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New in Coagulation

Tuesday, January 3, 2017

What's New in Coagulation - January 2017

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.

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Popular Heartburn Medication Linked to Increased Stroke

A Danish study found that the drug used to treat stomach acid and heartburn have been linked to an increased risk of stroke. All of the four Proton pump inhibitors (PPIs) carried an increased risk however no risk was noted with histamine-2 blockers. This appears to be due to decreased production of nitric oxide resulting in endothelial dysfunction which was demonstrated in animal models.

PPIs are most likely a marker of increased risk rather than a direct cause of cardiovascular or neurovascular adverse outcomes. All results come from observational studies- not in randomized matched studies. Therefore the association indicates a causative effect. Results showed that the crude stroke incidence rates per 10,000 person-years were 88.9 for PPI use vs 55.7 for no PPI use. At the highest dose for these 4 PPIs, stroke risk increased from 33% to 79%. There were no increased risk at low doses.

These drugs should only be taken when indicated.

PJPAD at 10 Years: No CV Protection From Aspirin for Primary Prevention in Diabetics

A 10 year follow up to the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial found that low dose aspirin failed to reduce cardiovascular event. That trial involved 2539 patients with type 2 diabetes and no preexisting CV disease who were randomized to either aspirin (81 or 100 mg) daily or no aspirin. There was no significant difference between the primary end point of CV deaths (151 in aspirin group versus 163 in the non-aspirin group). Hemorrhagic events occurred in 6% of aspirin group versus 5% of those not taking aspirin, but GI bleeding occurred more often in the aspirin group (2%) however there was no intracranial hemorrhage.

New PAD Guidelines Stress Medical Management, Exercise

New U.S. guidelines for managing patients with peripheral artery disease (PAD) focus on medical therapy and structured exercise, as well as simply diagnosing this often underrecognized condition in at-risk patients. Guidelines were updated to recommend prescribing statins and antiplatelet therapy to these patients and dual therapy (aspirin and clopidogrel) may be appropriate in patients having vascular surgery or stenting.

Recommendations also include participation in a structured exercise program including walking and other exercise. Patients should not smoke nor be around second hand smoke. Flu shots are recommended to avoid cardiovascular complications.

Risk factors include being 65 or older and, among people 50 to 64, smoking, high cholesterol, high blood pressure, diabetes, or a family history of PAD. The document also underscores the importance of early recognition and treatment for PAD.

Increased VTE Risk for Men Starting Testosterone Therapy

Risk peaks in the first six months of homrone treatment, but overall odds are low

An increased risk of VTE peaks within 6 months of starting testosterone treatment. The rate is 1.63 versus those not taking testosterone. However after 6 months and upon stopping the treatment the rate falls to 1.0 and 0.68. Additional research is needed to investigate the incidence of the initial increase and the absence of risk with long term use.

Dabigatran May Be Better Than Warfarin After Bleeding Episode

Resuming any anticoagulant found safer than stopping the drugs in these cases

Dabigatran is less likely than warfarin to cause recurrent bleeding in atrial fibrillation patients who have experienced a major bleeding event based on data (2010-2012) from nearly 90,000 patients. Of those 1539 patients had a major bleeding event and ahlf resumed taking medication after the event. Stopping the anticoagulant increased the risk of stroke 23-34%. Patients on dabigatran were half as likely to have a major bleeding event over those taking warfarin.

More Frequent Creatinine Checks for Some Patients on Oral Anticoagulation

Patients on long term warfarin therapy and moderate renal impairment were most likely to develop severe impairment with a creatinine clearance < 30mL/min. This needs to be further investigated in patients receiving novel oral anticoagulants (NOACs). It is important to monitor renal function on patients on anticoagulants and adjusting the dose if needed. This may require more frequent than yearly monitoring to detect renal function deterioration. NOACs, unlike warfarin, are at least partly eliminated by the kidneys, so guidelines suggest that the dose may need to be reduced when patients have impaired kidney function.


Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A.

Haemophilia. 2016; (ISSN: 1365-2516)

Resuming any anticoagulant found safer than stopping the drugs in these cases

Mullins ES; Stasyshyn O; Alvarez-Román MT; Osman D; Liesner R; Engl W; Sharkhawy M; Abbuehl BE

INTRODUCTION: Primary factor VIII (FVIII) prophylaxis is the optimal treatment in children with severe haemophilia A. They are expected to benefit from extended half-life (T1/2 ) FVIII coverage by reduced infusion frequency while maintaining haemostatic efficacy.

AIMS: To determine immunogenicity, pharmacokinetics (PK), efficacy, safety and quality of life of prophylaxis with a polyethylene glycol (peg)-ylated FVIII (BAX 855) based on full-length recombinant FVIII (ADVATE) in paediatric previously treated patients (PTPs) with severe haemophilia A.

METHODS: PTPs <12 years without history of FVIII inhibitors received twice-weekly infusions of 50 ± 10 IU kg(-1) BAX 855 for ≥50 exposure days. Prophylactic dose increases to ≤80 IU kg(-1) were allowed under predefined conditions. PK was evaluated after single infusions of 60 ± 5 IU kg(-1).

RESULTS: T1/2 and mean residence time were extended 1.3- to 1.5-fold compared to ADVATE (n = 31), depending on the analysis used. The point estimate for the mean annualized bleeding rate in 66 subjects receiving a median of 1.9 weekly infusions of 51.3 IU kg(-1) of BAX 855 each was 3.04 (median 2.0); 1.10 (median 0) for joint and 1.16 (median 0) for spontaneous bleeds. Overall, 38% of subjects had zero bleeds. No bleeds were severe. Haemostatic efficacy was rated excellent or good for 90% of bleeds; 91% were treated with one or two infusions. In 8/14 subjects all target joints resolved. No subject developed FVIII inhibitors or persistent binding antibodies that affected safety or efficacy. No adverse reactions occurred.

CONCLUSION: Twice-weekly prophylaxis with BAX 855 was safe and efficacious in paediatric PTPs with severe haemophilia A.

Blood Group O Protects against Inhibitor Development in Severe Hemophilia A Patients.

Semin Throm Hemost. 2016; (ISSN: 1098-9064)

Resuming any anticoagulant found safer than stopping the drugs in these cases

Franchini M; Coppola A; Mengoli C; Rivolta GF; Riccardi F; Minno GD; Tagliaferri A;

Increasing evidence supports the link between ABO(H) blood group determinants and hemostasis. In particular, the ABO-related different glycosylation patterns of von Willebrand factor strongly influence its clearance and functional levels, and this may contribute to the inter-individual variations in the half-life of infused Factor VIII (FVIII) in hemophilia A (HA) patients. We investigated the role of ABO blood groups in regulating FVIII immunogenicity by evaluating their distribution in patients with severe (FVIII <1 IU/dL) HA according to inhibitor development and other known relevant factors. In a cohort of Italian severe HA patients (n=209), the ABO blood group distribution was similar to that in the healthy general population. However, the distribution of inhibitors, developed in 56 patients overall (26.8%), was significantly different in the four ABO phenotypes (O, 18.2%; A, 31.9%; B, 39.1%, AB, 25%; p=0.033); this difference seemed more pronounced when only high-titer inhibitors (overall, 21.1%) were considered (O, 11.4%; A, 27.7%; B, 34.8%; p=0.011). Relative risks in O versus non-O blood group were 0.55 (95% CI: 0.33-0.92) and 0.40 (95% CI: 0.21-0.77) for any and high-titer inhibitors, respectively. In a multivariate logistic regression, O blood group was shown to lower (approximately twofold) inhibitor risk, similarly with plasma-derived FVIII, whereas high-risk F8 mutations were associated with increased risk. However, the estimated effect of O blood type on inhibitor development was free from any significant correlation to other covariates, including presence of high-risk F8 mutations and type of replacement FVIII used. In this retrospective cohort of severe hemophiliacs, blood group O appears to protect against inhibitor development, with independent effects from other covariates. Larger prospective studies are needed to confirm this finding and to delve deeper into its pathophysiologic mechanisms.

Adherence to treatment regimen and bleeding rates in a prospective cohort of youth and young adults on low-dose daily prophylaxis for severe hemophilia A.

BMC Hematol. 2016; 16:26

Resuming any anticoagulant found safer than stopping the drugs in these cases

Mizrahi T; St. Louis J; Young NL; Ménard F; Zourikian N; Dubé E; Rivard GE

BACKGROUND: When availability and/or affordability of anti-hemophilic factor concentrates are limited, optimal prophylaxis regimens in severe hemophilia A (HA) remain to be determined. In selected situations, low-dose daily prophylaxis (LDDP) may be an effective and economical option. The goal of our study was to evaluate if subjects on a LDDP regimen could achieve adherence and good clinical outcome.

METHODS: Seventeen subjects (age between 15.2 and 28.4) on LDDP suffering from severe/moderate HA were followed prospectively for 2 to 3 years as part of a health-related quality of life (HRQoL) study. Bleeding and treatments data were collected using electronic diaries and validated every three months. The SF-36 questionnaire was administered at the beginning of the study and then every 6 months until the end of the study.

RESULTS: The subjects (mean age 22.0, median 21.9, standard deviation 4.06), were all from a single centre and on LDDP for at least 12 months as part of their routine care before entering the study. Fifteen subjects were prescribed a daily dose of 500 IU factor VIII (FVIII) and 2 subjects received 1000 IU FVIII per day, resulting into a median dose of 7.1 IU/kg/day (ranging from 4 to 13 IU/kg/day) and of 2591 IU/kg/year. Median adherence (the percentage of the prescribed daily dose received) was 84 % (mean 80 %, range 57 % to 94 %) throughout the study. Seventy-six bleeds in the 6 index joints and 51 other types of bleeds were observed throughout the study. The median annualized bleeding rate in joints (ABRjoints) was 0.7 and the median annualized bleeding rate for all bleeds (ABRall) was 1.6. The Physical Component and Mental Component Summary scores of SF-36, and the Hemophilia Joint Health Score were not significantly different over the course of the study (respective medians of 49.8, 52.4 and 16.0 at entry; vs. 52.5, 51.5 and 16.0 upon exit).

CONCLUSIONS: This prospective longitudinal study in youth and young adults shows that LDDP may be associated with low ABRs, adequate adherence and HRQoL comparable to previously reported.

Successful Use of Rivaroxaban in Postoperative Deep Vein Thrombosis of the Lower Limb Following Instability With Warfarin

A Case Report
Mario Schiavoni; Antonella Coluccia
J Med Case Reports. 2016;10(276)


Background: Evidence from clinical trials shows rivaroxaban to be effective for the treatment of deep vein thrombosis. Switching to rivaroxaban following failure of indirect anticoagulants in deep vein thrombosis has not been demonstrated in a real-life setting.

Case presentation: A 43-year-old white woman was switched from warfarin to rivaroxaban for the treatment of thrombosis of her right common femoral vein after saphenectomy. The reason for the switch was due to the instability of anti-coagulation therapy with vitamin K antagonists over a period of 3 months during which she did not reach the "therapeutic range" of prothrombin time-international normalized ratio.

The ineffectiveness of the conventional oral anticoagulant was confirmed by persistence of moderate-high values of fibrin D dimers (780 ng/ml) and by residual vein thrombosis at an ultrasound examination. Objectively, her right leg appeared to be still edematous and warm and pain was elicited by deep palpation. Rivaroxaban was administered after warfarin discontinuation (prothrombin time-international normalized ratio = 1.43) at a dosage of 15 mg every 12 hours for 3 weeks, followed by 20 mg once daily for 3 months. After this period, her objective symptoms significantly improved, with reduction of edema of her lower limb and pain relief. Her fibrin D dimer values returned to normal (210 ng/ml). An ultrasound showed recanalization of the obstructed venous segment.

Conclusions: In this case report, a switch to rivaroxaban from warfarin was shown to be effective and safe for the treatment of postoperative deep vein thrombosis, whereas standard oral anticoagulation therapy, which required dose adjustments over a period of 3 months, was not able to stabilize the therapeutic range of prothrombin time-international normalized ratio nor improve our patient's outcome.


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