May 2023: New In Coagulation

by Karen Medecke • May 08, 2023



Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.


VTE Risk in Recurrent Ovarian Cancer Increases With More Lines of Chemotherapy

In patients that received three or more rounds of chemotherapy, 80% were found to have VTE. A retrospective study showed this occurred in up to ¾ of patients while on chemotherapy. This did not seem to impact survival but was associated with significant morbidity including hospital admission and bleeding complications due to anticoagulation. In ovarian cancer the rate of VTE was one in five patients possibly due to the heavily treated nature of these patients.

The data was collected from patients with epithelial ovarian cancer at the Cleveland Clinic (2007-2020) receiving second line therapy. There were 345 patients in the study of those 22% developed a VTE. These patients had no significant differences when compared to patients who did not have an event. VTE occurred in patients who received five lines of chemo versus four lines who did not develop a VTE. A DVT occurred in 40 patients, while a PE occurred in 30 patients. In the 56 patients who had a VTE , 44 had received three more than eight lines of chemotherapy, while 12 had received two lines. Making the number of treatments an independent risk factor for VTE.

Those with and without VTE had similar survival rates but 54.5% with VTE required hospitalization and 11.7% had bleeding complications which were related to anticoagulation.



High-Dose Prophylactic Anticoagulation Benefits Patients With COVID-19 Pneumonia

Studies that looked at different anticoagulant strategies have shown contrasting results. Patients with hypoxemic COVID-19 pneumonia are at increased risk of thrombosis and anticoagulant related bleeding. No study looked at the effectiveness of three anticoagulation strategies: High does prophylactic (HD-PA), standard dose (SD-PA) and therapeutic anticoagulation (TA).

An open label ANTICOVID trial included 334 adults age 18 years and older that were hospitalized and treated for hypoxemic COVID 19 pneumonia between April 2021-December 2021 from 23 centers in France. Patients with a mean age of 58.3 years, 2/3 men were randomly assigned: SD-PA n=116, HD-PA n=11, TD n=112 with LMWH for 14 days or until weaned from supplemental oxygen for 48 consecutive hours. Patients had no macrovascular thrombosis at the start of the study. HD-PA dose was twice the SD-PA dose. Primary outcomes were all cause mortality and time to clinical improvement. Secondary outcome was safety and efficacy at day 28 including thrombosis, major bleeding and all cause death.

Primary outcome results were similar among the groups. All cause death rates were 14% for SD-PA, 12% for HD-PA and 13% for TA, with time to clinical improvement as 8 days, 9 days and 8 days respectively. HD-PA was associated with a reduced risk of de novo thrombosis of up to four-fold when compared to SD-PA with no increase in major bleeding. TA was not associated with any improvement in any outcomes. he significant reduction in the use of HD-PA supports the use of this.

The study limitations include open label design and small sample set, as well as the predominance of the Delta variant which may have contributed to a lower mortality rate.



Tranexamic Acid May Not Prevent Hemorrhage After C- Section

A randomized trial looked at 11,000 women in US hospitals that were assigned to either TXA or a placebo post umbilical cord clamping. TXA is not approved for pre umblical clamping. This cohort had a maternal age around 30; 39% white; mean BMI 35.7 for both groups) undergoing C-section were randomly assigned to receive either 1 gram TXA diluted in saline or IV saline (placebo) 10 minutes post clamping. Hemorrhage is responsible for 28% of maternal deaths worldwide and the second most common cause of maternal death in the US. Results showed that there was no difference in the primary outcome of maternal death or blood transfusion (3.6% vs 4.3% respectively. There was greater than 1 liter of blood loss in 7.5% of the TXA group and 8.0% of the placebo group with one maternal death in this group. Based on these results, TXA is not recommended to prevent obstetrical hemorrhage. Results may be due to the TXA given too late, a larger trial needs to be conducted. Current recommendations are to use within 3 hours of delivery in women with hemorrhage. There was no increased risk in VTE when compared to the placebo group.



Standard-Dose DOAC Better for Kidney-Impaired Patients

A comparison between standard dose DOACs and low dose DOAC and warfarin in patients with kidney dysfunction performed better in patients with AF. The meta-analysis included 71,683 patients (mean age 70.6 years, 37% female). As creatine clearance levels decreased so did the risk of stroke and embolism. Mortality risk was also lower with regular dose DOAC. Bleeding risk was the same which doesn't support underdosing kidney dysfunction patients to prevent complications from anticoagulation and may actually increase their risk of stroke.

All DOACs are cleared renally, however at different rates, 27% for apixaban and up to 80% for dabigatran. Recommendations are based on creatine clearance rates.

  • For dabigatran, CrCl >30 mL/min (reduced dose for CrCl 15–30 mL/min)
  • For edoxaban and rivaroxaban, CrCl >50 mL/min (dose reduction for CrCl 15–50 mL/min)
  • For apixaban, CrCl >25 mL/min (dose adjustment when meeting two or more criteria for older age, lower weight, or poor kidney function)



Hibernating bears don’t get blood clots. Now scientists know why

A low level of a protein was found to be the reason that bears do not have blood clots while being immobile during hibernation. This was also found in mice, pigs and even in humans who have a sedentary lifestyle because of long term mobility problems. The protein heat shock protein 47 (HSP47) is found in the cells that make up connective tissues such as bone and cartilage and it is also found in platelets. HSP47 attaches to collagen which promotes platelet aggregation and occurs when there is a cut or injury, but it is dangerous when this platelet aggregation goes to the lungs. Developing drugs that would target HSP47 from functioning could be used in patients.

The study looked at blood samples from 13 hibernating wild brown bears. Platelets from those samples taken during hibernation were less likely to clump together when compared to samples collected during non-hibernating times. The seasonal difference showed the level of HSP47 in platelets to be one-fiftieth the amount found in active animals.

Studies were also conducted in mice. It was found that mice lacking the protein had less clots and lower levels of inflammation when compared to animal with HSP47. Also in pigs who had recently given birth, which leaves them immobile for 28 days, presented with lower levels of HSP47 than active pigs. This was also found in humans who had long term immobility due to spinal cord injury as well as in healthy volunteers who participated in a bed rest study for 27 days of immobility. Their levels of HSP47 levels decreased.

This is important to understand how human bodies regulate HSP47 is important so that potential drugs can be developed to find the right balance to prevent clots as well as excess bleeding. It is also important to understand how motionlessness prompts the body to make less HSP47.




JOURNAL CLUB



Low Thrombin Generation in Users of a Contraceptive Containing Estetrol and Drospirenone

Laure Morimont; Maud Jost; Ulysse Gaspard; Jean-Michel Foidart; Jean-Michel Dogné; Jonathan Douxfils J Clin Endocrinol Metab. 2023;108(1):135-143.

Abstract

Objective: To compare the impact on thrombin generation of the new combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone with ethinylestradiol (30 or 20 mcg) associated either with 150 mcg levonorgestrel or with 3 mg drospirenone.

Methods: Data were collected from the "E4/DRSP Endocrine Function, Metabolic Control and Hemostasis Study" (NCT02957630). Overall, the per-protocol set population included 24 subjects in the ethinylestradiol/levonorgestrel arm, 28 subjects in the ethinylestradiol/drospirenone arm, and 34 subjects in the estetrol/drospirenone arm. Thrombograms and thrombin generation parameters (lag time, peak, time to peak, endogenous thrombin potential, and mean velocity rate index) were extracted for each subject at baseline and after 6 cycles of treatment.

Results: After 6 cycles of treatment, ethinylestradiol-containing products arms show a mean thrombogram outside the upper limit of the reference range, that is the 97.5th percentile of all baseline thrombograms. On the other hand, the mean thrombogram of estetrol/drospirenone is within this reference interval. After 6 cycles of treatment, all thrombin generation parameters are statistically less affected by estetrol/drospirenone than ethinylestradiol-containing products.

Conclusions: In conclusion, an association of 15 mg estetrol with 3 mg drospirenone does not have an impact on thrombin generation compared with ethinylestradiol-containing products that, either associated with levonorgestrel or drospirenone, are able to increase the production of procoagulant factors and decrease the production of anticoagulant ones, shifting the patient to a prothrombotic state. Ethinylestradiol-containing products thus generate prothrombotic environments contrary to estetrol which demonstrates a neutral profile on hemostasis.



In atrial fibrillation epilepsy risk differs between oral anticoagulants: active comparator, nested case-control study

Katharina Platzbecker, Helge Müller-Fielitz, Ronja Foraita, Matthias J Koepp, Annemarie Voss, René Pflock, Roland Linder, Iris Pigeot, Tania Schink, Markus Schwaninger . EP Europace, euad087, 04 April 2023

ABSTRACT

Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC).

Methods and results: We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011–17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)].

Conclusion: In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy.



Prevalence of Antiphospholipid Antibodies and Association With Incident Cardiovascular Events

Yu Zuo, MD; Sherwin Navaz, BS; Wenying Liang, PhD; et alChun Li, MD; Colby R. Ayers, MS; Christine E. Rysenga, BS; Alyssa Harbaugh, BS; Gary L. Norman, PhD; E.Blair Solow, MD; Bonnie Bermas, MD; Oludamilola Akinmolayemi, MD; Anand Rohatgi, MD; David R. Karp, MD, PhD; Jason S. Knight, MD, PhD; James A. de Lemos, MD

JAMA Netw Open. 2023;6(4):April 4, 2023

Abstract

Importance The prevalence of antiphospholipid antibodies (aPL) and their association with future atherosclerotic cardiovascular disease (ASCVD) risk has yet to be thoroughly investigated.

Objective To determine the association between measurements of aPL at a single time point and ASCVD risk in a diverse population.

Design, Setting, and Participants This cohort study measured 8 aPL (anticardiolipin [aCL] IgG/IgM/IgA, anti– beta-2 glycoprotein I [aβ2GPI] IgG/IgM/IgA, and antiphosphatidylserine/prothrombin [aPS/PT] IgG/IgM) by solid-phase assays in plasma from participants of the Dallas Heart Study (DHS) phase 2, a multiethnic, population-based cohort study. Blood samples were collected between 2007 and 2009. The median follow-up was 8 years. Statistical analysis was performed from April 2022 to January 2023.

Main Outcomes and Measures Associations of aPL with future ASCVD events (defined as first nonfatal myocardial infarction, first nonfatal stroke, coronary revascularization, or death from cardiovascular cause) were assessed by Cox proportional hazards models, adjusting for known risk factors, medications, and multiple comparisons.

Results Among the 2427 participants (mean [SD] age, 50.6 [10.3] years; 1399 [57.6%] female; 1244 [51.3%] Black, 339 [14.0%] Hispanic, and 796 [32.8%] White), the prevalence of any positive aPL tested at a single time point was 14.5% (353 of 2427), with approximately one-third of those detected at a moderate or high titer; aCL IgM had the highest prevalence (156 individuals [6.4%]), followed by aPS/PT IgM (88 [3.4%]), aβ2GPI IgM (63 [2.6%]), and aβ2GPI IgA (62 [2.5%]). The IgA of aCL (adjusted hazard ratio [HR], 4.92; 95% CI, 1.52-15.98) and aβ2GPI (HR, 2.91; 95% CI, 1.32-6.41) were independently associated with future ASCVD events. The risk further increased when applying a positivity threshold of at least 40 units (aCL IgA: HR, 9.01 [95% CI, 2.73-29.72]; aβ2GPI IgA: HR, 4.09 [95% CI, 1.45-11.54]). Levels of aβ2GPI IgA negatively correlated with cholesterol efflux capacity (r=−0.055; P = .009) and positively correlated with circulating oxidized LDL (r=0.055; P=.007). aβ2GPI IgA– positive plasma was associated with an activated endothelial cell phenotype as evidenced by increased surface expression of surface E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1.

Conclusions and Relevance In this population-based cohort study, aPL detectable by solid-phase assays were present in a substantial proportion of adults; positive aCL IgA and aβ2GPI IgA at a single time point were independently associated with future ASCVD events. Longitudinal studies with serial aPL measurements are needed to further explore these findings.



The Association of Coagulation and Atrial Fibrillation

Martijn J. Tilly; Sven Geurts; Angelo M. Pezzullo; Wichor M. Bramer; Natasja M.S. de Groot; Maryam Kavousi; Moniek P.M. de Maat Europace. 2023;25(1):28-39.

Abstract

Aims: While atrial fibrillation (AF) is suggested to induce a prothrombotic state, increasing thrombotic risk, it is also hypothesized that coagulation underlies AF onset. However, conclusive evidence is lacking. With this systematic review and meta-analysis, we aimed to summarize and combine the evidence on the associations between coagulation factors with AF in both longitudinal and cross-sectional studies.

Methods and Results: We systematically searched for longitudinal cohort and cross-sectional studies investigating AF and thrombosis. For longitudinal studies, pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. For cross-sectional studies, we determined pooled standardized mean differences (SMDs) and 95% CIs. A total of 17 longitudinal and 44 cross-sectional studies were included. In longitudinal studies, we found significant associations between fibrinogen (HR 1.05, 95% CI 1.00–1.10), plasminogen activator inhibitor 1 (PAI-1) (HR 1.06, 95% CI 1.00–1.12), and D-dimer (HR 1.10, 95% CI 1.02–1.19) and AF incidence. In cross-sectional studies, we found significantly increased levels of fibrinogen (SMD 0.47, 95% CI 0.20–0,74), von Willebrand factor (SMD 0.96, 95% CI 0.28–1.66), P- selectin (SMD 0.31, 95% CI 0.08–0.54), ß-thromboglobulin (SMD 0.82, 95% CI 0.61–1.04), Platelet Factor 4 (SMD 0.42, 95% CI 0.12–0.7), PAI-1 (1.73, 95% CI 0.26–3.19), and D-dimer (SMD 1.74, 95% CI 0.36–3.11) in AF patients, as opposed to controls.

Conclusion: These findings suggest that higher levels of coagulation factors are associated with prevalent and incident AF. These associations are most pronounced with prevalent AF in cross-sectional studies. Limited evidence from longitudinal studies suggests a prothrombotic state underlying AF development.



Ancestry, Lipoprotein(a), and Cardiovascular Risk Thresholds

Sotirios Tsimikas, MD; Santica M. Marcovina, PHD, SCD
J Am Coll Cardiol. 2022;80(9):934-946.

Abstract

This study reviews ancestral differences in the genetics of the LPA gene, risk categories of elevated lipoprotein(a) [Lp (a)] as defined by guidelines, ancestry-specific Lp(a) risk, absolute and proportional risk, predictive value of risk thresholds among different ancestries, and differences between laboratory vs clinical accuracy in Lp(a) assays. For clinical decision-making, the preponderance of evidence suggests that the predictive value of Lp(a) does not vary sufficiently to mandate the use of ancestry-specific risk thresholds. This paper interprets the literature on Lp(a) and ancestral risk to support: 1) clinicians on understanding cardiovascular disease risk in different ancestral groups; 2) trialists for the design of clinical trials to ensure adequate ancestral diversity to support broad conclusions of drug effects; 3) regulators in the evaluation of the design and interpretation of results of Lp(a)-lowering trials with different Lp(a) inclusion thresholds; and 4) clinical laboratories to measure Lp(a) by assays that discriminate risk thresholds appropriately.



Aspirin vs Clopidogrel for Long-term Maintenance After Coronary Stenting in Patients With Diabetes

Tae-Min Rhee, MD; Jang-Whan Bae, MD; Kyung Woo Park, MD; et alSeung-Woon Rha, MD; Jeehoon Kang, MD; Heesun Lee, MD; Han-Mo Yang, MD; Soo-Heon Kwak; In-Ho Chae, MD; Won-Yong Shin, MD; Dae-Kyeong Kim, MD; Ju Hyeon Oh, MD; Myung Ho Jeong, MD; Yong Hoon Kim, MD; Nam Ho Lee, MD; Seung-Ho Hur, MD; Junghan Yoon, MD; Jung-Kyu Han, MD; Eun-Seok Shin, MD; Bon-Kwon Koo, MD; Hyo-Soo Kim, MD; for the HOST-EXAM Investigators

JAMA Cardiol. Published online April 12, 2023.

Abstract

Importance Selecting the optimal antiplatelet agent in patients who have received percutaneous coronary intervention is especially important in those with diabetes due to the heightened risk of ischemic events in this population. Studies on the efficacy and safety of clopidogrel vs aspirin for long-term maintenance after percutaneous coronary intervention in patients with diabetes are lacking.

Objective To investigate cardiovascular outcomes with clopidogrel vs aspirin in patients with and without diabetes.

Design, Setting, and Participants This was a post hoc analysis of the HOST-EXAM randomized clinical trial, an investigator-initiated, prospective, randomized, open-label, multicenter trial performed at 37 centers in Korea. Patients who received dual antiplatelet therapy without clinical events for 6 to 18 months after percutaneous coronary intervention with drug-eluting stents were enrolled from March 2014 to May 2018 with follow-up at 6, 12, 18, and 24 months. All 5438 patients in the original trial were included in this analysis, which was conducted from June to October 2021.

Interventions and Exposures Enrolled patients were randomized 1:1 to clopidogrel or aspirin monotherapy. Subgroup analyses were performed by the presence of diabetes.

Main Outcomes and Measures The main outcome was primary composite end point of all-cause death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and major bleeding (Bleeding Academic Research Consortium type 3 or 5) at 24-month follow-up.

Results Of 5438 patients (mean [SD] age, 63.5 [10.7] years; 1384 [25.5%] female), 1860 (34.2%) had diabetes (925 in the clopidogrel arm and 935 in the aspirin arm), and 5338 (98.2%) completed follow-up. The rate of the primary composite end point was significantly lower in the clopidogrel group compared to the aspirin group in patients with diabetes (6.3% vs 9.2%; hazard ratio [HR], 0.69; 95% CI, 0.49-0.96; P=.03; absolute risk difference [ARD], 2.7%; number needed to treat [NNT], 37) and without diabetes (5.3% vs 7.0%; HR, 0.76; 95% CI, 0.58-1.00; P=.046; ARD, 1.6%, NNT, 63; P for interaction=.65). The presence of diabetes was not associated with a difference in benefit observed with clopidogrel monotherapy over aspirin for the thrombotic composite end point (HR, 0.68; 95% CI, 0.45-1.04 for patients with diabetes vs HR, 0.68; 95% CI, 0.49-0.93 for those without; P for interaction=.99) and any bleeding with Bleeding Academic Research Consortium 2, 3, or 5 (HR, 0.65; 95% CI, 0.39-1.09 for patients with diabetes vs HR, 0.74; 95% CI, 0.48-1.13 for those without; P for interaction=.71).

Conclusion and Relevance In this study, clopidogrel monotherapy was associated with a lower rate of the primary composite end point compared to aspirin monotherapy as long-term maintenance therapy after dual antiplatelet therapy for coronary stenting in both patients with and without diabetes. Clopidogrel might thus be considered rather than aspirin in patients who have undergone coronary stenting and successfully completed dual antiplatelet therapy, regardless of diabetes status.



Dual Antiplatelet Therapy in Patients at High Bleeding Risk: Less Is More—More or Less

Davide Capodanno; Antonio Greco, Eur Heart J. 2023;44(11):969-971.

Abstract

Risk-based antithrombotic strategies after percutaneous coronary intervention (PCI). Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is indicated for patients undergoing PCI. Applying a risk stratification approach that considers the risk of both thrombosis and bleeding, each individual patient can be managed with a tailored antithrombotic regimen. If the two risks substantially equipoise, standard DAPT is indicated (i.e. aspirin plus a P2Y12 receptor inhibitor for 6 or 12 months, based on the clinical scenario). In patients with a prevailing thrombotic risk (left part of the figure), the intensity of the antithrombotic therapy can be increased by administering DAPT for a prolonged duration or by prescribing a dual-pathway inhibition therapy (i.e. ASA plus rivaroxaban 2.5 mg twice daily). Conversely, when the bleeding risk prevails (right part of the figure), the intensity of the antithrombotic therapy can be decreased by de-escalation to a reduced intensity regimen (i.e. switching from a potent P2Y12 receptor inhibitor to clopidogrel or reducing the P2Y12 receptor inhibitor dose) or by early discontinuation of DAPT with transition to a monotherapy with either ASA or a P2Y12 receptor inhibitor.