Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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FDA adds sodium citrate blood specimen tubes to shortage list
Light blue sodium citrate tubes are in short supply due to increased demand and supply chain issues according to the FDA. These have been added to the section 506J device shortage list due to the COVID-19 public health emergency.
Recommendations for the following strategies include:
- Do not include sodium citrate (light blue top) tubes in routine collections of a variety of specimens at the time of other blood sampling or IV insertion.
- Do not use sodium citrate (light blue top) tubes unless medically necessary.
- Do not use sodium citrate (light blue top) tubes as discard tubes; consider clear top or red stopper (no additive) tubes as an alternative.
- Limit allocation of 1.8mL sodium citrate (light blue top) tubes for difficult blood collections.
FDA OKs Oral Blood Thinner for Clots in Kids
The FDA has approved dabigatran as the first DOAC for treatment in children with venous thromboembolism. It is recommended that a blood thinner injection is received for at least 5 days first. It was also approved for preventing recurrent clots in children who have completed treatment for their first VTE. The drug has two age appropriate formulations: pellets for children from 3 months to 12 years and capsules for children age 8 years and older. Approval was based on the DIVERSITY trial. A 267 person, open label trial including children up to 18 years old. It was found to be non-inferior to standard of care in terms of the composite primary endpoint of complete thrombus resolution, and freedom from recurrent VTE or death. Additional safety data was provided by a single arm study of 214 children who required further anticoagulation after completing the study.
Pediatric VTE may arise as a secondary complication of conditions such as a venous catheter, cancer, infection, congenital heart disease, trauma, or surgery. FDA had approved dalteparin (Fragmin), as a subcutaneous injection, to treat VTE in children in 2019. Rivaroxaban has also been shown to work as a treatment for blood clots in children. Dabigatran can be reversed with idarucizumab.
Stroke Can Signal VITT After COVID Shot
Three patients who received the AstraZeneca COVID-19 vaccine in England presented with ischemic stroke. Most cased of vaccine induced thrombosis (VITT) involved cerebral venous sinuses not arterial thrombosis.
Ischemic stroke occurs due to a blockage in an artery to the brain. These cases demonstrate that ischemic stroke should be considered as part of VITT, and needs to be recognized as a cause due to specific treatment requirements. The risk of VITT is low about 1 in 100,000 and has characteristics of low platelet counts with the presence of platelet factor 4 (PF4) antibodies. All of these patients presented with arterial thrombosis, very low platelet counts, PF-4 antibodies and increased d-dimer levels. Stroke was associated with blockages of carotid and middle cerebral arteries.
VITT is a rare syndrome associated with the AstraZeneca adenoviral vector vaccine, which uses a chimpanzee adenovirus-based vector. It is used in England and other countries but not the U.S. Cerebral venous sinus thrombosis also has been reported in people who received the Johnson & Johnson COVID-19 vaccine, which uses a human adenovirus-based vector.
Recommendations by the CDC in the US advise caution in choosing the J&J vaccine in patients with a history of an immune episode of thrombocytopenia and thrombosis. ASH has provided recommendation about VITT diagnosis and treatment recommendations.
Case Series Offers Solution for Post-COVID Vax Clotting?
Intravenous immune globulin (IVIG) administration reduced the antibody induced platelet activation and helped resolve the effects of vaccine-induced thrombotic thrombocytopenia (VITT) in three patients following receipt of the AstraZeneca COVID-19 vaccine. All patients presented with arterial thrombotic events and two had VTE. All patients tested positive for platelet factor 4 (PF4) antibodies. However, following administration of IVIG, all three patients showed at least some reduction in reactivity in the presence of PF4.
No patients had evidence of new or progressive thrombosis following IVIG treatment. VITT mimics autoimmune HIT and high doses of IVIG helped to reduced platelet activation and the IVIG rapidly increases the platelet count and reduces hypercoagulability. All patients had a reduction in D-dimer levels and improvement in fibrinogen levels.
Upon suspicion of VITT patient were switched to argatroban or fondaparinux. Heparin administration should be avoided in patients with thrombosis with thrombocytopenia syndrome.
Chip under skin may identify stroke
A clinical trial that took place at Massachusetts General Hospital along with Medtronic have found that inserting a small chip under the skin many help to predict the likelihood of a second stroke, in particular in patient with AF. The chip can help monitor the heart rate and rhythm and detect AF in patients who previously experienced a crytogenic stroke with no identifiable cause. The study included 492 randomized patients who had 12 months of follow up after receiving either an insertable cardiac monitor within 10 days of an initial stroke or unusual care consisting of external cardiac monitoring through ECG or other tracking methods.
The chip is less than 1¾" long and 1/6" thick and called an insertable cardiac monitor in patients who experienced a stroke caused by narrowing of a large artery like the carotid artery, or blockage of a small artery deep in the brain where atrial fibrillation would be unexpected. The chip detected AF in 12.1% of AF patients compared to 1.8% with standard care.
Correct DOAC Dose Up in the Air for Many Afib Patients With Renal Dysfunction
An observational study in patients with chronic kidney disease (CKD) looked at their dosing of direct oral anticoagulant (DOAC). In the Prevention of Thromboembolic Events-European Registry in Atrial Fibrillation (PREFER in AF) and PREFER in AF Prolongation registries, atrial fibrillation (AF) in 1288 patients on dabigatran, edoxaban, or rivaroxaban ended up with a higher dose in 19% and 16% of cases according to the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas, respectively.
Meanwhile, those eligible for a Cockcroft-Gault DOAC dose increase would have been directed to reduced dosing in 24% and 23% of cases under MDRD and CKD-EPI criteria. The AF patients with Cockcroft-Gault-determined renal dysfunction who had an estimated glomerular filtration rate >50 mL/minute by the CKD-EPI formula tended to have a higher 1-year thromboembolic risk (4.1% vs 0.8%). A trend of more bleeding events among people with discordant renal function results was observed as well. Discrepancies between Cockcroft-Gault and MDRD or CKD-EPI were especially large in patients with a body weight ≤60 kg and a BMI ≥30.
The data supports the need for a reassessment of the best method to determine a renal indication for dose reduction of DOACs.
Dual Antiplatelet Therapy in Mild Stroke: Better at Lower BP?
The POINT trial looked at patients who had mild stroke or high risk TIA and found if they had lower blood pressure at presentation they had more benefit from dual antiplatelet therapy of aspirin and clopidogrel. If started within 12 hours of stroke it may further lower early risk for stroke recurrence.
There was a greater effect with dual antiplatelet versus aspirin alone in patients with low BP as compared to those with higher BP. There were 4781 patients in the trial of those 946 patients (19.8%) with baseline systolic BP <140 mm Hg, this group had a 64% reduction in recurrent stroke versus aspirin alone. In 3835 patients (80.2%) with systolic BP > 140 mmHg the risk of recurrent stroke was reduced by 21%.
There are two factors that contribute to recurrent strokes, new clots forming and traveling to the brain and the effect of high BP on the artery walls. These results may be due to the patient with high BP have a competing risk and they don’t benefit from the dual antiplatelet therapy, while those with lower BP and the reduced thrombotic effect due to dual antiplatelet therapy could produce a synergistic relationship to reduce stroke risk. Additional research is needed to duplicate these findings to determine if lowering BP and dual antiplatelet therapy within 12 hours of stroke will lower onset of early risk stroke recurrence.
New Data Suggest Cause of Post-COVID Vaccine Blood Clots
There have been about 100 cases of CV sinus thrombosis post COVID-19 vaccination with the AstraZeneca vaccine, while 12 cases have been reported after vaccination with the Johnson & Johnson vaccine, both are vector based. Based on a research group in Germany it was found that these patients develop antibodies against PF4 which results in thrombocytopenia and an increased risk in thrombosis particularly CVS thrombosis, or VITT.
In Germany, 62 cases of cerebrovascular events after COVID-19 vaccination were identified up until mid-April 2021. Forty-five cases of cerebral venous thrombosis were identified; 82% following AstraZeneca vaccination, 18% after Pfizer-BioNTech, and no cases after Moderna. Of these patients, 78% were females, 80% were below the age of 60, and 58% had antibodies against platelet factor 4, which highlights the underlying relationship. There were no cases of positive antibodies in patients with cerebral venous thrombosis who received the Pfizer-BioNTech vaccine.
Results demonstrate there is an increased risk for CVS thrombosis in females as opposed to males. The risk for CVS thrombosis is 10 time higher in patients who have COVID-19 as compared with those being vaccinated.
First Risk Score to Predict Bleeding Risk After TAVR
A scoring assessment has been developed to identify the risk of bleeding in patients after transcatheter aortic valve replacement (TAVR). Bleeding rates can be as high at 9% at 30 days and between 3-11% in the first year. The PREDICT-TAVR score includes six variables that were selected among 104 baseline variables from 5185 consecutive patients. It can be calculated by hand using a simple nomogram or web-based calculator and calculate the 30 day bleeding risk after TAVR and are assigned:
- blood hemoglobin (0 - 10 points)
- serum iron concentration (0 - 5 points)
- common femoral artery diameter (0 - 3 points)
- creatinine clearance (0 - 3 points)
- dual antiplatelet therapy (DAPT; 0 - 2 points)
- oral anticoagulation therapy (0 - 2 points).
In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days. The PREDICT-TAVT demonstrated a discriminatory power for bleeding events at 30 days. Patients were identified as low risk when have <8 points, moderate were 8-10 points and those at high risk were 10-12, with a very high risk being > 12 points. The groups that demonstrate high and very high score had bleeding rates as high as 12.6%. Guidelines recommend DAPT for 3-6 months post TAVR, but if you know a patient is at a high bleeding risk, you may not administer DAPT or anticoagulants for a long time.
PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes. The score cannot distinguish between minor or major bleeding.
DOAC Antidotes No Panacea for Fatal Bleeds
Death was often the result of severe bleeding due to direct oral anticoagulant (DOAC) use despite the use of a reversal agent, according to a meta-analysis. These reversal agents were associated with a 78.5% rate of effective hemostasis. When hemostasis was not achieved after a reversal agent the incidence of mortality reached 17.7% across 60 studies of people who had been treated with 4-factor prothrombin complex concentrates (4PCC; n=2,688), idarucizumab (Praxbind; n=1,111), or andexanet (Andexxa; n=936) for reversal of severe DOAC-associated bleeding.
The antidote Andexanet used for FXa inhibitors demonstrated a rate for up to 10.7% for thromboembolism when compared with a 4.3% when 4PCC was used, and a 3.8% rate when idarucizumab was used on patients on dabigatran. The findings of thromboembolism with andexanet may be due to a prothrombotic rebound effect since it has shown a transiently increase in thrombin generation. However, to understand the true effect comparative studies are needed.
DOACs in general have a 52% risk reduction in preventing ICH, with a 14% risk reduction in major bleeding when compared to warfarn making them the safer option over warfarin in patients with AF. The rebleeding rate was 13.2%, with most rebleeds being ICH. Over three-quarters of rebleeds occurred after resuming anticoagulation.
COVID Led to Higher Clot Risk in Veterans With IBD
In the VA system, older men who presented with inflammatory bowel disease (IBD) had an eight fold increased likely hood of developing a VTE during a SARS-CoV-2 infection. Even prior to the pandemic IBD patients are at a two-three fold increased risk for developing VTE compared with the general population. The ASH recommends that patients with severe COVID-19 but who don't have confirmed or suspected VTE should be anticoagulated. There is no study that has evaluated the risk of VTE for IDB patients who contract COVID-19.
There were 428 participants in the study, with an average age of 69, mostly white males with 54% having a diagnosis of ulcerative colitis and 46% having Crohn’s disease. Pre-existing conditions include hypertension (58%), diabetes mellitus (31%), and arrhythmia (20%). Chronic anticoagulant use was reported in 31% of patients. There was an increased risk of VTE in patients who were not taking anticoagulation medication prior to COVID-19 infections.
Infections such as COVID-19 can cause endothelial dysfunction caused by the infectious process increases thrombin production and terminates fibrinolysis which in turn promotes a hypercoagulable state. So, COVID-19 adds an additional risk on top of the already elevated risk in patients with IBS.
No Benefit to Postop Heparin Bridging in Patients Who Stop Warfarin for a Procedure
There is uncertainty as to whether there is a benefit to postoperative heparin bridging in patients with AF or those with a mechanical heart valve who stop warfarin prior to a procedure.
The PERIOP2 study enrolled 1471 patients with AF or mechanical valves who had to stop warfarin for a procedure. There were 821 patients randomized to LMWH dalteparin and 650 to take a placebo after the procedure. The rate of major thromboembolism within 90 days was not significantly different in the placebo and dalteparin groups (1.2% and 1.0%, respectively). There was also no significant difference in the rate of major bleeding in the placebo and dalteparin groups (2.0% and 1.3%, respectively).
There is no advantage to postoperative bridging with dalteparin in preventing major thromboembolism in patients with AF or mechanical heart valves.
SARS-CoV-2 and Stroke Characteristics
A Report From the Multinational COVID-19 Stroke Study Group
Shima Shahjouei, MD, MPH; Georgios Tsivgoulis, MD, PhD, MSc; Ghasem Farahmand, MD; Eric Koza, MD Candidate; Ashkan Mowla, MD; Alireza Vafaei Sadr, PhD; Arash Kia, MD; Alaleh Vaghefi Far, MD; Stefania Mondello, MD, PhD, MPH; Achille Cernigliaro, PhD, MPH; Annemarei Ranta, MD, PhD; Martin Punter, PhD, MD; et al
Background and Purpose: Stroke is reported as a consequence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in several reports. However, data are sparse regarding the details of these patients in a multinational and large scale.
Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke, intracranial hemorrhage, and cerebral venous or sinus thrombosis among SARS-CoV-2–infected patients. We further investigated the risk of large vessel occlusion, stroke severity as measured by the National Institutes of Health Stroke Scale, and stroke subtype as measured by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria among patients with acute ischemic stroke. In addition, we explored the neuroimaging findings, features of patients who were asymptomatic for SARS-CoV-2 infection at stroke onset, and the impact of geographic regions and countries' health expenditure on outcomes.
Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least 1 eligible stroke patient. Of 432 patients included, 323 (74.8%) had acute ischemic stroke, 91 (21.1%) intracranial hemorrhage, and 18 (4.2%) cerebral venous or sinus thrombosis. A total of 183 (42.4%) patients were women, 104 (24.1%) patients were <55 years of age, and 105 (24.4%) patients had no identifiable vascular risk factors. Among acute ischemic stroke patients, 44.5% (126 of 283 patients) had large vessel occlusion; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median National Institutes of Health Stroke Scale (8 [3–17] versus 11 [5–17]; P=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; P<0.001) in countries with middle-to-high health expenditure when compared with countries with lower health expenditure. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144 (37.8%) were asymptomatic at the time of admission for SARS-CoV-2 infection.
Conclusions: We observed a considerably higher rate of large vessel occlusions, a much lower rate of small vessel occlusion and lacunar infarction, and a considerable number of young stroke when compared with the population studies before the pandemic. The rate of mechanical thrombectomy was significantly lower in countries with lower health expenditures.
Trends in Venous Thromboembolism Anticoagulation in Patients Hospitalized With COVID-19
Valerie M. Vaughn, MD, MSc; Monica Yost, MPH; Chelsea Abshire, MPH; Scott A. Flanders, MD; David Paje, MD, MPH; Paul Grant, MD; Scott Kaatz, DO, MSc; Tae Kim, MHSA; Geoffrey D. Barnes, MD, MSc
IMPORTANCE Venous thromboembolism (VTE) is a common complication of COVID-19. It is not well understood how hospitals have managed VTE prevention and the effect of prevention strategies on mortality.
OBJECTIVE To characterize frequency, variation across hospitals, and change over time in VTE prophylaxis and treatment-dose anticoagulation in patients hospitalized for COVID-19, as well as the association of anticoagulation strategies with in-hospital and 60-day mortality.
DESIGN, SETTING, AND PARTICIPANTS This cohort study of adults hospitalized with COVID-19 used a pseudorandom sample from 30 US hospitals in the state of Michigan participating in a collaborative quality initiative. Data analyzed were from patients hospitalized between March 7,2020, and June 17, 2020. Data were analyzed through March 2021.
EXPOSURES Nonadherence to VTE prophylaxis (defined as missing 2 days of VTE prophylaxis) and receipt of treatment-dose or prophylactic-dose anticoagulants vs no anticoagulation during hospitalization.
MAIN OUTCOMES AND MEASURES The effect of nonadherence and anticoagulation strategies on in-hospital and 60-day mortality was assessed using multinomial logit models with inverse probability of treatment weighting.
RESULTS Of a total 1351 patients with COVID-19 included (median [IQR] age, 64 [52-75] years; 47.7% women, 48.9% Black patients), only 18 (1.3%) had a confirmed VTE, and 219 (16.2%) received treatment-dose anticoagulation. Use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased over time (adjusted odds ratio [aOR], 1.46; 95% CI,1.31-1.61 per week). Of 1127 patients who ever received anticoagulation, 392 (34.8%) missed 2 or more days of prophylaxis. Missed prophylaxis varied from 11% to 61% across hospitals and decreased markedly over time (aOR, 0.89; 95% CI, 0.82-0.97 per week). VTE nonadherence was associated with higher 60-day (adjusted hazard ratio [aHR], 1.31; 95% CI, 1.03-1.67) but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03). Receiving any dose of anticoagulation (vs no anticoagulation) was associated with lower in-hospital mortality (only prophylactic dose: aHR, 0.36; 95% CI, 0.26-0.52; any treatment dose: aHR, 0.38; 95% CI, 0.25-0.58). However, only the prophylactic dose of anticoagulation remained associated with lower mortality at 60 days (prophylactic dose: aHR, 0.71; 95% CI, 0.51-0.90; treatment dose: a HR, 0.92; 95% CI, 0.63-1.35).
CONCLUSIONS AND RELEVANCE This large, multicenter cohort of patients hospitalized with COVID-19, found evidence of rapid dissemination and implementation of anticoagulation strategies,including use of treatment-dose anticoagulation.
Anticoagulation Therapy in Patients With Coronavirus Disease 2019
Results From a Multicenter International Prospective Registry (Health Outcome Predictive Evaluation for Corona Virus Disease 2019 (HOPE-COVID19)
Francesco Santoro, MD, PhD; Ivan J. Núñez-Gil, MD, PhD; María C. Viana-Llamas, MD; Charbel Maroun Eid, MD; Rodolfo Romero, MD; Inmaculada Fernández Rozas, MD; Alvaro Aparisi, MD; Victor Manuel Becerra-Muñoz, MD; Marcos García Aguado, MD; Jia Huang, MD; Ludovica Maltese, MD; Enrico Cerrato, MD; Emilio Alfonso-Rodriguez, MD; Alex Fernando Castro Mejía, MD; Francisco Marin, MD; Sergio Raposeiras Roubin, MD; Martino Pepe, MD; Victor H. Moreno Munguia, MD; Gisela Feltes, MD; Jesus Varas Navas, MD; Bernardo Cortese, MD; Luis Buzón, MD; Cristoph Liebetrau, MD; Raquel Ramos-Martinez, MD; Antonio Fernandez-Ortiz, MD; Vicente Estrada, MD; Natale Daniele Brunetti, MD, PhD
Crit Care Med. 2021;49(6):e624-e633.
Objectives: No standard therapy, including anticoagulation regimens, is currently recommended for coronavirus disease 2019. Aim of this study was to evaluate the efficacy of anticoagulation in coronavirus disease 2019 hospitalized patients and its impact on survival.
Design: Multicenter international prospective registry (Health Outcome Predictive Evaluation for Corona Virus Disease 2019).
Setting: Hospitalized patients with coronavirus disease 2019.
Patients: Five thousand eight hundred thirty-eight consecutive coronavirus disease 2019 patients.
Interventions: Anticoagulation therapy, including prophylactic and therapeutic regimens, was obtained for each patient.
Measurements and Main Results: Five thousand four hundred eighty patients (94%) did not receive any anticoagulation before hospitalization. Two-thousand six-hundred one patients (44%) during hospitalization received anticoagulation therapy and it was not associated with better survival rate (81% vs 81%;
Conclusions: Anticoagulation therapy in general population with coronavirus disease 2019 was not associated with better survival rates but with higher bleeding risk. Better results were observed in patients admitted with respiratory failure and requiring invasive ventilation.
Use of Preventive Aspirin Among Older US Adults With and Without Diabetes
Elizabeth Y. Liu, BA1; Mohammed E. Al-Sofiani, MBBS, MSc1,2; Hsin-Chieh Yeh, PhD3,4,5; et alJustin B. Echouffo-Tcheugui, MD, PhD1; Joshua J. Joseph, MD6; Rita R. Kalyani, MD, MHS1,7
JAMA Netw Open. 2021;4(6):e2112210. doi:10.1001/jamanetworkopen.2021.12210
Importance The net benefit of aspirin for prevention of cardiovascular disease (CVD), particularly primary prevention, remains debated in people with and without diabetes. Recent studies suggest that the benefits of preventive aspirin may be outweighed by the potential for harm in older adults; therefore, it is important to monitor current aspirin use in order to minimize risk for future harm in the oldest segment of the population.
Objective To determine the prevalence of preventive aspirin use in older US adults with and without diabetes for both primary and secondary prevention by age, sex, and CVD risk category.
Design, Setting, and Participants This cross-sectional analysis used nationally representative data from the National Health and Nutrition Examination Survey from 2011 to 2018. A total of 7103 individuals 60 years or older with and without diabetes completed a questionnaire on preventive aspirin use. Statistical analyses were performed from July 1, 2019, to April 1, 2021.
Main Outcomes and Measures Preventive aspirin use was defined as participants' self-reported use of low-dose aspirin therapy based on their physician’s advice or their own decision.
Results A total of 7103 individuals (mean [SD] age, 69.6 [0.1] years; 45.2% men; 75.8% White participants) were evaluated. Overall, 61.7% of older US adults with diabetes vs 42.2% without diabetes used aspirin. Among people with diabetes, in multivariable logistic models adjusting for race, sex, education, CVD risk category, and body mass index, the likelihood of aspirin use in older vs younger age categories (reference: 60-69 years) did not differ. Among people without diabetes, aspirin use was significantly greater in older age categories vs the reference (model 3, 70-79 years, odds ratio [OR], 1.50; 95% CI, 1.23-1.83; model 3, ≥80 years, OR, 1.59; 95% CI, 1.24-2.04). An estimated 9.9 million US adults 70 years or older with or without diabetes reported taking aspirin for primary prevention. The likelihood of aspirin use for primary prevention in those at high vs low risk for CVD did not differ among older adults with diabetes (model 3, OR, 1.69; 95% CI, 0.65-4.39) but was significantly higher in those without diabetes (model 3, OR, 2.46; 95% CI, 1.63-3.71). Women vs men with diabetes were less likely to be using aspirin for primary prevention (model 3, OR, 0.63; 95% CI, 0.48-0.83).
Conclusions and Relevance This cross-sectional study found that preventive aspirin use was higher among older adults with diabetes than in those without diabetes. Results suggest that 9.9 million older US adults who previously took aspirin for primary prevention would not be recommended for its continued use, particularly among those with diabetes.