December 2024: New In Coagulation
by Donna Castellone • December 11, 2024
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Heart Attack Patients Who Receive Heparin ASAP Are Better Primed for Cath Lab
It has been determined that patients who are pretreated with a loading dose of unfractionated heparin as early as possible had a better likelihood of Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 of the infarct-related artery at diagnostic angiography before primary PCI compared with those who received it later in the cath lab according to the HELP PCI trial. Results were consistent across subgroups with no increased risk of major bleeding. However, the incidence of MACCE at 1 year were no different between early and late groups. But additional endpoints such as a reduced 30 day rate of MACCE was seen in the early pretreated UFH group as well as fewer heart failure hospitalization.
The study included 999 patients (18-80 with a median age of 59-60 years) 82% were men, and 43% had a history of smoking. All presented with STEMI and symptoms within 12 hours and were randomized to heparin given at first contact or in the cath lab. Both groups received aspirin and a P2Y12 inhibitor at full dose. Those who were excluded had CPR before randomization, a mechanical complication of myocardial infarction, active bleeding, and history of coronary artery bypass grafting surgery or heparin-induced thrombocytopenia.
The study was conducted at 36 centers in China and participants have been referred directly to these PCI capable hospitals. Heparin was from symptom to administrate 3.10 hours in the late group versus 2.85 in the early group. First medical contact to heparin time was 71 versus 35 minutes, and heparin to wire time was 12 versus 37 minutes. The antiplatelet ticagrelor was given to most patients.
New Data on DOAC Initiation After Stroke in AF: Final Word?
The OPTIMAS trial demonstrated that the initiation of a DOAC within 4 days post ischemic stroke associated with AF was noninferior to delayed initiation (7-10 days) for the composite outcome of ischemic stroke, intracranial hemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Also, there was a low rate of symptomatic hemorrhage regardless of stroke severity.
CATALYST was a meta-analysis that looked at four trials (TIMING, ELAN, OPTIMAS, and START) concerning this issue which showed a clear benefit of earlier initiation meaning within 4 days. These results are in contrast with current guideline recommendations of delaying DOAC initiation. A distinct advantage of early initiation is that patients will start prior to discharge ensuring the medication is prescribed.
AF accounts for 20-30% of ischemic strokes which are more severe than other stroke types. There were no pivotal trials of DOACs that did not include patients within 30 days of this type of stroke therefore it was unclear of when to begin treatment without the risk of ICH. The trial was conducted at 100 hospitals in the UK including 3648 AF patients randomly assigned to early (< 4days) or delayed (4-10 days) initiation of a DOAC. There was no restriction regarding stroke severity and patients with hemorrhagic transformation were allowed. Up to 35% of patients were taking a DOAC prior to stroke and 30% had revascularization with thrombolysis, thrombectomy or both. Up to 25% had moderate to severe stroke. Primary outcome occurred in 3.3% of both groups (composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days). Symptomatic ICH occurred in 0.6% in the early group versus 0.7% in the delayed group which was non-significant. One of the strengths of the trial was the large sample size and a broad population including patients at a higher bleeding risk allowing generalizability to the real world. It is possible that patients presenting with severe stroke may have a greater benefit with early initiation.
Thrombolysis Beneficial for 'Eye Stroke'?
The THEIA trial showed that thrombolysis used to treat central retinal artery occlusion or eye stroke appeared to improve visual acuity compared with oral aspirin, but was not statistically significant. There was improvement in the ability to read more of the vision group, and the aspirin control did better than expected, but the study was clearly underpowered, however there are 2 more ongoing trials. There were 17% of patients who received visual recovery in the alteplase arm.
Damage from central retinal artery occlusion is a rare event that causes severe vision loss in one eye and damage becomes irreversible after 4 hours and needneeds to be treated quickly. Up to one third of patients have a simultaneous asymptomatic hemispheric ischemia and are at an increased risk for further stroke. Prior results from studies using thrombolysis have been negative and showed a risk for ICH. But a meta-analysis suggested benefits if patients were treated within 4.5 hours.
THEIA was conducted at 16 centers in France, (n=70) occurrence was confirmed by an ophthalmologist and then referred to a stroke unit. They were randomized to receive either a standard dose of IV alteplase plus oral placebo or IV placebo plus oral aspirin. The primary outcome was improvement of visual acuity at 1 month. Both groups showed improvement 48.1% of the aspirin group and 65.5% of the thrombolysis group, however the OR of 1.10 was not statistically significant.
PRECISE-DAPT Score Predicts GI Bleeding Risk Among Post-PCI Patients
Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) should help to determine GI bleeding post PCI in patients on dual antiplatelet therapy. This remains a risk procedure in terms of morbidity and mortality. Using this bleeding score can predict GI bleeding among high and moderate risk patients. Guidelines from the American College of Cardiology and AHA recommend DAPT for 6-12 months post PCI, and possible shorter times in patients with lower ischemic risks but higher bleeding risks.
A retrospective study of patients on DAPT post PCI was conducted from 2014-2021 and looked at GI bleeding rates at 1 year. The PRECISE-DAPT score was evaluated as to it's predictive value. This categorizes patients based on low risk (≤ 17), moderate risk (18-24), and high risk (≥ 25) for bleeding. The score aims to optimize the balance between bleeding and ischemic risks. It looked at five criteria: age, creatinine clearance, hemoglobin, white blood cell count, and history of spontaneous bleeding.
The study looked at 1067 patients with a mean age of 62 in which 66.6% were male and 77.1% Hispanic. Of those 57.9% received clopidogrel and 42% received ticagrelor. In a median follow up of 2.2 years the GI bleeding rate was 2.5% at 1-year post-PCI among 27 patients and 3.7% for the study duration among 39 patients (41% were lower GI bleeds, 28% were upper GI bleeds, 15% were small bowel bleeds, and 15% were undetermined). There was no significant difference in patients on clopidogrel and ticagrelor. The majority of patients without GI bleeding had scores < 17, whereas the majority of patients with GI bleeding had scores > 24.
Big Blow to Anticoagulation Strategy Against Afib-Related Cognition Problems
The BRAIN-AF trial was stopped early (3.7 years versus 5 years) due to the failure to prevent cognitive impairment in people with existing AF by using anticoagulation to mitigate subclinical brain infarcts. Results showed a similar risk of cognitive decline, stroke or TIA whether AF patients with a low risk of stroke were assigned a lower dose of rivaroxaban or placebo. There was also no harm such as major bleeding. It remains unclear how cognition related to AF and whether they coexist due to shared risk factors. If the cause was from microemboli to the brain then the anticoagulation would be expected to work but this may only be one mechanism.
The study as conducted at 53 sites across Canada from 2015-2023 and included 1235 AF patients with an average age of 53 (30-62) with a low risk of stroke. A quarter of the patients were women and 95% were white. Participants were randomized to 15mg rivaroxaban or placebo. There was a low incidence of stroke of 0.8% across the whole cohort. Cognitive decline was by far the most common outcome (91.4%), with stroke (5.1%) and TIA (3.5%) less frequent.
Emerging AF treatment should incorporate measures of cognition from the start.
Is DOAC a Viable Option After Bioprosthetic Valve Surgery Even in Sinus Rhythm?
A trial ENBALV demonstrated that edoxaban was on par with warfarin as a 12 week thromboembolic prophylaxis after bioprosthetic valves surgical implant. The study was conducted in Japan on a population in sinus rhythm, but due to small numbers the results were inconclusive.
The trial included 410 patients (18-85) who had a bioprosthetic aortic or mitral valve or both. Those at a high bleeding risk were excluded but patients could have either sinus rhythm or AF (20%) and 17% were on anticoagulant prior to the trial. Patients were randomized for 12 weeks to either daily 30 or 60 mg edoxaban or daily warfarin. Treatment could be continued as per physician and follow up was a median of 98 days. Patients were only in the therapeutic range in the warfarin group about 19% of the time.
There was a lower rate of the primary outcome of stroke or systemic embolism at 0.5% compared with 1.5% on warfarin, but that was only 1 event versus 3 over 12 weeks. Major bleeding occurred in 4.1% of edoxaban patients versus 1.0% of warfarin patients with one fatal ICH in the warfarin group. An advantage of edoxaban is that it does not require frequent blood testing and could be an alternative for clinical use.
Guidelines recommend 3-6 months of anticoagulation post replacement but only warfarin is recommended and approved for this group of patients with sinus rhythm. More work is needed to establish DOAC as a treatment option in particular in managing bleeding.
Thrombectomy Tops Thrombolysis in Pulmonary Embolism Trial
The PEERLESS study (n=550) looked at large-bore mechanical thrombectomy compared to catheter-directed thrombolysis for pulmonary embolism which was found to be superior. This was despite the rates of mortality, major bleeding or ICH were similar however differences were seen in clinical deterioration and ICU admission. Patients given thrombolysis were three times more likely to experience clinical deterioration including cardia arrest, respiratory failure, and hypotension. The ICU admission rate was 90 fold higher as well as the rate for longer than 24 hour admission was two times higher. However ICU admission for PE is driven by local practice as well as a protocol in place for thrombolysis.
Patients undergoing thrombectomy had less dyspnea as well as a shorter postprocedural length of stay (3.3 vs 4.0 days) and a shorter total hospital stay (4.5 vs 5.3 days).
Lack of Clinical Benefit of Andexanet Flummoxes FDA Panel
The ANNEXA-1 trial demonstrated that Andexanet alfa has the ability to control hematoma volume change at 12 hours in DOAC users with ICH. Andexanet is a recombinant modified human FXa protein that binds FXa inhibitors to restore thrombin generation. Patients were randomized to either a high or low dose regimen based on their last dose of DOAC. The primary endpoint was a composite of expansion of hematoma by 35% or less. However FDA advisors questioned if this was meaningful without other supporting evidence of clinical benefit.
The trial showed that the drug helped people with acute ICH on FXa inhibitors which was its main benefit, but there was no benefit seen in improving neurologic status or survival. It is clear the drug works, but there was no evaluation of how a patient feels, functions or survives and there may be an increase in thrombosis. Up to 14.6% of patients at day 30 presented with thrombotic events. This is compared with 6.9% of patients receiving PCC with death resulting in 2.5% versus 0.9% respectively.
Presently, adexanet has accelerated approval based on the initial study in 2018, they are waiting for full approval. PCC are used without any approval. Andexanet still holds the indication of reversal of rivaroxaban or apixaban.
For AF, LAA Rivals Anticoagulants After Ablation
The OPTION trial demonstrated that a left atrial appendage (LAA) closure device provided thromboembolic protection equivalent to DOAC post alation for AF as well as a lower risk of bleeding. Making it an option for first line treatment. This was an open label study conducted in 106 sites in 10 countries, in 1600 AF patients at a moderate risk of stroke with a planned ablation. Average age was 69 and one third were women. Up to 10% had a previous stroke or TIA. There were 803 patients randomized to LAA closure, 9 were unsuccessful and 41 did not receive the device. The LAA group were treated with the WATCHMAN FLX and compared to the DOAC group. Up to 40% of this group also underwent ablation. Rates of primary efficacy composite endpoint at 36 months including death from any cause (3.8% vs 4.5%), stroke (1.2% vs 1.3%), and systemic embolism were similar (5.3% vs 5.8%) establishing significance and noninferiority. There were 92% of patients who completed the follow-up. Bleeding rates were lower in the LAA closure group (8.5% vs 18.1%). Anticoagulation was discontinued in the LAA closure group after 90 days in 80% of this cohort and fewer patients remained on anticoagulation in this group (10.1% vs 84.8%).
JOURNAL CLUB
Derivation and Validation of the PRECISE-HBR Score to Predict Bleeding After Percutaneous Coronary Intervention
David van Klaveren, Dik Heg, Lorenz Räber, Mitchell W. Krucoff, Sergio Raposeiras-Roubän, Jurriën M. ten Berg and Marco Valgimigli
Abstract
Background: Accurate bleeding risk stratification after percutaneous coronary intervention (PCI) is important for treatment individualization. However, there is still an unmet need for a more precise and standardized identification of high bleeding risk patients. We derived and validated a novel bleeding risk score by augmenting the PRECISE-DAPT score with the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria.
Methods: The derivation cohort comprised 29,188 patients undergoing PCI, of whom 1136 (3.9%) had a Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding at 1 year, from four contemporary real-world registries and the XIENCE V USA trial. The PRECISE-DAPT score was refitted with a Fine-Gray model in the derivation cohort and extended with the ARC-HBR criteria. The primary outcome was BARC 3 or 5 bleeding within 1 year. Independent predictors of BARC 3 or 5 bleeding were selected at multivariable analysis (p<0.01). The discrimination of the score was internally assessed with apparent validation and cross-validation. The score was externally validated in 4578 patients from the MASTER DAPT trial and 5970 patients from the STOPDAPT-2 total cohort.
Results: The PRECISE-HBR score (age, estimated glomerular filtration rate, hemoglobin, white-blood-cell count, previous bleeding, oral anticoagulation, and ARC-HBR criteria) showed an area under the curve (AUC) for 1-year BARC 3 or 5 bleeding of 0.73 (95% CI, 0.71–0.74) at apparent validation, 0.72 (95% CI, 0.70–0.73) at cross-validation, 0.74 (95% CI, 0.68–0.80) in the MASTER DAPT, and 0.73 (95% CI, 0.66–0.79) in the STOPDAPT-2, with superior discrimination than the PRECISE-DAPT (cross-validation: Δ AUC, 0.01; p=0.02; MASTER DAPT: Δ AUC, 0.05; p=0.004; STOPDAPT-2: Δ AUC, 0.02; p=0.20) and other risk scores. In the derivation cohort, a cut-off of 23 points identified 11,414 patients (39.1%) with a 1-year BARC 3 or 5 bleeding risk ≥4%. An alternative version of the score, including acute myocardial infarction on admission instead of white-blood-cell count, showed similar predictive ability.
Conclusions: The PRECISE-HBR score is a contemporary, simple 7-item risk score to predict bleeding after PCI, offering a moderate improvement in discrimination over multiple existing scores. Further evaluation is required to assess its impact on clinical practice.
Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial
Xia Meng, MD; Shuya Li, MD; Hongguo Dai, MD; etalGuozhi Lu, MD; Weiwei Wang, MD; Fengyuan Che, MD; Yu Geng, MD; Minghui Sun, MD; Xiyan Li, MSc; Hao Li, PhD; Yongjun Wang, MD
Abstract
Importance Tenecteplase is a bioengineered variant of alteplase with greater fibrin specificity and a longer half-life, allowing single-bolus administration. Evidence on the treatment effect of tenecteplase 0.25 mg/kg in Chinese patients with acute ischemic stroke (AIS) is limited.
Objective To establish the noninferiority of tenecteplase to alteplase in patients with AIS within 4.5 hours of symptom onset.
Design, Setting, and Participants The ORIGINAL study was a multicenter, active-controlled, parallel-group, randomized, open-label, blinded end point, noninferiority trial conducted between July 14, 2021, and July 14, 2023. Participants were recruited from 55 neurology clinics and stroke centers in China and were eligible if they had AIS with a National Institutes of Health Stroke Scale score of 1 to 25 with measurable neurologic deficit and were symptomatic for at least 30 minutes without significant improvement.
Interventions Patients were randomized (1:1) within 4.5 hours of symptom onset to receive intravenous tenecteplase (0.25 mg/kg) or intravenous alteplase (0.9 mg/kg).
Main Outcomes and Measures The primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 (no symptoms or no significant disability) at day 90, tested for noninferiority (risk ratio [RR] margin, 0.937). Safety end points included symptomatic intracerebral hemorrhage (per European Cooperative Acute Stroke Study III definition) and 90-day all-cause mortality.
Results Among the 1489 patients randomized, 1465 patients were included in the full analysis set (732 in the tenecteplase group; 733 in the alteplase group) and 446 (30.4%) were female. The primary outcome occurred in 72.7% (532/732) of patients receiving tenecteplase and 70.3% (515/733) receiving alteplase (RR, 1.03 [95% CI, 0.97-1.09]; noninferiority threshold met). Symptomatic intracerebral hemorrhage occurred in 9 patients (1.2%) in each group (RR, 1.01 [95% CI, 0.37-2.70]). The 90-day mortality rate was 4.6% (34/732) in the tenecteplase group and 5.8% (43/736) in the alteplase group (RR, 0.80 [95% CI, 0.51-1.23]).
Conclusions and Relevance In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was noninferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile. Findings from this study support tenecteplase as a suitable alternative to alteplase in this setting.
Anti-factor Xa and activated partial thromboplastin time strategies for unfractionated heparin dosing after HeartMate 3 left ventricular assist device implantation
Iris Feng , Paul A Kurlansky, Tanner R Powley, Melissa A Hynds, Christine G Yang, Andrew Eisenberger, Jonathan M Hastie, Lauren D Sutherland, Melana Yuzefpolskaya, Paolo C Colombo, Gabriel T Sayer, Nir Y Uriel, Yoshifumi Naka, Koji Takeda
Artif Organs, 2024 Oct 8.
Abstract
Background: No clear guidelines exist for perioperative anticoagulation management after durable left ventricular assist device insertion. In this study, we sought to compare outcomes between anti-factor Xa (FXa) and activated partial thromboplastin time (aPTT) in monitoring unfractionated heparin (UFH) dosing after HeartMate 3 (HM3) insertion.
Methods: This is a single-center retrospective review of patients who received UFH after HM3 insertion between 01/2020-12/2022. Post-operative UFH dose was titrated by aPTT goal 45-60 sec (n = 53) or FXa goal 0.1-0.2 U/mL (n = 59). Baseline differences between cohorts were balanced by inverse probability treatment weighting.
Results: At baseline, unadjusted FXa patients were more likely to be white (47.5% vs. 35.8%, p < 0.001), INTERMACS 1-2 (69.5% vs. 47.2%, p = 0.013), have history of coronary artery disease (66.1% vs. 43.4%, p = 0.026), and lower eGFR (54.1 vs. 63.7 mL/min/1.73 m2, p = 0.029) compared to the aPTT group. After adjusting for several bleeding/thrombosis risk factors, 97.5% of FXa and 91.0% of aPTT patients reached therapeutic levels with comparable UFH duration and maximum dose. Moreover, in-hospital mortality (2.5% vs. 3.1%, p = 0.842), major bleeding events (4.2% vs. 9.2%, p = 0.360), and thromboembolic events (21.8% vs. 10.1%, p = 0.151) remained without significant differences between FXa and aPTT cohorts. There was a high degree of variability in FXa (r2 = 0.20) and aPTT (r2 = 0.22) values for any given UFH dose.
Conclusions: No differences in frequency of bleeding or thromboembolic events were observed in this study between FXa versus aPTT cohorts after HM3 implantation. More longitudinal studies are warranted to determine whether or not one assay is superior to the other.
Anticoagulation Monitoring Using Activated Clotting Time in Patients Receiving Extracorporeal Membrane Oxygenation: A Meta-Analysis of Correlation Coefficients
Sasa Rajsic , Daniel Schwaiger, Lukas Schausberger, Robert Breitkopf, Benedikt Treml, Dragana Jadzic, Christoph Oberleitner, Zoran Bukumiric
J Cardiothorac Vasc Anesth, 2024 Nov;38(11):2651-2660
Abstract
Design: Systematic literature review and meta-analysis of correlation coefficients (Scopus and PubMed, up to July 13, 2024).
Prospero: CRD42023448888 SETTING: All retrospective and prospective studies PARTICIPANTS: Patients receiving ECMO support INTERVENTION: Anticoagulation monitoring during ECMO support MEASUREMENTS AND MAIN RESULTS: Nineteen studies were included in the analysis, and the meta-analysis encompassed 16 studies. The vast majority of studies (n = 15) found a weak correlation, and no study reported a strong correlation between ACT and UFH infusion dose. The meta-analysis (n = 12,625 samples) identified a weak correlation, with a pooled estimate of correlation coefficients of 0.132 (95% confidence interval 0.03-0.23). The most common adverse events were hemorrhage (pooled incidence, 45%) and thrombosis (30%), and 47% of the patients died during their hospital stay.
Conclusions: Even though ACT is a widely used UFH monitoring tool in ECMO patients, our meta-analysis found a weak correlation between ACT and UFH infusion dose. New trials are needed to investigate the role of emerging tools and to clarify the most appropriate monitoring strategy for patients receiving ECMO support.
Transitioning between therapeutic anticoagulants: a clinicians guide to switching patients to or from DOAC therapy
Benilde Cosmi, Michelangelo Sartori
Expert Rev Cardiovasc Ther, 2024 Oct;22(10):589-602.
Abstract
Introduction: The transition to or from direct oral anticoagulants (DOACs) is common in clinical practice.
Areas covered: A literature search was conducted on PubMed, Google Scholar, and UpToDate up to March 2024 for conditions and approaches for transitioning from one agent to the other. No randomized clinical trials were retrieved except for two studies regarding switching to DOAC in well-conducted vitamin K antagonist (VKA) therapy. A narrative review was conducted addressing the conditions for switching from one agent to the other, such as thromboembolic events and major bleeding during anticoagulation, development or worsening of kidney or liver failure, initiation of interfering drugs, adverse events such as allergic reactions, frailty, patients' preferences, and affordability. During transitions from one anticoagulant to the other, the risk of both thromboembolic and bleeding complications should be minimized. The current approaches for such transitions are derived from those employed in clinical trials evaluating DOAC and from product information.
Expert opinion: Many uncertainties remain regarding those circumstances requiring a change in anticoagulant strategies, as they lack evidence-based guidance. It can be envisaged that the problem of switching to and from DOAC will need additional studies especially addressing the conditions and the best approach to such transitions.
Prothrombin complex concentrate for direct factor Xa inhibitor-associated bleeding or before urgent surgery
Abstract
Introduction: Factor Xa inhibitor (FXaI)-associated bleeding events are common and associated with substantial morbidity. Systematic evaluation of widely available, effective, and affordable FXaI bleed management strategies is needed.
Materials and methods: We conducted a single-center retrospective cohort study of FXaI-treated patients presenting to a tertiary academic medical center from January 2018 to May 2019 who received 25-50 IU/kg 4F-PCC for either FXaI-associated major bleeding or urgent surgery. The primary outcome was hemostatic efficacy, and the safety outcome was the 30-day risk of thromboembolism.
Results: PCC was used to treat FXaI-associated bleeding in 83 cases (79.1%) and was given before urgent surgery in 22 cases (20.9%). Sixty-six patients were on apixaban, 38 were on rivaroxaban and one patient was on edoxaban. Intracranial hemorrhage (ICH) and gastrointestinal bleeding accounted for most bleeds (74.7%). Median interval between last DOAC intake and presentation to triage was 9 h [IQR 5.3-14.8] and median PCC dosing was 40.0 IU/kg [IQR 28.5-46.6]. Forty-two patients (40.0%) had pre-PCC FXaI levels drawn with median FXaI levels of 114.5 ng/mL [IQR 70.0-175.0]. Effective hemostasis occurred in 66.7% [95%CI 55.4-76.3] of patients receiving PCC for bleeding and surgical hemostasis was rated as normal in 95.5% (95%CI 76.5-100.0) for patients having urgent surgery. The 30-day risk of thromboembolism was 7.6% [95%CI 3.7-14.5] and 22.9% [95%CI 15.8-31.8] of patients died.
Conclusions: PCC for FXaI-associated bleeding was associated with hemostatic efficacy in two-thirds of patients and thromboembolic events were uncommon. PCC represents a promising treatment strategy for FXaI-associated bleeding.
Limitations of a platelet count-based clinical decision support system to facilitate diagnosis of heparin-induced thrombocytopenia
Brian C Westbrook, Laura J Taylor, Eric Wallace, Marisa B Marques, Jori E May
Thromb Res 2024 Nov:243:109171.
Abstract
Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin exposure with potential for significant morbidity and mortality. Early identification and treatment can prevent catastrophic thrombosis. Herein, we report the performance of a platelet count-based clinical decision support system (CDSS) where providers received a notification when a patient had a platelet count decline of ≥50%. In the 90-day study period, the CDSS sent 302 notifications on 270 patients. Notifications were frequently inappropriate; 25% had an expected platelet count decline (organ donation, stem cell transplant), an inaccurate count, or no heparin exposure. Patient testing for HIT prompted by the CDSS was not in accordance with best practice guidelines in most circumstances. For example, 36% had a low probability 4Ts score, while 42% with an intermediate or high probability 4Ts score were not tested. Due to concern for lack of efficacy, the CDSS was discontinued. Analysis of an 8-month period before and after discontinuation showed a significant decrease in the number of enzyme immunoassays ordered (547 vs. 386) without a change in the number of patients with HIT identified (13 vs. 13) or the rate of thrombosis in those with confirmed HIT (62% vs. 62%). In conclusion, a CDSS based on platelet count decline contributed to "alert fatigue" via inappropriate notification and did not improve evidence-based HIT testing. In addition, its removal did not decrease or delay HIT identification. Additional efforts are needed to better define how CDSS can support the rapid diagnosis and appropriate treatment of patients with HIT.
Discovery of a new lead molecule to develop a novel class of human factor XIIa inhibitors
Anthony Dumas, Navneet Goyal, Madhusoodanan Mottamal, Daniel K Afosah, Rami A Al-Horani
J Thromb Thrombolysis 2024 Nov 1.
Abstract
Factor XIIa (FXIIa) is a plasma serine protease within the contact activation pathway. Inhibiting FXIIa could offer a viable therapeutic approach for achieving effective and safer anticoagulation without the bleeding risks that accompany the use of existing anticoagulants. Therefore, we investigated the anticoagulant properties of an amidine-containing molecule (inhibitor 1) to identify a potential lead molecule for subsequent development of FXIIa inhibitors. Results indicated that inhibitor 1 primarily inhibits human FXIIa with an IC50 value of ~30 µM. The inhibitor demonstrated variable selectivity against thrombin, factor IXa, factor Xa, factor XIa, and activated protein C. Michaelis-Menten kinetics indicated that the molecule is an active site inhibitor of FXIIa. Molecular modeling studies revealed that the molecule recognizes residues His57, Asp189, and Ala190 in FXIIa's active site. The inhibitor selectively and concentration-dependently prolonged the clotting time of human plasma under activated partial thromboplastin time assay conditions. The inhibitor did not exhibit significant cytotoxicity in human HEK293 cells and the in silico pharmacokinetics and toxicology data were comparable to known anticoagulants. This study introduces inhibitor 1 as a lead platform for further development as an anticoagulant to provide a more effective and safer approach to preventing and treating thromboembolic diseases.