by Donna Castellone, MS, MT (ASCP) SH •
June 16, 2022
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation. Please Note: many linked teasers require account/subscription in order to view full articles.
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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.
In patients with immune thrombocytopenia (ITP) antibodies are produced against platelets. Macrophages are responsible from destroying antibody coated platelets in ITP. An enzyme call Bruton kinase is critical to their function. This increases a patients risk of bruising, bleeding, death and quality of life. The drug rilzabrutinib is a Bruton kinase inhibitor that reduces macrophage activity and the production of anti-platelet antibodies without affecting the functionality of platelets.
The trial included 60 patients who had minor and transient adverse events. After 5.5 months of treatment 40% of patients experienced significant platelet response with a median time to develop a healthy platelet count of 10.5 days. This drug may provide a rapid risk in platelet count and an increase to a safe platelet number minimizing bleeding and causing the antibody to disappear without an increase risk in bleeding infrection, liver dysfunction or intolerance by patients.
The identification of gut microbiota in different stroke patients compared to controls can be important in the development of therapies that can improve stroke outcomes. Researchers found more than two dozen bacteria associated with a range of stroke subtypes and strains specifically associated with worse stroke severity 6 hours and 24 hours after the event.
Previously gut microbiota have been identified in dementia risk, cardiovascular disease, multiple sclerosis relapse and now a possible link between a stroke risk. Microbiota was analyzer from 89 patients following an ischemic stroke and compared to 12 controls. They identified multiple taxa associated ischemic stroke risk such as Fusobacterium and Lactobacillus. Others that were seen in the acute phase at 6 hours (Prevotella copri, Negativibacillus) and at 24 hours (Lentisphaeria). They also identified one class (Kiritimatiellae), one genus (Acidaminococcus), and one species (Paraprevotella xylaniphila) that are related to poor functional outcome 3 months after ischemic stroke.
Using data from the Flemish Gut Flora Project and the MEGASTROKE consortium, researchers identified 26 bacteria species associated with acute ischemic stroke or one of its subtypes. Of these, genus Ruminococcus was associated with all four outcomes.
Postprocedure protocol for Watchman 2.5 device consists of aspirin 81 to 325 mg indefinitely and warfarin for 45 days. Of the 31,994 patients implanted only 1 in 10 received this protocol. According to the National Cardiovascular Data registry LAAO Registry the most common discharge medications were warfarin and aspirin in 36.9% of patients, followed by a direct oral anticoagulant (DOAC) and aspirin (20.8%), warfarin alone (13.5%), DOAC only (12.3%), and dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (5%). Up to 70% of the patients (mean age 76) in the registry had a history of clinically relevant bleeding.
Adverse events occurred at 45 days in 5.7% of patients on warfarin and aspirin, 4% on warfarin alone, 5.2% on DOAC and aspirin, 3.8% on DOAC, 5.5% on DAPT. The take home message is to suggest omitting aspirin and discharging patients on DOAC or warfarin reduces major adverse events without increasing thrombotic events.
Women with systemic lupus erythematosus (SLE) experience worse outcomes after an acute stroke than the general population and men do not. In more than 1.5 million cases of stroke women with SLE are more likely to be hospitalize for longer and less likely to be released into their home environment. This was not found to be the case with men with SLE. This points to the need for effective and targeted treatment strategies to minimize adverse stroke outcomes in female SLE patients.
Patients with SLE are at a higher risk for developing atherosclerosis which is a risk factor for ischemic stroke. The risk for death after a stroke is 68% higher in people with SLE than in those without SLE.
A review of the National Inpatient Sample database of information of 1581430 hospitalized stroke patients in the US included 6100 SLE female and 940 SLE male patients, the remainder were used as the controls. SLE patients were 10 years younger median age of 60 for women, 61 for men and 71 for controls. No difference was found in the type of stroke between SLE and controls 89% had ischemic stroke and 11% had a hemorrhagic stroke. It was found that women with SLE were 21% more likely to die than patients without SLE and were 20% more likely to have a prolonged hospital stay as well as 28% less likely to have a routine home discharge were compared with patients who did not have SLE. Men with SLE were 24% less likely to die than the no SLE population but results were not statistically significant.
Tenecteplase is given in a single dose making it more practical and easier to administer than alteplase which is administered as a bolus plus an infusion. This makes the ability for tenecteplase to be initiated faster than alteplase in a mobile stroke unit resulting in signs of improved efficacy versus the standard of care using alteplase.
The TASTE-A study looked at 104 patients with ischemic stroke who were within 4.5 hours of symptom onset and eligible for thrombolytic treatment randomized to receive either alteplase or Tenecteplase prior to being transported to a hospital. Median patient age was 73. The results showed that the primary endpoint volume of the perfusion lesion on arrival by CT was statistically significantly smaller with Tenecteplase versus alteplase. At 90 days there were no significant differences observed between patients. There were no symptomatic ICH but there were four asymptomatic ICH in the tenecetplase and five in the alteplase.
The study also showed that patients treated with tenecteplase had a significantly shorter time from CT imaging in the mobile stroke unit to the start of thrombolytic treatment (median 13 minutes) compared with patients treated with alteplase (median 19 minutes). The TASTE A study supports that the single bolus administration of Tenecteplase works quicker than alteplase by 10% bolus then influsion of the rest over 1 hour has a slower effect on opening the artery.
Due to the risk of a rare blood clotting condition the FDA is limiting those who can receive the Johnson and Johnson COVID-19 vaccine. This vaccine should be given only to people 18 and older who don't have access to other vaccines and for those whom other vaccines are not clinically appropriate or it is the only vaccine they choose to receive. The clotting condition of thrombosis with thrombocytopenia syndrome (TTS) which occurred 1 to 2 weeks post vaccine is the reason to limit the use of the vaccine.
There are 16.9 million people vaccinated with the J&J vaccine, 76.5 million with Moderna and 126.3 million with Pflizer. There have been 60 confirmed cases of TTS with nine fatal cases. The cause of the blood clotting is not known.
Acute inflammatory disease is believed to increase the risk for cerebrovascular events. An increase in cardiovascular and cerebrovascular events is also see during flu season. There has also been an observational link between influenza vaccination and a reduced risk for stroke.
The INTERSTROKE study was a large international case-control study that looked at 13, 447 cases of patients within 5 days of their first stroke with matched controls. Patients were asked if they had febrile illness in the previous 4 weeks and if they had received flue vaccination the previous year. Up to 8.7% of the patients who had acute ischemic stroke had an acute febrile illness in the previous 4 weeks versus 5.8% in control patients. The association was apparent in Australia, China, North America and Western Europe and not seen in other parts of the world. There were no association between acute febrile illness and acute cerebral hemorrhage.
Having a flu vaccine in the prior year was strongly associated with a lower risk for either an ischemic or hemorrhagic stroke. This association was seen in all region of the world except for Africa and South Asia however vaccination rates in these regions were very low. Stroke rates were even lower when individuals had multiple annual vaccinations for example for every year for the previous 5 years. However this may be due to a bias due to these patients may have received more medical attention and more aware of stroke risks.
Changes in the new guidelines on aspirin in the primary prevention of cardiovascular disease which was released by the UD preventive Services Task Force:
This is for the secondary prevention setting in the absence of major contraindications with the recommendation of a low 75-100mg daily:
- Do not use aspirin in men and women above the age of 60, they were given a D recommendation to avoid aspirin use.
- Age 40-59, a C recommendation was given for select men and women who have a 10 year CVD risk score of at least 10% without an increased risk for bleeding.
These recommendations differ from the 2016 recommendation in the age ranges. In 2016 the ranges were 50-69 and a 10 year CVD risk score of 10% of higher to consider aspirin use with a B recommendation but data were in sufficient for those below 50 and above 70. The evidence for primary prevention in CVD events and stroke remain stable but there is a substantial increase in the risk for bleeding that is seen that increases with age. This doubles for each decade after the age of 60 and there is less use for aspirin prevention in colorectal and other cancers. In patients with a high CVD risk there is evidence presented for continuing aspirin in 60-69 year olds for both men and women and if their risk score is 20% or higher. The Women's health study showed that the greatest benefits were in women above the age of 65.
Balancing the risk for bleeding and the benefits of aspirin in the terms of CVD reduction can be aided by the use of a decision support tool. Aspirin Guide is available online in iOS for iPhone which has a calculator for CVD risk and bleeding scored.
The relationship between intrapartum oxytocin and obstetric hemorrhage is not well understood. A retrospective cohort analysis looked at 2232 patients who received intrapartum oxytocin it was seen that those who were exposed for 12 or more hours had a 52% increased risk of obstetric hemorrhage when compared to those exposed for less than 12 hours. It was not associated with an increased risk of hemorrhage related morbidity. They also had a 26% greater mean quantitative blood loss. There were no significant differences among cesarean deliveries.
An analysis of the MASTER DAPT study revealed that patients at a high bleeding risk who underwent percutaneous coronary intervention (PCI) 1 month of DAPT was associated with a similar rate of major adverse cardiac or cerebral events but a lower bleeding risk than a longer duration of DAPT. This was even seen in patients undergoing complex PCI. Discontinuation of DAPT at a median of 34 days in comparison of 6.5 months showed similar rates of net adverse clinical events and major adverse cardiac or cerebral events and a lower rate of major or clinically relevant nonmajor bleeding.
These results are a substudy from the MASTER DAPT looking at patients who had complex PCI and had more advance CAD with higher short and long ter risk of ischemic events. Complex PCI is defined as three vessels treated, three or more stents implanted, three or more lesions treated, bifurcation with two stents implanted, total stent length over 60mm or chronic total occlusion as the target lesion. Additionally, left main and graft stenting were added. Of the 4579 patients in the main study 1196 patients had complex PCI. Of those, 74% had one criteria that qualified them as complex but there was a significant minority with two or more criteria.
The results showed that the outcomes of net adverse clinical outcome and major adverse cardiovascular events were similar for both antiplatelet treatment groups and there was no difference between the results in patients receiving complex PCI and non complex PCI. The shorter DAPT group showed a lower rate of major clinically relevant nonmajor bleeding.
When there is no triggering event for a DVT an unknown cancer should be considered as a cause. Many times when thrombosis is diagnosed a malignant tumor is present in about 15% of cases including tumors of the brain, pancreas, lungs and GI tract.
Cartilaginous exostoses (osteochondromas) are benign bone tumors that can degenerate, which are then referred to as secondary chondrosarcomas. Chondrosarcomas account for about 20% of malignant bone tumors. There have been rare cases of chondrosarcomas infiltrating into vessels and metastasizing, which can lead to thromboembolisms.
Only 30% of cancer patients are aware that they are at a great risk of DVT than the general population. A survey to increase awareness and education across healthcare practioners and patients was implemented regarding cancer awareness for thrombosis (CAT). The survey included 6 countries and involved 1365 patients and caregivers. Data showed that up to 20% of cancer patients will experience VTE which is 4-5 higher than the general population. Most patients became aware of CAT when they suffered a blood clot.
Up to 87% of respondents were aware that taking a walk could reduce their risk and 75% understood that stopping smoking could reduce risk, while 63% knew hydration could help and 55% understood that stretching legs could reduce risk. While symptom of DVT were well known up to 73% were aware of swelling, 71% shortness of breath were a sign of PE while less than half knew that cramping pain or tenderness could be a sign of DVT. Only 33% knew that irregular heartbeat could be a sign of PE.
The results of the survey indicate that there is a need for more in-depth discussions between the not only the physician and patient but every member of the health care team.
In the FOCUS study (Follow-up after aCUte pulmonary emboliSm) large study of patients with acute pulmonary embolism (PE), chronic thromboembolic pulmonary hypertension (CTEPH) was rare, but post-pulmonary embolism impairment (PPEI) was not. This study identified patients who continued shortness of breath or exhaustion and a poor quality of life.
There were 1017 acute PE patients with a median age of 64 with 45% female evaluated at 3, 12 and 24 months. Primary outcomes were CTEPH and PPEI defined as a combination of persistent or worsening clinical functional, biochemical or imagining parameters during follow-up. CTEPH was diagnosed in 1.6% of patients with a 2.3% incidence at 2 years. There were 880 patients evaluated for PPEI with a 2 year cumulative incidence of 16%. These patients had a higher risk of rehospitalization and death and worse quality of life compared with those without PPEI. Follow up has shown that 1 in 5 patient post PE have had new cardiopulmonary diagnosis and require a new from of treatment beyond the PE and may have undiagnosed medical conditions that need equal attention/awareness and work-up.
There are patients with AF who suffer an ischemic stroke while on a DOAC or a VKA. The mortality rate is just over 12% within 3 months in these patients and close to 20% after one year. Additional strategies are needed for these patients not only for additional stroke prevention but also death.
Using the dataset from the COMBINE AF study of more than 70,000 people with AF 1163 patients were identified that had an ischemic stroke while on an anticoagulant, 37.3% received a standard-dose DOAC, 25% received a lower-dose DOAC, and 37.7% received a VKA.
Recurrent stroke rate was 7% at year 1 and 10.3% at 2 years while post stroke mortality was very high 12.4% at 90 days and 18.1% at 1 year. The risk of recurrent stroke and death were higher in patients with AF on anticoagulant therapy who have no prior stroke history.
The study highlights an unmet medical need among a subset of patients with AF and to understand the type of recurrent infarct and management of other vascular factors.
A Prespecified Subanalysis of the ELDERCARE–AF Randomized Clinical Trial
Kuroda M, Tamiya E, Nose T, et al. JAMA Cardiol. Published online April 13, 2022.
Importance Long-term use of oral anticoagulants (OACs) is necessary for stroke prevention in patients with atrial fibrillation (AF). The effectiveness and safety of OACs in extremely older patients (ie, aged 80 years or older) with AF and at high risk of bleeding needs to be elucidated.
Objective To examine the effects of very low-dose edoxaban (15 mg) vs placebo across 3 age strata (80-84 years, 85-89 years, and ≥90 years) among patients with AF who were a part of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE–AF) trial.
Design, Setting, and Participants This prespecified subanalysis of a phase 3, randomized, double-blind, placebo-controlled trial was conducted from August 5, 2016, to December 27, 2019. Patients with AF aged 80 years or older who were not considered candidates for standard-dose OACs were included in the study; reasons these patients could not take standard-dose OACs included low creatinine clearance (<30 mL per minute), low body weight (≤45 kg), history of bleeding from critical organs, continuous use of nonsteroidal anti-inflammatory drugs, or concomitant use of antiplatelet drugs. Eligible patients were recruited randomly from 164 hospitals in Japan and were randomly assigned 1:1 to edoxaban or placebo.
Interventions Edoxaban (15 mg once daily) or placebo.
Main Outcomes and Measures The primary efficacy end point was the composite of stroke or systemic embolism. The primary safety end point was International Society on Thrombosis and Hemostasis–defined major bleeding.
Results A total of 984 patients (mean [SD] age: age group 80-84 years, 82.2 [1.4] years; age group 85-89 years, 86.8 [1.4] years; age group ≥90 years, 92.3 [2.1] years; 565 women [57.4%]) were included in this study. In the placebo group, estimated (SE) event rates for stroke or systemic embolism increased with age and were 3.9% (1.2%) per patient-year in the group aged 80 to 84 years (n=181), 7.3% (1.7%) per patient-year in the group aged 85 to 89 years (n=184), and 10.1% (2.5%) per patient-year in the group aged 90 years or older (n=127). A 15-mg dose of edoxaban consistently decreased the event rates for stroke or systemic embolism with no interaction with age (80-84 years, hazard ratio [HR], 0.41; 95% CI, 0.13-1.31; P=.13; 85-89 years, HR, 0.42; 95% CI, 0.17-0.99; P = .05; ≥90 years, HR, 0.23; 95% CI, 0.08-0.68; P = .008; interaction P = .65). Major bleeding and major or clinically relevant nonmajor bleeding events were numerically higher with edoxaban, but the differences did not reach statistical significance, and there was no interaction with age. There was no difference in the event rate for all-cause death between the edoxaban and placebo groups in all age strata.
Conclusions and Relevance Results of this subanalysis of the ELDERCARE–AF randomized clinical trial revealed that among Japanese patients aged 80 years or older with AF who were not considered candidates for standard OACs, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism consistently across all 3 age strata, including those aged 90 years or older, albeit with a higher but nonstatistically significant incidence of bleeding.