September 2023: New In Coagulation
by Donna Castellone, MS, MT(ASCP)S • September 07, 2023
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Daily Aspirin Challenged in Primary Stroke Prevention: ASPREE
A secondary analysis of the ASPREE (n=19,114) trial showed that seniors (>/= 70 years) who took low dose aspirin for primary prevention had no risk reduction for strokes. This was a large randomized trial (56% female, median age 74), 9525 participants were assigned to daily aspirin and 9589 to placebo and followed a median of 4.7 years. Subjects who took 100mg/d of aspirin were compared to those who took a placebo there was a 38% increase of risk for intracranial bleeding. Any benefit that aspirin may provide in primary prevention, is offset by the increased risk for major bleeding. This was seen in several other studies leading to the recommendation of the US Preventative Services Task Force again routine prescription of aspirin for primary prevention in adults 60 years and older.
No significant different was seen in rate of stroke occurrence (4.7% aspirin, 4.6% placebo). There were no significant differences in the rates of ischemic, hemorrhagic or fatal strokes. The risks for IC bleed was 1.1% for aspirin and 0.8% for placebo.
Anticoagulants for Cancer-Related VTE: What Works Best?
When compared with LMWH, DOACs have a decreased risk of VTE, major bleeding as well as mortality in cancer patients. In a retrospective study of 5100 patients (mean age, 66.3 years); a majority (69.8%) were White, 15.7% were Black, and 7.6% were Hispanic. EMRs from adults with primary cancer including lung, colorectal, gynecologic, and urologic and acute VTE were included. Nearly half of patients (49.3%) filled prescriptions for DOACs, 29.2% for LMWH, and 28.6% for warfarin. Both LMWH and warfarin were associated with an increased risk of VTE (1.47 and 1.46) when compared with DOACs. LMWH was associated with an increased risk of bleeding and all cause mortality. This was not seen in warfarin or DOACs. This study reinforces the safety and efficacy in this patient population. However limitations of the study include the bias in the database, identifying patients by ICD codes and a lack of radiologic evidence for VTE.
Routine Thromboprophylaxis for Advanced Ovarian Cancer?
VTE is very high during neoadjuvant chemotherapy for advanced epithelial ovarian cancer. Routine thromboprophylaxis may be required. When 154 cased of this type were reviewed at the Mayo clinic VTE were discovered due to symptoms and not screening.
The investigation showed that 33 women (21.4%) developed VTEs; 22 VTEs (66.67%) occurred between diagnosis and surgery; four (12.12%) were present at diagnosis, and seven (21.21%) occurred after surgery. There were no statistically significant differences in risk factors that included age, BMI, functional status, histology, Khorana score and history of smoking in women who did or did not develop a VTE. In the cohort, 11 women (33.3%) received a direct-acting oral anticoagulant (DOAC) to treat a VTE between VTE diagnosis and 180 days after interval cytoreductive surgery.
The study suggests that up to 2/3 of VTE may have been preventable. However, the study had limitations due to its small size therefore being underpowered to identify risk factors associated with an increased risk of VTE.
Surveillance Still Not an Option for Many With Subsegmental Pulmonary Embolism
Based on current guideline restrictions (CHEST), results from a retrospective study showed that only one person out of 229 (0,4%) low risk adults received structured surveillance for subsegmental PE. This is due to extensive exclusion criteria such as active cancer, asthma, pregnancy and suggestions of right ventricular dysfunction. There is debate as to the best treatment for subsegmental PE patients who have clots contained with the subsegmental pulmonary arteries (3- 12% of the PE population). The guidelines recommend surveillance as opposed to anticoagulation for these PE patients who do not present with DVT. This would include instructions for when to seek medical attention and ultrasonography to evaluate for DVT. In high risk subsegmental PE patients the suggestion is for the patient to receive anticoagulation.
Current literature suggests that patients with subsegmental PE should be treated like proximal PE with anticoagulation unless they may be at a increased risk of bleeding. Those people should be treated with structured surveillance. Patients should be evaluated based on their risk.
This study reviewed patient records from 2017-2021 at 21 centers, and included 666 patients with acute subsegmental PE with 229 low risk individuals. In the low risk group 52.4% were men, average age 58. Most of the patients were non-Hispanic white (56%), followed by Black patients (15%), Hispanic or Latino patients (14%), and Asian patients (14%). At 90 days the low risk group had no cases of recurrent VTE, one patient had a non fatal hemorrhage on anticoagulation. It was noted that when using a stricter version of CHEST criteria, eligible patients dropped to 6.6%,of low risk patients and 2.3% of the full outpatient group.
LAAO Tied to Fewer Post-Fall Bleeds Than DOACs in AF
In patients with AF and previous stroke a study suggests that left atrial appendage occlusion (LAAO) translates to fewer injuries and less bleeding from falls than anticoagulation. More than 1250 patients were prospectively followed with AF and a previous ischemic stroke. Half were treated with DOACs and the other half underwent LAAO (n = 696 and 570, respectively) and all were followed for 2 years.
Up to 20% of patients had falls 22.6% of LAAO-treated patients and 22.7% of DOAC-treated patients sustained a fall (mean age 78.9 years, 57.4% male and 79.1 years, 52.5% male respectively).and patients on DOACs had significantly more several injuries and longer hospitalization when compared to those with LAAO and not on anticoagulation, they had a 70% lower risk for major bleed, the risk for major post-fall bleeding was lower in the LAAO vs the DOAC group (4.7% vs 15.2%). This is the first study done in this cohort, previous studies looked at LAAO for people at risk for bleeding. An aging population has an increased risk (1 in 5) of falling. In patients with a history of stroke, LAAO may be a better option and resulting in less bleeding and shortened hospital stays after a traumatic fall.
Thrombectomy Improves Outcomes in Pediatric Stroke
A case controlled study looked at 52 pediatric patients with acute stroke and compared functional outcomes at 3 months in patients who received thrombectomy versus those who did not. The study included 26 patients in each cohort, either receiving mechanical thrombectomy or medical treatment alone. The investigators matched patients by site and side of occlusion, age, and sex. Patients who had the procedure had significantly improved clinical outcomes. Thrombectomy in patients with large vessel occlusion is standard of care in adults.
Patients were scored using the modified Rankin Score to measure the degree of disability after a stroke. 53.8% of patients who were managed conservatively had poor outcomes (moderate disability or greater) at 3 months. Those who underwent mechanical thrombectomy had improved outcomes at 3 months. Information was collected from 2011-2022. This is a rare occurrence in the pediatric population.
It is important to note that this is a heterogeneous condition since in children stroke may have different etiologies. However this study shows that thrombectomy is a good option for some children with LVO stroke.
Adenovirus May Trigger Thrombocytopenia, Thrombosis, Case Studies Suggest
Two cases (5 year old by and 58 year old women) have demonstrated that a symptomatic human adenovirus may trigger a life threatening prothrombotic anti-platelet factor 4 (PF4) disorder which is similar to vaccine-induced immune thrombotic thrombocytopenia (VITT). Nasal swab testing revealed human adenovirus, but negative for 18 other pathogens.
The child had GI symptoms and respiratory symptoms occurred in the women both had fever and had severe thrombocytopenia, coagulopathy and thrombosis in about 5 days. The child had a fatal cerebral venous sinus thrombosis along with multiple arterial strokes, and ST-segment elevation MI. The women presented with DVT. Neither patient had been exposed to heparin which is associated with HIT. However, anti-PF4 assays found VITT like antibodies to PF4 in both patients, similar to those seen in patients post COVID vaccines. The women had a MODERNA shot 15 months prior, however mRNA vaccines are not associated with VITT. However the vaccines that did cause VITT are adenoviral vector vaccines. These cases are novel findings.
If a patient presents a history of viral illness with thrombocytopenia and thrombosis the following week an anti-PF4 disorder should be considered. In patients with VITT it is important to block the antibodies ability to activate platelets which is done with intravenous immunoglobulin which is different than using an anticoagulant for thrombosis.
COVID prompted the rare occurrence of VITT, and the linking to adeno-virus. This has helped to identify an issues that previously was unknown.
Clot Risk Factors Emerge for Cancer Patients With COVID-19
A registry study that included 4988 hospitalized patients with cancer as well as SARS-CoV-2 infection were included from March 2020 – December 2021. A median age of 69 years, majority were male and in which one-fifth of patients were Black, 16% were Hispanic, and 51% were white. About half were current or former smokers and 36% had a body mass index of 30 or above. About 20% were on anticoagulation prior to hospital admission, and 30% were taking aspirin, mostly low-dose. In this cohort, 1869 had some treatment 3 months prior to COVID-19 infection, while 3119 had no treatment prior to exposure. Of these patients 31% had metastatic disease, 41% active cancer, 11% history of VTE and 34% had a high risk of VTE based on their type of cancer (lymphoma, lung, kidney, uterus, bladder, pancreas, ovaries, stomach, esophagus and testicles.)
Those who were treated in the 3 months prior had a 33% higher risk of VTE when compared to those who had no treatment. Those patients who had a history of VTE, regardless of treatment, had a threefold higher risk of another event, black patients had a higher risk of VTE when compared to white patients. No association was observed with regard to arterial thrombosis (ATE) when compared to the reference group (5%). However use of antiplatelets in ATE demonstrated an increased risk possibly due to a higher underlying risk of arterial clots in these patients. Thromboembolism contributed to a higher rate of mortality at 30 days as well as admission to ICU, and mechanical ventilation.
Rates of thromboembolic events occur in 11% of the population with 7% VTE and 4% ATE. In this cohort VTE was higher across treatment types: checkpoint inhibitors (12%), chemotherapy (10%), VEGF inhibitors/TKIs (10%), immunomodulators (8%), and endocrine therapy (7%). Limitations include that it is a registry based study and there is a potential for bias and missing data for certain variables.
Rush to DOACs Spells Trouble for Frail Warfarin Users
The open-label FRAIL-AF trial found that if a frail older people have a stable INR on warfarin it is best for them to remain on that course of treatment versus switching to a DOAC. The trail focused on frail elderly people with nonvalvular AF. Patients who were randomized to DOAC ended up with an elevated risk for major or clinically relevant non-major bleeding with no beneficial reduction in thrombotic events. It was stopped early due to the results.
The open-label FRAIL-AF trial found that if a frail older people have a stable INR on warfarin it is best for them to remain on that course of treatment versus switching to a DOAC. The trail focused on frail elderly people with nonvalvular AF. Patients who were randomized to DOAC ended up with an elevated risk for major or clinically relevant non-major bleeding with no beneficial reduction in thrombotic events. It was stopped early due to the results.
JOURNAL CLUB
Ischemic Stroke in the Setting of Supratherapeutic International Normalized Ratio Following Coronavirus Disease 2019 Infection
Gokhan Demir; Rama Hommos; Sally Sami Al-Sirhan; Hashem Abu Serhan; Muhannad Haddadin; Umar Bin Rashid; Yamane Chawa J Med Case Reports. 2023;17(223)
Abstract
Background: SARS-CoV-19 infection is associated with an increased risk of thrombotic events. We present a case of acute middle cerebral artery ischemic stroke in a patient with SARS-CoV-19 infection despite being on warfarin with supratherapeutic INR (International Normalized Ratio).
Case Presentation: A 68-year-old Caucasian female with multiple comorbidities was admitted to the hospital with symptoms of upper respiratory tract infection. A rapid antigen test confirmed the diagnosis of COVID-19 pneumonia, and intravenous remdesivir was initiated. On the fifth day of admission, the patient experienced sudden onset confusion, slurred speech, left-sided hemiplegia, right-sided eye deviation, and left-sided facial droop. Imaging studies revealed an occlusion of the distal anterior M2 segment of the right middle cerebral artery, and an MRI of the brain confirmed an acute right MCA infarction. Notably, the patient was receiving warfarin therapy with a supratherapeutic INR of 3.2.
Conclusions: This case report highlights the potential for thromboembolic events, including stroke, in patients with COVID-19 infection, even when receiving therapeutic anticoagulation therapy. Healthcare providers should be vigilant for signs of thrombosis in COVID-19 patients, particularly those with pre-existing risk factors. Further research is necessary to understand the pathophysiology and optimal management of thrombotic complications in COVID-19 patients.
Association between serum alkaline phosphatase levels in late pregnancy and the incidence of venous thromboembolism postpartum: a retrospective cohort study
Qian Li e, Hongfei Wang e, Huafang Wang. Jun Deng. Zhipeng Cheng, Wenyi Lin. et al. E Clinical Medicine, August 2023 VOLUME 62
Abstract:
Two previous studies found alkaline phosphatase (ALP) levels were related with the development of venous thromboembolism (VTE) in hospitalised patients. VTE is a leading cause of death during pregnancy and postpartum. No prior study has investigated the associations of ALP levels and VTE postpartum, and the related mechanisms remain unclear. This study aimed to investigate the associations between ALP levels and VTE postpartum, and to reveal the potential mechanisms.
Methods
In this retrospective cohort study, we included pregnant women who planned to deliver at the Department of Obstetrics and Gynecology in the three designated hospitals in a multicentre cohort of pregnant women in Wuhan, China, during two recruitment periods of January 1, 2018 to December 31, 2019, and May 14, 2020 to March 25, 2022. A total of 10,044 participants with serum ALP and whole blood hemoglobin measurements in late pregnancy (median, 37 (35, 39) weeks) were enrolled. The participants' incidences of VTE (deep venous thrombosis and/or pulmonary embolism) postpartum were confirmed from the medical records. Pregnant women with new-onset VTE postpartum (within 6 weeks after delivery) were confirmed as VTE cases.
Findings
Approximately 0.8% (79/10,044) of the pregnant women were diagnosed with VTE postpartum. In the unadjusted model, pregnant women with the lowest quintile of serum ALP levels (≤116 U/L) in late pregnancy had higher risk of VTE postpartum compared with those with the highest quintile (≥199 U/L) (OR, 2.83 [1.32, 6.05]). After adjusting for covariates of demographic, life style, birth outcomes, and other liver enzymes, pregnant women with the lowest quintile of serum ALP levels (≤116 U/L) in late pregnancy had increased risk of VTE postpartum compared with those with the highest quintile (&lge;199 U/L) (OR, 2.48 [1.14, 5.40]). A one standard deviation decrease of ln-transformed ALP levels were associated with elevated risk of VTE postpartum (OR, 1.29 [1.02, 1.62]). Significant negative associations of ALP with VTE were found in the unadjusted and adjusted models. The negative associations between ALP and VTE remained consistent in sensitivity analyses among participants with non-GDM, single pregnancy, non-preeclampsia, non-postpartum hemorrhage, non-extremely/very preterm and cesarean delivery. Decreased serum ALP levels significantly (
Interpretation
This study suggested that low serum ALP levels in late pregnancy were associated with increased risk of VTE postpartum, and the ALP-associated VTE risk may be partially mediated by hemoglobin, suggesting that serum ALP in late pregnancy could be a promising biomarker for the prediction of VTE postpartum.
Management of Gastrointestinal Bleeding and Resumption of Oral Anticoagulant Therapy in Patients With Atrial Fibrillation
Anne-Céline Martin; Robert Benamouzig; Isabelle Gouin-Thibault; Jeannot Schmidt, Am J Cardiovasc Drugs. 2023;23 (4):407-418.
Abstract
Direct oral anticoagulants (DOACs) are recommended for the prevention of thromboembolism in patients with atrial fibrillation (AF), and are now preferred over vitamin K antagonists due to their beneficial efficacy and safety profile. However, all oral anticoagulants carry a risk of gastrointestinal (GI) bleeding. Although the risk is well documented and acute bleeding well codified, there is limited high-quality evidence and no guidelines to guide physicians on the optimal management of anticoagulation after a GI bleeding event. The aim of this review is to provide a multidisciplinary critical discussion of the optimal management of GI bleeding in patients with AF receiving oral anticoagulants to help physicians provide individualized treatment for each patient and optimize outcomes. It is important to perform endoscopy when a patient presents with bleeding manifestations or hemodynamic instability to determine the bleed location and severity of bleeding and then perform initial resuscitation. Administration of all anticoagulants and antiplatelets should be stopped and bleeding allowed to resolve with time; however, anticoagulant reversal should be considered for patients who have life- threatening bleeding or when the bleeding is not controlled by the initial resuscitation. Anticoagulation needs to be timely resumed considering that bleeding risk outweighs thrombotic risk when anticoagulation is resumed early after the bleeding event. To prevent further bleeding, physicians should prescribe anticoagulant therapy with the lowest risk of GI bleeding, avoid medications with GI toxicity, and consider the effect of concomitant medications on potentiating the bleeding risk.
Contemporary trends and barriers to oral anticoagulation therapy in Non-valvular atrial fibrillation during DOAC predominant era
Ojasav Sehrawat, Anthony H Kashou, Holly K Van Houten, Ken Cohen, Henry Joe Henk, Bernard J Gersh, Neena S Abraham, Jonathan Graff-Radford, Paul A Friedman, Konstantinos C Siontis, Peter A Noseworthy, Xiaoxi Yao
Int J Cardiol Heart Vasc. eCollection 2023 Jun.
Abstract
There is a need to reassess contemporary oral anticoagulation (OAC) trends and barriers against guideline directed therapy in the United States. Most previous studies were performed before major guideline changes recommended direct oral anticoagulant (DOAC) use over warfarin or have otherwise lacked patient level data. Data on overuse of OAC in low- risk group is also limited. To address these knowledge gaps, we performed a nationwide analysis to analyze current trends. This is a retrospective cohort study assessing non-valvular AF identified using a large United States de-identified administrative claims database, including commercial and Medicare Advantage enrollees. Prescription fills were assessed within a 90-day follow-up from the patient's index AF encounter between January 1, 2016, and December 31, 2020. Among the 339,197 AF patients, 4.4%, 8.0%, and 87.6% were in the low-, moderate-, and high-risk groups (according to CHA2DS2-VASc score). An over (29.6%) and under (52.2%) utilization of OAC was reported in low- and high-risk AF patients. A considerably high frequency for warfarin use was also noted among high-risk group patients taking OAC (33.1%). The results suggest that anticoagulation use for stroke prevention in the United States is still comparable to the pre-DOAC era studies. About half of newly diagnosed high-risk non-valvular AF patients remain unprotected against stroke risk. Several predictors of OAC and DOAC use were also identified. Our findings may identify a population at risk of complications due to under- or over-treatment and highlight the need for future quality improvement efforts
Anticoagulation in Patients with Liver Cirrhosis: Friend or Foe?
Adonis A Protopapas, Christos Savopoulos, Lemonia Skoura, Ioannis Goulis
Review Dig Dis Sci, 2023 Jun;68(6):2237-2246.
Abstract
Concepts regarding the status of the coagulation process in cirrhosis are rapidly changing. Instead of a disease defined by excessive bleeding risk, recent studies have shown cirrhosis to be associated with a fragile state of rebalanced hemostasis, easily swayed in either direction, thrombosis, or bleeding. These findings, combined with the ever-growing population of patients with cirrhosis with an indication for anticoagulation (AC) and the emergence of the non-alcoholic fatty liver disease epidemic, have prompted a reexamination of the use of AC in patients with cirrhosis, either as a treatment for a concurrent thrombotic disorder or even as a possible therapeutic option that could influence the natural course of the disease and its complications. In recent years, a significant number of studies have been formulated to evaluate these possibilities. These studies evaluated, among others, the efficacy and safety of AC in thrombotic disorders or thrombotic complications of cirrhosis, its effect on survival, and the class of anticoagulants which is more suitable for patients with cirrhosis, depending on disease severity. This review examines recent studies investigating the use of AC in patients with cirrhosis and attempts to provide a simple guide for clinicians regarding the use of AC in patients with cirrhosis and its potential risks and benefits.
Treatment of Cancer-Associated Thrombosis: Recent Advances, Unmet Needs, and Future Direction
Tzu-Fei Wang, Alok A Khorana, Giancarlo Agnelli, Dan Bloomfield, Marc P Bonaca, Harry R Büller, Jean M Connors, Shinya Goto, Zhi-Cheng Jing, Ajay K Kakkar, Yasser Khder, Gary E Raskob, Gerald A Soff, Peter Verhamme, Jeffrey I Weitz, Marc Carrier
2023 Jul 5;28(7):555-564
Abstract
Cancer-associated thrombosis, with the incidence rising over the years, is associated with significant morbidity and mortality in patients with cancer. Recent advances in the treatment of cancer-associated venous thromboembolism (VTE) include the introduction of direct oral anticoagulants (DOACs), which provide a more convenient and effective option than low-molecular-weight heparin (LMWH). Nonetheless, important unmet needs remain including an increased risk of bleeding in certain patient subgroups such as those with gastroesophageal cancer, concerns about drug-drug interactions, and management of patients with severe renal impairment. Although DOACs are more convenient than LMWH, persistence can decline over time. Factor XI inhibitors have potential safety advantages over DOACs because factor XI appears to be essential for thrombosis but not hemostasis. In phase II trials, some factor XI inhibitors were superior to enoxaparin for the prevention of VTE after knee replacement surgery without increasing the risk of bleeding. Ongoing trials are assessing the efficacy and safety of factor XI inhibitors for the treatment of cancer-associated VTE.
Association of Direct Oral Anticoagulation Management Strategies With Clinical Outcomes for Adults With Atrial Fibrillation
Catherine G Derington, Glenn K Goodrich, Stanley Xu, Nathan P Clark, Kristi Reynolds, Jaejin An, Daniel M Witt, David H Smith, Maureen O'Keeffe-Rosetti, Daniel T Lang, P Michael Ho, T Craig Cheetham, Angela C Comer, Jordan B King
JAMA Netw Open 2023 Jul 3;6(7):e2321971.
Abstract
Importance: Anticoagulation management services (AMSs; ie, warfarin clinics) have evolved to include patients treated with direct oral anticoagulants (DOACs), but it is unknown whether DOAC therapy management services improve outcomes for patients with atrial fibrillation (AF).
Objective: To compare outcomes associated with 3 DOAC care models for preventing adverse anticoagulation-related outcomes among patients with AF.
Design, setting, and participants: This retrospective cohort study included 44 746 adult patients with a diagnosis of AF who initiated oral anticoagulation (DOAC or warfarin) between August 1, 2016, and December 31, 2019, in 3 Kaiser Permanente (KP) regions. Statistical analysis was conducted from August 2021 through May 2023.
Exposures: Each KP region used an AMS to manage warfarin but used distinct approaches to DOAC care: (1) usual care (UC) by the prescribing clinician, (2) UC plus an automated population management tool (PMT), or (3) pharmacist-managed AMS care. Propensity scores and inverse probability of treatment weights (IPTWs) were estimated. Direct oral anticoagulant care models were first indirectly compared using warfarin as a common comparator within each region and then directly compared across regions.
Main outcomes and measures: Patients were followed up until the first occurrence of an outcome (composite of thromboembolic stroke, intracranial hemorrhage, other major bleeding, or death), discontinuation of KP membership, or December 31, 2020.
Results: Overall, 44 746 patients were included: 6182 in the UC care model (3297 DOAC; 2885 warfarin), 33 625 in the UC plus PMT care model (21 891 DOAC; 11 734 warfarin), and 4939 in the AMS care model (2089 DOAC; 2850 warfarin). Baseline characteristics (mean [SD] age, 73.1 [10.6] years, 56.1% male, 67.2% non-Hispanic White, median CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65-74 years, female sex] score of 3 [IQR, 2-5]) were well balanced after IPTW. Over a median follow-up of 2 years, patients who received the UC plus PMT or AMS care model did not have significantly better outcomes than those who received UC. The incidence rate of the composite outcome was 5.4% per year for DOAC and 9.1% per year for warfarin for those in the UC group, 6.1% per year for DOAC and 10.5% per year for those in the UC plus PMT group, and 5.1% per year for DOAC and 8.0% per year for those in the AMS group. The IPTW-adjusted hazard ratios (HRs) for the composite outcome comparing DOAC vs warfarin were 0.91 (95% CI, 0.79-1.05) in the UC group, 0.85 (95% CI, 0.79-0.90) in the UC plus PMT group, and 0.84 (95% CI, 0.72-0.99) in the AMS group (P = .62 for heterogeneity across care models). When directly comparing patients receiving DOAC, the IPTW-adjusted HR was 1.06 (95% CI, 0.85-1.34) for the UC plus PMT group vs the UC group and 0.85 (95% CI, 0.71-1.02) for the AMS group vs the UC group.
Conclusions and relevance: This cohort study did not find appreciably better outcomes for patients receiving DOAC who were managed by either a UC plus PMT or AMS care model compared with UC.