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Posts Tagged ‘Prothrombin time’


Do Novel Anticoagulants Affect the PT/INR? The Cases of  XARELTO (rivaroxaban) or PRADAXA (dabigatran)

Curators: Vivek Lal, MBBS, MD, FCIR, Justin D Pearlman, MD, PhD, FACC

and

Article Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/16/2019

More of Xarelto’s scripts came from Medicare Part D patients in Q2 of this year compared with last, according to J&J’s earnings presentation. And J&J was on the hook for a bigger share of patient costs in Medicare Part D’s donut hole. Congress implemented the donut hole change last year, forcing drugmakers to pay more to move patients out of the coverage gap.

Once J&J gets a few quarters ahead of those changes, Xarelto should start turning in more impressive growth percentages, Duato said. How? J&J plans to grow Xarelto’s market share and volume in existing uses, plus focus on launches in new indications, Duato said, though he didn’t specify exactly how it’ll pump up that volume.

Bristol-Myers Squibb and Pfizer’s rival drug Eliquis is surely facing some of the same issues—the donut hole provision, for instance—but its sales look much healthier. While BMS hasn’t yet released second-quarter results, it did report a 36% boost to U.S. Eliquis sales in the first quarter, to $1.2 billion. For comparison, J&J’s Xarelto posted a 6.3% decrease to $542 million for the same period in the U.S.

SOURCE

J&J execs have plenty to brag about in pharma. Why downplay Xarelto, Zytiga woes?

https://www.fiercepharma.com/pharma/j-j-strives-for-above-market-growth-despite-challenges-for-zytiga-xarelto?mkt_tok=eyJpIjoiWldFNE1EY3dNemhoWWpOaiIsInQiOiJcL1BuSDVXcWZmMDd6NE9YQjV0S2ZRSTVKMnpWb3dZXC9NS3Q3NWlyb3BWUlBpZEF3SjZpUWdtTWRvemhIQ0hBa0lxa0h4WEdSc1p4XC9oTTQ2cmVpSG10dGJSTmp3cmJOMWNlb2xPNXVFeExVZ3d6cHJFdkFDc052NkUxMWozWitEaiJ9&mrkid=993697

 

UPDATED ON 7/21/2016

Xarelto Lawsuits

The blood-thinner Xarelto can cause uncontrolled bleeding — a dangerous and possibly fatal side effect for which there is no antidote. Plaintiffs who say they were harmed by the drug and family members who lost loved ones to severe bleeding filed lawsuits against Bayer, the drug’s maker. They claim Bayer failed to warn them and manufactured a faulty drug.

SOURCE

https://www.drugwatch.com/xarelto/lawsuit/

 

UPDATED on 8/4/2014

A cost-analysis model for anticoagulant treatment in the hospital setting

 

Journal of Medical Economics

July 2014, Vol. 17, No. 7 , Pages 492-498 (doi:10.3111/13696998.2014.914032)

 

 

aJanssen Scientific Affairs, LLC,

Raritan, NJ

USA

bAnalysis Group, Inc.,

Boston, MA

USA

cGroupe d’analyse, Ltée,

Montréal, Québec

Canada

dJanssen Scientific Affairs, LLC,

Raritan, NJ

USA

 

Address for correspondence: 

Lynn Huynh, Associate

Analysis Group, Inc.,

111 Huntington Ave. Tenth Floor, Boston, MA 02199

USA. Tel.: 617-425-8189; Fax: 617-425-8001

 

Abstract

Background:

Rivaroxaban is the first oral factor Xa inhibitor approved in the US to reduce the risk of stroke and blood clots among people with non-valvular atrial fibrillation, treat deep vein thrombosis (DVT), treat pulmonary embolism (PE), reduce the risk of recurrence of DVT and PE, and prevent DVT and PE after knee or hip replacement surgery. The objective of this study was to evaluate the costs from a hospital perspective of treating patients with rivaroxaban vs other anticoagulant agents across these five populations.

Methods:

An economic model was developed using treatment regimens from the ROCKET-AF, EINSTEIN-DVT and PE, and RECORD1-3 randomized clinical trials. The distribution of hospital admissions used in the model across the different populations was derived from the 2010 Healthcare Cost and Utilization Project database. The model compared total costs of anticoagulant treatment, monitoring, inpatient stay, and administration for patients receiving rivaroxaban vs other anticoagulant agents. The length of inpatient stay (LOS) was determined from the literature.

Results:

Across all populations, rivaroxaban was associated with an overall mean cost savings of $1520 per patient. The largest cost savings associated with rivaroxaban was observed in patients with DVT or PE ($6205 and $2742 per patient, respectively). The main driver of the cost savings resulted from the reduction in LOS associated with rivaroxaban, contributing to ∼90% of the total savings. Furthermore, the overall mean anticoagulant treatment cost was lower for rivaroxaban vs the reference groups.

Limitations:

The distribution of patients across indications used in the model may not be generalizable to all hospitals, where practice patterns may vary, and average LOS cost may not reflect the actual reimbursements that hospitals received.

Conclusion:

From a hospital perspective, the use of rivaroxaban may be associated with cost savings when compared to other anticoagulant treatments due to lower drug cost and shorter LOS associated with rivaroxaban.

 

SOURCE

http://informahealthcare.com/doi/abs/10.3111/13696998.2014.914032

 

 

Introduction

Justin D Pearlman, MD, PhD, FACC

The classic medication for chronic anti-coagulation is coumadin, but it is problematic. Coumadin impedes the production of coagulation proteins that depend on vitamin K (factors 7, 9, 10, and 2, in order of half-lifes, which range 2-72 hours). Consequently, a change in dose today does not have full impact for 2-3 days. Physicians and pharmacists have difficulties adjusting the dose to its target effect on the biomarker test International Normalized Ratio (INR). The therapeutic range is very narrow. A change in intake of leafy green vegetables can have profound impact (by changing intake of vitamin K). A change in virtually any medication or vitamin that can bind to albumin can also profoundly change the INR to a life-threatening level, because 80% of coumadin is inactivated by binding to albumin, and displacement of coumadin by other agents can boost the effective circulating amount. Those limitations, and the need for testing each month and each medication change have stimulated the development of alternatives. For example, rivaroxaban is a new anticogulant that focuses on factor 10 (factor X), deemed as good as coumadin without the need for the blood tests. In fact, INR test for rivaroxaban is misleading, as values may range as high at 7 (“DANGER”) at normal therapeutic dosing. The following reviews some of the data on that unexpected issue. Physicians not aware of this “false positive” have demanded stoppage of therapy due to the inapplicable spuriously high INR values.

UPDATED on 9/25

Dabigatran versus Warfarin in Patients with Mechanical Heart Valves

Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves.

RESULTS

The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding.

CONCLUSIONS

The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.)

SOURCE

N Engl J Med 2013; 369:1206-1214 September 26, 2013 DOI: 10.1056/NEJMoa1300615

UPDATED on 9/23

ESC: Edoxaban Bests Warfarin on Safety in VTE

By Peggy Peck, Editor-in-Chief, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Action Points

AMSTERDAM — Edoxaban, a novel factor Xa inhibitor, met its primary endpoints in a trial that pitted it against warfarin for treatment of symptomatic venous thromboembolism (VTE).

Among more than 8,000 patients with deep-vein thrombosis (DVT) or pulmonary embolism (PE), 130 (3.2%) of the patients treated with edoxaban had a recurrent, symptomatic VTE versus 146 (3.5%) warfarin-treated patients, a hazard ratio of 0.89 (95% CI 0.70-1.13, P<0.004 for non-inferiority), Harry R. Büller, MD, of the Academic Medical Center, Amsterdam, reported in a Hot Line session at theEuropean Society of Cardiology meeting here.

The safety endpoint was bleeding (major or clinically relevant non-major bleeding), and in that analysis edoxaban was superior to warfarin, as 8.5% of the edoxaban patients had bleeding events versus 10.3% of the patients in the warfarin group (P=0.004 for superiority).

Moreover, edoxaban appeared to work best in the highest-risk patients — 938 patients with pulmonary embolism and right ventricular dysfunction assessed by N-terminal pro-brain natriuretic peptide levels. In those patients, the recurrent VTE rate was 3.3% in the edoxaban group versus 6.2% in the warfarin group, Büller said.

Based on the results in that very high risk population, Büller predicted that clinicians treating those patients will consider that efficacy profile when selecting an oral Factor Xa inhibitor.

The study, from the Hokusai VTE Investigators, was simultaneously published online by the New England Journal of Medicine.

In the highly competitive oral anticoagulant group, those numbers look good, but at first blush the two already approved Factor Xa inhibitors, rivaroxaban (Xarelto) and apixaban (Eliquis) looked better when they were studied in VTE.

In EINSTEIN-VTE, rivaroxaban had a recurrent symptomatic VTE rate of 2.1%, and 8.1% of patients met the safety endpoint.

Likewise, in another VTE trial — AMPLIFY-EXT — apixaban (2.5 mg or 5 mg twice a day) had a recurrent or VTE-related death rate of 1.7%, and 3.2% of the patients who received low-dose apixaban reached the safety endpoint, as did 4.3% of patients treated with 5 mg of apixaban.

Patrick T. O’Gara, MD, American College of Cardiology president-elect, praised the design of the trial, but he agreed that “for mortality benefit, apixaban does appear to have the edge.”

That apixaban benefit, O’Gara said, is militated by the fact that patients need to take the drug twice daily, while “edoxaban is once a day, as is rivaroxaban.”

Asked if there was a specific population that might benefit from edoxaban versus rivaroxaban or apixaban, O’Gara, who is director of clinical cardiology at Brigham and Women’s Hospital and a professor at Harvard Medical School, said the findings from the Hokusai researchers did not provide that answer.

The attempt at a cross-trial comparison drew harsh criticism from Elliott Antman, MD, principal investigator in a trial of edoxaban for prevention of stroke in patients with atrial fibrillation (ENGAGE-AF).

Antman, who like O’Gara is a Harvard professor, said that comparing the edoxaban VTE results to EINSTEIN-VTE or AMPLIFY-EXT would only lead to false conclusions. “You could repeat the rivaroxaban trial 100 times and still not achieve data that can be compared.”

Stavros V. Konstantinides MD, PhD, of the Medical University in Mainz, Germany, who was the ESC discussant for the paper, said that, despite the advantage of once-daily dosing of edoxaban, “apixaban has the best safety profile so far.”

Moreover, unlike the VTE studies of apixaban and rivaroxaban, all patients in the Hokusai trial received heparin for 5 days. After that heparin run-in, patients were randomized to edoxaban or to warfarin. The median duration of heparin after randomization was 7 days.

Antman said that design best replicated real-world clinical practice, in which heparin is usually started before warfarin.

Buller noted that he was an investigator for the EINSTEIN-VTE study, “and after that the thinking was maybe we don’t need low molecular weight heparin, but now I think we need to reconsider that assumption.”

The Hokusai-VTE trial recruited 4,921 patients with DVT and 3,319 patients with PE. Patients initially were treated with heparin, and then were randomized to edoxaban (60 mg or 30 mg) or warfarin. There was an overlap of the heparin therapy when warfarin was started.

During a press conference, Keith Fox, MBChB, chair of the ESC scientific program, asked Buller if that overlap could have increased bleeding risk in the warfarin arm, thus introducing bias, but Buller said the overlap merely allowed warfarin to reach therapeutic range.

The edoxaban regimen “may be less handy, especially for early-discharge patients… [though] some doctors may feel more comfortable starting with low molecular weight heparin and then switching to edoxaban for the one-third of patients with severe PE,” Konstantinides said.

He added, “The NOACs [new oral anticoagulants] have shown efficacy and safety. Now, the test under real life conditions begins. They have to prove efficacy and safety there. I expect that. And they now must justify the high cost by showing … an improvement in patient treatment satisfaction and quality of life and, hopefully, a reduction in healthcare costs … with lower hospitalizations.”

The average age of patients in the Hokusai study was 56-57, and just over half were men.

Patients were enrolled from January 2011 through October 2012 at 439 centers in 37 countries.

About 40% of patients were treated for a year, and 80% of the edoxaban group was adherent to study treatment. Among the warfarin patients, average time in therapeutic range was 63.5%.

The study was supported by Daiichi-Sankyo, which is developing edoxaban.

Buller reported personal fees from Daichi Sankyo during the study, as well as grant support and personal fees from Bayer Health Care and Pfizer. He also received personnal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Isis Pharmaceuticals, and ThromboGenics outside the submitted work.

Antman has a research grant from Daiichi-Sankyo through Brigham and Women’s Hospital. O’Gara said he had no financial disclosures.

SOURCE

http://www.medpagetoday.com/MeetingCoverage/ESC/41301?isalert=1#!

END of UPDATE

Introduction

Author: Vivek Lal, MBBS, MD, FCIR

Pathological thromboembolism, as seen in Myocardial Infarction or stroke, led to the use of low dose aspirin as an-antiplatelet drug, as a prophylaxis for subsequent intravascular thrombotic episodes.  Aspirin, an irreversible Cyclo-oxygenase inhibitor, resulted in a reduction of the production of Thromboxane A2, which in itself is a powerful vaso-constrictor and a platelet aggregator.   Certain limitation with the use of aspirin necessitated the search for newer anti-platelet drugs, with a quicker onset of action, quick termination of action on cessation of treatment, and minimal side effects like bleeding.  ADP inhibitors like Clopidogrel, which inhibits the ADP dependent activation of Glycoprotein IIb/IIIa receptors, was the next in the armamentarium of these drugs.  Later, oral anti-coagulants like coumadin (warfarin sodium) were added to anti-platelet approach, to tackle the overactive coagulation cascade in pathological intravascular thrombosis.  Warfarin is a drug which counters the effects of Vit-K on the synthesis of coagulation factors in the liver.  Thus, all green leafy vegetables, which contain high amounts of Vit-K, will interfere with the action of Warfarin.   Moreover, warfarin is extremely prone to drug interations, owing to its biotransformation by hepatic microsomal enzymes, which are also metabolizing many other drugs.  Thus, a therapeutic drug monitoring of warfarin action is mandatory, which, is a big limitation to its use.  The quest for pharmacologically superior oral anticoagulants, as compared to Warfarin, reached an important milestone with the discovery of two major drugs, Dabigatran and Rivaroxaban.  Both these drugs are Direct Thrombin Inhibitors, though the indications and adverse events are somewhat different.  This post will discuss Rivaroxaban pharmacology in brief, and address certain clinical issues.

Question: Does rivaroxaban or dabigatran affect the PT or INR? Can either be monitored using the PT or INR?

Response from Jenny A. Van Amburgh, PharmD, CDE

Assistant Dean of Academic Affairs and Associate Clinical Professor, School of Pharmacy, Northeastern University; Director of the Clinical Pharmacy Team and Residency Program Director, Harbor Health Services, Inc., Boston, Massachusetts

Warfarin is the most commonly used anticoagulant for the prevention of thrombosis or stroke. Because of a narrow therapeutic window, it requires regular coagulation monitoring of the prothrombin time (PT)/international normalized ratio (INR).[1] As such, the inconvenience of frequent blood draws remains a major burden. For the first time in over 50 years, 2 new oral anticoagulants, dabigatran, a direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor, were approved by the US Food and Drug Administration. While these anticoagulants carry similar side effects to warfarin, such as risk for gastrointestinal bleeding and intracranial hemorrhage, INR and PT monitoring are not required. How then are providers to gauge the safety and efficacy of the medication in a patient? Can clinicians monitor these medications with the conventional coagulation assays, or are they rendered useless?[1]

The effect of both dabigatran and rivaroxaban on commonly used coagulation assays has been evaluated in the literature, both in vitro and in vivo. The usefulness of these tests relates directly to the medications’ mechanisms of action. For both agents, the use of an INR to determine the effectiveness and safety is meaningless because INR is calibrated for use with vitamin K antagonists (such as warfarin) only.[1] Although use may be associated with an increase in INR, this increase does not relate to the effectiveness of therapy or provide a linear correlation of concentration and effect that is seen when measuring warfarin levels.[2,3] In some instances, point-of-care INR measurements have been drawn on patients using dabigatran; however, the results have failed to correlate to appropriateness in therapy and have varied greatly case by case.[4]

As dabigatran directly inhibits thrombin, PT measures lack the sensitivity to detect therapeutic levels.[1,5] Often, if this assay is measured in patients taking dabigatran, a subtherapeutic level is noted, regardless of concentration of dabigatran.[6] More appropriate assays for dabigatran may be activated partial thromboplastin time (aPTT), diluted thrombin time (TT), or ecarin clotting time (ECT). These tests are better able to capture changes throughout the clotting cascade. Using aPTT may underestimate high levels and could be used more as a qualitative assessment of activity instead of a quantitative assessment.[7] Where available and if desired, monitoring via the diluted TT or ECT has proved a more useful measure for dabigatran.[1]

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Information from Industry

Unlike dabigatran, studies have demonstrated a correlation between the levels of rivaroxaban and PT through inhibition of factor Xa, but not to the same extent as warfarin.[8] In some instances, the use of PT monitoring for this medication may be useful. A linear response between PT and rivaroxaban can be seen; however, the accuracy of the test improves when concentrations of rivaroxaban are higher. Additionally, the use of PT for monitoring rivaroxaban can be difficult because the measurement differs greatly depending on the reagent used to determine PT. Calibrating PT assays to assess rivaroxaban appropriately is an option currently being evaluated.[8]

In conclusion, the INR is not a viable option when assessing the use of dabigatran or rivaroxaban. Additionally, PT is not a viable option when monitoring a patient on dabigatran. However, PT may be an option for monitoring select patients on rivaroxaban until more reliable standardized tests are developed. Methods of measuring the effectiveness of these agents are currently being developed and tested; however, until they are made available, the existing tests may be adapted to be used in a more effective manner.

The author wishes to acknowledge the assistance of Jacqueline M. Kraft, PharmD, Ngoc Diem Nguyen, PharmD, and Phillipa Scheele, PharmD, PGY1 Residents, and Michael P. Conley, PharmD, and Nga T. Pham, PharmD, CDE, AE-C, Assistant Clinical Professors at Northeastern University — School of Pharmacy and Harbor Health Services, Inc., Boston, Massachusetts.

References

  1. Favaloro EJ, Lippi G. The new oral anticoagulants and the future of haemostasis laboratory testing. Biochem Med (Zagreb). 2012;22:329-341.
  2. Dager WE, Gosselin RC, Kitchen S, Dwyre D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother. 2012;46:1627-1636. Abstract
  3. Samama MM, Martinoli JL, LeFlem L, et al. Assessment of laboratory assays to measure rivaroxaban — an oral, direct factor Xa inhibitor. Thromb Haemost. 2010;103:815-825. Abstract
  4. O’Riordan M. Falsely elevated point-of-care INR values in dabigatran-treated patients. Heartwire. July 7, 2011.http://www.theheart.org/article/1251461.do. Accessed January 11, 2013.
  5. Halbmayer WM, Weigel G, Quehenberger P, et al. Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. Clin Chem Lab Med. 2012;50:1601-1605. Abstract
  6. Lindahl TL, Baghaei F, Blixter IF, et al. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost. 2011;105:371-378. Abstract
  7. Freyburger G, Macouillard G, Labrouche S, Sztark F. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res. 2011;127:457-465. Abstract
  8. Hillarp A, Baghaei F, Fagerberg Blixter I, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost. 2011;9:133-139. Abstract

SOURCE

http://www.medscape.com/viewarticle/778063

PRADAXA (dabigatran)

COMPARE TO WARFARIN FOR AFIB NOT CAUSED BY A HEART VALVE PROBLEM

PRADAXA represents progress in helping to reduce the risk of stroke due to atrial fibrillation (AFib) not caused by a heart valve problem.

Review the chart below to compare PRADAXA and warfarin (also known as Coumadin® or Jantoven®). And find out why your doctor may choose PRADAXA. Remember, only your doctor can decide which treatment may be right for you.

Medication type:
Both PRADAXA and warfarin are anticoagulants. These blood-thinning medicines help to stop clots by targeting factors your blood needs to form clots.PRADAXA and warfarin work differently to help reduce the risk of stroke due to AFib not caused by a heart valve problem.
PRADAXA is a direct thrombin inhibitor that helps to stop clots from forming by working directly on thrombin.PRADAXA is not for use in people with artificial (prosthetic) heart valves Warfarin is a vitamin K antagonist that helps to stop clots from forming by interfering with vitamin K—a vitamin your body needs to form clots.
Stroke risk reduction:
PRADAXA and warfarin help to stop clots by targeting factors your blood needs to form clots.
In a clinical trial of more than 18,000 people, PRADAXA 150 mg capsules was proven superior to warfarin at reducing the risk of stroke. Warfarin has been extensively studied and prescribed by doctors to help reduce the risk of stroke in people with AFib since 1954.
How you take the medication: PRADAXA is taken by mouth 2 times each day. Warfarin is taken by mouth once every day.
Dosing options: PRADAXA comes in 75 mg and 150 mg strengths.Your doctor will decide which dose is right for you based on a simple kidney function test. Warfarin comes in 1 mg, 2 mg, 2-1/2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7-1/2 mg, and 10 mg strengths.Your doctor will decide which dose is right for you. He or she will adjust your dose based on the results ofregular blood tests.Based on these tests, your doctor will determine your dose and adjust it, if necessary.
Monitoring: No need for regular blood tests.PRADAXA has been clinically proven to help reduce the risk of stroke in people with AFib not caused by a heart valve problem. And, unlike warfarin, there is no need for regular blood tests to see if your blood-thinning level is in the right range.
Learn more 
Requires regular blood test.Warfarin has also been proven to be an effective blood thinner. When you take warfarin, you need to have a regular blood test to measure International Normalized Ratio (INR) to determine the time it takes for your blood to clot.
Dietary restrictions: No dietary restrictionsPRADAXA requires no changes to your diet. Dietary restrictions requiredWhen you take warfarin, you need to limit foods high in vitamin K, such as large amounts of leafy green vegetables and some vegetable oils. This is because Vitamin K can affect the way warfarin works in your body.You may also need to limit alcohol, cranberry juice, and products containing cranberries.

SOURCE

https://www.pradaxa.com/compare-warfarin.jsp

 XARELTO (rivaroxaban)

WHAT IS XARELTO®?

XARELTO® is a prescription medicine used to reduce the risk of stroke and blood clots in people with atrial fibrillation, not caused by a heart valve problem. For patients currently well managed on warfarin, there is limited information on how XARELTO® and warfarin compare in reducing the risk of stroke.

XARELTO® is also a prescription medicine used to treat deep vein thrombosis and pulmonary embolism, and to help reduce the risk of these conditions occurring again.

XARELTO® is also a prescription medicine used to reduce the risk of forming a blood clot in the legs and lungs of people who have just had knee or hip replacement surgery.

IMPORTANT SAFETY INFORMATION

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT XARELTO®?

  • For people taking XARELTO® for atrial fibrillation:
  • People with atrial fibrillation (an irregular heart beat) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. XARELTO® lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking XARELTO®, you may have increased risk of forming a clot in your blood.
  • Do not stop taking XARELTO® without talking to the doctor who prescribes it for you. Stopping XARELTO® increases your risk of having a stroke.
  • If you have to stop taking XARELTO®, your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.
  • XARELTO® can cause bleeding, which can be serious, and rarely may lead to death. This is because XARELTO® is a blood thinner medicine that reduces blood clotting. While you take XARELTO® you are likely to bruise more easily and it may take longer for bleeding to stop.

You may have a higher risk of bleeding if you take XARELTO® and take other medicines that increase your risk of bleeding, including:

  • Aspirin or aspirin-containing products
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Warfarin sodium (Coumadin®, Jantoven®)
  • Any medicine that contains heparin
  • Clopidogrel (Plavix®)
  • Other medicines to prevent or treat blood clots

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:

  • Unexpected bleeding or bleeding that lasts a long time, such as:
    • Nosebleeds that happen often
    • Unusual bleeding from gums
    • Menstrual bleeding that is heavier than normal, or vaginal bleeding
  • Bleeding that is severe or that you cannot control
  • Red, pink, or brown urine
  • Bright red or black stools (looks like tar)
  • Cough up blood or blood clots
  • Vomit blood or your vomit looks like “coffee grounds”
  • Headaches, feeling dizzy or weak
  • Pain, swelling, or new drainage at wound sites

Spinal or epidural blood clots (hematoma): People who take a blood thinner medicine (anticoagulant) like XARELTO®, and have medicine injected into their spinal and epidural area, or have a spinal puncture, have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:

  • A thin tube called an epidural catheter is placed in your back to give you certain medicine
  • You take NSAIDs or a medicine to prevent blood from clotting
  • You have a history of difficult or repeated epidural or spinal punctures
  • You have a history of problems with your spine or have had surgery on your spine

If you take XARELTO® and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have tingling, numbness, or muscle weakness, especially in your legs and feet.

XARELTO® is not for patients with artificial heart valves.

WHO SHOULD NOT TAKE XARELTO®?

Do not take XARELTO® if you:

  • Currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO® if you currently have unusual bleeding.
  • Are allergic to rivaroxaban or any of the ingredients of XARELTO®.

WHAT SHOULD I TELL MY DOCTOR BEFORE OR WHILE TAKING XARELTO®?

Before taking XARELTO®, tell your doctor if you:

  • Have ever had bleeding problems
  • Have liver or kidney problems
  • Have any other medical condition
  • Are pregnant or plan to become pregnant. It is not known if XARELTO® will harm your unborn baby. Tell your doctor right away if you become pregnant while taking XARELTO®. If you take XARELTO® during pregnancy, tell your doctor right away if you have bleeding or symptoms of blood loss.
  • Are breastfeeding or plan to breastfeed. It is not known if XARELTO® passes into your breast milk. You and your doctor should decide if you will take XARELTO® or breastfeed.

Tell all of your doctors and dentists that you are taking XARELTO®. They should talk to the doctor who prescribed XARELTO® for you before you have any surgery, medical or dental procedure.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way XARELTO® works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about XARELTO®?”

Especially tell your doctor if you take:

  • Ketoconazole (Nizoral®)
  • Itraconazole (Onmel™, Sporanox®)
  • Ritonavir (Norvir®)
  • Lopinavir/ritonavir (Kaletra®)
  • Indinavir (Crixivan®)
  • Carbamazepine (Carbatrol®, Equetro®, Tegretol®, Tegretol®-XR, Teril™, Epitol®)
  • Phenytoin (Dilantin-125®, Dilantin®)
  • Phenobarbital (Solfoton™)
  • Rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®)
  • St. John’s wort (Hypericum perforatum)

Ask your doctor if you are not sure if your medicine is one listed above. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

HOW SHOULD I TAKE XARELTO®?

Take XARELTO® exactly as prescribed by your doctor.

Do not change your dose or stop taking XARELTO® unless your doctor tells you to.

    • Your doctor will tell you how much XARELTO® to take and when to take it.
    • Your doctor may change your dose if needed.

If you take XARELTO® for:

    • Atrial Fibrillation: Take XARELTO® 1 time a day with your evening meal. If you miss a dose of XARELTO®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
    • Blood clots in the veins of your legs or lungs:
      • Take XARELTO® once or twice a day as prescribed by your doctor.
      • Take XARELTO® with food at the same time each day.
      • If you miss a dose of XARELTO®:
        • and take XARELTO® 2 times a day: Take XARELTO® as soon as you remember on the same day. You may take 2 doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.
        • and take XARELTO® 1 time a day: Take XARELTO® as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
    • Hip or knee replacement surgery: Take XARELTO® 1 time a day with or without food. If you miss a dose of XARELTO®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
  • If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take XARELTO®.
  • Your doctor will decide how long you should take XARELTO®. Do not stop taking XARELTO® without talking to your doctor first.
  • Your doctor may stop XARELTO® for a short time before any surgery, medical or dental procedure. Your doctor will tell you when to start taking XARELTO®again after your surgery or procedure.
  • Do not run out of XARELTO®. Refill your prescription for XARELTO® before you run out. When leaving the hospital following a hip or knee replacement, be sure that you have XARELTO® available to avoid missing any doses.
  • If you take too much XARELTO®, go to the nearest hospital emergency room or call your doctor right away.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF XARELTO®?

Please see “What is the most important information I should know about XARELTO®?”

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You are also encouraged to report side effects to the FDA: visit http://www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc., at 1-800-JANSSEN (1-800-526-7736).

Please see full Prescribing Information, including Boxed Warnings, and Medication Guide.

SOURCE

http://www.xarelto-us.com/?utm_source=google&utm_medium=cpc&utm_campaign=Branded+-+2013&utm_term=rivaroxaban&utm_content=Rivaroxaban|mkwid|soKteU2bx_dc|pcrid|29821628975

Figure-1 : Targets for anti-coagulant drugs in the coagulation cascade

Targets for anticoagulant drugs in the coagulation cascade

Pharmacology of Rivaroxaban 

Rivaroxaban, chemically an oxazolidinone derivative, is a directly acting Coagulation factor Xa inhibitor, acting on both free Factor Xa as well as that bound to the Prothrombinase complex.  It has a good oral bioavailability (~ 80-100%) and a rapid onset of action, with peak plasma concentrations being achieved in about 2-4 hours of oral intake.  It is about 95% plasma protein bound, with an aVd of about 50L.  It is partly metabolized in liver and excreted both unchanged as well as inactive metabolites in the urine, so also in the feces.  Strong CYP3A4 inhibitors like Ketoconazole, Ritonavir, Clarithromycin, Conivaptan etc can increase the pharmacodynamic effects of Rivaroxaban by a gross reduction in its metabolism.   Weaker CYP3A4 inhibitors like Amiodarone, Azithromycin, Diltiazem, Dronaderone, Erythromycin, Felodipine, Quinidine, Ranolazine, Verapamil maybe used with Rivaroxaban except in renal impairment.  Similarly, enzyme inducers like Rifampicin can decrease the plasma concentrations of Rivaroxaban.

Indications : Prophylaxis of stroke and systemic embolism in patients of atrial fibrillation, treatment and prevention of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE).

Dosage : 10-20 mg with or without food, depending on the indication.

Adverse Effects : As with any other anticoagulant, an increased risk of bleeding. An increased risk of stroke after discontinuation of the drug in atrial fibrillation, and spinal and epidural hematomas.

Therapeutic monitoring : Both Dabigatran and Rivaroxaban do not mandate a therapeutic monitoring clinically, as in the case of Warfarin.  Moreover, both Prothrombin Time (PT) as well as the International Normalized Ratio (INR) are not suitable to measure the pharmacodynamic profile of Rivaroxaban for various reasons1.  Development of novel methods of assays, for instance Anti Factor Xa assay which utilizes rivaroxaban containing plasma calibrators, may provide optimal therapeutic monitoring modalities for Rivaroxaban in the future.

Figure – 2 : PT and aPTT dependent on plasma concentration of anticoagulant drugs.

(A) rivaroxaban (experimental data from internal studies);

(B) DX-9065a (experimental data from the literature, and

(C) ximelagatran (experimental data for PT and aPTT from the literature. aPTT, activated partial thromboplastin time; INR, international normalized ratio; PT, prothrombin time.

PT

Riva

There is some concern regarding a spurious rise in the INR values if a patient stabilized on warfarin is switched over to Rivaroxaban.  This concern is ill-founded since it is already mentioned above that INR is not a suitable  investigation to give an indication of Rivaroxaban pharmacodynamics.   Moreover, no suitable litrerature is available which can explain the rise in INR values on Rivaroxaban administration.  It may require some additional clinical studies to throw some light on this clinical anomaly.

Figure-3 : Annualized Incidence of Complications of Rivaroxaban

complic

REFERENCE

  1. Lindhoff-Last et al. Assays for measuring Rivaroxaban : Their suitability and Limitations. Ther Drug Monitoring Dec 2010 (32, Issue 6): 673-79.

RESOURCES

Burghaus R, Coboeken K, Gaub T, Kuepfer L, et al. (2011) Evaluation of the Efficacy and Safety of Rivaroxaban Using a Computer Model for Blood Coagulation. PLoS ONE 6(4): e17626. doi:10.1371/journal.pone.0017626

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017626


Coumadin

Copyright © McGraw-Hill Education, LLC.  All rights reserved.
Hurst’s The Heart
 > Part 6. Rhythm and Conduction Disorders > Chapter 40. Atrial Fibrillation, Atrial Flutter, and Atrial Tachycardia > Atrial Fibrillation > Treatment > Anticoagulation > Antithrombotic Agents >

Rivaroxaban

Burghaus R, Coboeken K, Gaub T, Kuepfer L, et al. (2011) Evaluation of the Efficacy and Safety of Rivaroxaban Using a Computer Model for Blood Coagulation. PLoS ONE 6(4): e17626. doi:10.1371/journal.pone.0017626

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017626

Other articles published on this Open Access Online Scientific Journal include the following:

Xarelto (Rivaroxaban): Anticoagulant Therapy gains FDA New Indications and Risk Reduction for: (DVT) and (PE), while in use for Atrial fibrillation increase in Gastrointestinal (GI) Bleeding Reported

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Coagulation: Transition from a familiar model tied to Laboratory Testing, and the New Cellular-driven Model


Coagulation: Transition from a familiar model tied to Laboratory Testing, and the New Cellular-driven Model

 

Curator: Larry H. Bernstein, MD, FCAP 

Short Title: Coagulation viewed from Y to cellular biology.

PART I.

Summary: This portion of the series on PharmaceuticalIntelligence(wordpress.com) isthe first of a three part treatment of the diverse effects on platelets, the coagulation cascade, and protein-membrane interactions.  It is highly complex as the distinction between intrinsic and extrinsic pathways become blurred as a result of  endothelial shear stress, distinctly different than penetrating or traumatic injury.  In addition, other factors that come into play are also considered.  The second part will be directed toward low flow states, local and systemic inflammatory disease, oxidative stress, and hematologic disorders, bringing NO and the role of NO synthase in the process.   A third part will be focused on management of these states.

Coagulation Pathway

The workhorse tests of the modern coagulation laboratory, the prothrombin time (PT) and the activated partial thromboplastin time (aPTT), are the basis for the published extrinsic and intrinsic coagulation pathways.  This is, however, a much simpler model than one encounters delving into the mechanism and interactions involved in hemostasis and thrombosis, or in hemorrhagic disorders.

We first note that there are three components of the hemostatic system in all vertebrates:

  • Platelets,
  • vascular endothelium, and
  • plasma proteins.

The liver is the largest synthetic organ, which synthesizes

  • albumin,
  • acute phase proteins,
  • hormonal and metal binding proteins,
  • albumin,
  • IGF-1, and
  • prothrombin, mainly responsible for the distinction between plasma and serum (defibrinated plasma).

According to WH Seegers [Seegers WH,  Postclotting fates of thrombin.  Semin Thromb Hemost 1986;12(3):181-3], prothrombin is virtually all converted to thrombin in clotting, but Factor X is not. Large quantities of thrombin are inhibited by plasma and platelet AT III (heparin cofactor I), by heparin cofactor II, and by fibrin.  Antithrombin III, a serine protease, is a main inhibitor of thrombin and factor Xa in blood coagulation. The inhibitory function of antithrombin III is accelerated by heparin, but at the same time antithrombin III activity is also reduced. Heparin retards the thrombin-fibrinogen reaction, but otherwise the effectiveness of heparin as an anticoagulant depends on antithrombin III in laboratory experiments, as well as in therapeutics. The activation of prothrombin is inhibited, thereby inactivating  any thrombin or other vulnerable protease that might otherwise be generated. [Seegers WH, Antithrombin III. Theory and clinical applications. H. P. Smith Memorial Lecture. Am J Clin Pathol. 1978;69(4):299-359)].  With respect to platelet aggregation, platelets aggregate with thrombin-free autoprothrombin II-A. Aggregation is dependent on an intact release mechanism since inhibition of aggregation occurred with adenosine, colchicine, or EDTA. Autoprothrombin II-A reduces the sensitivity of platelets to aggregate with thrombin, but enhances epinephrine-mediated aggregation. [Herman GE, Seegers WH, Henry RL. Autoprothrombin ii-a, thrombin, and epinephrine: interrelated effects on platelet aggregation. Bibl Haematol 1977;44:21-7.]

A tetrapeptide, residues 6 to 9 in normal prothrombin, was isolated from the NH(2)-terminal, Ca(2+)-binding part of normal prothrombin. The peptide contained two residues of modified glutamic acid, gamma-carboxyglutamic acid. This amino acid gives normal prothrombin the Ca(2+)-binding ability that is necessary for its activation.

Abnormal prothrombin, induced by the vitamin K antagonist, dicoumarol, lacks these modified glutamic acid residues and that this is the reason why abnormal prothrombin does not bind Ca(2+) and is nonfunctioning in blood coagulation. [Stenflo J, Fernlund P, Egan W, Roepstorff P. Vitamin K dependent modifications of glutamic acid residues in prothrombin.  Proc Natl Acad Sci U S A. 1974;71(7):2730-3.]

Interestingly, a murine monoclonal antibody (H-11) binds a conserved epitope found at the amino terminal of the vitamin K-dependent blood proteins prothrombin, factors VII and X, and protein C. The sequence of polypeptide recognized contains 2 residues of gamma-carboxyglutamic acid, and binding of the antibody is inhibited by divalent metal ions.  The antibody bound specifically to a synthetic peptide corresponding to residues 1-12 of human prothrombin that was synthesized as the gamma-carboxyglutamic acid-containing derivative, but binding to the peptide was not inhibited by calcium ion. This suggested that binding by divalent metal ions is not due simply to neutralization of negative charge by Ca2+. [Church WR, Boulanger LL, Messier TL, Mann KG. Evidence for a common metal ion-dependent transition in the 4-carboxyglutamic acid domains of several vitamin K-dependent proteins. J Biol Chem. 1989;264(30):17882-7.]

Role of vascular endothelium.

I have identified the importance of prothrombin, thrombin, and the divalent cation Ca 2+ (1% of the total body pool), mention of heparin action, and of vitamin K (inhibited by warfarin).  Endothelial functions are inherently related to procoagulation and anticoagulation. The subendothelial matrix is a complex of many materials, most important related to coagulation being collagen and von Willebrand factor.

What about extrinsic and intrinsic pathways?  Tissue factor, when bound to factor VIIa, is the major activator of the extrinsic pathway of coagulation. Classically, tissue factor is not present in the plasma but only presented on cell surfaces at a wound site, which is “extrinsic” to the circulation.  Or is it that simple?

Endothelium is the major synthetic and storage site for von Willebrand factor (vWF).  vWF is…

  • secreted from the endothelial cell both into the plasma and also
  • abluminally into the subendothelial matrix, and
  • acts as the intercellular glue binding platelets to one another and also to the subendothelial matrix at an injury site.
  • acts as a carrier protein for factor VIII (antihemophilic factor).
  • It  binds to the platelet glycoprotein Ib/IX/V receptor and
  • mediates platelet adhesion to the vascular wall under shear. [Lefkowitz JB. Coagulation Pathway and Physiology. Chapter I. in Hemostasis Physiology. In ( ???), pp1-12].

Ca++ and phospholipids are necessary for all of the reactions that result in the activation of prothrombin to thrombin. Coagulation is initiated by an extrinsic mechanism that

  • generates small amounts of factor Xa, which in turn
  • activates small amounts of thrombin.

The tissue factor/factorVIIa proteolysis of factor X is quickly inhibited by tissue factor pathway inhibitor (TFPI).The small amounts of thrombin generated from the initial activation feedback

  • to create activated cofactors, factors Va and VIIIa, which in turn help to
  • generate more thrombin.
  • Tissue factor/factor VIIa is also capable of indirectly activating factor X through the activation of factor IX to factor IXa.
  • Finally, as more thrombin is created, it activates factor XI to factor XIa, thereby enhancing the ability to ultimately make more thrombin.

 

Coagulation cascade

Coagulation cascade (Photo credit: Wikipedia)

Coagulation Cascade

The procoagulant plasma coagulation cascade has traditionally been divided into the intrinsic and extrinsic pathways. The Waterfall/Cascade model consists of two separate initiations,

  • intrinsic (contact)and
    • The intrinsic pathway is initiated by a complex activation process of the so-called contact phase components,
      • prekallikrein,
      • high-molecular weight kininogen (HMWK) and
      • factor XII

Activation of the intrinsic pathway is promoted by non-biological surfaces, such as glass in a test tube, and is probably not of physiological importance, at least not in coagulation induced by trauma.

Instead, the physiological activation of coagulation is mediated exclusively via the extrinsic pathway, also known as the tissue factor pathway.

  • extrinsic pathways

Tissue factor (TF) is a membrane protein which is normally found in tissues. TF forms a procoagulant complex with factor VII, which activates factor IX and factor X.

  • common pathway which ultimately merge at the level of Factor Xa

Regulation of thrombin generation. Coagulation is triggered (initiation) by circulating trace amounts of fVIIa and locally exposed tissue factor (TF). Subsequent formations of fXa and thrombin are regulated by a tissue factor pathway inhibitor (TFPI) and antithrombin (AT). When the threshold level of thrombin is exceeded, thrombin activates platelets, fV, fVIII, and fXI to augment its own generation (propagation).

Activated factors IX and X (IXa and Xa) will activate prothrombin to thrombin and finally the formation of fibrin. Several of these reactions are much more efficient in the presence of phospholipids and protein cofactors factors V and VIII, which thrombin activates to Va and VIIIa by positive feedback reactions.

We depict the plasma coagulation emphasizing the importance of membrane surfaces for the coagulation processes. Coagulation is initiated when tissue factor (TF), an integral membrane protein, is exposed to plasma. TF is expressed on subendothelial cells (e.g. smooth muscle cells and fibroblasts), which are exposed after endothelium damage. Activated monocytes are also capable of exposing TF.

A small amount, approximately 1%, of activated factor VII (VIIa) is present in circulating blood and binds to TF. Free factor VIIa has poor enzymatic activity and the initiation is limited by the availability of its cofactor TF. The first steps in the formation of a blood clot is the specific activation of factor IX and X by the TF-VIIa complex. (Initiation of coagulation: Factor VIIa binds to tissue factor and activates factors IX and X). Coagulation is propagated by procoagulant enzymatic complexes that assemble on the negatively charged membrane surfaces of activated platelets. (Propagation of coagulation: Activation of factor X and prothrombin).  Once thrombin has been formed it will activate the procofactors, factor V and factor VIII, and these will then assemble in enzyme complexes. Factor IXa forms the tenase complex together with its cofactor factor VIIIa, and factor Xa is the enzymatic component of the prothrombinase complex with factor Va as cofactor.

Activation of protein C takes place on the surface of intact endothelial cells. When thrombin (IIa) reaches intact endothelium it binds with high affinity to a specific receptor called thrombomodulin. This shifts the specific activity of thrombin from being a procoagulant enzyme to an anticoagulant enzyme that activates protein C to activated protein C (APC).  The localization of protein C to the thrombin-thrombomodulin complex can be enhanced by the endothelial protein C receptor (EPCR), which is a transmembrane protein with high affinity for protein C.  Activated protein C (APC) binds to procoagulant surfaces such as the membrane of activated platelets where it finds and degrades the procoagulant cofactors Va and VIIIa, thereby shutting down the plasma coagulation.  Protein S (PS) is an important nonenzymatic  cofactor to APC in these reactions. (Degradation of factors Va and VIIIa).

Blood Coagulation (Thrombin) and Protein C Pat...

Blood Coagulation (Thrombin) and Protein C Pathways (Blood_Coagulation_and_Protein_C_Pathways.jpg) (Photo credit: Wikipedia)

The common theme in activation and regulation of plasma coagulation is the reduction in dimensionality. Most reactions take place in a 2D world that will increase the efficiency of the reactions dramatically. The localization and timing of the coagulation processes are also dependent on the formation of protein complexes on the surface of membranes. The coagulation processes can also be controlled by certain drugs that destroy the membrane binding ability of some coagulation proteins – these proteins will be lost in the 3D world and not able to form procoagulant complexes on surfaces.

Activated protein C resistance

Activated protein C resistance (Photo credit: Wikipedia)

Assembly of proteins on membranes – making a 3D world flat

  • The timing and efficiency of coagulation processes are handled by reduction in dimensionality
  • – Make 3 dimensions to 2 dimensions
  • Coagulation proteins have membrane binding capacity
  • Membranes provide non-coagulant and procoagulant surfaces
  • – Intact cells/activated cells
  • Membrane binding is a target for anticoagulant drugs
  • – Anti-vitamin K (e.g. warfarin)

Modern View

It can be divided into the phases of initiation, amplification and propagation.

  • In the initiation phase, small amounts of thrombin can be formed after exposure of tissue factor to blood.
  • In the amplification phase, the traces of thrombin will be inactivated or used for amplification of the coagulation process.

At this stage there is not enough thrombin to form insoluble fibrin. In order to proceed further thrombin  activates platelets, which provide a procoagulant surface for the coagulation factors. Thrombin will also activate the vital cofactors V and VIII that will assemble on the surface of activated platelets. Thrombin can also activate factor XI, which is important in a feedback mechanism.

In the final step, the propagation phase, the highly efficient tenase and prothrombinase complexes have been assembled on the membrane surface. This yields large amounts of thrombin at the site of injury that can cleave fibrinogen to insoluble fibrin. Factor XI activation by thrombin then activates factor IX, which leads to the formation of more tenase complexes. This ensures enough thrombin is formed, despite regulation of the initiating TF-FVIIa complex, thus ensuring formation of a stable fibrin clot. Factor XIII stabilizes the fibrin clot through crosslinking when activated by thrombin.

Platelet Aggregation

The activities of adenylate and guanylate cyclase and cyclic nucleotide 3′:5′-phosphodiesterase were determined during the aggregation of human blood platelets with

  • thrombin, ADP
  • arachidonic acid and
  • epinephrine

[Aggregation is dependent on an intact release mechanism since inhibition of aggregation occurred with adenosine, colchicine, or EDTA.  (Herman GE, Seegers WH, Henry RL. Autoprothrombin ii-a, thrombin, and epinephrine: interrelated effects on platelet aggregation. Bibl Haematol 1977;44:21-7)].

The activity of guanylate cyclase is altered to a much larger degree than adenylate cyclase, while cyclic nucleotide phosphodiesterase activity remains unchanged. During the early phases of thrombin- and ADP-induced platelet aggregation a marked activation of the guanylate cyclase occurs whereas aggregation induced by arachidonic acid or epinephrine results in a rapid diminution of this activity. In all four cases, the adenylate cyclase activity is only slightly decreased when examined under identical conditions.

Platelet aggregation induced by a wide variety of aggregating agents including collagen and platelet isoantibodies results in the “release” of only small amounts (1–3%) of guanylate cyclase and cyclic nucleotide phosphodiesterase and no adenylate cyclase. The guanylate cyclase and cyclic nucleotide phosphodiesterase activities are associated almost entirely with the soluble cytoplasmic fraction of the platelet, while the adenylate cyclase is found exclusively in a membrane bound form. ADP and epinephrine moderately inhibit guanylate and adenylate cyclase in subcellular preparations, while arachidonic and other unsaturated fatty acids moderately stimulate (2–4-fold) the former.

  1. The platelet guanylate cyclase activity during aggregation depends on the nature and mode of action of the inducing agent.
  2. The membrane adenylate cyclase activity during aggregation is independent of the aggregating agent and is associated with a reduction of activity and
  3. Cyclic nucleotide phosphodiesterase remains unchanged during the process of platelet aggregation and release.

Furthermore, these observations suggest a role for unsaturated fatty acids in the control of intracellular cyclic GMP levels. Arachidonic acid, once deemed essential, is a derivative of linoleic acid. (Barbera AJ. Cyclic nucleotides and platelet aggregation effect of aggregating agents on the activity of cyclic nucleotide-metabolizing enzymes. Biochimica et Biophysica Acta (BBA) 1976; 444 (2): 579–595. http://dx.doi.org/10.1016/0304-4165(76)90402-5).

Leukocyte and platelet adhesion under flow

The basic principles concerning mechanical stress demonstrated by Robert Hooke (1635-1703) proved to be essential for the understanding of pathophysiological mechanisms in the vascular bed.

In physics, stress is the internal distribution of forces within a body that balance and react to the external loads applied to it. Stress is a 2nd order tensor. The hemodynamic conditions inside blood vessels lead to the development of superficial stresses near the vessel walls, which can be divided into two categories:

a) circumferential stress due to pulse pressure variation inside the vessel;

b) shear stress due to blood flow.

The direction of the shear stress vector is determined by the direction of the blood flow velocity vector very close to the vessel wall. Shear stress is applied by the blood against the vessel wall. Friction is the force applied by the wall to the blood and has a direction opposite to the blood flow. The tensions acting against the vessel wall are likely to be determined by blood flow conditions. Shear stresses are most complicated during turbulent flow, regions of flow recirculation or flow separation.

The notions of shear rate and fluid viscosity should be first clearly apprehended, since they are crucial for the assessment and development of shear stress. Shear rate is defined as the rate at which adjacent layers of fluid move with respect to each other, usually expressed as reciprocal seconds. The size of the shear rate gives an indication of the shape of the velocity profile for a given situation.  The determination of shear stresses on a surface is based on the fundamental assumption of fluid mechanics, according to which the velocity of fluid upon the surface is zero (no-slip condition). Assuming that the blood is an ideal Newtonian fluid with constant viscosity, the flow is steady and laminar and the vessel is straight, cylindrical and inelastic, which is not the case. Under ideal conditions a parabolic velocity profile could be assumed.

The following assumptions have been made:

  1. The blood is considered as a Newtonian fluid.
  2. The vessel cross sectional area is cylindrical.
  3. The vessel is straight with inelastic walls.
  4. The blood flow is steady and laminar.

The Haagen-Poisseuille equation indicates that shear stress is directly proportional to blood flow rate and inversely proportional to vessel diameter.

Viscosity is a property of a fluid that offers resistance to flow, and it is a measure of the combined effects of adhesion and cohesion. It increases as temperature decreases. Blood viscosity (non-Newtonian fluid) depends on shear rate, which is determined by blood platelets, red cells, etc. Moreover, it is slightly affected by shear rate changes at low levels of hematocrit. In contrast, as hematocrit increases, the effect of shear rate changes on blood viscosity becomes greater. Blood viscosity measurement is required for the accurate calculation of shear stress in veins or microcirculation.

It has to be emphasised that the dependence of blood viscosity on hematocrit is more pronounced in the microcirculation than in larger vessels, due to hematocrit variations observed in small vessels (lumen diameter <100 Ìm). The significant change of hematocrit in relation to vessel diameter is associated with the tendencyof red blood cells to travel closer to the centre of the vessels. Thus, the greater the decrease in vessel lumen, the smaller the number of red blood cells that pass through, resulting in a decrease in blood viscosity.

Shear stress and vascular endothelium

Endothelium responds to shear stress through various pathophysiological mechanisms depending on the kind and the magnitude of shear stresses. More specifically, the exposure of vascular endothelium to shear forces in the normal value range stimulates endothelial cells to release agents with direct or indirect antithrombotic properties, such as prostacyclin, nitric oxide (NO), calcium, thrombomodulin, etc.  The possible existence of so-called “mechanoreceptors” has provoked a number of research groups to propose receptors which “translate” mechanical forces into biological signals.

Under normal shear conditions, endothelial as well as smooth muscle cells have a rather low rate of proliferation. Changes in shear stress magnitude activate cellular proliferation mechanisms as well as vascular remodeling processes. More specifically, a high grade of shear stress increases wall thickness and expands the vessel’s diameter, so that shear stress values return to their normal values. In contrast, low shear stress induces a reduction in vessel diameter. Shear stresses stimulate vasoregulatory mechanisms which, together with alterations of arterial diameter, serves to maintain a mean shear stress level of about 15 dynes/cm2. The presence of low shear stresses is frequently accompanied by unstable flow conditions (e.g. turbulence flow, regions of blood recirculation, “stagnant” blood areas).

(Papaioannou TG, Stefanadis C. Vascular Wall Shear Stress: Basic Principles and Methods. Hellenic J Cardiol 2005; 46: 9-15.)

Leukocyte adhesion under flow in the microvasculature is mediated by binding between cell surface receptors and complementary ligands expressed on the surface of the endothelium. Leukocytes adhere to endothelium in a two-step mechanism: rolling (primarily mediated by selectins) followed by firm adhesion (primarily mediated by integrins). These investigators simulated the adhesion of a cell to a surface in flow, and elucidated the relationship between receptor–ligand functional properties and the dynamics of adhesion using a computational method called ‘‘Adhesive Dynamics.’’ This relationship was expressed in a one-to-one map between the biophysical properties of adhesion molecules and various adhesive behaviors.

Behaviors that are observed in simulations include firm adhesion, transient adhesion (rolling), and no adhesion. They varied the dissociative properties, association rate, bond elasticity, and shear rate and found that the unstressed dissociation rate, kro, and the bond interaction length, γ, are the most important molecular properties controlling the dynamics of adhesion.

(Chang KC, Tees DFJ and Hammer DA. The state diagram for cell adhesion under flow: Leukocyte rolling and firm adhesion. PNAS 2000; 97(21):11262-11267.)

The study of the effect of leukocyte adhesion on blood flow in small vessels is of primary interest to understand the resistance changes in venular microcirculation when blood is considered as a homogeneous Newtonian fluid. When studying the effect of leukocyte adhesion on the non-Newtonian Casson fluid flow of blood in small venules; the Casson model represents the effect of red blood cell aggregation. In this model the blood vessel is considered as a circular cylinder and the leukocyte is considered as a truncated spherical protrusion in the inner side of the blood vessel. Numerical simulations demonstrated that for a Casson fluid with hematocrit of 0.4 and flow rate Q = 0:072 nl/s, a single leukocyte increases flow resistance by 5% in a 32 m diameter and 100 m long vessel. For a smaller vessel of 18 m, the flow resistance increases by 15%.

(Das B, Johnson PC, and Popel AS. Computational fluid dynamic studies of leukocyte adhesion effects on non-Newtonian blood flow through microvessels. Biorheology  2000; 37:239–258.)

Biologists have identified many of the molecular constituents that mediate adhesive interactions between white blood cells, the cell layer that lines blood vessels, blood components, and foreign bodies. However, the mechanics of how blood cells interact with one another and with biological or synthetic surfaces is quite complex: owing to the deformability of cells, the variation in vessel geometry, and the large number of competing chemistries present (Lipowski et al., 1991, 1996).

Adhesive interactions between white blood cells and the interior surface of the blood vessels they contact is important in inflammation and in the progression of heart disease. Parallel-plate microchannels have been useful in characterizing the strength of these interactions, in conditions that are much simplified over the complex environment these cells experience in the body. Recent computational and experimental work by several laboratories have attempted to bridge this gap between behavior observed in flow chamber experiments, and cell surface interactions observed in the microvessels of anesthetized animals.

We have developed a computational simulation of specific adhesive interactions between cells and surfaces under flow. In the adhesive dynamics formulation, adhesion molecules are modeled as compliant springs. One well-known model used to describe the kinetics of single biomolecular bond failure is due to Bell, which relates the rate of dissociation kr to the magnitude of the force on the bond F. The rate of formation directly follows from the Boltzmann distribution for affinity. The expression for the binding rate must also incorporate the effect of the relative motion of the two surfaces. Unless firmly adhered to a surface, white blood cells can be effectively modeled as rigid spherical particles, as evidenced by the good agreement between bead versus cell in vitro experiments (Chang and Hammer, 2000).

Various in vitro, in vivo, and computational methods have been developed to understand the complex range of transient interactions between cells, neighboring cells, and bounding surfaces under flow. Knowledge gained from studying physiologically realistic flow systems may prove useful in microfluidic applications where the transport of blood cells and solubilized, bioactive molecules is needed, or in miniaturized diagnostic devices where cell mechanics or binding affinities can be correlated with clinical pathologies.

(King MR. Cell-Surface Adhesive Interactions in Microchannels and Microvessels.   First International Conference on Microchannels and Minichannels. 2003, Rochester, NY. Pp 1-6. ICMM2003-1012.

P-selectin role in adhesion of leukocytes and sickle cells blocked by heparin

Vascular occlusion is responsible for much of the morbidity associated with sickle cell disease. Although the underlying cause of sickle cell disease is a single nucleotide mutation that directs the production of an easily polymerized hemoglobin protein, both the erythrocyte sickling caused by hemoglobin polymerization and the interactions between a proadhesive population of sickle cells and the vascular endothelium are essential to vascular occlusion.

Interactions between sickle cells and the endothelium use several cell adhesion molecules. Sickle red cells express adhesion molecules including integrin, CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine, and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, vascular cell adhesion molecule-1 (VCAM-1), CD36, and integrins. Activation of endothelial cells by specific agonists enhances adhesion by inducing the expression of cellular adhesion molecules and by causing cell contraction, which exposes extracellular matrix proteins, such as thrombospondin (TSP), laminin, and fibronectin. Initial events likely involve the adhesion of sickle erythrocytes to activated endothelial cells under laminar flow. The resultant adhesion of cells to the vascular wall creates nonlaminar and arrested flow, which propagates vascular occlusion by both static and flow adhesion mechanisms. It is likely too that the distinct mechanisms of adhesion and of regulation of endothelial cell adhesivity pertain under dissimilar types of flow.

The expression of adhesion molecules by endothelial cells is affected by cell agonists such as thrombin, histamine, tumor necrosis factor  (TNF-), interleukin 1 (IL-1), platelet activating factor (PAF), erythropoietin, and vascular endothelial growth factor (VEGF), and by local environmental factors such as hypoxia, reperfusion, flow, as well as by sickle erythrocytes themselves. An important effector in sickle cell vascular occlusion is thrombin. Increased thrombin activity correlates with sickle cell disease pain episodes. In addition to generating fibrin clot, thrombin also acts on specific thrombin receptors on endothelial cells and platelets. Work from our laboratory has demonstrated that thrombin treatment causes a rapid increase of endothelial cell adhesivity for sickle erythrocytes under static conditions

We have also reported that sickle cell adhesion to endothelial cells under static conditions involves P-selectin. Although P-selectin plays a major role in the tethering, rolling, and firm adhesion of leukocytes to activated endothelial cells, its contribution to the initial steps is singular and essential to the overall adhesion process. Upon stimulation of endothelial cells by thrombin, P-selectin rapidly translocates from Weibel-Palade bodies to the luminal surface of the cells. Others have shown that sickle cell adhesion is decreased by unfractionated heparin, but the molecular target of this inhibition has not been defined. We postulated that the adhesion of sickle cells to P-selectin might be the pathway blocked by unfractionated heparin. Heparin is known to block certain types of tumor cell adherence, TSP-independent sickle cell adherence, and coagulation processes that are active in sickle cell disease. In one uncontrolled study, prophylactic administration of heparin reduced the frequency of sickle cell pain crises. The role of P-selectin in the endothelial adhesion of sickle red blood cells, the capacity of heparin to block selected P-selectin–mediated adhesive events, and the effect of heparin on sickle cell adhesion suggest an association among these findings.

We postulate that, in a manner similar to that seen for neutrophil adhesion, P-selectin may play a role in the tethering and rolling adhesion of sickle cells. As with neutrophils, integrins may then mediate the firm adhesion of rolling sickle erythrocytes. The integrin  is expressed on sickle reticulocytes and can mediate adhesion to endothelial cells, possibly via endothelial VCAM-4. The endothelial integrin, V3, also mediates sickle cell adhesion to endothelial cells. Other 1 and 3 integrins may also fulfill this role.

In this report we demonstrate that the flow adherence of sickle cells to thrombin-treated human vascular endothelial cells also uses P-selectin and that this component of adhesion is inhibited by unfractionated heparin. We also demonstrate that sickle cells adhere to immobilized recombinant P-selectin under flow conditions. This adhesion too was inhibited by unfractionated heparin, in a concentration range that is clinically attainable. These findings and the general role of P-selectin in initiating adhesion of blood cells to the endothelium suggest that unfractionated heparin may be useful in preventing painful vascular occlusion. A clinical trial to test this hypothesis is indicated.

(Matsui NM, Varki A, and Embury SH.  Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin  Blood. 2002; 100:3790-3796)

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