidity and mortality of TXA, all of which necessitate further clinical trials on its usage and safety in various clinical settings. Therefore, this review aims to help acute care physicians navigate through the clinical evidence available for TXA treatment, develop appropriate dose regimens whilst minimizing harm, as well as understand its broadening scope of applications [5].

TXA is a synthetic lysine-analogue antifibrinolytic [6] that competitively inhibits the activation of plasminogen to plasmin; at high concentrations it non-competitively blocks plasmin, thus TXA inhibits the dissolution and degradation of fibrin clots by plasmin. The binding of TXA to plasminogen is 6 to 10 times more potent that of ε-ACA [7]. TXA has been shown to increase thrombus formation in a dose-dependent fashion in animal models, in contrast to aprotinin, which inhibits thrombus formation [8].

Evidence from numerous studies show that TXA inhibits plasmin-induced platelet activation during extracorporeal circulation, such as cardiopulmonary bypass (CPB) used in cardiac surgery [9–12]. There are multiple factors that lead to bleeding following CPB, and fibrinolysis is one of the few that can be mitigated by pharmacological intervention. TXA also reduces excessive bleeding after CPB by several other mechanisms. Firstly, plasmin-platelet interaction leads to the selective release of ADP-granules from platelets, which is triggered by platelet surface contact with the extracorporeal circuit. Soslau et al. [13] found that platelet dense-granule ADP content in patients loaded with TXA pre-CPB were higher compared to those loaded with TXA post-CPB, with a strong inverse relationship to blood loss. The same investigators estimated the EC50 (half maximal effective concentration) of TXA required for the inactivation of plasmin-induced platelet aggregation during CPB to be ≤ 15 µg mL-1 in vitro; thrombin activation of platelets was also inhibited by plasmin-TXA binding to platelet receptors. Thus, one may conclude that there are several pathways explaining the preservation of platelet function by TXA during CPB.

Secondly, TXA possibly attenuates the inflammatory response and related hemodynamic instability in patients undergoing CPB. Hyperfibrinolysis probably plays a significant role in this inflammatory response. In a randomized controlled trial (RCT) of 50 patients undergoing CPB, TXA reduced significantly several of the biochemical markers of inflammatory response [14]: IL-6, fibrin separation products, creatine-kinase (CK) and plasminogen activator inhibitor. Patients receiving TXA had reduced incidences of inflammatory response and vasoplegic shock, fewer mean hours of norepinephrine use (1.2 vs 25.4 h) and fewer hours of mechanical ventilation (6.5 vs 12 h) in intensive care after CPB. In a larger RCT, IL-6 had a direct relationship with temperature, D-dimer, troponin I, CK, and lactic acid after CPB [15]. Furthermore, giving additional post-CPB TXA significantly reduced the relative risk (RR 2.5) of inflammatory response compared to pre-CPB TXA dosing alone.

Thirdly, hyperfibrinolysis contributes to coagulopathy in trauma and has an estimated incidence of 15% [16]. In trauma, tissue damage causes the release of tissue plasminogen activator induced by tissue ischemia and endothelial injury [17]. Point-of-care testing by rotational thromboelastometry allows rapid identification of patients with hyperfibrinolysis in trauma — a state associated with greater INR derangements, lower fibrinogen and higher mortality rates [18, 19] when compared to physiologic fibrinolysis. TXA use in trauma thus has physiologic justification, butthe diagnosis of hyperfibrinolysis is crucial before initiating treatment.

Lastly, there is a beneficial interaction of TXA with desmopressin: if the fibrinolytic activity of desmopressin via the transient release of tissue plasminogen activators [11, 20] is abolished by TXA preparation, desmopressin exerts salutary effect on platelet activation, significantly reducing postoperative blood loss and transfusion [21].

The main purpose of TXA is the reduction of perioperative bleeding and transfusion requirements in both cardiac and non-cardiac surgery. There are clear benefits both from the mortality-morbidity and economic-cost perspectives. In a recent meta-analysis of over 100 RCTs that compared TXA vs no TXA or a placebo in more than 10,000 patients undergoing surgery [22], there was overwhelming evidence that TXA reduces the probability of transfusion by 38%. Moreover, a cumulative meta-analysis suggests that this evidence has been available for more than 10 years. Although the same study showed that fewer deaths occurred in the TXA group (RR 0.61,95% CI 0.38 to 0.98), this became uncertain when analysis was restricted to the trials with adequate concealment. Similarly, the Cochrane Review of the effect of antifibrinolytics on blood-loss and transfusion of allogeneic blood [3] found that TXA significantly reduced blood transfusion by 39%, representing an absolute risk reduction of 18%. However, TXA was not associated with decreased mortality in all surgeries.

Since the publication of findings by Mangano et al. [23] and Karkouti et al. antifibrinolytic choice in cardiac surgery has shifted from aprotinin to TXA and ε-ACA. This was due to the concern that aprotinin may be associated with an increased risk of cardiovascular or cerebral vascular events, as well as renal dysfunction or failure. In a propensity-score matched analysis (n = 10,870) of patients at high risk of blood loss in cardiac surgery, Karkouti et al. [2] reported an increased risk of renal toxicity of aprotinin when compared with TXA with a potential increase in mortality, whilst both antifibrinolytics had similar hemostatic effectiveness. Subsequently, in a 5-year follow-up of (n = 4,374) patients having CABG surgery [24], Mangano et al. found aprotinin to be associated with increased mortality compared with a control,TXA and ε-ACA.

The use of TXA was further propelled by the BART [25] trial (Blood Conservation Using Antifibrinolytics in a Randomized Trial) published by Fergusson et al. [25], who compared the use of aprotinin, TXA and ε-ACA in high-risk cardiac surgery patients. Alarmingly, the 30-day mortality rate, was 6% for the aprotinin group vs 3.9% for TXA (R R1.5 5) and 4.0% for ε-ACA (RR 1.52); however, there was a modest reduction in the risk of massive bleeding in the aprotinin group compared with the two lysine-analogues. This led to the withdrawal of FDA and Health Canada approvals for aprotinin [26]. On the other hand, critics of BART have noted that in the high-risk patient subset, aprotinin may possibly have a better benefit/risk profile [27]. Indeed, this is supported by the propensity-score (n = 1,544) matched study by Karkouti et al. [28]

Knowledge of the efficacy of TXA vs a control in reducing blood loss and transfusion in cardiac surgery has been available for decades [29, 30]. Recent meta-analyses confirm this notion. A report by Henry et al. [31] stated a relative risk of blood transfusion with TXA of 0.68 with –300 mL of blood saved while Ngaage et al. [32] reported an odds ratio of 0.53 with –298 mL of blood saved. Although a comparison of TXA with a placebo showed a reduction in the number of reoperations caused by blood loss [3, 32], once again the benefit of reduced reoperation numbers due to blood loss is even more convincing with high-dose aprotinin [3, 31]. Even though TXA is approximately 7-times more potent than ε-ACA, they were comparable in relative riskand actual volume of blood loss in cardiac surgery [3]. Moreover, TXA did not show a decreased risk of mortality in cardiac surgery in the a forementioned meta-analyses.

While the BART protocol TXA regimen —30 mg kg-1 loading dose followed by 16 mg kg-1 h-1 infusion during surgery with an added 2 mg kg-1 in the circuit is in the high-dose range [33, 34], it has been nevertheless widely adopted by many cardiac surgical centers since the publication of BART. Early dose-response studies in cardiac surgery by Horrow et at. [35] found thata prophylactic loading dose of 10 mg kg-1 with infusion at 1 mg kg-1 h-1 was optimal, when compared to six incremental loading doses from 2.5 to 40 mg kg-1 followed by 0.25 mg to 4 mg kg-1 h-1 infusion. Later, several authors found inconsistent plasma concentrations [36, 37] with the Horrow regimen when the pharmacokinetic influence of the circuit and patient renal function were included in analysis. A recent RCT pitted the Horrow regimen against the higher BART regimen in cardiac surgery patients [38], and it found that although a high dose of TXA does not reduce the incidence of blood product transfusion up to day 7 (63% low dose vs 60% high dose), it is more effective than a low dose of TXA in decreasing transfusion (2.5 vs 4.1 U), blood loss (590 vs 820 mL), and repeat surgery (2.5% vs 6%). A subgroup analysis of high-risk patients with dual antiplatelet therapy or having complex surgery showed a further reduced incidence of transfusion and suggests that a high dose of TXA may be better in that group.

Many patients undergoing cardiac surgery receive aspirin and/or clopidogrel preoperatively. There is evidence that TXA partially corrects arachidonic acid-induced (aspirin) and ADP-induced (clopidogrel) platelet aggregation defects [39] detected by multiple electrode aggregometry, in patients on dual-antiplatelet therapy, concurring with the plasmininduced platelet inhibition [10] by the redistribution and degradation of glycoprotein Ib and IIb/IIIa receptors.

The efficacy of TXA in major pediatric surgery reproduces what was found in the adult population. In a metaanalysis of over 2,000 pediatric patients undergoing cardiac or scoliosis surgery the authors found no evidence that TXA was inferior in the reduction of blood loss vs aprotinin at 24 h. Indeed, TXA reduced blood loss by 11 mL kg-1 (95% CI 9 to 13 mL kg-1),and reduced packed red cell transfusion by 4 mL kg-1 (95% CI 2 to 7 mL kg-1). In scoliosis surgery, TXA significantly reduced blood loss by 682 mL (95% CI 214 to 1,149 mL). A recent RCT comparing TXA with a control (n = 150) in pediatric patients undergoing cardiac surgery [41] demonstrated a reduction of blood loss but not the units of blood transfused at 24 h. Similarly, a retrospective study (n = 231) of pediatric patients having cardiac surgery [42] found that TXA significantly reduced blood loss and reduced the amount of blood transfused intraoperatively, as well as at 48 h. Moreover, the authors found a reduction in the number of patients requiring blood transfusion (45/103 vs 77/127, P = 0.012) at 48 hours. Interestingly, both studies did not find differences between cyanotic and acyanotic subgroups. However, according to Faraoni et al. [43] in their meta-analysis of pediatric cardiac surgery and TXA, there is much heterogeneity in the data from RCTs: transfusion policies were ill-defined, with variability in regimens and data on TXA effect on morbidity and mortality. However, these authors found that in the 848 patients included in the analysis, the amount of red cells, platelet and fresh frozen plasma transfused showed decreasing trends between TXA and the control. Despite recent pharmacokinetic studies on pediatric populations [44, 45] the ideal dose regimen of TXA in pediatric cardiac surgery is still unknown [46]. In vitro studies in neonates have shown a significantly lower plasma concentration (–6.5 µg mL-1 vs-17 µg mL-1) required to prevent hyperfibrinolysis when compared to adults [45]; this would set the basis of future clinical trials on dosing regimens and risk-benefit balance.

Faraoni and Goobie also performed a systematic review [47] on the use of antifibrinolytics in pediatric non-cardiac surgery and concluded that in pediatric spine surgery (mainly scoliosis correction) and craniosynostosis surgery, TXA did decrease blood loss and transfusion requirements. An older Cochrane meta-analysis [48] found antifibrinolytics as a class in scoliosis surgery reduced blood loss by 426 mL and the amount of blood transfused by 327 mL; no subgroup analysis on the effect of TXA alone was carried out. There are few RCTs [49–51] on TXA use in pediatric scoliosis surgery. Thus, the safety profile of TXA use in pediatric spinal surgery remains unresolved.

Basta et al.. [52] conducted a separate systematic review on major pediatric surgery (cardiac, spinal and craniofacial) and found that antifibrinolytics reduced blood loss and transfusion volumes, particularly in craniofacial surgery. Craniosynostosis is not an uncommon pediatric disease requiring early surgical intervention and is associated with considerable blood loss [53]. There are two RCTs of TXA vs control in craniosynostosis surgery [54, 55]: Goobie et al. showed significant decrease in blood loss of 54 mL kg-1 and decreased volume of blood transfused by 23 mL kg-1; Dadure et al. [55] found a decrease in transfusion requirement by 85% (11 to 1.6 mL kg-1) intraoperatively and by 57% (16.6 to 7.2 mL kg-1) postoperatively. Moreover, Goobie et al. [44] describes a dose regimen for craniosynostosis using a two-compartment model, suggesting a 10 mg kg-1 loading TXA followed by a 5 mgkg-1 h-1 infusion to produce a threshold plasma concentration of 16 µg mL-1.

The reduction of blood loss in orthopedic surgery is of great importance, especially in hip or knee arthoplasty and spinal surgery. Pharmacological treatment with TXA is making a resurgence in orthopedic surgery. Indeed, antifibrinolytic use in orthopedic surgery is supported by a meta-analysis by Kagoma et al. [56], which found a reduction in blood loss, relative risk of transfusion (RR 0.52) and no increased risk of thromboembolism; the dose of TXA administered ranged between 10–15 mg kg-1. A large retrospective analysis by Poeran et al. [57] studied the perioperative use of TXA in knee or hip arthroplasty (n = 872,416). Patients who received TXA had lower rates of blood transfusion (7.7 vs 20.1%), fewer thromboembolic events (0.6 vs 0.8%), and reduced incidence of acute renal failure (1.6 vs 1.8%) as well as combined complications (1.9 vs 2.6%). With an increasing dose of TXA (none, < 1 g, ~ 2 g and > 3 g), there were decreasing odds (OR 0.31 to 0.38) of blood transfusion, and no significant increased risk of complications.

Moreover, its efficacy and safety profile in orthopedic surgery is further supported by two meta-analyses of TXA use in primary hip [58] and knee [59] arthoplasty. In hip surgery, Sukelk ef al. [58] found that TXA reduced intraoperative blood loss by 104 mL and postoperative blood loss by 172 mL (n = 350). There was also a proportional reduction of patients requiring blood transfusion (risk difference –0.20). In total knee replacement, Alshryda et al. [59] found significant reduction in blood loss by 591 mL (n = 763). It should be noted that there was significant heterogeneity in the trials. Subgroup analysis of high dose TXA (> 4 g) showed a reduction in transfusion requirements with homogeneity. In both meta-analyses there was no evidence of increased risk of thromboembolic events due to TXA. In addition, the use of the tourniquet in knee arthroplasty can activate local fibrinolysis apart from standard tissue trauma [60] and adds justification for TXA use. A meta-analysis of intravenous TXA use (n = 581) in spinal surgery by Yang et al. [61] had comparable findings to pediatric scoliosis surgery: there was reduction in postoperative blood loss by 389.21 mL and the amount of blood transfused by 134.55 mL with TXA. A RCT of Intravenous TXA use in cervical laminoplasty also found a decrease in blood loss (264 mL) but not intraoperative blood loss [62]; again there was no increase in complications.

The topical use of TXA has been examined in a Cochrane review by Ker et al. [63] Although the authors found reliable evidence that topical TXA reduces bleeding and blood transfusion in surgical patients, the risk of thromboembolism is unclear, as many studies do not report this complication orare underpowered. Topical administration results in a ten-fold less plasma concentration of TXA when compared to intravenous administration [8, 64], with a potential reduction In adverse effects. Although topical TXA has been studied in cardiothoracic [65–68], orthopedic [64, 69–72], otorhinolaryngologic [73, 74] and orthognathic [75–77] surgeries, high-quality trials are lacking.

Topical TXA in knee arthoplasty has been reviewed in a meta-analysis [78] while Pantell et al. showed that topical TXA reduced postoperative drain output (–268 mL), total blood loss (–220 mL), hemoglobin drop (i0.94 g dL-1) and transfusion risk (RR 0.47, 95% CI 0.26 to 0.84); there was no increase in thromboembolisms. The authors examined the subgroup using > 2 g of topical TXA and found that these patients had a significantly less transfusion requirement (RR 0.41, P = 0.05). Similarly in a separate review of RCTs [72], Zhang et al. [72] also found the intra-articular injection of TXA in knee arthroplasty found a reduction of blood loss (396 mL), relative transfusion risk (RR 0.22), drainage output and hemoglobin drop; there was no increased risk of thromboembolism. Once again there was significant heterogeneity in these trials. Two RCTs [69, 70] by Alshryda et al. found that intra-articular injection of TXA in primary total hip (n = 161) and knee (n = 157) arthroplasty reduced the absolute risk of blood transfusion by 19.6% and 15.4%, respectively, and reduced blood loss, hemoglobin drop, as well as decreased the cost per episode by £ 305 and £ 333 respectively. Moreover, there was decreased length of stay in knee surgery by 1.2 days without increased in thromboembolic events. All these findings cumulatively support the topical use of TXA in orthopedic surgery.

In a meta-analysis of topical antifibrinolytic use in cardiac surgery (n = 622), Abrishami et al. [79] found reduced postoperative blood loss and transfusion requirements in patients undergoing on-pump cardiac surgery. Mahaffey et al. [80] (n = 160) found that combined intravenous and topical TXA was associated with decreased chestdrain outputat 3, 6 and 12 h postoperatively. Even though the total amount of TXA was higher in the combined group, less TXA (4.1 g vs 5.1 g) was given intravenously compared with the control. In addition, there was no increase in adverse events. Spegar et al. [81 ] studied the augmentation of systemic TXA by topical application (2.5 g in 250 mL saline into pericardial cavity) in valvular surgery (n = 100) and found intergroup variance on blood loss and fresh frozen plasma buta non-significant decrease in the volume of blood loss in the augmented group. In contrast, Fawzy et al. [66] in their RCT (n = 38) found a decrease in postoperative blood loss (–626 mL vs –1,040 mL) and platelet transfusion (median units 0 vs 2) using 1 g TXA in 100 mL saline into the pericardial cavity. Similar regimens used in two other RCTs found that topical TXA did reduce postoperative blood loss in cardiac surgery without increased risk of adverse events [67, 68].

TXA application in trauma is supported by firm clinical evidence. The most convincing multicenter RCT in trauma [82] to date is the comparison of TXA vs placebo in over 20,000 patients by the CRASH-2 collaborators. Patients were assigned to a placebo or IV loading of 1 g TXA within 8 h of trauma then followed by IV infusion of 1 g TXA over 8 h. It showed that all-cause mortality was reduced in the TXA group (RR 0.91), and death due to bleeding was significantly reduced (RR 0.85). Subsequent analysis showed that early treatments 1 h from injury) reduced the risk of death from bleeding (RR 0.68), while treatment given after 3h of injury seemed to increase the risk of death due to bleeding [83].

It is important to remember that physiologic fibrinolysis and even fibrinolytic shutdown occurs in trauma, and not just hyperfibrinolysis. In a recent study (n = 180) of patients with an Injury Severity Score of > 15, there was a sizeable portion (64%) of patients with fibrinolysis shutdown per thromboelastometry at 30 min [84]. The distribution of mortality was U-shaped relative to the fibrinolysis system, the physiologic group had lowest mortality (5%), and the hyperfibrinolysis (44%) and shutdown (26%) groups had higher mortality. This supports the employment of careful patient selection when using exogenous inhibition of fibrinolytic system. The use of thromboelastometry will help prevent indiscriminate TXA therapy.

The use of antifibrinolytics in intracranial hemorrhage (ICH) and particularly aneurysmal subarachnoid hemorrhage (SAH) has been investigated for decades, with earlier findings of decreased re-bleeding rates butincreased risk of stroke. New strategies were introduced for the prevention of cerebral vasospasm with shorter antifibrinolytic intervention periods [85]. There is renewed interest in TXA and ε-ACA for these patients. The earlier position is outlined in the review of antifibrinolytics vs a control in ICH by the Cochrane Stroke Group [86]: the treatment did not benefit patient outcome and death was not reduced. Treatment did reduce risk of re-bleeding (OR 0.55) with some heterogeneity across the trials. However, there was an increased risk of ischemic stroke (OR 1.39), again with heterogeneity in the trials. In drawing conclusions from these results, the authors did not support the routine use of antifibrinolytics in aneurysmal SAH. In contrasta study [87] by Roos et al. [87] did not show rates of increased ischemic stroke, namely delayed cerebral ischemia from vasospasm, probably because patients in this trial were given calcium channel antagonist nimodipine and hypervolemic therapy concurrently.

Since this meta-analysis, new strategies using antifibrinolytics in short duration have shown promise of reduced re-bleeding with fewer adverse events [88–91]. Although the mechanism for re-bleeding is multifactorial, increased fibrinolysis and decreased platelet-plug stability are implicated [92]. The risk of re-bleeding is highest in the first 6 h after aneurysmal SAH, with a poor prognosis as assessed by a reduction of the Glasgow Outcome Scale from 40% to 80% and a mortality rate of 20% to 60% [92]. Hillman et al. [91] in their RCT (n = 505) compared early intravenous TXA with a control in patients with SAH for short duration (up to 72 h) and found a significant reduction of early re-bleeding from 10.8% to 2.4% and an 80% reduction in the mortality rate in the early rebleeders. Using evidence from transcranial Doppler and clinical measurements, recent literature shows a resurgence of TXA as a part of protocol therapy alongside other preventative strategies for vasospasm in the acute phase of aneurysm SAH, prior to aneurysm closure [88, 93].

As traumatic ICH includes epidural, subdural and subarachnoid hemorrhage, the use of TXA has been gaining increasing interestsince CRASH-2 [82]. A nested RCT within CRASH-2 by Perel et al. [94] reviewed the rate of ICH growth in 270 patients, and they found no moderate benefits (total hemorrhage growth and/or new ischemic lesions) nor harmful effects with certainty in traumatic brain injury. More recently, Sprigg et al. [95] performed a pilot RCT comparing TXA vs a control in spontaneous intracerebral hemorrhage — the first trial studying this application — and found it feasible to use intravenousTXA early with good tolerability. As a result, two large multicenter trials — namely TICH-2 (International) [95] and STOP-2 (Australia) [97] — are in progress to evaluate the efficacy and safety of TXA in the setting of spontaneous intracerebral hemorrhage.

Orthotopic liver transplantation (OLT) is associated with significant blood loss and the need for transfusion of blood products, with fibrinolysis being a major player in this [98, 99]. There has been clinical evidence for the use of antifibrinolytics in OLT for over three decades; previously aprotinin was commonly used in OLT and trials demonstrated potential advantages (antioxidant, anti-inflammatory) of aprotinin over TXA [100]. There is one meta-analysis which has studied the use of antifibrinolytics including TXA and aprotinin in OLT (n = 1,407), while Molenaar et al. [101] found that both drugs reduced intraoperative blood and fresh frozen plasma requirements.

There are several studies which have compared the efficacy of TXA with aprotinin in OLT. In one RCT (n = 127), prophylactic TXA had similar efficacy to aprotinin [102] in terms of blood and component transfusions both intraoperatively and at 24 h. There were neither differences in mortality and complications nor in coagulation laboratory data collected intraoperatively, except aPTT. Similar results were found by Ickx et al. [103] (n = 51), with the additional finding of inhibition of fibrinolysis by both TXA and aprotinin vs a control. Gurusamy et al. [104] addressed different strategies of decreasing blood loss in OLT in their Cochrane review. Although with respect to aprotinin and TXA, they concluded that the clinical trials had been biased, there were no differences in 60-day mortality rates, re-transplantation risk or thromboembolic events in the TXA group vs the control and no difference between aprotinin and TXA in mortality or thromboembolism risk. Massicotte et al. [105] analyzed 400 patients undergoing OLT who had received antifibrinolytics and found no difference between TXA and aprotinin in blood loss (1082 vs 1007 mL), blood transfused per patient (0.5 vs 0.5 U), final hemoglobin (93 vs 95 g L-1), percentage of transfusion-free cases (80 vs 82%) orthe 1-year survival rate (85.1 vs 87.4%). Interestingly, preoperative hemoglobin correlated with 1-year survival and transfusion requirements.

Gorlinger [106] analyzed ROTEM® (rotational thromboelastometry) in 642 OLTs and suggests using prophylactic administration only in fulminant liver failure or reduced maximal clot firmness, which indicates a high-risk for hyperfibrinolysis. Although 60% of patients displayed hyperfibrinolysis during OLT, only 40% who showed early hyperfibrinolysis during prehepaticand anhepatic phases, required antifibrinolytics. In the neohepatic phase, only patients with increased fibrinolysis and clinical bleeding were treated. This selection by point-of-care testing is aimed at reducing iatrogenic prothrombotic risk.

TXA use has also been investigated for blood conservation in hepatectomy performed for tumor resection. These studies showed promising efficacy, according to a RCT by Wu et al. [107] (n = 214). Although a Cochrane review addressed use of pharmacological intervention for blood conservation in liver resection, and found that aprotinin and TXA significantly reduced the risk of allogeneic blood transfusion compared with a control [108], this review included a few small RCTs. A survey of Canadian hepatobiliary surgeons showed that even though low central venous pressure strategy was used commonly during liver resection, other conservation strategies including TXA were rarely employed [109]. High quality RCTs on perioperative morbidity and mortality are needed to assess pharmacological intervention for blood conservation in hepatectomy.

As menorrhagia is a common illness affecting women’s health and quality of life, TXA has been used as a form of treatment for over four decades. A recent review [110] placed its efficacy in the reduction of menstrual blood loss by 34 to 59%. An earlier Cochrane review [111 ] on the use of antifibrinolytics (TXA and its precursor) in heavy menstrual bleeding found that TXA vs a placebo significantly reduced mean blood loss (mean difference –94 mL). TXA also significantly reduced blood loss when compared to mefenamic acid, norethisterone and etamsylate; there was no difference in adverse effects between TXA and the other agents. A recent RCT also found reductions in menstrual blood loss by a new oral formulation of TXA that was both statistically significant (> 50 mL) and clinically meaningful to patients, at doses > 3.9 g day-1 for up to 5 days of the cycle [112]. This reinforced the findings of a greater quality of life with TXA use in women with menorrhagia in an early uncontrolled study [113] (n = 849), who were assessed by a questionnaire based on one designed by Edlund et al. [114].

A Cochrane review [115] analyzed two RCTs (n = 453) comparing TXA vs a control in women having a caesarean section or vaginal delivery [116,117], and the authors found that blood loss of > 400 mL was less common and mean blood loss was lower in the TXA group vs the control (mean difference –75 mL). A recent meta-analysis on TXA in pregnancy and postpartum [118] by Peisidis et al. [118] included several quasi-blinded trials [119–121] excluded from the above Cochrane review, and found a combined estimated decrease of blood loss by 32.5 mL in TXA pre-caesarean section vs a control. A similar effect of TXA was found in a separate meta-analysis by Ferrer ef al. [122] in a reduction of postpartum blood loss by 92 mL compared with the control.

Ducloy-Bouthers et al. [123] (n = 144) demonstrated that a high-dose TXA (4 g infusion over 1 h followed by 1 g h-1 for 6 h) vs a control — in women with greater than 800 mL postpartum hemorrhage — was effective in reducing blood loss (173 vs 221 mL). Moreover, the TXA group had a shorter duration of hemorrhage, less progression to severe postpartum hemorrhage and less incidence of transfusion. This trial was underpowered to detect rare adverse effects. A RCT (n = 439) by Gungorduk et al. [124] showed that TXA — 1 g given intravenously over 5 min at the delivery of the anterior shoulder — reduced blood loss during the 3rd and 4th stage of labor compared to the control (261.5 vs 349.98 mL), significantly higher hematocrit and hemoglobin levels on day one, with no major complications at a three week follow-up. Gungorduk et al. [125] also performed a RCT (n = 660) of pre-caesarean intravenous TXA vs control, and found a significantly lower mean blood loss, a lower proportion of women with severe postpartum hemorrhage (> 1,000 mL blood loss) and a lower risk of additional uterotonlcs used. Finally, three new RCTs [126–128] comparing pre-caesarean section intravenous TXA vs a control have shown a reduction of intraoperative and post-caesarean blood loss without increased adverse events such as thromboembolism. Determining the different obstetric and gynecological settings in which TXA may be beneficial remains a critical question for future research.

A common minor surgery where post-operative bleeding remains a big issue is tonsillectomy. A meta-analysis of the use of TXA in tonsillectomy [129] (n = 180), showed a reduced volume of blood loss but not the number of patients with post-tonsillectomy hemorrhage. Albirmawy et al. [73] found that post-resection topical TXA in pediatric adenoldectomy led to a reduction of blood loss during surgery, decreased postoperative bleeding and transfusion.

Lastly, several old trials support the use of  TXA in hereditary angioneurotic edema [130, 131]. The biological mechanism involves the inhibition of the complement system by TXA in the presence C1 esterase deficiency and partial normalization of plasma kinin activation [130]. In Japan, TXA is approved for conditions such as urticarial swelling. Itch, eczema, drug eruptions or toxicoderma [8], in which local hyperfibrinolysis and inflammation are involved [131].

The use of TXA iin upper gastrointestinal bleeding was reviewed in a Cochrane meta-analysis, and although TXA use vs a control reduced mortality risk, the effect was lost in a subgroup analysis stratified for bias control and in an sequential analysis [132]. No such benefit was demonstrated in TXA vs other anti-ulcer therapy. Although five serious cases of thromboembolic events occurred in the TXA group, this was not statistically significant. No RCTs were found assessing TXA use in upper gastrointestinal bleeding in liver disease [133]. The use of TXA in hemoptysis from any cause was reviewed by the Cochrane Collaboration [134], and TXA vs a control significantly reduced bleeding time (mean difference –19.47 h), without any difference in side-effects.

Topical administration of TXA to the central nervous system of animals has been shown to cause seizures in a dose-related fashion [135, 136], this correlates with human reports of seizures induced by accidental intrathecal injections of TXA [136–138]. Recently a dose-response relationship of TXA has been proposed as a modifiable risk factor for seizures for patients undergoing cardiac surgery [139]. TXA crosses the blood-brain barrier and penetrates the eye, and produces cerebrospinal fluid concentration levels around 10% of the plasma concentration [8]. Likewise, it diffuses into and out of synovial membranes and joint fluid. It is now clear from current literature that moderate to high doses of TXA in cardiac surgery are associated with an increased risk of seizures [139, 140]. In a multivariate analysis of over 11,000 patients after cardiac surgery, Sharma et al. [142] found TXA to be a strong independent predictor for the development of postoperative generalized seizures [141] (OR 14.3); in addition, patients with seizures had a 2.5 times higher mortality rate. Similarly, in a propensity-score adjusted analysis (n = 4883) Koster et al. [143] showed that moderate dosing of TXA in cardiac surgery doubled the rate of post-CPB seizure and in-hospital mortality. Similar concerns over the increasing trend of post-CPB seizure in pediatric patients have led to the substitution of TXA by ε-ACA in a major European center for pediatric cardiac surgery.

The postulated mechanism was TXA binding to GABAA receptors, subsequently blocking GABAA-medlated inhibition in the CNS [144, 145]. Recently, Lecker et al. [145] have demonstrated that TXA is structurally similar to glycine, and competitively inhibits glycine inhibitory receptors in the cortical and spinal cord neurons in rats; TXA also inhibited the GABAA receptors in cortical and spinal cord neurons. Both TXA dis-inhibitory pathways cause increased excitatory synaptic drive evidenced by seizure-like events in cortical slices induced at TXA concentrations of 31 µg mL-1 (200 µM), similar to that measured in CSF of patients undergoing CPB. Finally, peak CSF TXA concentrations occurred when the infusions were stopped after CPB, later than peak serum levels. When taken together, this explains the late-onset of unexpected seizures in patients emerging from anesthesia after CPB. Moreover, ε-ACA had 10-fold less potency in glycine receptor inhibition, and aprotinin had no inhibitory potency.

There are various dose regimens for different indications cited by clinical trials; initially an effective plasma concentration of TXA for antifibrinolysis was reported to be 5–10 µg mL-1 [147] or 10–16 µg mL-1 [13, 147, 148]. Subsequently, Dowd et al. [37] proposed the dosing scheme later adopted in the BART study, in order to ensure plasma levels which would achieve complete inhibition of fibrinolysis for cardiac patients undergoing CPB, namely a loading dose 30 mg kg-1, maintenance infusion at 16 mg kg-1 hr-1 with an additional 2 mg kg-1 in the circuit [25, 37]. Sharma et al. [150] conducted a pharmacokinetic study of the BART regimen in cardiac surgery and demonstrated that plasma TXA concentrations were consistently higher than suggested levels aiming to achieve 100% (> 100 ug mL-1) and 80% inhibition (> 10 µg mL-1) of tissue plasminogen activator and these levels remained high for up to 6 hours post-operatively. Approximately 95% of TXA is excreted via the urine unchanged, and excretion decreases with increasing plasma creatinine levels. The dosage adjustment for renal-impaired patients remains an unknown; Jang et al. [151] used the 2 compartment model to guide a simulated reduction of the maintenance infusion rate according to the GFR of patients during CPB to achieve > 100 µg mL-1 threshold plasma concentrations. Please see full paper, which just got published. It would be beneficial for readers to have access toiIt.

Despite the fact that TXA is minimally metabolized in the body, precautions should be taken with prothrombotlc medications [152] used concomitantly. According to the Cyklokapron® product information [6], these medications include combination hormone contraceptives, factor IX, Xa and Vila complex concentrates, anti-inhibitor coagulant concentrates, thrombin, batroxobln or hemocoagulase.

There is currently no clinical evidence that the use of TXA increases the risk of thromboembolic events, namely myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism according to meta-analyses and clinical trials cited in the general [22, 63], trauma [82], orthopedic [48, 56, 58, 59, 78], cardiac [25, 32, 153] or obstetric & gynecological [111, 112, 119, 123] settings. However, there are reports of catastrophic intracardiac or intrapulmonary thromboses [154], whose putative cause was antifibrinolytic use, albeit none involved TXA. The meta-analysis of antifibrinolytics In OLT (n = 1,407) by Molenaar et al. [101] found no increased risk of hepatic artery thromboses or thromboembolism. Ngaage et al. [32] in their meta-analysis of TXA in cardiac surgery noted that thromboembolic events (myocardial infarction and neurologic complication) and mortality observed were few but not increased compared to non-treatment groups; the authors still warn against the indiscriminate use of TXA. In patients with menorrhagia, TXA was not associated with an increased thromboembolism risk in a nested case-control study [155] (n = 686), whereas other therapy groups had a significantly increased risk, suggesting that menorrhagia is prothrombotic. Finally, Perel et al. [63] were uncertain about the increased risk of thromboembolism and stroke in a Cochrane review of TXA in emergency surgery; only three trials met the criteria for inclusion and the number of events observed were small.

Overall, the cumulative evidence shows that TXA is a well-tolerated drug when delivered orally, intravenously and/or topically. Gastrointestinal disturbance, allergic skin reaction, visual disturbance occur more commonly [8] and seizures less commonly at high concentrations.

There are still important questions of mortality and morbidity of TXA use in surgery. One may expect that a reduction of transfusion would translate into reduction in mortality and morbidity. As mentioned above, Ker et al. [22] found fewer deaths (RR 0.61) occurred in the TXA group in their meta-analysls, albeit with uncertainty of adequate concealment. The overall potential forincreased thromboembolism risk with TXA remains uncertain. The safety profile and dose regimens of TXA in cardiac and non-cardiac surgeries in the pediatric population requires further investigation, as previous studies are underpowered to detect differences in adverse effects [47].

The adjustment of TXA in renal impairment warrants further investigation, especially given the at-risk patient group undergoing cardiac surgery. There is no universally accepted dose regimen despite definite concerns of seizure risk of high-dose TXA.

Given the link between inflammatory response and coagulation-fibrinolysis systems and the likely attenuation of inflammatory response by TXA in CPB [14, 15], clinicians ought to identify at-risk patients who may benefit from its treatment.

There are several case reports of young, healthy individuals developing ischemic cerebral events after TXA use, especially those with heterozygous MTFR C677T genes (methylene tetrafolate transferase) [156]. In the meta-analyses and large clinical trials, the risk of stroke, pulmonary thromboembolism and deep venous thrombosis with TXA use remains uncertain. The interaction of pharmacology with genetic factors is an exciting field for research.

Several ongoing multicenter RCTs on TXA are worth following. The STOP-AUST trial [98] is comparing early (≤ 4.5 h of stroke onset) intravenous TXA use with a placebo in patients with confirmed intracerebral hemorrhage by CT angiography contrast extravasation — a biomarker of likely hematoma growth. The hypothesis is that TXA will reduce intracerebral hematoma growth at 24 h. CRASH-3 is an international pragmatic trial quantifying the effect of early TXA (the same regimen as CRASH-2) on mortality and morbidity in 10,000 patients with traumatic brain injury [157]. Lastly, Shakur et al. [158] is leading an international pragmatic trial, a.k.a. the WOMAN trial, on the use of TXA in 15,000 women with a clinical diagnosis of postpartum hemorrhage, with the authors hypothesizing a reduction of mortality and/or hysterectomy. This trial has a large third world representation with an obvious contextual relevance. In view of the thromboticand bleeding complications of cardiac surgery [5], Myles et al. is leading a multicenter RCT (ATACUS, n = 4,600) investigating aspirin and TXA in CABG surgery [159]. It is a 2 × 2 factorial trial assessing whether aspirin. TXA, or both can reduce mortality and/or morbidity afterelective CABG. Ischemic (renal, cerebral, bowel) complication is a secondary endpoint. This will yield important data on TXA in cardiac surgery.

TXA as an antifibrinolytic treatment applied in a perioperative setting has strong pharmacological and clinical grounds. Although there are other situations in which the use of TXA is desirable, these require definitive trials on morbidity and mortality. TXA administration should be based on clinical judgment, guided by patient history, thromboelastometry, laboratory and radiologic investigation, and tailored to the treatment location and capacity for intervention and transfusion. Future reviews should include guidelines on TXA dose regimens minimizing seizure risk, and conclusions regarding the thromboembolic risk. The ongoing research outlined will help answer these questions.

  1. The authors declare no financial disclosure.
  2. The authors declare no conflict of interest.

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  89. Starke RM, Kim GH, Fernandez A et al.: I mpact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Stroke 2008; 39: 2617–2621. doi: 10.1161/STROKEAHA.107.506097.
  90. Harrigan MR, Rajneesh KF, Ardelt AA, Fisher WS: Short-term antifibrinolytic therapy before early aneurysm treatment in subarachnoid hemorrhage: effects on rehemorrhage, cerebral ischemia, and hydrocephalus. Neurosurgery 2010; 67: 935–939; discussion 939–940.
  91. Elillman J, Fridriksson S, Nilsson O, Yu Z, Saveland EI, Jakobsson K-E: Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002; 97: 771–778.
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  98. Steib A, Gengenwin N, Freys G, Boudjema K, Levy S, Otteni JC: Predictive factors of hyperfibrinolytic activity during liver transplantation in cirrhotic patients. Br J Anaesth 1994; 73: 645–648.
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  114. Edlund M, Andresson K, Rybo G, Lindoff C, Astedt B, Schoultz B: Reduction of menstrual blood loss in women suffering from idiopathic menorrhagia with a novel antifibrinolytic drug (Kabi 2161 ). BJOG An I nt J Obstet Gynaecol 1995; 102: 913–917.
  115. Novikova N, Hofmeyr GJ: Tranexamic acid for preventing postpartum haemorrhage. Cochrane database Syst Rev 2010; 7: CD007872.
  116. Yang H, Zheng S, Shi C: Clinical study on the efficacy of tranexamic acid in reducing postpartum blood lose: a randomized, comparative, multicenter trial. Zhonghua Fu Chan Ke Za Zhi 2001; 36: 590–592.
  117. GaiM, Wu L, Su Q, Tatsumoto K: Clinical observation of blood loss reduced by tranexamic acid during and after caesarian section: a multi-center, randomized trial. Eur J Obstet Gynecol Reprod Biol 2004; 112: 154–157.
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  119. Gohel M, Patel P, Gupta A, Desai P: Efficacy of tranexamic acid in decreasing blood loss during and after cesarean section: A randomized case controlled prospective study. J Obstet Gynecol India 2007; 57: 227–230.
  120. Sekhavat L, Tabatabaii A, Dalili M, Farajkhoda T, Tafti AD: Efficacy of tranexamic acid in reducing blood loss after cesarean section. J Matern Fetal Neonatal Med 2009; 22: 72–75. doi: 10.1080/14767050802353580.
  121. Gobbur V, Shiragur S, Jhanwar U, Tehalia M: Efficacy of tranexamic acid in reducing blood loss during lower segment caesarean section. Int J Reprod Contracept Obstet Gynecol 2014; 3: 414.
  122. Ferrer P, Roberts I, Sydenham E, Blackhall K, Shakur H: Anti-fibrinolytic agents in post partum haemorrhage: a systematic review. BMC Pregnancy Childbirth 2009; 9: 29. doi: 10.1186/1471-2393-9-29.
  123. Ducloy-Bouthors A-S, Jude B, Duhamel A et al.: High-dosetranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care 2011; 15: R117. doi: 10.1186/cc10143.
  124. Gungorduk K, Ascoğlu O, Yldrm G, Ark C, Tekirdağ AI, Besmoglu B: Can intravenous injection of tranexamic acid be used in routine practice with active management of the third stage of labor in vaginal delivery? A randomized controlled study. Obstet Gynecol Surv 2013; 68: 673–675.
  125. Gungorduk K, Yildirim G, Asicioğlu O, Gungorduk Ozgu C,Sudolmus S, Ark C: Efficacy of intravenous tranexamic acid in reducing blood loss after elective cesarean section: a prospective, randomized, double-blind, placebo-controlled study. Am J Perinatol 2011; 28: 233–239. doi: 10.1055/S-0030-1268238.
  126. Xu J, Gao W, Ju Y: Tranexamic acid for the prevention of postpartum hemorrhage after cesarean section: a double-blind randomization trial. Arch Gynecol Obstet 2013; 287:463–468. doi: 10.1007/S00404-012-2593-y.
  127. Movafegh A, Eslamian L, Dorabadi A: Effect of intravenous tranexamic acid administration on blood loss during and after cesarean delivery. Int J Gynaecol Obstet 2011; 115: 224–226. doi: 10.1016/j.ijgo.2011.07.015.
  128. Sentürk MB, Cakmak Y, Yildiz G, Yildiz P: Tranexamic acid for cesarean section: a double-blind, placebo-controlled, randomized clinical trial. Arch Gynecol Obstet 2013; 287: 641–645. doi: 10.1007/S00404-012-2624-8.
  129. Chan CC, Chan YY, Tanweer F: Systematic review and meta-analysis of the use of tranexamic acid in tonsillectomy. Eur Arch Otorhinolaryngol 2013; 270: 735–748. doi: 10.1007/S00405-012-2184-3.
  130. Sheffer AL, Fearon DJ, Austen KF, Rosen FS: Tranexamic acid: preoperative prophylactic therapy for patients with hereditary angioneurotic edema. J Allergy Clin Immunol 1977; 60: 38–40.
  131. Laurberg G: Plasma kinin activation in tranexamic acid treated patients with hereditary angioneurotic edema. Arch Dermatol Res 1978; 262: 153–156.
  132. Gluud LL, Klingenberg SL, Langholz E: Tranexamic acid for upper gastrointestinal bleeding. Cochrane database Syst Rev 2012; 1: CD006640.
  133. Marti-Carvajal AJ, Sold I, Marti-Carvajal PI: Antifibrinolytic amino acids for upper gastrointestinal bleeding in patients with acute or chronic liver disease. Cochrane database Syst Rev 2012; 9: CD006007. doi: 10.1002/14651858.CD006007.pub3.
  134. Prutsky G, Domecq JP, Salazar GA, Accinelli R: Antifibrinolytic therapy to reduce haemoptysis from any cause. Cochrane database Syst Rev 2012; 4: CD008711. doi: 10.1002/14651858.CD008711.pub2.
  135. Schlag M, Hopf R, Zifko U, Redl H: Epileptic seizures following cortical application of fibrin sealants containing tranexamic acid in rats. Acta Neurochir (Wien) 2002; 144: 63–69.
  136. Pellegrini A, Giaretta D, Chemello R, Zanotto L, Testa G: Feline generalized epilepsy induced by tranexamic acid (AMCA). Epilepsia 1982; 23: 35–45.
  137. Mohseni K, Jafari A, Nobahar MR, Arami A: Polymyoclonus seizure resulting from accidental injection of tranexamic acid in spinal anesthesia. Anesth Analg 2009; 108: 1984–1986. doi: 10.1213/ane.0b013e3181a04d69.
  138. Sabzi F, Teimouri H, Zokai A:Myoclonus, seizure, and ventricular fibrillation after intrathecal injection of tranexamic acid. J Tehran Univ Elear Cent 2009; 4: 253–255.
  139. Kaabachi O, Eddhif M, Rais K, Zaabar MA: I nadvertent intrathecal injection of tranexamic acid. Saudi J Anaesth 2011; 5: 90–92. doi: 10.4103/1658-354X.76504.
  140. Manji RA, Grocott FtP, Leake J et al: Seizures following cardiac surgery: the impact of tranexamic acid and other risk factors. Can J Anaesth 2012; 59: 6–13. doi: 10.1007/sl2630-011-9618-z.
  141. Murkin JM, Falter F Granton J, Young B, Burt C, Chu M: High-dose tranexamic acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg 2010; 110: 350v353. doi: 10.1213/ANE.0b013e3181c92b23.
  142. Sharma V, Katznelson R, Jerath A et al.: The association between tranexamic acid and convulsive seizures after cardiac surgery: a multivariate analysis in 11 529 patients. Anaesthesia 2014; 69: 124–130. doi:10.1111/anae.l 2516.
  143. Foster A, Borgermann J, Zittermann A, Lueth JU, Gillis-Januszewski T, Schirmer U: Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome. Br J Anaesth 2013; 110: 34–40. doi: 10.1093/bja/aes310.
  144. Martin K, Breuer T, Gertler R et al.: Tranexamic acid versus c-aminocaproic acid: efficacy and safety in paediatric cardiac surgery. Eur J Cardiothorac Surg 2011; 39: 892–897. doi: 10.1016/j.ejcts.2010.09.041.
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Corresponding author:
Marcin Wqsowicz, MD
Department of Anesthesia EN3-438,
Toronto General Elospital, 200 Elizabeth St,
Toronto, ON M5G2C4, Canada
Tel.: 1 (416) 340-3567, fax: 1 (416) 340-3698

Received: 10.02.2015
Accepted: 22.02.2015

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Homeschooling Resources for Families in Oak Glen California2018-05-20T11:13:46+00:00

Homeschooling Resources in Oak Glen, California

homeschool texas

If you’re one of the many of mom and dads looking for an alternative to the Godless Oak Glen public schools system you’re at the right website! Great Homeschool Conventions is the top rated source of everything Homeschooling in Oak Glen, CA. Wwe are proud to provide the best Homeschool Curriculum, Programs, Textbooks, Materials, Lesson Plans, Resources, and some of the best conferences you’ll ever attend! If you are new homeschooling, Great Homeschool Conventions will come see youto the revolution. If you currently live in Oak Glen, CA or are moving to the area and are interested in homeschooling, you probably have many questions about how homeschooling works in Oak Glen, CA.

The top question we get asked is What homeschool laws does Oak Glen, California have? Given California’s political agenda might be hard to believe but yes California allows homeschooling. However, given the number of lawsuits we can interpret that California is not a homeschooling friendly state. Nevertheless families who seek the best education for their kids are today choosing homeschooling more often than the state of California would like. Several California-based publications have acused Great Homeschool Conventions of pushing the home schooling agenda, as with all fake news, we have never said that home school is a better option but if this what you want we want to be sure you have the best information at your disposal.

Top Homeschooling Programs in Oak Glen, California

Finding accredited homeschool curriculum, programs, textbooks, materials, lesson plans, and resources in Oak Glen, California is not as easy as one may think. Possibly that is why Great Homeschool Conventions events have grown to become an annual most go to the event. Here you’ll be able to commingle from well-known speakers like Attorney Judy Sarden, Stacy Farrell, and Dr. Angela Gonzales as well as some of the top vendors of home schooling curriculum, programs, textbooks, and lesson plans. When it’s all said and done our goal is that American kids have the best education available. Kids in the US have more choices than their counterparts in South America and the United Kingdom. Those are public school, private school, and home school. But, given the current ranking of the US education system many parents are looking for alternative options. For the great majority of stay-at-home parents private school is not something that can afford making home school the obvious choice. For additional information on how GreatHomeschoolConventions.Com can help you get started with home school for your kids, please visit out our blog.

Oak Glen Homeschooling Programs Article

It doesn’t seem to be just those diagnosed with Attention Deficit Disorder (ADD) that have a difficult time paying attention or staying on task. To be diagnosed with ADD, one of several criteria to be met is that the inattentiveness must be negatively affecting the individual, usually socially and/or academically. With that said, many individuals struggle with attentiveness but fall short of the criteria necessary for a diagnosis of ADD.

boy daydreamingBefore we discuss focus issues in general, let’s look at ADD.

First of all, “Attention Deficit Disorder (ADD)” is a misnomer. These kiddos don’t have an issue with paying attention. They have an issue paying attention to what we want them to pay attention to. If you are the parent of a child with ADD or have ADD yourself (remember, the fruit doesn’t fall far from the tree), you know this to be true. Contrary to common belief, individuals with ADD actually have the ability to hyper-focus when they are engaged and interested. In fact, this ability to fixate and hyper-focus is one of the many strengths that accompany this style of thinking. The problem is that when it comes time to “pay attention” to something that is not of interest to them, we see their eyes glaze over as they venture off into their own self-created world of thought and imagination.

As parents, we have come to recognize this look often in our children, ADD or not. (Actually, sometimes we are guilty of this ourselves.)

[tweet “Have you wondered why your child can focus on their video game or TV but not school work?”]

For more info please visit our events schedule

So, the first question is this: What is focus?

Let’s start this conversation by defining the word focus.

The Oxford Dictionary defines focus as “an act of concentrating interest or activity on something.” The act of focusing, therefore, allows us to shift our attention onto a subject or activity without being distracted by our environment or our thoughts. This is an important skill to have. When we focus, our brain actually sees what our eyes are seeing and hears what our ears are hearing. When we are not focused, our brain sees what we think our eyes are seeing and hears what we think our ears are hearing. (That was a really important sentence, so if you didn’t get it, read it again.) When we bring information in while in a non-focused state, we misperceive what we are seeing or hearing.

How often has this happened to you when speaking to your child?

You: “Go upstairs and get your shoes. We are leaving in ten minutes.”

Ten minutes later, you find them watching television

You: “What are you doing? I said we have to leave.”

Your child: “You didn’t say that. You said I could finish my show.”

We think they are being disobedient, but often they actually heard what they thought they heard, not what was actually said. This is misperception and it is what happens when we take information in while in a non-focused state. Their perception of reality is just as true to them in that instance as yours is to you. So, you are now having a conflict from two separate realities. There is no winner in this case.

The next question is this: Can we teach someone to focus if they can’t do it naturally?

As parents, we find ourselves constantly telling our children to focus, concentrate, pay attention, stop fidgeting, and listen. But we often don’t teach them how.

How do you focus? Maybe you are focused on what you are reading here or maybe you drifted off and starting thinking about what to cook for dinner. If you wandered in your thoughts, come on back because this is important. How do you focus? Can you explain how you do it or what it feels like? You might be able to explain the feeling of being focused, but you probably can’t explain how you do it. You just do it.

boy daydreaming during schoolWhen our kiddos start a new sport or a new subject, we don’t expect them to know how to do it without giving them some instruction. But when it comes to focusing, we expect them to just somehow know how to do it on command. The majority of kids will figure this out on their own, but many won’t. If your child is super imaginative and creative, they may need some extra tools to help them consciously focus at will. And, if they don’t acquire some tools, they may start to struggle with some aspects of their life that can end up looking like dyslexia, AD(H)D, processing disorders, and so on.

In my practice, I specialize in working with gifted and talented individuals that struggle with the ability to bring their state of focus under their conscious control. There are several simple, tangible methods that we use in the office to empower children (as young as five years old) and adults with the ability to focus consciously in any given moment. With some guidance, most individuals can learn these techniques within an hour. As with any new tool, they must then practice using their new tool until it simply becomes part of their identity—just like riding a bike.

Here are some suggestions you can implement today

The Gift of Learning

Read the book The Gift of Learning by Ronald Davis. There are wonderful tools in the book that you can give your child to help them focus. These are the same tools I use in my office.

The Zone

Ask your child, “You know how you sometimes get in ‘the zone’ when you are [playing your video game, reading your book…]? You know how that feels?” Wait for the “yes” response. Then ask, “Can you get that feeling right now?” When they can do that, praise them and tell them, “That is focus. When people say focus, that is the feeling they are talking about.”

“Get your focus.”

When you need to tell your kiddo something, start by saying, “(name), I need to tell you something important. Can you get your focus?” Then give them the information and have them repeat it back to you. Saying their name first, and then having them get their focus will build a neural pathway that connects hearing their name with getting focused.

Take breaks.

When doing school work, let them take frequent breaks. Every twenty to thirty minutes is great.

Encourage movement.

Let them stand up, walk on a treadmill, bounce on a yoga ball, chew gum, tap on the table, pace back and forth, or whatever works for them to aid in focusing. Just as stimulants seem to calm the ADD brain (the opposite effect of their original intent) allowing for focus, the movement seems to do the same thing. The individual with ADD can feel calmer and focused when they are allowed to move.

Don’t have your kiddo look you in the eye.

The human face is extremely distracting because of the movements, expressions, and sounds when speaking. When you need to talk to them, get their initial attention by meeting their eyes, and then let them look away so they can process the information you are giving them.

These are just a few suggestions.

[tweet “As a child, Albert Einstein was “forever adrift within his dreams.” Yet he learned how to focus.”]

Remember, Albert Einstein’s teacher told his mother, “He is forever adrift within his dreams.” Albert learned to control his inattentiveness and changed the world with what he termed “thought experiments.”

All great things are created in the worlds of thought and imagination. Don’t stifle your child’s creativity and imagination. Support their strengths and empower them with tools to overcome their obstacles.

Searches Related to Homeschooling Curriculum Oak Glen, California


New Home Inspections

New Construction?

A new construction home can still have problems that you want to find before moving in. Remember that if you find the issue before closing, you can have the builder fix them before you close. Once you close on the home, any issues you find will be repaired by the warranty service for the builder, and that can sometimes take much longer.

We have seen holes in the roof, missing siding (usually on the second floor area where it cannot be seen from the ground), attic vents not vented to the exterior, ductwork that is not connected, plumbing backups due to construction material in the drains, missing insulation, and an array of other issues.


What are the most common mistakes made by scientists using technologies such as laser diffraction and dynamic light scattering to measure particle size?

How can these mistakes be avoided?

How can some of the most common causes of poor reproducibility be used to create experiments to validate your method?

This webinar will focus on the issues of unstable samples, poor backgrounds and poor analysis choices. None of these issues are complex, and awareness of potential issues and how to avoid them will result in significant improvements in the quality of your measurements.


Denver: Intro to Service Oriented Architecture w/ Julia Lee

This is a past event

38 people went

Location image of event venue

Service-based architectures have transformed the way web apps are built, so let's talk more about what makes them a powerful and fundamental concept for building scalable, reliable, and easy to build and maintain web applications! Never heard of a service? Curious to learn about when you should and shouldn't use one? Want to learn from Gusto's experience building out our first services (and when we chose to stick with the monolith)? Come join us!

Julia Lee

Hey there! My name is Julia and I am a full-stack developer in San Francisco working at Gusto, where I have the opportunity to combine my enthusiasm for tackling engineering challenges and building useful software that empowers people. Not sure how a payroll/hr/benefits platform empowers people? Just ask! In my time at Gusto, I've worked on building out our first services and laying foundation for inter-service communication during our shift toward a service-oriented architecture. My other interests include playing soccer and generally being active outside - I care deeply about the natural world and would love to chat if you have ideas for how software can be used to better protect our planet!

6:00-6:30 - Mingle, Eat/Drink, and Welcome/Housekeeping

6:45 - Presentation

Parking Suggestions

A block or so north on that same side of the road is a lot that allows cheaper parking after 6pm (I think either $2 or $4 for the evening). Before 6pm it is employee parking.

There is also street parking in the Highland neighborhood across the bridge or at the nearby park. There are plenty of 2 hour street parking, but there should also be spots for longer than that if you can find them.

Code of Conduct:


Ventilation Effectiveness - EQc2

Intent To provide additional outdoor air ventilation to improve indoor air quality (IAQ) and promote occupant comfort, well-being and productivity

Requirements For mechanically ventilated buildings, demonstrate a zone air distribution effectiveness (E3) greater than or equal to 0.9 as determined by ASHRAE 62-2004

For naturally ventilated spaces demonstrate a distribution and laminar flow pattern that involves not less than 90% of room or zone for 95% of hours of occupancy


Constantin Brancusi - Quotes

There are 11 quotes by Constantin Brancusi at Find your favorite quotations and top quotes by Constantin Brancusi from this hand-picked collection . Feel free to share these quotes and sayings on Facebook, Pinterest, Tumblr & Twitter or any of your favorite social networking sites.

Create like a god, command like a king, work like a slave. ---->>>

Architecture is inhabited sculpture.

Architecture is inhabited sculpture.

There hasn't been any art yet. Art is just beginning. ---->>>

They are imbeciles who call my work abstract. That which they call abstract is the most realistic, because what is real is not the exterior but the idea, the essence of things. ---->>>

Theories are patterns without value. What counts is action. ---->>>

Simplicity is not an objective in art, but one achieves simplicity despite one's self by entering into the real sense of things. ---->>>

Things are not difficult to make; what is difficult is putting ourselves in the state of mind to make them. ---->>>

What is real is not the external form, but the essence of things... it is impossible for anyone to express anything essentially real by imitating its exterior surface. ---->>>

To see far is one thing, going there is another. ---->>>

Don't look for obscure formulas or mystery in my work. It is pure joy that I offer you. Look at my sculptures until you see them. Those closest to God have seen them. ---->>>

Nationality: Romanian
Born: February 19, 1876
Birthplace: Hobița, Romanian United Principalities
Die: 03-16, 1957
Occupation: Sculptor


Updated Line Pointing at the SMT D. Muders, June 1998 Line pointing provides a possibility to check the telescope pointing during heterodyne observations on the left flange where no bolometer is available. It will be mainly used with the CO 2-1, 3-2 and 4-3 lines observed towards evolved stars. We use the list of sources compiled by C. Loup et al., A&AS, 99, 291, (1993). It contains 444 sources and it lists several names per source so that you should be able to use your favorite name. The Loup catalog is stored on the VAX computers in KDATA:[SMT.CAT]. There are two versions: LOUP1950.CAT (B1950 coordinates) and LOUP2000.CAT (J2000 coordinates). It is recommended to check also the papers about CO observations of evolved stars and Mira variables by Stanek et al. (ApJS, 100, 169, (1995)) and by Young (ApJ, 445, 872, (1995)). Copies of all these papers are provided in the "Submillimeter Calibration" folder in the control room. Although the Loup catalog contains 444 sources, not all of them are suited for line pointing. Some are too weak, others are extended in CO (e.g. IRC+10216). Be careful about choosing sources. Stanek et al. provide some sample CO maps to estimate the source sizes. The SMTO provides a special catalog with sources that have been checked to be OK for line pointing. This catalog is KDATA:[SMT.CAT]LPOINT.CAT. It has also been converted to Xephem's EBD format and the sources can be displayed in the XEPHEM window by selecting KDATA:[SMT.CAT]LPOINT.EDB as the objects database. Line pointing is implemented via the LPOINT (On-Off) and LWPOINT (Wobble- switched) commands in OBST. It sets up an observation of a cross of N On/Off type measurements per axis (azimuth / elevation) relative to a given reference position. The syntax is similar to the POINT and PSWITCH/WSWITCH commands, e.g. LPOINT -120 0/NUM 3/TIME 15 15/LEN 50/ON 3/BE AOSB or LWPOINT -120 0/NUM 3/TIME 15 15/LEN 50/ON 3/BE AOSB would observe 3 points on each arm spaced by 25" with a reference point at (-120",0"). The integration time per point is 15 seconds. The /ON 3 qualifier tells LPOINT to observe 3 ON's per OFF (recommended under good weather conditions, /ON 2 or /ON 1 otherwise). See HELP LPOINT or HELP LWPOINT in OBST for more details. The /BE adverb selects the backend to be used for the fit. It must be one of the backends currently enabled by the BACKEND command. Preferably, one of the broadband AOS (AOSA or AOSB) should be used to avoid virtual memory problems in VAX CHEF. The default at startup is "*" which means all enabled backends would be used. This is not recommended since it would lead to resampling to the smallest bandwidth (e.g. 8 MHz for the 62.5 kHz part of the filterbanks), thus making fits impossible for the typical line widths seen in the CO stars. One can, however, select individual parts of the filterbank to be used in the line pointing fits. The names are FBSA for the 62.5 kHz part, FBSB for the 250 kHz part and FBSC for the 1 MHz part. The LPOINT observation is reduced and displayed in the online display (CHEF). It subtracts a baseline of order 1 off all spectra and calculates the line area. It needs source specific velocity windows to do that. Those windows are specified in the catalog using the four new OBSINP commands VLOW, VHIG, WLOW and VHIG. VLOW and VHIG define a window for the baseline calculation (like SET MODE X in CLASS). This is necessary because of edge effects (e.g. isolator in the SIS230). The second pair (WLOW, WHIG) defines a line window for the area calculation (like SET WINDOW in CLASS). The Loup catalogs already contain those velocities. If you want to use your own catalog you must provide those parameters. A typical line in the catalog would be: SNAM=o Cet ; SLAM=02 16 49.11S; SBET=-03 12 22.4; - VLSR=+47; VLOW=-14; VHIG=108; WLOW=36; WHIG=58; Note the dash at the end of the first line. This is the continuation character. The head of that catalog section must contain the extra parameters: COMMON: SBAS=1 INDIVIDUAL: SNAM SLAM SBET VLSR VLOW VHIG WLOW WHIG CHEF writes those velocity windows are written in the CLASS spectrum header so that they can later be used for the fit. The online CHEF mails the fit results to OBST where they can be used with CORRECTION F F, etc. like with a continuum pointing. The new LPOINT command in CHEF does the fitting and mailing. It can also be used offline for later analysis (e.g. using baselines of different order or different velocity intervals). The syntax is: LPOINT [[[[[[[[|*] ] ] ] ] ] The starting scan number must be given, the other parameters are optional. One can specify a range of scan numbers to sum several scans for better signal-to-noise ratio. Currently, it is not possible to sum scans with different COL*/NULE values. That means that one can not take the corrections between scans. A "*" tells LPOINT to use wildcards (scan number range) or to fetch the velocties from the header, take a baseline of order 1 and to use all available backends. LPOINT expects the line pointing spectra in the current input file opened by FILE IN in CHEF. The backend name can be either the names used in LPOINT and LWPOINT (AOSA, AOSB, AOSC, FBSA, FBSB and FBSC) or the "TELESCOPE" names used in CLASS (SMT-10M-B30, SMT-10M-B40, SMT-10M-B50, SMT-10M-B71, SMT-10M-B72 and SMT-10M-B73).