November 2024: New In Coagulation
by Donna Castellone • November 05, 2024
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Marstacimab Gets FDA Nod for Hemophilia A or B Without Inhibitors
A prophylactic treatment, marstacimab (Hympavzi), was approved by the FDA to reduce or prevent bleeding episodes in hemophilia A and B patients over the age of 12 that did not have inhibitors. It works by targeting the Kunitz 2 domain of tissue factor pathway inhibitor (TFPI), a natural anticoagulation protein that functions to prevent the formation of blood clots and restore hemostasis. It is the first anti-TFPI approved in the U.S. for the treatment of hemophilia A or B. Approval was granted based on the phase III BASIS trial. This included 116 adult and pediatric male patients (severe hemophilia A or B). Patients (n=33) received usual care with replacement factor on demand or (n=83) received prophylaxis. They were then followed up with marstacimab prophylaxis for 12 months. The annualized bleeding rate (ABR) for treated bleeds fell from a mean of 38 in the observational period to 3.2 after being treated with marstacimab. This resulted in a 91.6% reduction in rate during the 12 month active treatment period.
Among those who had received routine prophylaxis as usual care, the ABR fell from a mean of 7.85 during the observational period to 5.08 after treatment with marstacimab, translating into a 35.2% reduction in mean ABR.
AFib Linked to Severe Adverse Events After UACDT for Thrombolysis
A tool in treating PE is ultrasound-assisted catheter-directed thrombolysis (UACDT). This is a pharmacomechanical system that uses catheter-delivered ultrasound waves to blood clots to enhance delivery of thrombolytic agents. It was found to have serious adverse outcomes in patients with AF. In a retrospective review of cases (2016-2021), results showed that patients with AF were more likely to have acute respiratory failure, shock or bleeding complication with any clot dissolving procedure.
In 6430 cases, 645 patients had AF (51.9% male, ¾ white) with a mean age of 67.4 with significantly more comorbidities. Patients with AF were at a threefold higher risk of bleeding and a higher likelihood of acute kidney injury. These patients are on anticoagulation and changing it may make a difference. Also it was recommended to test patients for as antidrug antibodies or mutations in MTHFR, the gene that encodes for methylenetetrahydrofolate reductase.
The study limitations included the use of coding information which can be inaccurate with regard to medication, treatment or death after discharge.
The Role of Genomics in ITP
ITP is an acquired autoimmune disorder, but there may be a hereditary component since in some families multiple members have ITP. In patients who have a hereditary platelet disorder do not have ITP, their low platelet count is due to an underlying condition versus 'primary ITP or 'secondary ITP'. This is where the low platelet count is due to an immune attack on platelets. A group of medical conditions known as inborn errors of immunity (IEI) or primary immune dysregulation (PIRD) that can cause secondary ITP. This can be due to change in the genome that can impact the immune system and can cause secondary ITP rather than infection.
SNPs or single nucleotide polymorphisms, can cause variations in genes and may be more common in patients with chronic or refractory ITP. There are several studies that are looking at the association between immune function and ITP in both pediatric and adult patients. This suggests that all pediatric patients with chronic ITP should be screened for an IEI or autoinflammatory disease.
Heavy Menstrual Bleeding in ITP
One in five people have heavy menstrual bleeding (HMB). This is defined as a period lasting longer than 7 days, soaking through one or more pad or tampon every hour for several hours, doubling up with pads and tampons, passing clots larger than a quarter. This can be caused by irregular ovulation, fibroids, medication effects, infection and bleeding disorders including ITP.
The i-WISh study was a cross- sectional survey study that included 1507 patients in 13 countries, which 65% were female of those 40% reported HMB at ITP diagnosis and of those 80% stated symptoms were severe. They did not find a correlation between platelet count and HMB. However, many studies did not have a well defined definition of HMB.
In addition to treating ITP, in patients with HMB additional treatments may include Tranexamic Acid or estrogen/progestin pill or progestin IUD.
Superficial Venous Thrombosis for Primary Care Physicians
Superficial vein thrombosis (SVT) (previously called superficial thrombophlebitis) has an underlying pathology of thrombus formation in a superficial vein with additional surrounding inflammation of the vessel wall rather than infection of the vein. The saphenous veins and branches of the lower limbs are most affected. SVT is presented in primary care at a rate of 10%, however treatment is poorly defined. Antibiotics have no role, unless there is infection of cellulitis.
Diagnosis of SVT include pain, warmth, redness and swelling and a palpable cord is present suggesting presence of a thrombus. Recurrent SVT at different sites, can be associated with underlying malignancy called Trousseau syndrome. If SVT is in the subcutaneous fat of the breast in can be associated with breast cancer and called Mondor disease. Risk factors for SVT include malignancy, immobilization, inherited thrombophilia, similar to those for DVT and PE. Up to 1 in 5 patients with SVT are found to have DVT and 4% will have an associated PE. Patients presenting with below the knee SVT are at a low risk for thrombosis and can be managed with anti-inflammatory therapy and compression hose.
Anticoagulant is recommended in patients with a high risk that could progress to DVT and possible PE. Guidelines for antithrombotic therapy for vascular disease recommend prophylactic doses of fondaparinux or rivaroxaban for 45 days in particular in patients with an SVT length greater or equal to 5 cm and over 3 cm from the saphenofemoral or saphenopopliteal junctions.
Stroke Survivors With Afib Could Start DOACs Earlier
The OPTIMAS trial determined it is safe to start DOAC therapy without delay after acute ischemic stroke in people with AF. Stroke survivors were randomized to early or delayed DOAC and had the same recurrent rate of 3.3% at 90 days as well as a very low incidence of ICH (0.6% vs 0.7%). These results do not support the recommendation of current guidelines for delaying OAC to 14 days in this cohort due to the risk of ICH. Share on Facebook. Opens in a new tab or window.
OPTIMAS was a multicenter open-label trial of 3621 patients with a mean age of 78.5. Included were 45.3% women and 93.7% were white. It was conducted at 100 U.K. hospitals from 2019 to 2024. Patients were survivors of acute ischemic strokes related to Afib and were randomized to early or late DOAC administration (apixaban or edoxaban). Early administration occurred at 3.1 days and the later group as 8.3 days. Patients were excluded if they had a coagulopathy, parenchymal hematoma type 2 or increased bleeding risk.
JOURNAL CLUB
Routine Protamine Administration for Bleeding in Transcatheter Aortic Valve Implantation
The ACE-PROTAVI Randomized Clinical Trial
Pieter A. Vriesendorp, MD, PhD, MSc; Shane Nanayakkara, MBBS, PhD; Samuel Heuts, MD, PhD; Jocasta Ball, PhD; Jaya Chandrasekar, MD; Ronald Dick, MBBS; Kawa Haji, MBChB, PhD; Nay Min Htun, MBBS, PhD; David McGaw, MBBS, PhD; Samer Noaman, MBChB, PhD; Sonny Palmer, MBBS, DMedSci; Sesto Cairo, MBBS; Mark Shulman, MBBS, MPH, PhD; Enjarn Lin, MBBS, BMedSci; Stuart Hastings, MBBS; Benedict Waldron, BSc, MBBS; George Proimos, MBBS, BSc; Kean H. Soon, MBBS, PhD; Matias B. Yudi, MBBS; Adam Zimmet, MBBS; Dion Stub, MBBS, PhD; Antony S. Walton, MBBS
Importance Vascular complications after transfemoral transcatheter aortic valve implantation (TAVI) remain an important cause of procedure-related morbidity. Routine reversal of anticoagulation with protamine at the conclusion of transfemoral TAVI could reduce complications, but data remain scarce.
Objective To evaluate the efficacy and safety of routine protamine administration after transfemoral TAVI.
Design, Setting, and Participants The ACE-PROTAVI trial was an investigator-initiated, double-blind, placebo-controlled randomized clinical trial performed at 3 Australian hospitals between December 2021 and June 2023 with a 1-year follow-up period. All patients accepted for transfemoral TAVI by a multidisciplinary heart team were eligible for enrollment.
Interventions Eligible patients were randomized 1:1 between routine protamine administration and placebo.
Main Outcomes and Measures The coprimary outcomes were the rate of hemostasis success and time to hemostasis (TTH), presented as categorical variables and compared with a χ2 test or as continuous variables as mean (SD) or median (IQR), depending on distribution. The major secondary outcome was a composite of all-cause death, major and minor bleeding complications, and major and minor vascular complications after 30 days, reported in odds ratios (ORs) with 95% CIs and
Results The study population consisted of 410 patients: 199 patients in the protamine group and 211 in the placebo group. The median (IQR) patient age in the protamine group was 82 (77-85) years, and 68 of 199 patients receiving protamine (34.2%) were female. The median (IQR) patient age in the placebo group was 80 (75-85) years, and 89 of 211 patients receiving the placebo (42.2%) were female. Patients receiving up-front protamine administration had a higher rate of hemostasis success (188 of 192 patients [97.9%]) than patients in the placebo group (186 of 203 patients [91.6%]; absolute risk difference, 6.3%; 95% CI, 2.0%-10.6%;
Conclusions and Relevance In the ACE-PROTAVI randomized clinical trial, routine administration of protamine increased the rate of hemostasis success and decreased TTH. The beneficial effect of protamine was reflected in a reduction in minor vascular complications, procedural time, and postprocedural hospital stay duration in patients receiving routine protamine compared with patients receiving placebo.
Low-Dose Direct Oral Anticoagulation vs Dual Antiplatelet Therapy After Left Atrial Appendage Occlusion
The ADALA Randomized Clinical Trial
Xavier Freixa, PhD; Ignacio Cruz-González, PhD; Pedro Cepas-Guillén, PhD; Xavi Millán, PhD; Pablo Antúnez-Muiños, MD; Eduardo Flores-Umanzor, PhD; Lluís Asmarats, PhD; Ander Regueiro, PhD; Sergio López-Tejero, PhD; Chi-Hion Pedro Li, PhD; Laura Sanchis, PhD; Josep Rodés-Cabau, PhD; Dabit Arzamendi, PhD
Abstract
Importance Optimal antithrombotic therapy after percutaneous left atrial appendage occlusion (LAAO) is not well established as no randomized evaluation has been performed to date.
Objective To compare the efficacy and safety of low-dose direct oral anticoagulation (low-dose DOAC) vs dual antiplatelet therapy (DAPT) for 3 months after LAAO.
Design, Setting, and Participants The ADALA (Low-Dose Direct Oral Anticoagulation vs Dual Antiplatelet Therapy After Left Atrial Appendage Occlusion) study was an investigator-initiated, multicenter, prospective, open-label, randomized clinical trial enrolling participants from June 12, 2019, to August 28, 2022 from 3 European sites. Patients who underwent successful LAAO were randomly assigned 1:1 to low-dose DOAC vs DAPT for 3 months after LAAO. The study was prematurely terminated when only 60% of the estimated sample size had been included due to lower recruitment rate than anticipated due to the COVID-19 pandemic.
Interventions The low-dose DOAC group received apixaban, 2.5 mg every 12 hours, and the DAPT group received aspirin, 100 mg per day, plus clopidogrel, 75 mg per day, for the first 3 months after LAAO.
Main Outcomes and Measures The primary end point was a composite of safety (major bleeding) and efficacy (thromboembolic events including stroke, systemic embolism, and device-related thrombosis [DRT]) within the first 3 months after successful LAAO. Secondary end points included individual components of the primary outcome and all-bleeding events.
Results A total of 90 patients (mean [SD] age, 76.6 [8.1] years; 60 male [66.7%]; mean [SD] CHADS-VASc score, 4.0 [1.5]) were included in the analysis (44 and 46 patients in the low-dose DOAC and DAPT groups, respectively). A total of 53 patients (58.8%) presented with previous major bleeding events (60 gastrointestinal [66.7%] and 16 intracranial [17.8%]). At 3 months, low-dose DOAC was associated with a reduction of the primary end point compared with DAPT (2 [4.5%] vs 10 [21.7%]; hazard ratio, 0.19; 95% CI, 0.04-0.88;
Conclusions and Relevance This was a small, randomized clinical trial comparing different antithrombotic strategies after LAAO. Results show that use of low-dose DOAC for 3 months after LAAO was associated with a better balance between efficacy and safety compared with DAPT. However, the results of the study should be interpreted with caution due to the limited sample size and will need to be confirmed in future larger randomized trials.
Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage
Stuart J Connolly, Mukul Sharma, Alexander T Cohen, Andrew M Demchuk, Anna Członkowska, Arne G Lindgren, Carlos A Molina, Daniel Bereczki, Danilo Toni, David J Seiffge, David Tanne, Else Charlotte Sandset, Georgios Tsivgoulis, Hanne Christensen, Jan Beyer-Westendorf, Jonathan M Coutinho, Mark Crowther, Peter Verhamme, Pierre Amarenco, Risto O Roine, Robert Mikulik, Robin Lemmens, Roland Veltkamp, Saskia Middeldorp, Thompson G Robinson, Truman John Milling Jr, Vitor Tedim-Cruz, Wilfried Lang, Anders Himmelmann, Per Ladenvall, Mikael Knutsson, Ella Ekholm, Andrew Law, Amanda Taylor, Tetyana Karyakina, Lizhen Xu, Kate Tsiplova, Sven Poli Bernd Kallmünzer, Christoph Gumbinger, Ashkan Shoamanesh; ANNEXA-I Investigators
N Engl J Med 2024 May 16;390(19):1745-1755.
Abstract
Background: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied.
Methods: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death.
Results: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days.
Conclusions: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke.
Antiplatelets for Cardiovascular Disease in Non-valvular AF with Rivaroxaban: A Subanalysis of the EXPAND Study
Koichi Kaikita, Shinichiro Uchiyama, Hirotsugu Atarashi, Hiroshi Inoue, Takanari Kitazono, Takeshi Yamashita, Wataru Shimizu, Takanori Ikeda, Masahiro Kamouchi, Koji Fukuda, Hideki Origasa, Hiroaki Shimokawa
Abstract
Aim: In this subanalysis of the EXPAND study, we evaluated the risks and benefits of rivaroxaban plus antiplatelet therapy (APT) for patients with non-valvular atrial fibrillation (NVAF) complicated by stable coronary artery disease (CAD), ischemic stroke, or peripheral artery disease (PAD).
Methods: From the EXPAND study population (n=7,141), patients with NVAF complicated by stable CAD (n=886), ischemic stroke (n=1,231), or PAD (n=160) were included. Patients complicated by any of them were set as ALL (n=2,030). Patients were all treated with rivaroxaban (10 or 15 mg/day) with (+) or without (-) APT. Efficacy outcomes were symptomatic stroke＋systemic embolism (SE), symptomatic stroke＋SE＋myocardial infarction＋cardiovascular death, and all-cause death. Safety outcomes included major and any bleeding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for differences between the APT(+) and APT(-) groups.
Results: There were no significant differences in the efficacy outcomes between the APT(+) and APT(-) groups in the ALL cohort or in the CAD and STROKE sub-cohorts. In the PAD subcohort, the HR [95% CI] for all-cause death in the APT(+) group increased (4.43 [1.05-18.71]; p=0.043). In the APT(+) group, the HR [95% CI] for any bleeding increased in the ALL cohort (1.28 [1.01-1.62]; p=0.044) and STROKE subcohort (1.42 [1.01-2.01]; p=0.047), and for major bleeding in the CAD subcohort (2.00 [1.01-3.93]; p=0.046).
Conclusions: Rivaroxaban with APT did not reduce ischemic outcomes in patients with stable CAD or ischemic stroke; however, it did increase the risk of bleeding in patients with stable CAD or ischemic stroke.
Challenges in laboratory testing of patients suspected of antiphospholipid syndrome: practical implications for clinicians
Katrien M J Devreese, Denis Wahl
Pol Arch Intern Med 2024 Sep 24:16849.
Abstract
This paper focuses on the laboratory tests necessary for the diagnosis of antiphospholipid syndrome (APS). Diagnosis starts with the selection of patients suspicious of having APS. The timing related to the clinical event is important to avoid false classification of APS patients. For the interpretation of the test results of antiphospholipid antibodies (aPL) understanding of all pitfalls and interferences is necessary. Lupus anticoagulant (LA) measurement remains a complex procedure with many pitfalls and interferences. The effect of anticoagulant therapy, the main confounder of LA measurement, can be overcome by removal agents for direct oral anticoagulants (DOAC) or by considering assays as Taipan snake venom time / Ecarin clotting time not affected by antivitamin K therapy and anti-Xa DOAC. However, both procedures have limitations. Solid-phase assays for anticardiolipin antibodies (aCL) and anti-β2-glycoprotein 1 antibodies (aβ2GPI) show inter-assay differences. Diagnosis is based on the measurement of three groups of aPL: LA, aCL and aβ2GPI, of IgG and IgM isotype. This allows to make antibody profiles that helps in identifying patients at risk. Other aPL, such as antibodies against the domain I of β2GPI and anti-phosphatidylserine-prothrombin antibodies may be useful in risk stratification of APS patients and in some specific situations of patients with incomplete antibody profile, but are not needed for diagnosis. Laboratory diagnosis of APS remains challenging. To increase the diagnostic efficacy and reliability, an integrated interpretation of all results and an interpretative comment should be provided on the laboratory report. Therefore, a close interaction between clinical pathologists and clinicians is mandatory.
Effectiveness and Safety of the Coadministration of Rifampin and Warfarin versus Direct Oral Anticoagulants: A Cohort Study
Ju-Chieh Wung, Chia-Chen Hsu, Chi-En Wang, Yaa-Hui Dong, Chia-Chieh Lin, Szu-Yu Wang, Shih-Lin Chang, Yuh-Lih Chang
Adv Pharmacol Pharm Sci 2024 Sep 25:2024
Abstract
Introduction: Pharmacokinetic studies have shown that rifampin reduces the levels of oral anticoagulants during the initiation of coadministration, raising concerns about an increased thrombotic risk, but there are limited comparative clinical outcomes between rifampin and warfarin compared with direct oral anticoagulants (DOACs). This study aimed to evaluate the effectiveness and safety of concurrent use of rifampin and warfarin versus DOACs, with assessments of outcome-associated factors and oral anticoagulant (OAC) management quality.
Methods: A total of 142 patients given rifampin plus warfarin (
Results: The median Charlson Comorbidity Index and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score of the two groups were 2 and 3, respectively. The incidence rate of composite ischemic or thromboembolic events was 2.16 and 1.44 per 10,000 patient-days in the warfarin and DOAC groups, respectively, with an adjusted hazard ratio (HR) of 0.41 (95% confidence interval [CI] 0.02-7.34). The incidence rate of composite major bleeding or clinically relevant nonmajor bleeding events was 1.58 and 1.52 per 10,000 patient-days in the warfarin and DOAC groups, respectively, with an adjusted HR of 1.12 (95% CI 0.32-4.45). The risk of composite bleeding events increased with a higher HAS-BLED score (HR: 1.62, 95% CI: 1.02-2.63). Moreover, 34.3% of warfarin users maintained a percent time in therapeutic range of above 50%. Furthermore, 77.9% of DOAC users received appropriate dosing.
Conclusion: No significant differences were observed in terms of the incidence of thrombotic or bleeding events between the two groups during coadministration. In addition, a higher HAS-BLED score was associated with a greater risk of bleeding events regardless of the class of OACs used. Finally, close monitoring of bleeding events should be considered.
Outcomes in Children with Provoked Venous Thrombosis and Antiphospholipid Antibodies: Findings from the Kids-DOTT Trial
Blood Adv, 2024 Sep 25:bloodadvances.
Abstract
Few studies have prospectively evaluated the incidence and outcomes in children with provoked venous thromboembolism (VTE) and transient or persistent antiphospholipid antibodies (aPL). We compared outcomes of patients <21 years old with a first-episode acute provoked VTE and positive aPL at diagnosis enrolled in the Kids-DOTT trial. aPL were tested at enrollment and, when positive, repeated at 6 weeks post-VTE. Subsequent testing was performed at discretion of the treating hematologist. Of 524 patients, 116 (22%) had positive aPL at enrollment. At follow-up, 70 (60%) had transient (n=66) or low titer aPL (n=4), 11 (10%) had persistent aPL meeting criteria for antiphospholipid syndrome (APS), and 35 (30%) had no repeat testing. Patients with APS were older (15.8 vs. 9.9 years, p=.014), and had a statistically significant higher risk of symptomatic recurrent VTE (18% vs. 1%, OR: 12.2 [1.4 - 108], p= .025), and a statistically non-significant but clinically meaningful difference in the risk of anticoagulant-related clinically-relevant bleeding (9% vs. 0%, OR: 20.1 [0.7 - 558], p=0.077) compared to those in the transient or low titer aPL group. In conclusion, aPL are common in young patients with acute provoked VTE and are mostly transitory and clinically insignificant. Patients with APS and provoked VTE appear to have an increased risk of recurrent VTE compared to patients with transitory or low titer aPL. Future collaborative studies should investigate the optimal VTE management of children with provoked VTE who meet criteria for APS.