What's New in Coagulation - September 2017

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

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Gene Therapy Corrects Factor VIII Levels in Hemophilia A

A gene for Factor VIII packaged in a viral vector has demonstrated the ability to maintain levels of FVIII after 1 year. This eliminated spontaneous bleeds as well as the need for infusions during trauma or surgery. Six out of seven patients have maintained normal FVIII levels with the outsider being at about 20%. Gene therapy can maintain FVIII levels and may only have to be given once or twice in a lifetime. Even if low levels can only be achieved this can also prevent bleeding and the need for factor infusions.

A phase ½ study patients received a single IV dose containing various number of the viral genomes of adeno-associated virus type 5 containing a shortened, B-domain-deleted form of the FVIII gene (AAV5-FVIII; BMN270, BioMarin). The B domain was deleted because the size of the FVIII gene has previously hampered gene therapy.

Fifteen patients were enrolled; for those receiving a dose of 6 x1013 vg/kg, levels began to rise to the lower limit of normal at 8 weeks and in the midrange of normal up to 52 weeks. Those at a lower dose of 4 x 1013 vg/kg produced lower levels up to 40% in 16 weeks which persisted up to 52 weeks. Western blot analysis of plasma from the subjects showed that they were expressing the B-domain-deleted FVIII heavy chain coded for by the genome in the viral vector.

The target levels were >5%, however in both dose ranges the ABR has become zero. In the high dose group the pretreatement ABR was 16.5 versus the low dose group with an ABR of 8. Exogenous FVIII usage was reduced to zero versus 138.5 in the high dose group and 155.5 in the lower dose group. No inhibitors have been developed.

Liquid Biopsy Reads RNA Collected by Platelets to Diagnose Cancer

Platelets do not have a nucleus, therefore they do not have RNA, however they may gather RNA in their travels. This may come from tumors and absorbed by platelets. Researchers in The Netherlands designed a liquid biopsy test called thromboSeq which can diagnose non-small-cell lung cancer with close to 90% accuracy by detecting tumor RNA absorbed by circulating platelets. Encouraged by these results, the researchers suggest that thromboSeq might also show promise in detecting other cancers.

This test utilizes particle-swarm intelligence (PSO), which is a type of algorithm inspired by the way birds and insects swarm and self-organize to efficiently adapt to their environment. Tumor educated platelets interact with tumors versus platelets in a cancer free patient who will contain a different compilation of RNA. These algorithms can identify early and late stage NSCLC independent of smoking habits, blood storage and inflammation. Liquid based biopsy cancer may potentially be able to detect all cancers at an early stage as well as tumor type stratification.

Over 700 people were studied and found that early stage cancer was accurately diagnosed in 81% of early stage patients and 88% of late stage. Patients with chronic and inflammatory disease were also included to make sure the algorithm is screening for cancer specific RNA. There are plans to optimize the algorithm to further understand the mechanism and to hopefully start clinical trials.

Thromboembolism Risk Doubled in Cancer Patients

In the six months post a cancer diagnosis, patients have a significantly increased risk of arterial thromboembolism. The greatest incidence is seen in lung cancer patients. Cancer patients are twice as likely to develop an ischemic stroke and or MI in this period, with the risk disappearing after 1 year. Arterial thrombotic events in these patients have a greater 30 day mortality risk. Since cancer is such a heterogenous disorder, attributing this to a single cause is complicated.

Individual cancer histology plays a role via its effects on the clotting system but also that cancer treatments vary by cancer type and certain cancer treatments appear to increase the risk of heart attack and stroke, and the differences in treatment by cancer type will obviously reflect that. The first step is to determine how to reduce the risk in these patients. They are predisposed not only to developing thrombosis but also to bleeding, as chemotherapy can affect their bleeding risk, on top of which they undergo numerous invasive procedures. The risks and benefits of using anticoagulants need to be demonstrated in clinical trials.

Investigation of population data from the Surveillance Epidemiology and End Results (SEER) database which is linked to Medicare claims. Newly diagnosed patients with several types of cancer were identified and matched to controls without the disease (n=279,719). The incidence of ATE at 6 months was 4.7% versus 2.2% in controls, with the highest risk in lung cancer at 8.3%. After that time risk decreased and resolved by 1 year. However, the 30 day cumulative mortality was higher 17.6% in cancer patients versus 11.6% in controls.


Reversal Strategies for Non-vitamin K Antagonist Oral Anticoagulants: A Critical Appraisal of Available Evidence and Recommendations for Clinical Management

A Joint Position Paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and European Society of Cardiology Working Group on Thrombosis

Eur Heart J. 2017;38(22):1710-1716.

Alexander Niessner; Juan Tamargo; João Morais; Lorenz Koller; Sven Wassmann; Steen Elkaer Husted; Christian Torp-Pedersen; Keld Kjeldsen; Basil S. Lewis; Heinz Drexel; Juan Carlos Kaski; Dan Atar; Robert F. Storey; Gregory Y. H. Lip; Freek W. A. Verheugt; Stefan Agewall

Risk of Bleeding With Non-vitamin K Antagonist Oral Anticoagulants

Bleeding is the main adverse effect when using oral anticoagulants (OACs). The risk of major bleeding with vitamin K antagonists (VKAs) is dependent on the quality of anticoagulation control and estimated to be ~1.3/100 patients/year in patients with INR 2.0-3.0.[1,2] Multiple limitations of VKAs stimulated the development of non-vitamin K antagonist oral anticoagulants (NOACs) acting directly on coagulation factors, including factor FIIa (thrombin) and FXa. Pharmacological properties of the NOACs relevant for bleeding are summarized in the supplement including Supplementary material online, Table S1 and their main effects are summarized in Supplementary material online, Table S2 The risk of bleeding in patients managed with NOACs was properly assessed in the four landmark Phase III trials in patients with atrial fibrillation (AF; ). Major bleeding was the principal safety outcome in RE-LY,[3,4] ARISTOTLE,[5] and ENGAGE AF.[6] In ROCKET-AF, the primary safety endpoint was the composite of major and non-major clinically relevant bleeding.[7] The risk of major bleeding was significantly reduced with dabigatran 110 mg b.i.d., apixaban and both doses of edoxaban[3–6] while the bleeding rates for dabigatran 150 mg b.i.d. and rivaroxaban were similar to those with warfarin ().


While available clinical data for specific antidotes of NOACs are limited, it is very likely that these agents will successfully reverse the effect of NOACs as measured by specific coagulation tests. Another perceived advantage is the lack of a pro-thrombotic effect of the agent itself. However, uncontrolled studies will not give a definite answer to the question whether the clinical outcome will be improved. In the absence of specific antidotes, CFCs and/or haemodialysis for dabigatran may be a valuable alternative and may be used in addition to specific reversal agents in case of liver or renal failure. Before considering the use of a reversal agent for NOACs, a comprehensive pharmacological and clinical assessment of the usually complex situation of a critically ill patient is essential (). Furthermore, a set of general measures should precede the use of a reversal agent, as depicted in Figure 1. While the availability of specific reversal agents will increase the confidence in the benefit of NOACs in clinical practice, an overuse of specific reversal agents (beyond the tested indications) is of unclear advantage for patients. Prevention of bleeding in patients with NOACs by managing the bleeding risk of the patient and by respecting dose-reduction criteria[61] and contraindications remains essential. Even in patients who have survived life-threatening bleeding, restarting anticoagulation therapy is associated with reduced risks of thromboembolic events and mortality without increasing the risk of bleeding.[62] Thus, a timely restart of anticoagulant therapy (or alternative therapeutic strategies such as left atrial appendage occlusion) should be considered depending on the cause and the reversibility of the index bleeding event.

Consensus Statements

  • Global coagulation tests are not appropriate for measuring successful reversal of NOAC effects (ex vivo studies). Specific coagulation tests for the respective NOAC should be used.
  • CFCs should be used in case of life-threatening bleeding or emergency surgery in NOAC-treated patients when a specific reversal agent is not available or there are signs of systemic coagulopathy. There is no consistent superior effect of a specific CFC (ex vivo studies and animal studies). Pro-thrombin complex concentrates should be preferred over rFVIIa based on the inherent pro-thrombotic risk.
  • Idarucizumab, the first reversal agent tested in critically ill patients, is effective in reversing the effect of dabigatran measured by specific coagulation tests (uncontrolled clinical study) and has been approved by the European Medicines Agency and the U.S. Food and Drug Administration. Andexanet α targets the effect of direct and indirect FXa inhibitors and has been successfully tested in healthy volunteers so far. Ciraparantag (PER977) is designed to antagonize direct and indirect FXa inhibitors as well as dabigatran. In a Phase I study, PER977 was safe and well tolerated. Once approved by regulatory authorities, the use of specific antidotes for NOACs should be restricted to life-threatening bleeding or emergency surgery. Discontinuation of NOACs may be sufficient due to their rather short half-life for other situations requiring improved haemostasis. The effect of reversal agents on the clinical outcome in critically ill patients can only be assessed in controlled trials.
  • While specific antidotes for NOACs may not have an inherent pro-thrombotic effect, the sudden termination of anticoagulation in patients with a significant pro-thrombotic risk may cause thromboembolic events (Phase III study). The time point of restarting anticoagulation may therefore be crucial for the net clinical benefit.

General Care of the Pregnant Patient in the Intensive Care Unit

Timothy M.E. Crozier, MBBS (Hons), FRACP, FCICM, MPH

Semin Respir Crit Care Med. 2017;38(2):208-217.

Abstract and Introduction

Pregnant women represent a small subset of all intensive care unit (ICU) admissions and may require intensive care for "obstetric" or "nonobstetric" reasons. Women may be admitted to the ICU at any stage of pregnancy or in the postpartum period. Pregnancy may be discovered at the time of admission to the ICU. Pregnancy impacts on ICU care in a variety of ways and requires a multidisciplinary approach to management. Pregnancy is associated with considerable physiological changes that affect most organ systems, including an expansion in blood volume, an increase in minute ventilation, and an increased risk of thrombosis. The enlarging uterus may be associated with mechanical complications due to compression and displacement of other structures. The growing fetus places considerable demands upon the mother, being reliant on maternal systems for oxygenation, nutrition and disposal of carbon dioxide, and other waste products. This "second patient" must be considered when managing the pregnant woman. Optimal management of the mother usually constitutes best treatment for the fetus. Maternal shock and physiological disturbance, medications, and ionizing radiation from diagnostic imaging may have harmful effects on the unborn child. Delivery of the fetus for either maternal or fetal indications may be necessary and should be planned for, even if considered unlikely to be required. Care of the postpartum woman has its own challenges, including managing lactation and facilitating mother/infant contact. In this article, the general care aspects of ICU treatment of the pregnant woman will be discussed, including monitoring, physiological target setting, and general supportive care.

Ischemic Stroke Complicating Thrombolytic Therapy With Tenecteplase for ST Elevation Myocardial Infarction

Salim Arous; Meryem Haboub; Mohamed El Ghali Benouna; Tarik Bentaoune; Rachida Habbal

J Med Case Reports. 2017;11(154)


Hemorrhagic complications are quite common in the rare cases where thrombolysis is performed. Ischemic stroke in the aftermath of thrombolysis for a ST elevation myocardial infarction is a very rare and paradoxical complication. With these observations in mind we report two interesting cases of ischemic stroke which occurred after fibrinolytic therapy with tenecteplase for a ST elevation myocardial infarction.

Case Presentation:
The first case was a 56-year-old African man who presented with an acute infero-basal ST elevation myocardial infarction 6 hours after chest pain onset. Thrombolysis with tenecteplase was performed and few minutes later an ischemic stroke occurred. The second patient was a 65-year-old African man who presented with an acute infero-basal ST elevation myocardial infarction 5 hours after chest pain onset. Thrombolysis was performed and 10 hours later an ischemic stroke occurred.

Hemorrhagic stroke is not the only complication of thrombolysis, ischemic stroke can occur even if it is an extremely rare complication. The two cases on which we report shed light on the association between fibrinolytic therapy and ischemic stroke, the pathophysiology of which is not well understood.

Patients With Cirrhosis Who Have Coronary Artery Disease Treated With Cardiac Stents Have High Rates of Gastrointestinal Bleeding, but No Increased Mortality

T. Krill; G. Brown; R. A. Weideman; D. J. Cipher; S. J. Spechler; E. Brilakis; L. A. Feagins

Aliment Pharmacol Ther. 2017;46(2):183-192.

Abstract and Introduction

Patients with coronary artery disease (CAD) treated with stents require dual antiplatelet therapy (DAPT). For cirrhotics, who often have varices and coagulopathy, it is not clear if the risk of gastrointestinal bleeding (GIB) should preclude use of DAPT.

To compare GIB and mortality rates in cirrhotics with CAD treated medically or with stents.

Using institutional databases, we identified patients with cirrhosis and CAD treated with stents or medical therapy between January 2000-September 2015. Primary outcomes were GIB and mortality.

We identified 148 cirrhotics with CAD; 68 received stents (cases), 80 were treated with medical therapy (controls). Cases and controls had similar demographics, comorbidities, MELD scores and clinical presentation; DAPT was used in 98.5% of cases vs 5% of controls. The incidence of GIB was significantly higher in cases than controls (22.1% vs 5% at 1 year, P=.003; 27.9% vs 5% at 2 years, P=.0002), whereas all-cause mortality was similar (20.6% vs 21.3%). No patient required surgery or angiography for GIB, and no known patients died due to GIB. Multivariate analysis revealed use of a proton pump inhibitor (PPI) was highly protective against GIB (OR=0.26, 95%CI=0.08-0.79).

CAD treatment with stents in our cirrhotics was associated with a significantly increased risk of GIB, but no adverse effects on survival. Although it remains unclear whether the cardiovascular benefits of stents outweigh the GIB risk, our findings suggest that DAPT should not be withheld from stented cirrhotics for fear of GIB. Moreover, the use of a PPI should be strongly considered.