December 2021: New In Coagulation

by Donna Castellone, MS, MT (ASCP) SH • December 08, 2021



Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.


Women Remain Most at Risk of Brain Vein Clots After J&J Vaccine

The highest risk of cerebral venous sinus thrombosis (CVST) was found in women receiving the J&J vaccine between the ages of 30-39, and 40-49. Women in general have a 5.1 fold higher risk post vaccine than prior to the pandemic. However, the absolute risk was still very low. The reason for this is unclear but it appears that concomitant CVST risk factors or antibody production might be involved. CVST occurred 15 days post vaccine. There were also six cases of CVST with thrombocytopenia which occurred within 6-13 days of vaccination.

When reviewing CVST cases prepandemic there were 39 cases reported and 29 were associated with a predisposing VTE risk factor with a median age of 41.

 

No Link Between TRT for Hypogonadism and Blood Clots, Study Finds

It has been speculated for some time whether testosterone replacement therapy (TRT) increased the risk of blood clots. The concern is that testosterone might increase the risk of DVT in men, as estrogen replacement therapy increases the risk of DVT in women. A 2019 age-adjusted analysis linked TRT to greater than twofold higher rates of venous thromboembolism in general in men with hypogonadism.

A study compared two groups of men with hypogonadism and found that those who suffered from DVT had similar risks whether they had TRT or not (34.96% versus 33.04%). There were 1.85 million men with hypogonadism were followed for 12 months. The 1.16% of then that developed DVT were not more likely to be on TRT. This suggests that TRT doesn't increase the risk, however more prospective research is needed. Risks and benefits of TRT need to be considered in all patients.

 

Ticagrelor Steps It Up for Stroke Patients With Impaired Clopidogrel Metabolism

The CHANCE-2 study was conducted at 202 centers in China in which 11,255 patients were screened. They enrolled 6412 patients who had a recent minor ischemic stroke or TIA and carried at least on CYP2C19 loss of function allele. Patients had a median age of 64.8 years and one third were women. The cohort was split between intermediate clopidogrel metabolizers (harboring one CYP2C19 loss-of-function allele; 78%) and poor metabolizers (harboring two or more such alleles; 22%). Patients were then randomized within 24 hours to either ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2 through 90) and placebo clopidogrel, or a group getting clopidogrel (300 mg on day 1 followed by 75 mg once daily on days 2 through 90) and placebo ticagrelor. Both groups received aspirin for 21 days. (180 mg on day 1 followed by 90 mg twice daily on days 2 through 90) and placebo clopidogrel, or a group getting clopidogrel (300 mg on day 1 followed by 75 mg once daily on days 2 through 90) and placebo ticagrelor. Both groups received aspirin for 21 days.

Survivors that carried the CYP2C19 loss of function alleles had better prevention when taking ticagrelor versus clopidogrel as an add on to aspirin. Subsequent strokes at 90 days occurred in 6.0% of ticagrelor versus 7.6% of those on clopidogrel. Severe or moderate bleeding rates were the same at 0.3% in both groups, with a slight increase in minor bleeds in the ticagrelor group of 5.3% versus 2.5% in the clopidogrel group.

Limitations including the study being performed on all Chinese cohort.

 

LAA Closure Holds Up Against NOACs

A 402 patient study of patients from stroke, TIA, systemic embolism, CV death and major or non major clinically relevant bleeding was conducted to look at late device related thrombus and leaks in patients with LAA closure and the Amulet or Watchman device. Results showed it remained noninferior to non-Vitamin K oral anticoagulants for the primary composite of safety and efficacy at 3.5 years. Bleeding rates were similar in both groups, but non procedural clinically relevant bleeding was significantly more common in the NOAC group. However up to 8.5% of the LAA closure group ended up on anticoagulants either due to treatment of VTE or for prevention.

LAA closure had hazard ratios of 0.68 (95% CI 0.39-1.20) for cardiovascular death and 1.14 (95% CI 0.56-2.30) for all-stroke or transient ischemic attack.

 

Gastrointestinal Damage Nearly Universal With Antiplatelet Use After PCI

Results of the OPT-PEACE trial found that all patients post percutaneous coronary intervention (PCI) on antiplatelets developed some form of GI injury, with those being on one antiplatelet had less occurrence. The trial was1028 double-blind randomized patients and conducted at 29 Chinese centers. Mean age was 57 and three in four were men. Patients included who had successful PCI with DES. Patients with a low bleeding risk who had capsule endoscopy, 783 had no other GI injuries were enrolled and give clopidogrel and aspirin for 6 months after that time another endoscopy was performed and 505 were randomized to one of three arms: one continuing DAPT, one just aspirin and one just clopidogrel. There were no adverse events or deaths at 12 months and reported GI symptoms were similar across the regimens. However, in a subset of patients lacking GI lesions after the initial 6 months of DAPT, those randomized to clopidogrel trended more GI mucosal injuries versus aspirin alone (96.2% vs 92.4%).

A limitation of the trial was the study was performed only on East Asian population.

 

Short DAPT Just as Good for High-Bleeding Risk Stenting After MI

The MASTER-DAPT trial demonstrated that for high risk bleeding patients a shorter duration of dual antiplatelet therapy (DAPT) was just as safe for those receiving novel stent after acute MI. Stopping DAPT at 30 days didn’t yield significantly different outcomes regardless if patients had a prior MI.

Abbreviated DAPT was defined as an immediate discontinuation of the anticoagulant in the regimen at randomization, while a single antiplatelet was continued to 1 year, or 5 months if an OAC was indicated. The non-abbreviated DAPT group received a full regimen for at least 2 months post randomization or 5 months if OAC used and antiplatelet monotherapy was continued to 1 year. DAPT duration was a median of 34 days in the abbreviated group compared with 193 days among controls.

There were 1780 patients who had an MI in the prior year in which 95% were acute at the time of the procedure. The prior MI group was more likely to continue P2Y12 inhibitors than aspirin after stopping anticoagulation. All cause mortality, MI, stroke and clinically relevant bleeding were similar between those getting anticoagulant in their DAPT regimen. Ischemic events showed the same pattern with no significant difference between groups.

One issue raised is if these results could be applied to other stent types.

 

Aspirin Flops Again for Dementia Prevention

Analysis conducted of the ASCEND trial on 15,000 diabetes patients demonstrated that dementia was no less common on those randomized to aspirin or placebo whether defined narrowly or broadly which included cognitive impairment, delirium or confusion, use of dementia medications and referral to memory clinic or geriatric psychiatry. The cognitive scores were essentially the same. The trial suggests there is little chance of cognitive harm from aspirin but a plausible benefit. These results were consistent with the ASPREE trial findings.

ASCEND also showed a reduction in major cardiovascular events with aspirin but an increase in major bleeding, resulting in no group in which the benefits would outweigh the risks.

 

Tranexamic Acid Eased Blood Loss During Myomectomy

An analysis of 71 patients undergoing myomectomy were compared with cases treated with TXA versus those who were not. Blood loss, blood transfusion administration and operative time were all measures. There were 26 cases that received TXA and 45 who did not. Average blood loss was 236ml, while all patients underwent procedures 53% undergoing laparoscopic and 40% undergoing robot assisted procedures. Mean age was 34, with 60% of participants that were Black, demographic characteristics and fibroid characteristics were similar between groups. But patients who received TXA were two and a half years younger. Adverse events were similar, no patient experience anaphylaxis, and there was one case of thromboembolism in a patient who did not receive TXA.

The use of TXA in women with large uterine fibroids had reduced blood loss during myomectomies, as well as in patients who had fibroids with a total weight greater than 173 g. Additionally, patients whose largest fibroid was greater than 73 mm had lower levels of blood loss with TXA (229.2 mL vs 408.3 mL, P=0.01). No patient in the study required a blood transfusion, operating time was 4 hours and not significantly different between the two groups.

 

Two Anticoagulants -- When Used Correctly -- Similarly Protective Against Dementia

The GIRAF trail was an open label trial that included 200 people average age of 75, and 60% were men with AFib or atrial flutter in which patients were randomized to dabigatran (110 or 150 mg twice/day) or warfarin with a targeted INR of 2-3 once/day. Neurologists conducted cognitive testing at baseline and at 2 years.

Cognitive outcomes were mostly the same between dabigatran (Pradaxa) and warfarin (Coumadin) users with nonvalvular atrial fibrillation (Afib) and no baseline dementia, a randomized trial showed. There were better trends found for better memory with the DOAC and better attention with warfarin. However this can be attributed to chance in this small 200 person study.

The potential mechanism for AF related cognitive decline include silent cerebral infarction, cerebral hypoperfusion and microbleeds. Also, since the time spent in the therapeutic range was 69.9% for the warfarin group, subtherapeutic warfarin uses may be associated with increased dementia. But these retrospective finding can be limited due to the confounding presence of baseline dementia, and its associated comorbidities.

The attrition rate was high with only 83 people in the dabigatran group and 66 in the warfarin group made it to the 2 year cognitive evaluation.

 

Aspirin: How Low Can You Go?

The DUTCH TIA trial looked at the difference in efficacy between 30mg and 283 mg of aspirin with less bleeding at the lower dose. The finding showed that the frequency of death from vascular causes, nonfatal stroke or nonfatal MI was 14.7% in the group receiving 30mg of aspirin versus 15.2% in those in the 283 mg group. There were fewer bleeding complications in the 30 versus 283 (40 versus 50) and significantly less minor bleeding (49 versus 84). There were also less GI symptoms in the lower group. These studies took place in the 1980 and 1990s.

In a review conducted in 2002 it was stated that within a few days of beginning 75 mg of aspirin cyclo-oxygenase is inhibited in platelets and that high doses of 500-1500mg are no more effective than medium doses of 150-325 or low doses of 75-159 mg/day. This supported 75-150mg for long term prevention of serious vascular events in high risk patients. When an immediated antithrombotic effect is required a loading dose of 150-300mg will produce rapid and complete inhibition of thromboxane mediated platelet aggregation.

While 30mg may be just as effective as doses >75mg, patients may be best served by staying with the dose that has been studied extensively and found to be effective in the largest number of patients.

 

Oral Factor XIa Inhibitor Cuts Post-Op VTE Risk: AXIOMATIC-TKR

Factor XI s a target for new anticoagulants since evidence has shown that FXI is important for thrombosis but dispensable for hemostasis. In a phase 2 study, the oral FXIa inhibitor milvexian given across a range of doses has been associated with a lower risk of VTE post knee arthroplasty when compared with subcutaneous enoxaparin without an increase in bleeding. It has showed a high degree of efficacy and safety.

Previous studies of parenteral factor XI inhibitors have shown that abelacimab is superior to enoxaparin for VTE prevention after knee surgery and that factor XIa inhibition with osocimab is noninferior.

The AXIOMATIC-TKR trial, 1242 patients post knee arthroplasty were randomly assigned to receive one of seven doses of milevexian (n=941)(25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or once-daily enoxaparin 40 mg (n=301) administered subcutaneously. Subjects in the once-daily 25mg group was stopped early due to insufficient efficacy and added to the 50mg group. The primary endpoint was VTE confirmed by venography or all cause death.

Results were as follows: Among patients taking milvexian twice daily, VTE occurred in 21% taking 25 mg, 11% taking 50 mg, 9% taking 100 mg, and 8% taking 200 mg. A dose-response relationship was also present in the milvexian once-daily groups, with VTE reported in 25% on 25 mg, 24% on 50 mg, and 7% on 200 mg, compared with 21% of patients taking once-daily enoxaparin.

The findings for VTE compared with enoxaparin were significant for the once-daily milvexian groups at 50, 100 and 200 mg and for twice-daily milvexian 200 mg. In addition, the combined 12% incidence of VTE in the twice-daily milvexian groups was significantly lower than the trial's prespecified benchmark of 30%. The principle safety outcome of bleeding occurred in 4% of patients on both milvexian and enoxaparin, while adverse events were reported in 39% of patients on milvexian and 38% of patients on enoxaparin.

There is no reversal agent currently available for milvexian however the drug has a short half life of 12 hours. However it is possible rot use tranexamic acid to manage bleeding and possibly very low doses of factor VIIa.

 

Stroke Thrombectomy Alone Fails Noninferiority to Bridging tPA

The SWIFT-DIRECT trial was a randomized trial that enrolled patients with acute ischemic stroke due to occlusion of the internal carotid artery or the M1 segment of the middle cerebral artery. The study was conducted at 48 sites in seven European countries and Canada. Subjects were randomly assigned to IV alteplase (0.9 mg/kg) plus mechanical thrombectomy with the Solitare device or direct mechanical thrombectomy with the same device. Treatment was open label with blinded endpoints. Median age was 72 with 50% of patients were women. There were 423 patients to treatment and 408 were included in the analysis, of that 201 participants received direct mechanical thrombectomy and 207 received IV thrombolysis plus thrombectomy. Primary outcome was functional independence and secondary outcomes included mortality at 90 days.

Results demonstrated a good functional outcome of 57% in patients who underwent direct thrombectomy and 65% among patients who received IV thrombolysis prior to undergoing thrombectomy. The result failed to demonstrate noninferiority of direct mechanical thrombectomy compared to combination therapy.

 

VTE Can Occur in Moderate COVID-19

A European study has found an elevated risk of venous thromboembolism (VTE) in COVID-19 patients who were not critically ill. The researchers tracked 2,292 patients who came to hospital emergency rooms with mild or moderate COVID-19 but without VTE. Four weeks later, VTE had developed in roughly 1 of every 200 mildly ill patients who had not been hospitalized and nearly 5 of every 200 moderately ill patients overall.

They conclude that doctors caring for mildly and moderately ill COVID-19 patients need to be aware of these risks, "especially in patients with moderate COVID-19 requiring hospitalization."

 

Potent Antiplatelet Not a Good Idea for Moderate COVID-19

Patients were randomized to receive an antiplatelet drug along with therapeutic heparin have fewer organ support free days through day 21 than those who received usual care without a P2Y12 inhibitor. In a Bayesian analysis there was a 81% likelihood that P2Y12 inhibitors were worse than placebo which terminated the trail of 562 patients. The study doesn't support the use of these agents in this moderate COVID-19 cohort. The trial included a population with confirmed SARS-CoV-2 with at least one higher-risk criterion -- elevated D-dimer, ages 60 to 84, need for more than 2 L/min oxygen, hypertension, diabetes, impaired kidney function, cardiovascular disease, or obesity.

Patients were randomized to 14 days of treatment with ticagrelor being the preferred P2Y12 inhibitor and used in 63% of patients. Median duration was 6 days. Major thrombotic events or in hospital death occurred more often in those on a P2Y12 inhibitor with a three fold increase in major bleeding.

The P2Y12 trial is ongoing for critically ill patients, defined as those needing high-flow oxygen, mechanical ventilation, vasopressors, inotropes, or extracorporeal membrane oxygenation support.

 

Hemophilia Gene Therapy Looks Like a Winner

Results from gene therapy for hemophilia A showed good results in 16/18 patients who were followed up for four years. A vector delivered agent called SPK-8011 increased levels of Factor VIII.

The cohort included 18 adult men aged 18-52 with FVIII activity less than 2% (less than 1% in 17 patients). There were more than a dozen different hemophilia A genotypes represented. Four doses were tested from 5×1011to 2×1012 vector genomes per kg of body weight. Initial response was substantial factor VIII expression. Follow up was a mean of 36.6 months with a 1 year mean activity of 11% using a one stage assay and 6.9% with a chromogenic assay.

Bleeding events fell by an average of 91.5% from pretreatment baseline, and that16 patients no longer required prophylactic FVIII infusions. The other 2 patients had immune responses to the AVV vector which initially increased FVIII levels, which then dropped off in a few months. Glucocorticoids were administered, however they did not improve response. These two patients also had short term reactions to the treatment including vomiting, muscle and back pain and elevated ALT.

Six other patients had milder ALT elevations which were attributed as signs of cellular immune response to the AAV capsid protein which resolved with steroid treatment. Overall, their findings support SPK-8011 as a viable approach for long term amelioration of hemophilia A.

 


JOURNAL CLUB

 

Diffuse Prothrombotic Syndrome After ChAdOx1 nCoV-19 Vaccine Administration

Nicole Ceschia; Valentina Scheggi; Anna Maria Gori; Angela Antonietta Rogolino; Francesca Cesari; Betti Giusti; Franco Cipollini; Niccolò Marchionni; Brunetto Alterini; Rossella Marcucci

J Med Case Reports. 2021;15(496)

Abstract and Introduction

Background: Vaccine-induced immune thrombotic thrombocytopenia is emerging as one of the most relevant side effects of adenoviral-based vaccines against coronavirus disease 2019. Given the novelty of this disease, the medical community is seeking new evidence and clinical experiences on the management of these patients.

Case Presentation: In this article, we describe the case of a 73-year-old Caucasian woman who presented with diffuse prothrombotic syndrome, both in the arterial and venous districts, following the first dose administration of ChAdOx1 CoV-19 vaccine. The main thrombotic sites included the brain, with both a cortical ischemic lesion and thromboses of the left transverse and sigmoid sinuses and the lower limbs, with deep venous thrombosis accompanied by subsegmental pulmonary thromboembolism. The deep venous thrombosis progressively evolved into acute limb ischemia, requiring surgical intervention with thromboendoarterectomy. Anticoagulation was maintained throughout the whole hospitalization period and continued in the outpatient setting using vitamin K antagonists for a recommended period of 6 months.

Conclusions: This case describes the management of vaccine-induced immune thrombotic thrombocytopenia in a complicated clinical scenario, including multisite arterial and venous thromboses. Given the complexity of the patient presentation, this case may implement the comprehension of the mechanisms and clinical features of this disease; it also provides a picture of the challenges related to the management, often requiring a multidisciplinary approach.