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New in Coagulation

Wednesday, January 3, 2018

What's New in Coagulation - January 2018

Written By Donna Castellone, MS, MT (ASCP) SH | LinkedIn

Want to be in the know? Check out our monthly compilation of the latest studies, guidelines, and discussions in coagulation.

Please note - many linked teasers require registered account/subscription in order to view the full articles. Medscape registration is free of charge.

Lytic Therapy, Clot Removal in DVT Doesn't Prevent Post-thrombotic Syndrome

A randomized comparison looked at treatment of DVT using thrombolytic agents, thrombectomy versus anticoagulation therapy. Post-thrombotic syndrome occurs in about half of patients with proximal DVT despite anticoagulation. The results of the comparison showed there was no difference in risk of post-thrombotic syndrome over 24 months (47% and 48% respectively). However, more invasive treatment was associated with a higher risk of major bleeding. Major bleeding within 10 days occurred in 1.7% of the pharmacomechanical-thrombolysis group vs 0.3% in the control group (P=0.049).

The trial included 692 patients with acute proximal DVT; 355 on warfarin alone, and 337 with anticoagulation plus pharmacomechanical thrombolysis. The outcome of PTS included a Villalta score of 5 or higher or the presence of a leg ulcer with DVT at 6 to 24 months.

The rate of recurrent venous thromboembolism within 24 months was 12% in pharmacomechanical-thrombolysis group. This included one fatal pulmonary embolism at 6 months. Among patients assigned to the control group, 8% had a recurrent venous thromboembolism (P=0.09).

There is controversy about the value of pharmacomechanical catheter-directed thrombolysis, which in this trial entailed catheter delivery of tPA to the thrombus along with thrombus aspiration or maceration in patients with DVT.

Results are disappointing that there is no difference in treatment. Research is needed to figure out why PTS develops, there are many unanswered questions in particular in the era of direct oral anticoagulants.

ACC Issues Guidance for Managing Bleeds From Oral Anticoagulants

A consensus document containing decision pathways to manage minor bleeding in patients on oral anticoagulants has been issued by the American College of Cardiology. This document aids in assessment of severity of the bleed, how to use reversal agents and when to restart anticoagulation. There are six algorithms and seven tables that are included in the document.

It addresses bleeding that arises from treatment with a DOAC-dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals), apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), or edoxaban (Savaysa/Lixiana, Daiichi Sankyo) - or a vitamin K antagonist (warfarin), for any indication, including atrial fibrillation (AF) in the absence of a prosthetic valve or venous thromboembolism.

One aspect that is critical is the assessment of major versus non major bleeding. Major bleeding is defined as "bleeding that is associated with hemodynamic compromise, occurs in an anatomically critical site, requires transfusion (≥2 U of packed red blood cells), or results in a hemoglobin drop ≥2 g/dL." All other bleeding is defined as nonmajor bleeding.

In patients on OAC, the bleeding assessment is important in treatment and to preserve organ function. Measurement of anticoagulation is key. In patients on vitamin K antagonists a PT/INR should be performed. Patients on dabigatran should have a dilute thrombin time, or ecarin clotting time while those on apixaban, edoxaban or rivaroxaban would be a chromogenic anti-Xa assay. These tests are not widely available. It also discusses reversal of OAC which include prothrombin complex concentrate, plasma, vitamin K and idarucizumab for dabigatran.

New Updates in Stroke and Parkinson Disease

1: A study published in the European Heart Journal, whether, if you treat AF with anticoagulation, you can prevent the development of dementia. A number of studies which basically show that people with AF have an increased risk for dementia. The study identified 444,106 patients who had AF in which the risk of developing dementia was reduced About half of them were anticoagulated and the other ones were not anticoagulated, for dementia was reduced by almost 30% in patients who were anticoagulated with either DOACs or warfarin.

2: In a study that investigated secondary stroke prevention and smoking in patients over a period of 5 years. The investigators looked at patients who at baseline had the event-stroke or TIA-and smoked; then they looked at patients who quit smoking in the next 5 years. This percentage at the beginning was about 30%, and 42% of these patients stopped smoking. What they observed was a risk reduction of 35% for a recurrent stroke, myocardial infarction, and vascular death if people stopped smoking. The benefit was very clear for stroke and death. It was not significant for myocardial infarction.

3: The third study looked at Parkinson's disease and the effect of caffeine and the possible impact on symptoms. A publication in Neurology investigated whether caffeine given twice daily in a dose of 200 mg in a period of between 6 and 18 months has an impact on the symptoms of Parkinson's disease. The study randomized 120 patients to either twice daily caffeine or placebo. No benefit was demonstrated in neurologic symptoms of Parkinsons. What the study does not answer is whether caffeine has a preventive effect on the cause of Parkinson's disease.

4: The last study was published in Annals of Neurology and investigated whether traumatic brain injury is a predictor of Parkinson's disease. The investigators identified almost 89,000 patients who had Parkinson's disease and 118,000 controls around the age of 65 years. They looked at the connection between traumatic brain injury in the past 5 years to the incidence of Parkinson's disease. They found that there was a 64% increase in the risk of developing Parkinson's disease if the traumatic brain injury was within the past 5 years. The risk increased with a shortening of the time interval between traumatic brain injury and Parkinson's disease. Now, whether there is a causal relationship or whether the traumatic brain injury happened due to falls-because the patients already started having motor symptoms of Parkinson-s disease-cannot be answered by this study. It also has no impact on patient handling because you cannot prevent traumatic brain injury or falls to prevent Parkinson's disease. At least it is an interesting study, indicating that head trauma and brain trauma might be risk factors for Parkinson's disease.

Commercial Air Transport Feasible for Aneurysmal Subarachnoid Hemorrhage

A study conducted in France showed that patients from rural areas who have aneurysmal subarachnoid hemorrhage (SAH) can be safely transported long distances on a plane to be sent to specialty treatment centers. There were 119 patients over 10 years in which 91 patients were transported. None of those patients had recurring hemorrhage, nor did they experience significant complications due to the transport. Median time between diagnosis and arrival at the treatment center was 32 hours. The 30 day fatality rate was 14.6% for treated cases.

The transferred patients differed significantly in some ways from those who were not. The surgery patients were significantly younger, on average, than those who had symptomatic treatment in Martinique (53-54 vs. 66 years). The median Glasgow Coma Score at diagnosis was significantly higher among transferred patients (15) than among those treated with surgery (6) or for symptoms (3). Brain aneurysm can be fatal in up to 40% of patients within a month after disease. There were no encounters of any complications during transport. The safety and the model for stroke system of care appears to have improved patient outcomes using commercial flights.


Tofacitinib and ruxolitinib, which are both Janus kinase (JAK) inhibitors have raised concerns about thromboembolic events. They are used in treatment of RA. As a result, baricitinib another JAK inhibitor for RA has been delayed by the FDA. These drugs act by suppressing one or more of the JAK enzymes (JAK1, JAK2, JAK3, and TYK2) and downregulating the JAK-STAT pathway. This inhibition reduces transcription and expression of genes involved in a wide variety of processes, including immunity, and cell proliferation.

The FDA Adverse Event reporting system database reported errors and complaints. The data set included 190 patients on ruxolitinib, 115 on tofacitinib and 12 on extended release. Complaints included pulmonary thrombosis (tofacitinib, 16; ruxolitinib, 9; tofacitinib XR, 3), pulmonary embolism (PE) (tofacitinib, 36; ruxolitinib, 55; tofacitinib XR, 3), portal vein thrombosis (tofacitinib, 0; ruxolitinib, 11; tofacitinib XR, 0), deep vein thrombosis (DVT; tofacitinib, 18; ruxolitinib, 40; tofacitinib XR, 1), and thrombosis (tofacitinib, 43; ruxolitinib, 75; tofacitinib, 5). Upon postmarketing review of the three FDA-approved JAK inhibitors, they did not find elevated reporting rates for DVT and PE specifically. However, the FAERS data indicated that pulmonary thrombosis may potentially be a class-wide issue for JAK inhibitors. Portal vein thrombosis may also be a potential risk for ruxolitinib.

Questions regarding the analysis was the small number of patients, and that the database may not have an accurate representation of all treated patients as well as the inflammatory process of the disease population. This report offers no comparison with analysis of biologic agents (eg, anti-[tumor necrosis factors]) or conventional synthetic [disease-modifying antirheumatic drugs] (methotrexate). There needs to be more evidence including a large database and real-world evidence. Something to consider is that both myelofibrosis and polycythemia vera are inherently associated with an increased risk of thrombosis and are both treated with JAK inhibitors.


A Test in Context: D-dimer

Jeffrey I. Weitz; James C. Fredenburgh; John W. Eikelboom

J Am Coll Cardiol. 2017;70(19):2411-2420.

Abstract and Introduction

D-dimer is a soluble fibrin degradation product that results from ordered breakdown of thrombi by the fibrinolytic system. Numerous studies have shown that D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis. Consequently, D-dimer has been extensively investigated for the diagnosis of venous thromboembolism (VTE) and is used routinely for this indication. In addition, D-dimer has been evaluated for determining the optimal duration of anticoagulation in VTE patients, for diagnosing and monitoring disseminated intravascular coagulation, and as an aid in the identification of medical patients at high risk for VTE. Thus, quantification of D-dimer levels serves an important role in guiding therapy. This review: 1) describes how D-dimer is generated; 2) reviews the assays used for its detection; and 3) discusses the role of D-dimer determination in these various conditions.

Thrombolysis in Postoperative Stroke

Nicolas Voelkel, MD; Nikolai Dominik Hubert, MSc; Roland Backhaus, MD; Roman Ludwig Haberl, MD; Gordian Jan Hubert, MD

Stroke. 2017;48(11):3034-3039.

Abstract and Introduction

Background and Purpose: Intravenous thrombolysis (IVT) is beneficial in reducing disability in selected patients with acute ischemic stroke. There are numerous contraindications to IVT. One is recent surgery. The aim of this study was to analyze the safety of IVT in patients with postoperative stroke.

Methods: Data of consecutive IVT patients from the Telemedical Project for Integrative Stroke Care thrombolysis registry (February 2003 to October 2014; n=4848) were retrospectively searched for keywords indicating preceding surgery. Patients were included if surgery was performed within the last 90 days before stroke. The primary outcome was defined as surgical site hemorrhage. Subgroups with major/minor surgery and recent/nonrecent surgery (within 10 days before IVT) were analyzed separately.

Results: One hundred thirty-four patients underwent surgical intervention before IVT. Surgery had been performed recently (days 1-10) in 49 (37%) and nonrecently (days 11-90) in 85 patients (63%). In 86 patients (64%), surgery was classified as major, and in 48 (36%) as minor. Nine patients (7%) developed surgical site hemorrhage after IVT, of whom 4 (3%) were serious, but none was fatal. One fatal bleeding occurred remotely from surgical area. Rate of surgical site hemorrhage was significantly higher in recent than in nonrecent surgery (14.3% versus 2.4%, respectively, odds ratio adjusted 10.73; 95% confidence interval, 1.88-61.27). Difference between patients with major and minor surgeries was less distinct (8.1% and 4.2%, respectively; odds ratio adjusted 4.03; 95% confidence interval, 0.65-25.04). Overall in-hospital mortality was 8.2%. Intracranial hemorrhage occurred in 9.7% and was asymptomatic in all cases.

Conclusions: IVT may be administered safely in postoperative patients as off-label use after appropriate risk-benefit assessment. However, bleeding risk in surgical area should be taken into account particularly in patients who have undergone surgery shortly before stroke onset.


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