April 2022: New In Coagulation

by Donna Castellone, MS, MT (ASCP) SH • April 14, 2022

The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

Smartphone app can vibrate a single drop of blood to determine how well it clots

Researchers from the University of Washington have developed a plastic cup that contains a small copper particle and a chemical that begins the blood clotting process. This is attached to a smartphone and the camera monitors the movement of the particles which slows down and then stops as the clot forms. The accuracy of this method compares to the range of accuracy of analyzers in use in the laboratory. Measurements are collected at two points first when the user inserts the blood and second when the particle stops moving. The time it takes for the clot to form is the prothrombin time and the international normalized ration (INR) is also calculated.

Test results were compared on patients randomized patients using plasma, patients with known blood clotting disorders and both sets of patients had results that were similar to commercially available tests. The next set of testing looked at whole blood versus laboratory results. The device is still in a proof-of-concept stage.


Researchers uncover mechanism associated with severe COVID-19 blood clotting

Circulating antiphospholipid antibodies were found in blood samples from patients hospitalized for COVID-19. These are common in people with automimmune disorders and can target a persons organs and systems and can be activated in response to viral infections and activate other immune responses.

When these samples were compared to healthy controls, the COVID samples contained higher levels of IgG antibodies which are also associated with COVID-19 severity. IgG helps to bridge a gap between innate and adaptive immune responses that allows the body to recognize, respond and remember danger resulting in protecting the boday from illness and infection. When IgG was removed from these blood samples blood vessel stickiness decreased, however when these same IgG antibodies were add to the control samples, there was a blood vessel inflammatory response that could lead to clotting.

This study suggests that there may be a benefit to screening patients with COVID-19 or other forms of critical illness for antiphospholipids and other autoantibodies and at earlier point of infection to aid in the identification of people at risk for extreme blood clotting or vascular inflammation.


Triggers of Stroke: Anger, Emotional Upset, and Heavy Physical Exertion

The role of extreme physical or emotional stress as being a risk factor for stroke is unclear. In heart disease, emotional and physical stress are known causes in provoking ischemic events in particular in vulnerable patients. This includes constriction of coronary arteries or vessel obstruction due to prothrombic activity resulting in rupture of pre-existing atherosclerotic plaque.

In contrast, stroke etiology is heterogeneous and triggers are less obvious and evidence from large studies have been lacking. However the INTERSTROKE study included 13462 participants in 32 countries who had a first occurrence ischemic or hemorrhagic stroke with the goal to explore potentially modifiable risk factors for stroke and their importance for different populations worldwide. Results demonstrated that there are 10 modifiable vascular risk factors that contribute to risk over time. A questionnaire was administered within 72 hours. Results were started for age groups and traditional risk factors. Furthermore, triggers were placed into the individual context of pre-existing conditions: physical exertion stratified by level of individual baseline physical activity, and anger/emotional upset by pre-existing psychosocial factors, such as depression and presence of chronic stress.

Results showed that anger and emotional upset were present in 9.2% of participants and they also fell in the category of younger age, male sex, higher body mass index (BMI), higher education, and higher levels of baseline stress and depression. Heavy physical exertion was reported in 5.3% of cases and were more likely to be younger, more often male, current smokers, and not suffering from diabetes. Their baseline level of physical activity was higher, as was their systolic blood pressure on admission. The odds of suffering a stroke after heavy exercise were greatest in women and lowest in patients with normal BMI.

The study points to anger and emotional upset being common prior to stroke suggesting they could be stroke triggers. Physical exertion was associated with hemorrhagic stroke only and causality could not be drawn from these results. It is possible that negative emotions and stress can be a trigger for stroke and wearable devices may identify more potential triggers of stroke and delineate who is at risk.


Antithrombotics Harmful During Stroke Thrombectomy: MR CLEAN-MED

The results of the MR CLEAN-MED trial show that the use of aspirin and unfractionated heparin during endovascular treatment of acute ischemic stroke was associated with an increased risk of symptomatic intracranial hemorrhage. However, there was no evidence for benefit of functional outcomes. Up until now, no randomized trials have been conducted on periprocedure administration of antithrombotics therefore no guidelines provide recommendations for utilization.

The study was conducted at 15 centers in the Netherlands. There were 663 patients enrolled with ischemic stroke due to intracranial large vessel occlusion in the anterior circulation in which endovascular treatment could be initiated withing 6 hours of onset. Patients were randomized to receive either IV ASA or no ASA and a bolus dose of UFH followed by 1250IU/h for 6 hours, or a bolus follow by a low dose of UFH 500 IU/h or no UFH. The trial was stopped early due to safety concerns.

Rates of ICH were higher in those receiving ASA versus those who did not (14% versus 7%). It was also higher in those receiving UFH versus those who did not (13% vs. 7%) while the risk was non significant for death in those on aspirin and UFH.

Those patients on a moderate dose of UFH had a significantly increased risk of symptomatic ICH and death.


Tranexamic Acid After Trauma — Weighing the Benefits Against the Risks

One month post traumatic brain injury results of a systematic review and meta analysis show that tranexamic acid used for bleeding significantly lowers mortality.

However, an attempt to gain other insights about other outcomes such as clotting events due to treatment was impeded by the variability of the data of the studies in the analysis. Those treated had a 17% lower mortality rate which was a significant difference.

The analysis included 31 studies, 6 randomized controlled trials and 25 observational studies. Patients were 15 years or older and treated in the ED for traumatic injuries, traumatic brain injuries or both. When trying to pool the data for 24 hour mortality or overall mortality they found the data had too much variability across studies. The same was found in those with thrombotic events. It is difficult to combine data from randomized trials with low quality observational studies.


Untreated LVO Stroke Tied to Poor Outcomes in Children

A retrospective population based study of 200 children with large vessel occlusion (LVO) stroke who did not undergo mechanical thrombectomy were six times more likely to have significant disability than those who underwent the procedure. Most trials associated with LVO exclude children and neurologists hesitate to treat when they face a child with LVO stroke.

Data was collected on all patients for ischemic stroke younger than 17 years. The investigators assessed all patients for LVO on imaging and compared patients with LVO who did and did not undergo mechanical thrombectomy. The latter group was taken to represent the natural history of LVO stroke.

Included were 39 children with LVO stroke (mean age 8.2 years) and 122 children with non-LVO stroke (mean age 5.4 years).The proportion of male patients was 67.2% in the non-LVO group and 59% in the LVO group. This difference was not statistically significant. One patient in the non-LVO group and three in the LVO group received IV thrombolysis. No patients in the non-LVO group and 13 patients in the LVO group underwent thrombectomy.

Patients with LVO stroke who did not undergo thrombectomy (73%) at 3 months presented with a poor outcome. About 90% of children presented within 24 hours of the time they were last seen well, which refutes the idea that children present too late to receive reperfusion therapy. Most children do not present to a center that can treat a child for a stroke, so the need to transfer them quickly is important.


IBD-VTE Score Serves as Reminder to Assess Post-Discharge Risk

A scoring system may help to identify patients who are at risk for VTE after discharge from being treated for inflammatory bowel disease. It uses eight factors that can pose an excess risk for VTE in patients admitted for IBD in 90 days post discharge. These include advancing age, male, emergency admission, longer admission and ulcerative colitis. This evidence is to guide posthospitalization anticoagulation in patients hospitalized for IBD flares.

Data was collected from 102,000 patients (49,385 male) admissions between 2006 and 2019 using the Hospital Episode Statistics (HES) a data warehouse in England.

A multilevel logistic regression model was used to identify patient and admission factors that might influence the risk for VTE. A risk was seen in the 0-90 day period compared to 180-270 days later. VTE rates per 100,000 people in the 0-90 day postoperative period were 36.9 for emergency surgical admissions, and 15.6 for both nonsurgical emergencies and elective surgeries. Rates in the later period were a respective 0.84, 1.59, and 1.70.

The flip-side of VTE is of course the risk for postsurgical bleeding. While this is something clinicians need to be cognizant of there is "not generally increased risk" with some of the more commonly used anticoagulants.


Are Thrombolytics for Stroke Safe for Patients on NOACs?

Retrospective analysis from the GWTG-Stroke and ARAMIS suggest that giving IV alteplase to patients with stroke is not associated with an increased risk for bleeding.

The goal of being on NOACs is to prevent ischemic stroke associated with nonvalvular AF, however a portion of this patients present with stroke. Based on the analysis of the data taking NOACS in the past 7 days prior to receiving alteplase is safe. The primary endpoint was ICH within 36 hours after IV alteplase in patients taking NOACS compared with those who were not.

The analysis included 163,038 patients with a median age of 70 years 50.9% male with 1.4% of patients taking NOACs prior to stroke and 98.6% were not. Patients on NOACS had a higher prevalence of comorbidities and more severe strokes.

The rate of ICH was 3.7% in patient on NOACs and 3.2% in patients not on anticoagulants. There were no significant differences between the groups.


Extended Therapy for VTE: Does Anticoagulant Choice Matter?

Apixaban could be a better choice than warfarin for VTE. Patients who were prescribed the DOAC has fewer hospitalizations for recurrent VTE ( 9.8 vs 13.5) with no change in major bleeding (44.4 vs 47.1). The endpoints suggested no differences between rivaroxaban and apixaban, nor rivaroxaban and warfarin for continued therapy after the initial 90 days of oral anticoagulation. The study is small with limited statistical power but clinically important in detected differences between these treatments.

There are no randomized clinical trials that have directly compared DOACS with warfarin or with each other for extended treatment.

It is unlikely that an adequately powered randomized clinical trial will be conducted that compares all 3 outcomes across at least 3 therapies for extended treatment of patients with VTE. In contrast to the more than 60,000 patients included in this study, the ongoing RENOVE trial will compare full vs reduced doses of DOACs in 2200 participants with unprovoked VTE.

The recommendation from current guidelines suggests 3 months of anticoagulation for proximal DVT or PE. DOACs are preferred over vitamin K antagonists however any specific DOAC has been endorsed for initial or extended treatment.


More Clues Emerge for Brain Bleed Prognosis

The ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) study analyzed data from a prospectively recruited group of 1,000 patients each from non-Hispanic White, non-Hispanic Black, and Hispanic ethnicity who had spontaneous ICH. Among them, 2,568 patients (mean age 62.4 years, 41.6% women) had 3-month outcomes available.

Reviewing the outcome of the ERICH study cohort that looked at the validity of severity scores for ICH as related to outcomes it was noted that added white matter lesion burden on the initial CT scan boosted prognostication. That model had a significantly higher area under the curve receiver operator curve when compared with the ICH score alone.


Gene Therapy for Hemophilia A 'Transforming and Liberating'

In patients with hemophilia A receiving an infusion of valoctocogene roxaparovovec (AAV5-hFVIII-SQ) 1 year out have demonstrated a significant benefit. This is an adeno- associated virus based gene therapy vector that expresses a human factor VIII coding sequence designed to correct the central genetic defect in hemophilia A. Results from the phase 3 open label trial show that is was associated with improved endogenous FVIII clotting factor production and a significant decrease in bleeding.

In 132 patients at 49-52 weeks of follow up FVIII levels were at 41.9 IU/dL. A subgroup of 112 patients the mean use of factor concentrate at 4 weeks decreased by 98.6% and annualized rates of treated bleeding rates declined by 83.8%. It is unknown how long the treatment will last.


Aspirin Risks Unclear for Postpartum Bleeding

Previously it was thought that low dose aspirin is safe to continue up until delivery with minimal risk however now low dose aspirin may increase postpartum bleeding if it isn’t stopped 7 days prior to delivery.

Low dose aspirin is recommended at 12 weeks gestation in patients at high risk for preeclampsia, chronic hypertension, pregestational diabetes, renal disease, and autoimmune disease. These disorders are responsible for 6.6% of US pregnancy-related deaths.

This retrospective study looked at 16980 patients in which 11.3% were prescribed low-dose aspirin. Those who were prescribed aspirin were older (39 vs 24), 52.3% had a BMI > 30 kg/m2, compared with 22.9% of the non-aspirin group, and most were Hispanic and Black. Rates of diabetes, lupus, fibroids, anticoagulation, cesarean, and preterm delivery were all greater in the aspirin group. Composite endpoint bleeding was compared among those who did and did not bleed. Bleeding was defined as a blood loss of greater than 1000ml and a RBC transfusion.

Postpartum bleeding occurred in 14.7% of patients in the low-dose aspirin group versus 9.2% in the nonaspirin group. Meanwhile, 15% of those who discontinued aspirin within 7 days of delivery had postpartum bleeding, compared with 9% of those who discontinued aspirin at 7 or more days before delivery. The risk of bleeding was significantly greater among those who discontinued aspirin only in the last week before delivery.

At this time, this study should be used to make any clinical decisions. the study had a large sample size, it was limited by its retrospective reliance on EMR data, including the EMR medication list, and the researchers couldn't assess patient compliance or patient use of over-the-counter aspirin not recorded in the EMR.


Antiplatelets Don't Get Critically Ill COVID Patients Off Ventilation Sooner

There appeared to be a less than 20% relative benefit when using antiplatelet therapy in days alive and free of either respiratory or cardiovascular organ support in the ICU to 21 days. Results were found in the randomized 1,549 patient REMAP-CAP trial. There wasn't a benefit for either aspirin, P2Y12 inhibitors either combined or alone. However, survival to hospital discharge was numerically more common with the antiplatelet agents considered together 71.5% vs 67.9% among controls.

It is possible that antiplatelet therapy may reduce fatal complication of COVID-19 in critically ill patient while potentially increasing the need for organ support possibly through bleeding that may or may not be clinically evident such as alveolar hemorrhage. Major bleeding occurred in 2.1% vs 0.4% of controls.

Findings from the RECOVERY, ACTIV- 4A and ACTIV-4B trial have all agreed against the use of antiplatelet agents. For critically ill patients, heparin alone has appeared as the best as the standard prophylactic anticoagulation in trials.


ACG Weighs In on Antithrombotic Use During GI Bleeds, Endoscopy

Guidelines for managing patients on antithrombotics experiencing acute gastrointestinal (GI)bleeding or who are undergoing elective endoscopy have been published by the American College of Gastroenterology and Canadian Association of Gastroenterology (ACG-CAG). Antithrombotic drugs -- such as vitamin K antagonists or warfarin, direct-oral anticoagulants (DOACs), antiplatelet drugs, and acetylsalicylic acid (ASA) -- are commonly used to manage atrial fibrillation and ischemic heart disease, among other conditions, but can increase the risk for GI bleeding.

They focus on four key aspects: temporary interruption of anticoagulants and antiplatelets; reversal of anticoagulants and antiplatelets; periprocedural heparin bridging; postprocedural resumption of anticoagulants and antiplatelets.

Acute GI Bleeds

To manage patients with acute GI bleeds it is suggested that patients on warfarin, prothrombin complex concentrate (PCC) is suggested over FFP or vitamin K. Patients on DOACs should not be administered PCC, and those on DT! Should not be administer idarucizumab unless they have a life threatening bleed. Patients on Xa inhibitors should not receive andexanet alfa and patients on antiplatelet agents shouldn’t receive platelet transfusions. Those patients on secondary prevention cardiac ASA it is not recommended that ASA be held.

Elective Endoscopy

For those undergoing elective endoscopy and not at a high risk of thromboembolic events those on warfarin should continue without any temporary interruption. Bridging may be appropriate in those with mechanical valves, atrial fibrillation and undergoing certain types of surgery (e.g., cardiac valve replacement, carotid endarterectomy, and major vascular surgery).

Patients on DOACs should have their treatment interrupter prior to procedure. In those receiving dual antiplatelet therapy, P2Y12 receptors should be stopped while ASA can be continued while there was insufficient evidence on patients that are just on P2Y12 receptors alone. There is no consensus on how soon warfarin, DOACs, or P2Y12 inhibitors should be resumed following interruptions.

Guidelines incorporated the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to derive their recommendations. Most were conditional due to low certainty of the evidence.

Healthcare providers should incorporate this guideline in addition to patient-specific medical comorbidities, health status, and preferences to arrive at a patient-centered care approach.


Blood Clots More Likely With COVID Versus Pneumonia

The occurrence of blood clots occur more frequently (6.2%) in patient with COVID-19 versus patients with community acquired pneumonia (CAP) (3/9%). The positivity rate for VTE was 16.3% for COVID-19 patients and 9.2% for CAP patients. When reviewing CT pulmonary angiogram results for PE 3.2% of COVID patient were positive versus 1.7% of CAP patients. In addition. 3.3% of COVID patients had DVP based on a Doppler compared with 2.5% of CAP patients. These findings suggest that the true incidence of VTE may be underestimated in COVID-19 and may be higher that the 5% previously reported in in patients.

The retrospective study included 7509 hospitalized COVID patients from 23 hospitals in Utah compared to a control group of 4304 CAP patients at 16 hospital from 22017-2019 serving at the control group. The mean age of COVID patients was 57, and 50% were female. For CAP patients, mean age was 67, and 48% were female.

The study lacked a single group of radiologists interpreting VTE results, instead relying on radiologists from across the system. The radiologists were not blinded to clinical status or COVID-19 diagnosis among the patients, introducing potential bias into the study.




Comparison of Clopidogrel Monotherapy After 1 to 2 Months of Dual Antiplatelet Therapy With 12 Months of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome

Hirotoshi Watanabe, MD1; Takeshi Morimoto, MD2; Masahiro Natsuaki, MD3; et alKo Yamamoto, MD1; Yuki Obayashi, MD1; Manabu Ogita, MD4; Satoru Suwa, MD4; Tsuyoshi Isawa, MD5; Takenori Domei, MD6; Kyohei Yamaji, MD6; Shojiro Tatsushima, MD7; Hiroki Watanabe, MD7; Masanobu Ohya, MD8; Hideo Tokuyama, MD9; Tomohisa Tada, MD10; Hiroki Sakamoto, MD10; Hiroyoshi Mori, MD11; Hiroshi Suzuki, MD11; Tenjin Nishikura, MD12; Kohei Wakabayashi, MD12; Kiyoshi Hibi, MD13; Mitsuru Abe, MD14; Kazuya Kawai, MD15; Koichi Nakao, MD16; Kenji Ando, MD6; Kengo Tanabe, MD17; Yuji Ikari, MD18; Yoshihiro Morino, MD19; Kazushige Kadota, MD8; Yutaka Furukawa, MD20; Yoshihisa Nakagawa, MD21; Takeshi Kimura, MD1; for the STOPDAPT-2 ACS Investigators

JAMA Cardiol. Published online March 2, 2022.


Importance Clopidogrel monotherapy after short dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) has not yet been fully investigated in patients with acute coronary syndrome (ACS).

Objective To test the hypothesis of noninferiority of 1 to 2 months of DAPT compared with 12 months of DAPT for a composite end point of cardiovascular and bleeding events in patients with ACS.

Design, Setting, and Participants This multicenter, open-label, randomized clinical trial enrolled 4169 patients with ACS who underwent successful PCI using cobalt-chromium everolimus-eluting stents at 96 centers in Japan from December 2015 through June 2020. These data were analyzed from June to July 2021.

Interventions Patients were randomized either to 1 to 2 months of DAPT followed by clopidogrel monotherapy (n = 2078) or to 12 months of DAPT with aspirin and clopidogrel (n=2091).

Main Outcomes and Measures The primary end point was a composite of cardiovascular (cardiovascular death, myocardial infarction [MI], any stroke, or definite stent thrombosis) or bleeding (Thrombolysis in MI major or minor bleeding) events at 12 months, with a noninferiority margin of 50% on the hazard ratio (HR) scale. The major secondary end points were cardiovascular and bleeding components of the primary end point.

Results Among 4169 randomized patients, 33 withdrew consent. Of the 4136 included patients, the mean (SD) age was 66.8 (11.9) years, and 856 (21%) were women, 2324 (56%) had ST-segment elevation MI, and 826 (20%) had non–ST-segment elevation MI. A total of 4107 patients (99.3%) completed the 1-year follow-up in June 2021. One to 2 months of DAPT was not noninferior to 12 months of DAPT for the primary end point, which occurred in 65 of 2058 patients (3.2%) in the 1- to 2-month DAPT group and in 58 of 2057 patients (2.8%) in the 12-month DAPT group (absolute difference, 0.37% [95% CI, −0.68% to 1.42%]; HR, 1.14 [95% CI, 0.80-1.62]; P for noninferiority = .06). The major secondary cardiovascular end point occurred in 56 patients (2.8%) in the 1- to 2-month DAPT group and in 38 patients (1.9%) in the 12-month DAPT group (absolute difference, 0.90% [95% CI, −0.02% to 1.82%]; HR, 1.50 [95% CI, 0.99-2.26]). The major secondary bleeding end point occurred in 11 patients (0.5%) in the 1- to 2-month DAPT group and 24 patients (1.2%) in the 12-month DAPT group (absolute difference, −0.63% [95% CI, −1.20% to −0.06%]; HR, 0.46 [95% CI, 0.23-0.94]).

Conclusions and Relevance In patients with ACS with successful PCI, clopidogrel monotherapy after 1 to 2 months of DAPT failed to attest noninferiority to standard 12 months of DAPT for the net clinical benefit with a numerical increase in cardiovascular events despite reduction in bleeding events. The directionally different efficacy and safety outcomes indicate the need for further clinical trials.


Prasugrel Dose De-escalation Therapy After Complex Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome

Doyeon Hwang, MD1; Young-Hyo Lim, MD2; Kyung Woo Park, MD1; et alKook Jin Chun, MD3; Jung-Kyu Han, MD1; Han-Mo Yang, MD1; Hyun-Jae Kang, MD1; Bon-Kwon Koo, MD1; Jeehoon Kang, MD1; Yun-Kyeong Cho, MD4; Soon Jun Hong, MD5; Sanghyun Kim, MD6; Sang-Ho Jo, MD7; Yong Hoon Kim, MD8; Weon Kim, MD9; Sung Yun Lee, MD10; Young Dae Kim, MD11; Seok Kyu Oh, MD12; Jung-Hee Lee, MD13; Hyo-Soo Kim, MD1; for the HOST-RP-ACS investigators

JAMA Cardiol. Published online March 9, 2022. doi:10.1001/jamacardio.2022.0052


Importance De-escalation of dual-antiplatelet therapy through dose reduction of prasugrel improved net adverse clinical events after acute coronary syndrome (ACS), mainly through the reduction of bleeding without an increase in ischemic outcomes. However, whether such benefits are similarly observed in those receiving complex procedures is unknown.

Objective To investigate whether the benefits of prasugrel dose de-escalation therapy are maintained in the complex percutaneous coronary intervention (PCI) subgroup.

Design, Setting, and Participants This was a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS trial, a randomized, open-label, adjudicator-blinded, multicenter trial performed at 35 hospitals in South Korea. Study participants included patients with ACS who were receiving PCI. Data were collected from September 30, 2014, to December 18, 2015, and analyzed from September 17, 2020, to June 15, 2021.

Interventions and Exposures Patients were randomized to a prasugrel dose de-escalation (5 mg daily) at 1 month post-PCI group or a conventional (10 mg daily) group. Complex PCI was defined as having at least 1 of the following features: 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI, total stent length 60 mm or larger, left main PCI, or heavy calcification.

Main Outcomes and Measures The main analysis end points were MACE (major adverse cardiac event, a composite of cardiovascular death, nonfatal myocardial infarction, stent thrombosis, and repeat revascularization) at 1 year for ischemic outcomes, and BARC (Bleeding Academic Research Consortium) class 2 or higher bleeding events at 1 year for bleeding outcomes.

Results Of 2271 patients (mean [SD] age, 58.9 [9.0] years; 2024 [89%] male patients) for whom full procedural data were available, 705 patients received complex PCI, and 1566 patients received noncomplex PCI. Complex PCI was associated with higher rates of ischemic outcomes but not with bleeding outcomes. Prasugrel dose de-escalation did not increase the risk of MACE (hazard ratio [HR], 0.88; 95% CI, 0.47-1.66; P=.70 in complex PCI; HR, 0.81; 95% CI, 0.45-1.46; P=.48 in noncomplex PCI; P for interaction=.84) but decreased BARC class 2 or higher bleeding events (HR, 0.25; 95% CI, 0.10-0.61; P=.002 in complex PCI; HR, 0.62; 95% CI, 0.38-1.00; P=.05 in noncomplex PCI; P for interaction=.08), albeit with wide 95% CIs.

Conclusions and Relevance In this post hoc analysis of patients with ACS, prasugrel dose de-escalation compared with conventional therapy was not associated with an increased risk of ischemic outcomes but may reduce the risk of minor bleeding events at 1 year, irrespective of PCI complexity.


Intracranial Hemorrhage in the TST Trial

Pierre Amarenco, MD; Jong S. Kim, MD; Julien Labreuche, BST; Hugo Charles, BST; Maurice Giroud, MD; Philippa C. Lavallée, MD; Byung-Chul Lee, MD; Marie-Hélène Mahagne, MD; Elena Meseguer, MD; Norbert Nighoghossian, MD; Philippe Gabriel Steg, MD; Éric Vicaut, MD; Eric Bruckert, MD

Stroke. 2022;53(2):457-462.


Background and Purpose: Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH.

Methods: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of <70 mg/dL or 100±10 mg/dL, using statin or ezetimibe.

Results: Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38–4.04] and 2.32/1000 patient-years [95% CI, 1.61–3.03], respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01–6.31], P=0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00–5.62], P=0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH.

Conclusions:Targeting an LDL cholesterol of <70 mg/dL compared with 100±10 mg/dL in patients with atherosclerotic ischemic stroke nonsignificantly increased the risk of ICH. Incident ICHs were not associated with low LDL cholesterol. Uncontrolled hypertension and anticoagulant therapy were associated with ICH which has important clinical implications.


Preoperative Lower Extremity Motor Weakness Affects Deep Vein Thrombosis During the Perioperative Period of Lumbar Surgery

Takashi Imuro, MD; Mitsuru Saito, MD, PhD

Spine. 2022;47(3):E116-E123.


Study Design: Prospective cohort study.

Objective: The aim of this study was to assess preoperative factors in the development/exacerbation of deep vein thrombosis (DVT) in lumbar surgery and selectively perform lower-extremity venous ultrasonography (US) in patients at risk of perioperative deep vein thrombosis (DVT).

Summary of Background Data: DVT is often present before lumbar surgery and also can develop or is exacerbated postoperatively. An elevated D-dimer level is predictive of DVT but not in all patients or during every operative period. The level of the thrombogenic marker soluble fibrin monomer complex (SFMC) peaks early postoperatively.

Methods: The study enrolled 698 patients (396 males; 12– 91 years [346 patients aged ≥70 years] at surgery) undergoing surgery for lumbar degenerative diseases. Patients with D-dimer levels ≥0.5 μg/mL or with a lower-extremity manual muscle test (MMT) < grade 3 underwent preoperative US. All preoperative DVT-positive patients and patients with SFMC levels ≥20 μg/mL on postoperative day 1 (POD1) underwent US. Patients with pre- and postoperative femoral-vein DVT underwent screening for pulmonary embolism (PE).

Results: There were 251 patients with preoperative D-dimer levels ≥ 0.5 µg/mL, including 226 with MMT ≥ grade 3, 38 (16.8%) of whom were DVT-positive on US. In 48 patients with MMT

Conclusion: Preoperative DVT screening by US is advisable for patients with elevated D-dimer levels, lower extremities with MMT < grade 3, or DVT positivity. Postoperative US is advisable for patients with elevated SFMC levels on POD1.


Unfractionated Heparin Improves the Clinical Efficacy in Adult Sepsis Patients

Sifeng Fu; Sihan Yu; Liang Wang; Xiaochun Ma; Xu Li

BMC Anesthesiol. 2022;22(28)


Background: The anticoagulant treatment and clinical efficacy of heparin in sepsis remains controversial. We conducted a meta-analysis to estimate the clinical efficacy of unfractionated heparin (UFH) in adult septic patients.

Method: A systematic review of Medline, Cochrane Library, PubMed, Embase, WEIPU database, CNKI database, WANFANG database was performed from inception to January 2021. We included Randomized controlled trials (RCTs) and the main outcome was 28 d mortality. Data analysis was performed with Review Manager (RevMan) version 5.3 software. The meta-analysis included 2617 patients from 15 RCTs.

Results: Comparing to control group, UFH could reduce 28 d mortality (RR: 0.82; 95% CI: 0.72 to 0.94) especially for patient with Acute Physiology and Chronic Health Evaluation II (APACHE II) > 15, (RR: 0.83; 95% CI: 0.72 to 0.96). In UFH group, the platelet (PLT) (MD: 9.18; 95% CI: 0.68 to 17.68) was higher, the activated partial thromboplastin time (APTT) was shorter (MD: -8.01; 95% CI: − 13.84 to − 2.18) and the prothrombin time (PT) results (P > 0.05) failed to reach statistical significance. UFH decreased multiple organ dysfunction syndrome (MODS) incidence (RR: 0.61; 95% CI: 0.45 to 0.84), length of stay (LOS) in ICU (MD: -4.94; 95% CI: − 6.89 to − 2.99) and ventilation time (MD: -3.01; 95% CI: − 4.0 to − 2.02). And UFH had no adverse impact on bleeding (RR: 1.10; 95% CI: 0.54 to 2.23).

Conclusion: This meta-analysis suggests that UFH may reduce 28 d mortality and improve the clinical efficacy in sepsis patients without bleeding adverse effect.