Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Pathophysiology of COVID-19-associated coagulopathy and its impact on laboratory measures of coagulation
Investigation of laboratory parameters in COVID-19 are important to better understand the physiological mechanism of this disease as well as they are important in the treatment, recovery and survival rates of patients. The occurrence of the cytokine storm is a predictor for worse outcomes. This is an unregulated and excessive release of pro-inflammatory cytokines first to the lung and then throughout the body. Elevated inflammatory markers include CRP, serum amyloid, ferritin, procalcitonin, IL6, IL-10 and TNF-a. Presently it is not clear that immune hyperactivity, dysregulation of the inflammatory response to the viral infection or immune dysregulation causes the progression to severe COVID-19. The release may also contribute to the associated coagulopathy by activating endothelial cells and leukocytes, and in particular neutrophils. These neutrophils produce neutrophil extracellular traps (NETs) which then promote thrombus formation. The virus also has a direct interaction with the contact system, in particular FXII and plasma prekallikrein contributing to the highly prothrombotic environment including increased thrombin generation, fibrin formation, fibrinolysis, increased D-dimer levels and also the production of bradykinin. This increases vascular dilation and permeability.
Infections in general raise the risk of thrombosis and COVID-19 patients present with a range of thrombosis-related disorders. These include benign skin lesions on the feet to fatal blood clots. This effects 25-45% of critically ill patients resulting in DVT or PE. Up to 70% of patients who died had met the ISTH criteria for DIC. Elevated D-dimer levels were found to indicate a thrombotic risk in COVID-19 patients. However, it is well known that D-dimer levels increase with age, pregnancy, DIC, sepsis, inflammation, DVT, liver disease, malignancy, surgery, preeclampsia and trauma. Several studies have demonstrated the utility of increased D-dimer levels in relation to predicting death.
Other elevated coagulation markers in COVID-19 include prothrombin fragment 1+2, fibrinogen, von Willebrand factor, and FVIII. Both FVIII and VWF are markers of endothelial activation. VWF may also promote tethering of platelets to the inflamed endothelium which may result in platelet activation as shown by increased P-selection expression of platelets. PFA results showed decreased closure times which indicates platelet hyperactivity. Additionally, increased plasma levels of soluble thrombomodulin and PAI-1 have been reported. This results in the ability to attenuate clot formation. PAI-1 inhibits fibrinolysis, and elevated levels can cause thrombosis.
COVID-19 associated coagulopathy results in a hypercoagulable and highly prothrombotic state requiring treatment and monitoring.
Low-Risk TAVR at 2 Years: Thrombosis Concerns Creep In
Transcatheter aortic valve replacement (TAVR) outcome studies post 2 years, showed that in the PARTNER 3 trial, TAVT maintained good results but lost some of its early advantage over surgery. The trial included 1,000 people randomly assigned to transfemoral TAVR or SAVR. Low risk patients with symptomatic severe aortic stenosis, still favored those randomized to TAVR instead of surgical aortic valve replacement (SAVR) at 2 years. There were more deaths and strokes between 1-2 years in the TAVR group compared with the SAVR group. Follow up will continue for at least 10 years. There may be a benefit at 5 years in the SAVR group. Findings showed that valve thrombosis rates diverged through 2 years. TAVR had a higher rate at 1 year (1.0% vs, 0.2%) but grew to an excess by 2 years (2.6% vs. 0.7%). Valve thrombosis was found in three out of four asymptomatic patients during imaging. This may be the reason for the increase in stroke in the TAVR patients. Further work will be required before the use of TAVR is used in younger patients.
The ACA and the AHA guidelines recommend SAVR for people under 65 years of age and TAVR for those older than 80. People in the gray area have a choice of intervention using a shared decision process.
DOAC After Heart Valve Procedure?
Registry defines prevalent use with mechanical and bioprosthetic valves
DOACs are being used off label during prosthetic heart valves and mechanical heart valves. This was shown by the number of prescriptions given to valve patients. This can be risky in these patients, and trials are ongoing to provide definitive data, but so far data has suggested a safety concern.
Up to 4.66% of patients undergoing bioprosthetic heart valves were discharged with DOACs. The rate increased from 3.30% to 6.63% over 3 years. In patients with mitral valve replacement with bioprosthetics, DOACs increased from 3.94% to 7.72% over 3 years.
Safety data for these groups are a result of subgroup data from AF trials. Physicians may want to exercise caution until data is released from randomized clinical trials for DOAC use in these patients.
Carving Out a Niche for Low-Dose Edoxaban in Atrial Fibrillation
A new analysis of the ENGAGE AF-TIMI 48 trial shows support for low dose edoxaban in select AF patients. This analysis compared 2 edoxaban regimens and showed the low dose was associated with a significantly more favorable clinical outcome (stroke, systemic embolism, major bleeding, and death) than the standard full dose (7.26% vs 8.01%; hazard ratio [HR], 0.90; 95% CI, 0.84 - 0.98). The tradeoff was this dose was associated with a greater stroke/embolism risk.
The ELDERCARE-AF study found that endoxaban 15mg once daily reduced the risk for stroke or systemic embolism by 2/3 without fatal bleeds or ICH. In ENGAGE AF-TIMI 48, both the 60 mg and 30 mg doses were reduced by 50% in patients who had moderate renal insufficiency, weighed 60 kg or less, or required use of a strong P-glycoprotein inhibitor. A report in JACC found no difference between the 60mg and 30mg groups for secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) or tertiary (stroke/systemic embolism, life-threatening bleeding, or all-cause mortality). Bleeding occurred less frequently with the lower dose.
COVID-19: Antiplatelet Agents May Reduce Thrombotic Risk
COVID-19 patients with severe disease have a high level of platelet activation which contributes to the associated thrombotic issues, which suggests that antiplatelet agents should be considered in addition to anticoagulation. Autopsy results have found platelet rich thrombi in microvessels of the lung which impair oxygen exchange.
Clinician could consider giving an antiplatelet drug in patients who have a worsening COVID infection- even a lose dose aspirin. More information will be coming from clinical trials. Patients develop clots in both venous and arterial vascular beds despite standard pharmacologic prophylaxis with heparin. Endothelial injury, a common feature of viral infection, can alter hemostasis directly or indirectly. Viral or bacterial infections and inflammatory stimuli can induce tissue factor expression (a key activator of the blood coagulation cascade) not only in endothelial, but also in circulating, monocytes and granulocytes; these cells upon activation also release procoagulant microvesicles into the bloodstream. Platelets participate in inflammation and thrombotic responses in many viral infections.
Patients who present with a low platelet count suggests increased consumption due to platelet activation and thrombus formation. The cytokine storm seen in severe disease may also contribute to this process. In a study of 46 COVID patients, it was noted the level of tissue factor among circulating cells and microvesicles is significantly higher than in healthy people, with patients requiring ventilation having higher levels. Platelet activation was seen in P-selection expression and platelet leukocyte aggregate formation.
Plasma from COVID-19 patients were added to healthy plasma, and platelet activation was seen, but was blunted when incubated with an antiplatelet agent or IL-6 antibody. The study provides evidence that the coagulopathy reported in COVID-19 patients is supported by: 1) a sustained tissue factor expression by virtually all the cells in contact with blood and by the derived microvesicles; and 2) a massive platelet activation characterized by the formation of PLA that may be involved in the pulmonary microthrombi found in autoptic specimens.
NIH starting trial of blood clotting treatment for COVID-19
The NIH has launched three Phase 3 clinical trials to evaluate the safety and efficacy of anticoagulation in the prevention of blood clots in COVID-19 patients. Early in the pandemic it was noted that many patients who died from COVID hasd blood clots throughout their bodies including small blood vessels. This resulted in complications from organ damage to heart attack, stroke and PE. The ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) trial looks at the use of apixaban in discharged moderate to severe COVID-19. Another study is focused on hospitalized patients, while the third looks at patients who have not be hospitalized. The studies are being conducted at more than 100 sites around the world. It is a randomized placebo controlled trial.
AstraZeneca Vaccine Unfairly Under Fire Over Clot Risk?
The use of the AstraZeneca vaccine has been halted in several countries due to an observed thrombotic and bleeding risk. Cases of blood clots, and ICH have been noted as well as sudden death in recently vaccinated people. AstraZeneca stated it has seen no evidence of an increased risk of PE, DVT overall for specific age groups, genders, batches or particular countries. Incidence of occurrences of 15 DVT and 22 PE in 17 million recipients is lower than would be expected to occur naturally.
During the clinical trial, the number of thrombotic events were small and were lower in the vaccinated group, and no evidence of increased bleeding in over 60,000 participants. The EMA reemphasized that there is no indication the vaccine has caused these events. The vaccine reduces the disease and as a result reduces the thrombosis that occurs with COVID-19. Concerns that slowing down vaccination will cost lives and contribute to hesitancy. Some people may not be able to differentiate between an unrelated or coincidental VTE.
Op-Ed: COVID Shot While on a Blood Thinner?
A possible reason to not get the COVID-19 vaccination has to do with allergies, but not due to clots or patients being on anticoagulants. COVID-19 is associated with an increased risk of DVT or PE in the very sick, but not known if the vaccine would increase the risk for blood clots.
The vaccine is administered intra-muscularly with a small gauge needle and does not increase the risk of bleeding in patients on blood thinner such as Coumadin so it is reasonable to think the risk is not increased in patients on DOACs or enoxaparin of fondaparinux. The FDA call sheet recommends patients inform their provider if they have a bleeding disorder or on a blood thinner, but there is no guidance regarding this.
The CDC advisory committee recommends scheduling a vaccine prior to taking a blood thinner, using a fine gauge needle and applying pressure to the injection site. The ISTH recommends 5 minutes to reduce the risk of bruising. It also recommends that patients on Coumadin have an INR below 4.0 prior to getting the injection.
Holding tPA for All DOAC Users Not the Way to Go, Stroke Docs Say
Current guidance on the use of DOAC in stroke patients has created many questions and disagreements. The AHA and ASA have a class III recommendation against thrombolysis within 48 hours of last DOAC dose for fear of bleeding. There are several clinicians who disagree with this due to data that shows patients taking DOACs have similar bleeding risks to patients not on DOACs after thrombolytic therapy.
It has been suggested that stroke treatment patients could be selected for thrombolysis based on drug specific assays including thromboelastography as well as using reversal agents prior to thrombolysis. Thromboelastography measure the viscoelastic propertied of clotting blood and correlated with serum DOAC levels. Using this method has not yet been reported and needs to be more available. Also anticoagulant reversal prior to thrombolysis comes with a lack of data. Having POC tests available would greatly assist in being sure the DOAC has been reversed.
Decisions on how to treat a patient having an acute ischemic stroke while taking a DOAC, is a complex process in acute stroke management. POC testing would help in management of these patients.
Non-vitamin K oral Anticoagulants and Risk of Fractures
A Systematic Review and Meta-analysis
Pajaree Mongkhon; Laura Fanning; Kirstie H.T.W. Wong; Kenneth K.C. Man; Ian C.K. Wong; Wallis C.Y. Lau
Aims: Comparative fracture risk for non-vitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) among patients with atrial fibrillation (AF) remains unclear. This study aimed to provide summary relative risk (RR) estimates for associations between NOACs vs. VKAs and fracture risk.
Methods and Results: PubMed, EMBASE, and Cochrane Library were searched from 2010 to 26 May 2020. Observational studies investigating the association between NOACs vs. VKAs and fracture risk in patients with AF were included. The adjusted effect estimates were pooled using the DerSimonian–Laird random effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiological (MOOSE) guidelines were followed. Five observational studies comprising 269 922 patients and 4289 fractures were included. Non-vitamin K antagonist oral anticoagulants use was associated with a lower risk of any fractures compared to VKAs use, with moderate heterogeneity [pooled RR = 0.83, 95% confidence interval (CI): 0.75–0.92,
Conclusion: This large meta-analysis suggests that NOACs use was associated with a lower risk of fractures compared with VKAs. Fracture risks were similar between NOACs. These findings may help inform the optimal anticoagulant choice for patients with AF at high risk of fracture.
Association of Anticoagulant Therapy With Risk of Dementia Among Patients With Atrial Fibrillation
Daehoon Kim; Pil-Sung Yang; Eunsun Jang; Hee Tae Yu; Tae-Hoon Kim; Jae-Sun Uhm; Jong-Youn Kim; Jung-Hoon Sung; Hui-Nam Pak; Moon-Hyoung Lee; Gregory Y. H. Lip; Boyoung Joung
Aims: To investigate the risk of dementia in atrial fibrillation (AF) patients treated with different oral anticoagulants (OACs).
Methods and results: This observational, population-based cohort study enrolled 53 236 dementia-free individuals with non-valvular AF who were aged ≥50 years and newly prescribed OACs from 1 January 2013 to 31 December 2016 from the Korean National Health Insurance Service database. Propensity score matching was used to compare the rates of dementia between users of non-vitamin K antagonist oral anticoagulant (NOAC) (dabigatran, rivaroxaban, and apixaban) and warfarin and to compare each individual NOAC with warfarin. Propensity score weighting analyses were also performed. In the study population (41.3% women; mean age: 70.7 years), 2194 had a diagnosis of incident dementia during a mean follow-up of 20.2 months. Relative to propensity-matched warfarin users, NOAC users tended to be at lower risk of dementia [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.69–0.90]. When comparing individual NOACs with warfarin, all the three NOACs were associated with lower dementia risk. In pairwise comparisons among NOACs, rivaroxaban was associated with decreased dementia risk, compared with dabigatran (HR 0.83, 95% CI 0.74–0.92). Supplemental propensity-weighted analyses showed consistent protective associations of NOACs with dementia relative to warfarin. The associations were consistent irrespectively of age, sex, stroke, and vascular disease and more prominent in standard dose users of NOAC.
Conclusion: In this propensity-matched and -weighted analysis using a real-world population-based cohort, use of NOACs was associated with lower dementia risk than use of warfarin among non-valvular AF patients initiating OAC treatment.
Outcomes of Upper Gastrointestinal Bleeding Are Similar Between Direct Oral Anticoagulants and Vitamin K Antagonists
Claire Gouriou; Guillaume Bouguen; Pierre Lahmek; Agnes Pelaquier; Ramuntxo Arotcarena; Armand Garioud; Stephanie De Montigny-Lenhardt; Arnaud Pauwels; David Zanditenas; Claire Charpignon; Remi Combes; Stephane Nahon; Vincent Quentin
Aliment Pharmacol Ther. 2021;53(6):688-695.
Background: The increased risk of upper gastrointestinal bleeding (UGIB) related to direct oral anticoagulants (DOACs) as compared to vitamin K antagonists (VKA) remains debated.
Aims: To describe the epidemiology and outcomes of UGIB in patients treated with oral anticoagulants.
Methods: A prospective, multicentre study in French general hospitals enrolled all consecutive patients with UGIB during one year. Patients treated with oral anticoagulants were retrieved from the cohort. Main outcomes were mortality and rebleeding during the first 6 weeks and need for non-endoscopic treatment (surgery or interventional radiology).
Results: Among the 2498 patients included, 475 (19%) had an oral anticoagulant, mostly with VKA (267 patients [56.2%]). Baseline characteristics were similar between the groups except for renal failure and cirrhosis that were more prevalent in the VKA group. Gastroscopy was normal in 73 patients (15.3%); peptic lesions were the main cause of UGIB (n = 233, 49%). Endoscopic treatment was performed in 128 patients (26.9%), leading to bleeding resolution in 74% (n = 95). Mortality rate at 6 weeks was 12.4% (59 patients), and was higher in the VKA group compared to DOACs (16.1% vs 7.8%, P < 0.01). By multivariate analysis, only the Charlson index ≥ 5 and UGIB occurrring in in-patients were independently associated with mortality. Rebleeding (56 patients [11.8%]) and need for non-endoscopic treatment (18 patients [3.8%]) were not associated with the type of anticoagulant.
Conclusion: DOACs do not alter outcomes of UGIB as compared to VKA. Comorbidities and associated treatment are the most important factors worsening the prognosis of UGIB.