April 2023: New In Coagulation

by Donna Castellone, MS, MT (ASCP) SH • April 06, 2023

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.

Ascend Laboratories LLC. Issues Voluntary Nationwide Recall of Dabigatran Etexilate Capsules, USP 75 mg and 150 mg, Due to the Detection of N-Nitroso-dabigatran (NDAB) Impurity

A voluntary recall of Dabigatran Etcxilate Capsules have been recalled due to the presence of a nitrosamine above the established acceptable daily intake in both 75mg and 150 mg tablets. Nitrosamines are common in water and foods however when exposed above acceptable levels over period of time may increase the risk of cancer. There have not been any received reports of adverse events to date.

Thrombectomy Linked to Better High-Risk Pulmonary Embolism Outcomes

The FLAME observational study looked at large-bore mechanical thrombectomy in patients with high risk PE. It was associate with less major adverse outcomes when compared with other procedures. The FlowTriever was used for clot removal and when compared to other thrombus removal, clinical deterioration and major bleeding, it exceeded performance 17.0% versus 32.0%. It works by unloading the right ventricle, reversing the shock spiral, improving oxygenation. There was an in hospital mortality rate of 1.9% in these patients compared to 29.5% in patients treated with other therapies.

Limitations of this study was that it was not a randomized trial, but was performed in 11 centers using concurrently enrolled patient using EMR, and eliminating bias. Treatment was at the physician discretion. There were a total of 115 patients (age 62-64) in the study in which 68.9% patients were treated with FlowTriever, 23.0% just anticoagulation, 6.6% catheter-directed thrombolytic and surgical thrombectomy in 1.6%. There was one stroke case in the FlowTriever arm as compared to four in the other treatment groups. There were 22.6% device related complications in the FlowTriever arm versus 16.4% in the other arm, however non of them were device related tricuspid valve injury, cardiac injury, or pulmonary vascular injury.

FDA Approves Weekly Factor Therapy for Hemophilia A

Results from the phase III GENEr-8 trial results in 112 men with severe hemophilia A showed that a single infusion of the gene therapy valoctocogene roxaparvovec led to significantly reduced bleeding rates. Valoctocogene roxaparvovec is an adeno-associated virus (AAV) 5-based gene therapy vector that targets factor VIII complementary DNA expression in the liver. In patients who had previously received standard FVIII prophylaxis the mean change in the annualized treated bleeding rate decreased by 84.5% from baseline to week 104. Based on pharmacokinetic modeling it indicated that FVIII levels would remain in the mild hemophilia range for up to 5 years post gene transfer. The model suggests level at five years would be 11.8 and 5.7 IU/dL, and fall into the mild hemophilia range. Valoctocogene roxaparvovec is an adeno-associated virus (AAV) 5-based gene therapy vector that targets factor VIII complementary DNA expression in the liver It provides more consistent protection and less treatment burden. Previous study findings were reported at 52 weeks.

FVIII levels were measured by a chromogenic assay increased from baseline by a mean of 22.0 IU/dL in the intend to treat (ITT) population. A decrease in FVIII expression was observed between year 1 and 2. The most common adverse event at 2 years is the elevated alanine aminotransferase levels which was seen in 88.8% of participants. This was treated with immunosuppressants. All serious adverse events occurred within the first 52 weeks post infusion.

Tirofiban Superior to Aspirin in Stroke Without Large Occlusion

Patients do better with tirofiban than low dose aspirin post stroke that does not have a visible large or medium intracranial vessel occlusion. IV athrombolysis within a 4.5 hour window is a proven treatment for stroke, but 50% have neurologic deterioration or no improvement, and less than 10% of patients benefit. Another therapy, endovascular treatment (EVT) is a proven treatment in patients with large or medium vessel occlusion. As a result, up to 40% of patients are ineligible. In small vessel stroke, many patients become disabled since there is no proven treatment except early antithrombotic therapy for prevention.

The efficacy and safety of tirofiban has been evaluated in the SETIS and SaTIS trial, one was stopped for lack of efficacy and the second showed no beneficial outcome. It was then investigated if it would be effective in a more select group of patients. Tirofiban is a highly selective fast-acting, non-peptide glycoprotein (GP) IIb/IIIa platelet receptor inhibitor that has a rapid onset of action and a short half-life (about 2 hours), said Zi. Research shows GP IIb/IIIa antagonists are effective for the treatment of acute coronary syndromes.

In a double-blind trail, the RESCUE-BT2 included 1177 patients ( median age 68, 64% male) in China with acute ischemic stroke without large or medium occlusion. Patients had to present within 24 hours of symptom onset, less than 96 hours of symptom onset but within 24 hours of stroke progression and be ineligible for IVT or EVT. Primary endpoint was good outcome and was achieved in 29.1% of the tirofiban groups and 22.2% of the aspirin group. A secondary groups was mortality at 90 days, 3.81 in the tirofiban group and 2,65% if the aspirin group died during the study period. ICH was seen in 0.99% in the tirofiban group and none in the aspirin group. A limitation of the study is that it only included Asian patients.

McMaster University researchers trial potential hemophilia treatment

A global study using a once weekly injection of efanesoctocog alfa can prevent bleeding and result in near normal FVIII activity. Patients also had improved joint function and better health with less pain. It works by separating FVIII from its carrier von Willebrand Factor. This overrides its half-life allow for weekly injections as opposed to three times weekly. The study looked at 133 hemophilia patients.

Clot Risk Generally Low for COVID Outpatients

A retrospective study of 398,530 outpatients (mean age 44, 54% female) with confirmed COVID-19 ( Jan 2020- Jan 2021). VTE was confirmed in 0.1% of patients which is a rate that is not much higher than in the general population. Three-fourths of the cohort were white, 11% Asian or Pacific Islander, and 6% were Black. More than half (54%) self-reported Hispanic ethnicity. There were 292 VTE events reported, 57.5% were pulmonary emboli, 34.9% were lower extremity deep venous thromboses (DVT), 5.1% were upper extremity.

Higher rates were identified in certain groups 30 days post COVID diagnosis, in which some type of intervention may be beneficial. This included subjects with a prior VTE, those with primary or secondary thrombophilia and people aged 75-84 years. Clinical trials are needed to see if these groups will benefit from anticoagulation. This study was conducted prior to the use of vaccines. Previous research has shown unvaccinated or partially vaccinated outpatients with COVID have a 28 fold higher risk of VTE compared to vaccinated sujbects who have a 6 fold increase. Opens in a Current ASH guidelines do not recommend routine anticoagulation in COVID outpatients or those who have been hospitalized. Study was done prior to Omicron variants and results may not be transferable.

FREEDOM COVID: Full-Dose Anticoagulation Cut Mortality but Missed Primary Endpoint

The FREEDOM COVID trial was a randomized trial of non-critically ill hospitalized patients(n = 3398) conducted between August 2022- September 2022. Up to 40% of the patients in the intention to treat population were from India. Patients were randomized to a therapeutic dose of LMWH enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

Results demonstrated that a therapeutic dose of anticoagulation relative to a prophylactic dose reduced death from COVID at 30 days. The rates of events in India were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries (Latin American, Europe and Hong Kong), the rates were 22.78 and 20.4, respectively. These results showed there were varying thresholds for hospitalization that may affect patient prognosis and the potential of advanced therapies.

The therapeutic arm results were combined and compared to the prophylactic arm. There was a 30% risk deduction of mortality in the therapeutic arm. This arm was also associated with a lower rate of intubation/mechanical ventilation that was found to be statistically significant.

The larger composite primary endpoint was missed which was the endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met.

Bleeding differences between groups were not significant although slightly higher in the group with therapeutic enoxaparin (0.5%) versus prophylactic enoxaparin (0,1%) while therapeutic apixaban was at 0.3%.

Trial Suggests Anticoagulation 'Sweet Spot' for COVID in the ICU

The ANTICOVID trial included 334 patients (mean 58.3 years, 32.3% female; April- Dec 2021) who presented with hypoxemic COVID-19 pneumonia requiring oxygen. Most patients had the Delta variant. Patients were admitted within 72 hours of enrollment at 23 centers in France and did not present with any initial thrombosis seen on chest CT and selected with a low bleeding risk. Patients were randomly assigned to start open-label treatment with standard-dose prophylactic anticoagulation, a dose two times higher (HD-PA), or therapeutic dose anticoagulation using low-molecular-weight or unfractionated heparin for 14 days or until hospital discharge or weaning off of supplemental oxygen for 48 consecutive hours, whichever came first. Up to 89.5% of patients were in the ICU and 60.8% were on high flow nasal oxygen.

There was not a clear anticoagulation strategy that was more beneficial in the hypoxic and critically ill COVID-19 population. Higher dose prophylaxis did decrease thrombotic risk without an increase in major bleeding. This was not seen in therapeutic dose anticoagulation. Limitations included the open label design and the risk of bias making clinical improvement subjective. While detection bias can't be denied because potential events like incidental thrombosis were less likely to be investigated in patients treated with higher dose anticoagulants.


Factor XI Inhibitors: Cardiovascular Perspectives

Raffaele De Caterina; Domenico Prisco; John W. Eikelboom
Eur Heart J. 2023;44(4):280-292.


Possible forthcoming therapeutic indications for FXI/XIa inhibitors. Anticoagulants are the cornerstone for prevention and treatment of thrombosis but are not completely effective, and concerns about the risk of bleeding continue to limit their uptake. Animal studies and experience from patients with genetic coagulation factor XI deficiency suggesting that this factor is more important for thrombosis than for haemostasis raises the potential for drugs that target factor XI to provide safer anticoagulation. Multiple factor XI inhibitors are currently under evaluation in clinical trials, including parenterally administered antisense oligonucleotides, monoclonal antibodies, and orally active small-molecule inhibitors. Promising results of phase 2 trials in patients undergoing major orthopaedic surgery, and in those with end-stage kidney disease, atrial fibrillation and acute coronary syndromes have led to large phase 3 trials that are currently ongoing. We here review premises for the use of these agents, results so far accrued, ongoing studies, and perspectives for future patient care.

Incidence and Outcomes of Thromboembolic and Bleeding Events in Patients With Liver Cirrhosis in the USA

Xiaoquan Huang; Marwan S. Abougergi; Chenyu Sun; Dermot Murphy; Vikram Sondhi; Bing Chen; Xin Zheng; Shiyao Chen; Yichen Wang
Liver International. 2023;43(2):434-441.


Background & Aims: Understanding the epidemiology of bleeding and thromboembolism (clotting) in liver cirrhosis provides important data for future studies and policymaking; however, head-to-head comparisons of bleeding and clotting remain limited.

Methods: This is a populational retrospective cohort study using the US National Readmission Database of 2018 to compare the incidence and outcomes of bleeding and clotting events in patients with liver cirrhosis. The primary outcomes were the 11-month incidence proportion of bleeding and clotting events.

Results: Of 1 304 815 participants, 26 569 had liver cirrhosis (45.0% women, mean age 57.2 [SD, 12.7] years). During the 11-month follow-up, in patients with cirrhosis, for bleeding and clotting events, the incidence proportions was 15.3% and 6.6%; the risk-standardized all-cause mortality rates were 2.4% and 1.0%; the rates of intensive care intervention were 4.1% and 1.9%; the rates of rehabilitation transfer were .2% and .2%; the cumulative length of stays were 45 100 and 23 566 days; total hospital costs were 147 and 84 million US dollars; total hospital charges were 620 and 365 million US dollars. Compared to non-cirrhosis, liver cirrhosis was associated with higher rates of bleeding (adjusted hazard ratio, 3.02 [95% CI, 2.85–3.20]) and portal vein thrombosis (PVT) (18.46 [14.86–22.92]), and slightly lower risks of other non-PVT venous thromboembolic events (.82 [.75–.89]).

Conclusions: Bleeding is more common than thromboembolism in patients with liver cirrhosis, causes higher morbidity, mortality and resource utilization. Liver cirrhosis is an independent risk factor for bleeding and PVT, but not non-PVT thromboembolism including venous thromboembolism, acute myocardial infarction and ischemic stroke.

Use of direct-acting oral anticoagulants associated with improved survival and bypass graft patency compared with warfarin after infrageniculate bypass

David P Ebertz, Saideep Bose, Justin A Smith, Anuja L Sarode, Ravi N Ambani, Jae S Cho, Norman H Kumins, Vikram S Kashyap, Benjamin D Colvard
2022 Dec 20;S0741-5214(22)02633-7.


Objective: No consensus has yet been reached regarding the optimal antiplatelet and anticoagulant regimen for patients after lower extremity bypass. Usually, patients who have undergone below-the-knee bypass will begin oral anticoagulation therapy. Historically, the bypass has been with prosthetic conduits and the anticoagulation therapy has been warfarin. However, the use of direct-acting oral anticoagulants (DOACs) has been increasing owing to their relative ease of dosing. The goal of the present study was to evaluate whether a difference exists in the postoperative outcomes for patients who have undergone infrageniculate bypass stratified by the use of on DOACs vs warfarin.

Methods: The Vascular Quality Initiative infrainguinal bypass database was queried for all patients who had undergone infrageniculate bypass, been anticoagulation naive at baseline, and been discharged with anticoagulation therapy. A survival analysis was performed for patients for ≤2 years postoperatively to determine whether discharge with warfarin vs DOACs was associated with differences in overall mortality, loss of primary patency, risk of amputation, and risk of major adverse limb events (MALE). A multivariable Cox proportional hazards analysis was performed to control for differences in the baseline demographic factors between the two groups.

Results: During the study period (2007-2020) 57,887 patients had undergone infrageniculate bypass. Of these patients, 2786 had been anticoagulation naive and discharged with either warfarin (n = 1889) or DOACs (n = 897). Discharge with a DOAC was associated with a lower risk of overall mortality (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.47-0.83; P = .001), loss of primary patency (HR, 0.74; 95% CI, 0.62-0.87; P < .001), risk of amputation (HR, 0.70; 95% CI, 0.57-0.86; P = .001), and risk of MALE (HR, 0.83; 95% CI, 0.71-0.97; P = .017).

Conclusions: Anticoagulation-naive patients who had undergone infrageniculate bypass had had higher rates of overall survival, bypass patency, amputation-free survival, and freedom from MALE when discharged with a DOAC than with warfarin.

Evidence-Based Minireview: Full dose, modified dose, or no anticoagulation for patients with cancer and acute VTE and thrombocytopenia

Rushad Patell, Jeffrey I Zwicker
Hematology Am Soc Hematol Educ Program
2022 Dec 9;2022(1):312-315.


Co-incident venous thromboembolism and thrombocytopenia are frequent in patients with active malignancies. The optimal approach for anticoagulation in patients with cancer and thrombocytopenia is not established. Different strategies are often utilized including dose-reduced anticoagulation dictated by degree of thrombocytopenia or transfusing platelets in order to facilitate therapeutic anticoagulation. This minireview provides an overview of the data and we outline our approach toward anticoagulation in patients with venous thromboembolism and thrombocytopenia in the setting of cancer.

Safety and efficacy of prophylactic anticoagulation versus therapeutic anticoagulation in hospital-admitted COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials

Robin Rauniyar, Sandip Kuikel, Aman Mishra, Rohit Rauniyar, Shikha Yadav, Sahil Thapaliya, Amit Sharma Nepal, Rahul Rauniyar
2023 Feb;17(2):73-79.


Background: COVID-19 disease-related coagulopathy and thromboembolic complication, an important aspect of the disease pathophysiology, are frequent and associated with poor outcomes, particularly significant in hospitalized patients. Undoubtedly, anticoagulation forms a cornerstone for the management of hospitalized COVID-19 patients, but the appropriate dosing has been inconclusive and a subject of research. We aim to review existing literature and compare safety and efficacy outcomes of prophylactic and therapeutic dose anticoagulation in such patients.

Methods: We did a systematic review and meta-analysis to compare the efficacy and safety of prophylactic dose anticoagulation when compared with therapeutic dosing in hospitalized COVID-19 patients. We searched PubMed, Google Scholar, EMBASE and COCHRANE databases from 2019 to 2021, without any restriction by language. We screened records, extracted data and assessed the risk of bias in the studies. RCTs that directly compare therapeutic and prophylactic anticoagulants dosing and are not placebo-controlled trials were included. Analyses of data were conducted using the Mantel-Haenszel random-effects model (DerSimonian-Laird analysis). The study is registered with PROSPERO (CRD42021265948).

Results: We included three studies in the final quantitative analysis. The incidence of thromboembolic events in therapeutic anticoagulation was lower in comparison with prophylactic anticoagulation in hospitalized COVID-19 patients and reached statistical significance [RR 1·45, 95% CI (1.07, 1.97) I2 -0%], whereas major bleeding as an adverse event was found lower in prophylactic anticoagulation in comparison with therapeutic anticoagulation that was statistically significant [RR 0·42, 95% CI(0.19, 0.93) I2 -0%].

Conclusion: Our study shows that therapeutic dose anticoagulation is more effective in preventing thromboembolic events than prophylactic dose but significantly increases the risk of major bleeding as an adverse event. So, the risk-benefit ratio must be considered while using either of them.