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Archive for the ‘Coagulation Therapy and Internal Bleeding’ Category


Two Classes of Antithrombotic Drugs: Anticoagulants and Antiplatelet drugs

Reporter: Aviva Lev-Ari, PhD, RN
These drugs are used to treat
  • strokes,
  • myocardial infarctions,
  • pulmonary embolisms,
  • disseminated intravascular coagulation (DIC) and
  • deep vein thrombosis (DVT)
— all potentially life-threatening conditions.
THERAPEUTIC STRATEGIES
• Degrade fibrinogen/fibrin (fibrinolytic agents)
GOAL: eliminate formed clots
• Inhibit clotting mechanism (anticoagulants)
GOAL: prevent progression of thrombosis
• Interfere either with platelet adhesion and/or aggregation (antiplatelet drugs)
GOAL: prevent initial clot formation
Antithrombotic therapy has had an enormous impact in several significant ways.
  • Heparin has made bypass surgery and dialysis possible by blocking clotting in external tubing.
  • Antithrombotic therapy has reduced the risk of blood clots in leg veins (also known as deep-vein thrombosis or DVT), a condition that can lead to death from pulmonary embolism (a clot that blocks an artery to the lungs) by more than 70 percent. And most importantly,
  • it has markedly reduced death from heart attacks, the risk of stroke in people with heart irregularities (atrial fibrillation), and the risk of major stroke in patients with mini-strokes.

Antithrombotic Therapy

This article was published in December 2008 as part of the special ASH anniversary brochure, 50 Years in Hematology: Research That Revolutionized Patient Care.

Normally, blood flows through our arteries and veins smoothly and efficiently, but if a clot, or thrombus, blocks the smooth flow of blood, the result – called thrombosis – can be serious and even cause death. Diseases arising from clots in blood vessels include heart attack and stroke, among others. These disorders collectively are the most common cause of death and disability in the developed world. We now have an array of drugs that can be used to prevent and treat thrombosis – and there are more on the way – but this was not always the case.

Classes of Antithrombotic Drugs

Image Source: http://www.hematology.org/About/History/50-Years/1523.aspx

The most important components of a thrombus are fibrin and platelets. Fibrin is a protein that forms a mesh that traps red blood cells, while platelets, a type of blood cell, form clumps that add to the mass of the thrombus. Both fibrin and platelets stabilize the thrombus and prevent it from falling apart. Fibrin is the more important component of clots that form in veins, and platelets are the more important component of clots that form in arteries where they can cause heart attacks and strokes by blocking the flow of blood in the heart and brain, respectively, although fibrin plays an important role in arterial thrombosis as well.

There are two classes of antithrombotic drugs: anticoagulants and antiplatelet drugs. Anticoagulants slow down clotting, thereby reducing fibrin formation and preventing clots from forming and growing. Antiplatelet agents prevent platelets from clumping and also prevent clots from forming and growing.

Anticoagulant Drugs

The anticoagulants heparin and dicumarol were discovered by chance, long before we understood how they worked. Heparin was first discovered in 1916 by a medical student at The Johns Hopkins University who was investigating a clotting product from extracts of dog liver and heart. In 1939, dicumarol (the precursor to warfarin) was extracted by a biochemist at the University of Wisconsin from moldy clover brought to him by a farmer whose prize bull had bled to death after eating the clover.

Both of these anticoagulants have been used effectively to prevent clots since 1940. These drugs produce a highly variable anticoagulant effect in patients, requiring their effect to be measured by special blood tests and their dose adjusted according to the results. Heparin acts immediately and is given intravenously (through the veins). Warfarin is swallowed in tablet form, but its anticoagulant effect is delayed for days. Therefore, until recently, patients requiring anticoagulants who were admitted to a hospital were started on a heparin infusion and were then discharged from the hospital after five to seven days on warfarin.

In the 1970s, three different groups of researchers in Stockholm, London, and Hamilton, Ontario, began work on low-molecular-weight heparin (LMWH). LMWH is produced by chemically splitting heparin into one-third of its original size. It has fewer side effects than heparin and produces a more predictable anticoagulant response. By the mid 1980s, LMWH preparations were being tested in clinical trials, and they have now replaced heparin for most indications. Because LMWH is injected subcutaneously (under the skin) in a fixed dose without the need for anticoagulant monitoring, patients can now be treated at home instead of at the hospital.

With the biotechnology revolution has come genetically engineered “designer” anticoagulant molecules that target specific clotting enzymes. Anti-clotting substances and their DNA were also extracted from an array of exotic creatures (ticks, leeches, snakes, and vampire bats) and converted into drugs by chemical synthesis or genetic engineering. Structural chemists next began to fabricate small molecules designed to fit into the active component of clotting enzymes, like a key into a lock.

The first successful synthetic anticoagulants were fondaparinux and bivalirudin. Bivalirudin, a synthetic molecule based on the structure of hirudin (the anti-clotting substance found in leeches), is an effective treatment for patients with heart attacks. Fondaparinux is a small molecule whose structure is based on the active component of the much larger LMWH and heparin molecules. It has advantages over LMWH and heparin and has recently been approved by the FDA. Newer designer drugs that target single clotting factors and that can be taken by mouth are undergoing clinical testing. If successful, we will have safer and more convenient replacements for warfarin, the only oral anticoagulant available for more than 60 years.

Antiplatelet Drugs

Blood platelets are inactive until damage to blood vessels or blood coagulation causes them to explode into sticky irregular cells that clump together and form a thrombus. The first antiplatelet drug was aspirin, which has been used to relieve pain for more than 100 years. In the mid-1960s, scientists showed that aspirin prevented platelets from clumping, and subsequent clinical trials showed that it reduces the risk of stroke and heart attack. In 1980, researchers showed that aspirin in very low doses (much lower than that required to relieve a headache) blocked the production of a chemical in platelets that is required for platelet clumping. During that time, better understanding of the process of platelet clumping allowed the development of designer antiplatelet drugs directed at specific targets. We now have more potent drugs, such as clopidogrel, dipyridamole, and abciximab. These drugs are used with aspirin and effectively prevent heart attack and stroke; they also prolong the lives of patients who have already had a heart attack.

SOURCE 
Anticoagulation Drugs:
  • heparin (FONDAPARINUX HEPARIN (Calciparine, Hepathrom, Lipo-Hepin, Liquaemin, Panheprin)
  • warfarin – 4-HYDROXYCOUMARIN (Coumadin) WARFARIN (Athrombin-K, Panwarfin)
  • rivaroxaban (Xarelto)
  • dabigatran (Pradaxa)
  • apixaban (Eliquis)
  • edoxaban (Savaysa)
  • enoxaparin (Lovenox)
  • fondaparinux (Arixtra)
  • ARGATROBAN BIVALIRUDIN (Angiomax)
  • DALTEPARIN (Fragmin)
  • DROTRECOGIN ALFA (ACTIVATED PROTEIN C) (Xigris)
  • HIRUDIN (Desirudin)
  • LEPIRUDIN (Refludan)
  • XIMELAGATRAN (Exanta)

ANTIDOTES

  • PHYTONADIONE (Vitamin K1)
  • PROTAMINE SULFATE AMINOCAPROIC ACID (EACA) (generic, Amicar) (in bleeding disorders)
Antiplatelet Drugs
  • ACETYL SALICYLIC ACID (aspirin) 
  • clopidogrel (Plavix)
  • dipyridamole (Persantine)
  • abciximab (Centocor)
  • EPTIFIBATIDE (Integrilin)
  • TICLOPIDINE (Ticlid)
  • TIROFIBAN (Aggrastat)

THROMBOLYTICS

  1. ANISTREPLASE (APSAC; Eminase)
  2. STREPTOKINASE (Streptase, Kabikinase)
  3. TISSUE PLASMINOGEN ACTIVATORS (tPAs):
  • ALTEPLASE (Activase),
  • RETEPLASE (Retavase),
  • TENECTEPLASE (TNKase)
  • UROKINASE (Abbokinase)

Fibrinolytic Drugs

Fibrinolytic therapy is used in selected patients with venous thromboembolism. For example, patients with massive or submassive PE can benefit from systemic or catheter-directed fibrinolytic therapy. The latter can also be used as an adjunct to anticoagulants for treatment of patients with extensive iliofemoral-vein thrombosis.

Arterial and venous thrombi are composed of platelets and fibrin, but the proportions differ.

  • Arterial thrombi are rich in platelets because of the high shear in the injured arteries. In contrast,
  • venous thrombi, which form under low shear conditions, contain relatively few platelets and are predominantly composed of fibrin and trapped red cells.
  • Because of the predominance of platelets, arterial thrombi appear white, whereas venous thrombi are red in color, reflecting the trapped red cells.

SOURCE

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Advantages and Disadvantages of Novel Oral Anticoagulants (NOACs)

Reporter: Aviva Lev-Ari, PhD, RN

In the past four years, three novel oral anticoagulant (NOAC) medications have become available:
  • apixaban (Eliquis®),
  • dabigatran (Pradaxa®), and
  • rivaroxaban (Xarelto®). A fourth NOAC,
  • edoxaban (Savaysa™), has been submitted for approval by the US Food and Drug Administration …

Two small to moderate size trials have shown similar bleeding risk with other NOACs (VENTURE-AF with rivaroxaban [Xarelto] and RE-CIRCUIT with dabigatran [Pradaxa]) compared with vitamin K antagonists. In a non-formal “eyeball” meta-analysis with AXAFA-AFNET 5, combined death, stroke or transient ischemic attack, and major bleeding risk appeared to trend lower with a NOAC than vitamin K antagonist.

However, “differences in populations and procedures may well explain the different outcomes in bleeding rates and silent strokes with NOAC versus vitamin K antagonists,” suggested Blomstrom-Lundqvist.

Increased Bleeding is Main Issue With Newer Agents

Regardless of which agent is used, clinical practice and research has shifted focus to decreasing the risk of bleeding for patients on oral anticoagulants and antithrombotics. While the newer agents might be better than warfarin on several points, the more effective ability to prevent clotting also results in the unwanted consequence of increased bleeding. This sentiment was echoed multiple times by speakers at ACC.16. The most common bleeding complication with NOACs compared to warfarin is gastrointestinal (GI) bleeding.  The results of the Ruff meta-analysis favored warfarin over NOACs for rates of GI bleeds (whether results from dabigatran trials were included or not).

“Major bleeds, as well as minor bleeds, may be a problem because patients stop their treatments — not only their antithrombotic treatment, but also the ACE inhibitors, statins and all other life-saving therapies,” explained Freek Verheugt, M.D., FESC, FACC, FAHA, professor of cardiology, Heart-Lung Centre of the University Medical Centre of Nijmegen and chairman of the Department of Cardiology at Onze Lieve Vrouwe Gasthuis, The Netherlands.

Evolution of the Anticoagulant Nomenclature 

The approval of dabigatran (Pradaxa) in 2010 lead to the creation of the term new oral anticoagulants (NOACs). This term was changed to novel oral anticoagulants (NOACs) when rivaroxaban (Xarelto) came to the market in 2011. After apixaban (Eliquis) and edoxaban (Savaysa) were cleared, the name changed to direct oral anticoagulants (DOACs) and is the term used by the International Society of Thrombosis and Haemostasis. Alternative names for these agents are target-specific oral anticoagulants (TSOACs) and non-vitamin K oral anticoagulants (NOACs), the term used by the American College of Chest Physicians and the FDA. All of these acronyms refer to the same agents.

SOURCE

 

Warfarin Use May Not Bring Long-Term Stability for Atrial Fibrillation

Registry study finds INR values fluctuate over 18 months, even in patients considered “stable”

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FDA Approval marks first presentation of bivalirudin in frozen, premixed, ready-to-use formulation

Reporter: Aviva Lev-Ari, PhD, RN

 

Baxter Announces FDA Approval of Ready-to-Use Cardiovascular Medication Bivalirudin

Approval marks first presentation of bivalirudin in frozen, premixed, ready-to-use formulation

https://www.dicardiology.com/product/baxter-announces-fda-approval-ready-use-cardiovascular-medication-bivalirudin?eid=333021707&bid=1983307

Dosing and Uses

https://reference.medscape.com/drug/angiomax-angiox-bivalirudin-342137

 

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Shaun Coughlin from UCSF Cardiovascular Research Center to cardio group for the Novartis Institute for Biomedical Research in Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

 

The dean of the UCSF med school, Talmadge King, had this to say in his sendoff today:

Coughlin’s “research discoveries revealed a mechanism by which proteases regulate cellular behaviors including a key mechanism that controls blood platelet activation and clot formation. This work led to a new medical therapy for preventing heart attacks and strokes and has been honored by the American Heart Association’s Basic Science Award in 2003 and its Research Achievement Award in 2014. Among his numerous other awards are the Bristol-Myers Squibb Cardiovascular Research Award and the Distinguished Career Award from the International Society on Thrombosis and Haemostasis.”

SOURCE

https://endpts.com/top-ucsf-scientist-shaun-coughlin-joins-migration-to-big-pharma-leaping-to-novartis

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Inferior Vena Caval Filters: Device for Prevention of Pulmonary Embolism and Thrombosis

Reporter: Aviva Lev-Ari, PhD, RN

 

Requiem for Liberalizing Indications for Vena Caval Filters?

Samuel Z. Goldhaber

Guidelines

However, it is premature to hammer nails into the coffin and to gather as a medical community for a requiem that celebrates no indication for liberalizing indications for placing an IVC filter. Instead, we need to shift the focus of the questions that we investigate and pour resources into further randomized and observational trials of IVC filter insertion in special highrisk populations.

There remain important groups of patients who may benefit from IVC filters with reduction in PE and PE-associated mortality (Table 2). In some cases, tantalizing data suggest that these populations warrant filters. In other cases, we lack data to guide us. Patients with massive PE—accompanied by cardiogenic shock requiring vasopressors to support blood pressure—are desperately ill. They are clinically unstable. An additional PE under these circumstances can be the fatal blow. Data from the National Inpatient Sample and the International Cooperative PE Registry suggest that filters in these patients may be lifesaving.

Patients with severe PE who undergo acute surgical pulmonary embolectomy are vulnerable to recurrent PE, especially during the early postoperative period where full anticoagulation cannot be immediately implemented. I have had personal experience managing this type of patient where the embolectomy is successful but the patient dies of recurrent PE.19

Table 1. Generally Accepted Consensus Recommendations for IVC Filter Insertion in Patients With VTE

  • Major bleeding on full-dose anticoagulation
  • Major contraindication to full-dose anticoagulation
  • New-onset acute PE (especially recurrent PE) despite well-documented fulldose anticoagulation for an existing VTE

IVC indicates inferior vena caval; PE, pulmonary embolism; and VTE, venous thromboembolism.

 

Table 2. Special Populations Where Benefits of IVC Filter Insertion May Outweigh Risks

  • Massive PE or high-risk submassive PE
  • Surgical pulmonary embolectomy
  • Cancer patients with VTE or at high risk of VTE with concomitant high risk of bleeding if anticoagulated
  • Surgical patients (especially during preoperative evaluation) at high risk of VTE with concomitant high risk of bleeding if anticoagulated

IVC indicates inferior vena caval; PE, pulmonary embolism; and VTE, venous thromboembolism.

http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022730

References

1. Stein PD, Matta F, Hull RD. Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med. 2011;124:655–661. doi:10.1016/j.amjmed.2011.02.021.

2. Jia Z, Wu A, Tam M, Spain J, McKinney JM, Wang W. Caval penetration by inferior vena cava filters: a systematic literature review of clinical significance and management. Circulation. 2015;132:944–952. doi: 10.1161/ CIRCULATIONAHA.115.016468

3. Owens CA, Bui JT, Knuttinen MG, Gaba RC, Carrillo TC, Hoefling N, Layden-Almer JE. Intracardiac migration of inferior vena cava filters: review of published data. Chest. 2009;136:877–887. doi: 10.1378/ chest.09-0153.

4. Nicholson W, Nicholson WJ, Tolerico P, Taylor B, Solomon S, Schryver T, McCullum K, Goldberg H, Mills J, Schuler B, Shears L, Siddoway L, Agarwal N, Tuohy C. Prevalence of fracture and fragment embolization of Bard retrievable vena cava filters and clinical implications including cardiac perforation and tamponade. Arch Intern Med. 2010;170:1827–1831. doi: 10.1001/archinternmed.2010.316.

5. Angel LF, Tapson V, Galgon RE, Restrepo MI, Kaufman J. Systematic review of the use of retrievable inferior vena cava filters. J Vasc Interv Radiol. 2011;22:1522–1530.e3. doi: 10.1016/j.jvir.2011.08.024.

19. Aklog L, Williams CS, Byrne JG, Goldhaber SZ. Acute pulmonary embolectomy: a contemporary approach. Circulation. 2002;105:1416–1419.

Other related articles published in this Open Access Online Scientific Journal include the follwoing:

 

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

https://pharmaceuticalintelligence.com/2012/11/04/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/

Venous Thromboembolism (VTE): Blood Clots in Leg and Lungs – No. 3 Cardiovascular Killer Globally – Is Leading Cause of Premature Death and Disability in Hospitals

https://pharmaceuticalintelligence.com/2014/10/13/venous-thromboembolism-vte-blood-clots-in-leg-and-lungs-no-3-cardiovascular-killer-globally-is-leading-cause-of-premature-death-and-disability-in-hospitals/

The Relation between Coagulation and Cancer affects Supportive Treatments

https://pharmaceuticalintelligence.com/2015/10/19/the-relation-between-coagulation-and-cancer-affects-supportive-treatments/

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The presence of any Valvular Heart Disease (VHD) did not influence the comparison of Dabigatran [Pradaxa, Boehringer Ingelheim] with Warfarin

Reporter: Aviva Lev-Ari, PhD, RN

 

Event Rate and Outcome Risk, With vs Without Valvular Heart Disease

Outcome Valvular heart disease, event rate/y, % No valvular heart disease, event rate/y, % HR (95% CI)* P
Stroke, systemic embolic event 1.61 1.41 1.09 (0.88–1.33) 0.43
Major bleeding 4.36 2.84 1.32 (1.16–1.33) <0.001
Intracranial hemorrhage 0.51 0.41 1.20 (0.83–1.74) 0.32
All-cause mortality 4.45 3.67 1.09 (0.96–1.23) 0.18
*Adjusted using propensity scores

ORIGINAL RESEARCH ARTICLE

Comparison of Dabigatran versus Warfarin in Patients with Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial

Michael D. Ezekowitz, Rangadham Nagarakanti, Herbert Noack, Martina Brueckmann, Claire Litherland, Mark Jacobs, Andreas Clemens,Paul A. Reilly, Stuart J. Connolly, Salim Yusuf and Lars Wallentin

 http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020950

 

Results—There were 3950 patients with any VHD:

  • 3101 had mitral regurgitation,
  • 1179 tricuspid regurgitation,
  • 817 aortic regurgitations,
  • 471 aortic stenosis and
  • 193 mild mitral stenosis.

At baseline patients with any VHD had more

  • heart failure,
  • coronary disease,
  • renal impairment and
  • persistent atrial fibrillation.

Patients with any VHD had higher rates of

  • major bleeds (HR 1.32; 95% CI 1.16-1.5)

but similar

  • stroke or systemic embolism (SEE) rates (HR 1.09; 95% CI 0.88-1.33).

For D110 patients, major bleed rates were lower than warfarin (HR 0.73; 95% CI 0.56-0.95 with and HR 0.84; 95% CI 0.71-0.99 without VHD) and

For D150 similar to warfarin in patients with (HR 0.82; 95% CI 0.64-1.06) or without VHD (HR 0.98; 95% CI 0.83-1.15).

For D150 patients stroke/SEE rates were lower versus warfarin with (HR 0.59; 95% CI 0.37-0.93) and without VHD (HR 0.67; 95% CI 0.52-0.86) and similar to warfarin for D110 irrespective of presence of VHD (HR 0.97 CI 0.65-1.45 and 0.85 CI 0.70-1.10).

For intracranial bleeds and death rates for D150 and D110 were lower vs warfarin independent of presence of VHD.

Conclusions—The presence of any VHD did not influence the comparison of dabigatran with warfarin.

Clinical Trial Registration—URL: http://clinicaltrials.gov. Unique Identifier: NCT00262600.

SOURCES

http://circ.ahajournals.org/content/early/2016/08/05/CIRCULATIONAHA.115.020950

http://www.medscape.com/viewarticle/867482?nlid=108872_3866&src=WNL_mdplsfeat_160816_mscpedit_card&uac=93761AJ&spon=2&impID=1179558&faf=1

 

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Warfarin and Dabigatran, Similarities and Differences

Author and Curator: Danut Dragoi, PhD

 

What anticoagulants do?

An anticoagulant helps your body control how fast your blood clots; therefore, it prevents clots from forming inside your arteries, veins or heart during certain medical conditions.

If you have a blood clot, an anticoagulant may prevent the clot from getting larger. It also may prevent a piece of the clot from breaking off and traveling to your lungs, brain or heart. The anticoagulant medication does not dissolve the blood clot. With time, however, this clot may dissolve on its own.

Blood tests you will need

The blood tests for clotting time are called prothrombin time (Protime, PT) and international normalized ratio (INR). These tests help determine if your medication is working. The tests are performed at a laboratory, usually once a week to once a month, as directed by your doctor. Your doctor will help you decide which laboratory you will go to for these tests.

The test results help the doctor decide the dose of warfarin (Coumadin) that you should take to keep a balance between clotting and bleeding.

Important things to keep in mind regarding blood tests include:

  • Have your INR checked when scheduled.
  • Go to the same laboratory each time. (There can be a difference in results between laboratories).
  • If you are planning a trip, talk with your doctor about using another laboratory while traveling.
Dosage

The dose of medication usually ranges from 1 mg to 10 mg once daily. The doctor will prescribe one strength and change the dose as needed (your dose may be adjusted with each INR).

The tablet is scored and breaks in half easily. For example: if your doctor prescribes a 5 mg tablet and then changes the dose to 2.5 mg (2½ mg), which is half the strength, you should break one of the 5 mg tablets in half and take the half-tablet. If you have any questions about your dose, talk with your doctor or pharmacist.

What warfarin (Coumadin) tablets look like

Warfarin is made by several different drug manufacturers and is available in many different shapes. Each color represents a different strength, measured in milligrams (mg). Each tablet has the strength imprinted on one side, and is scored so you can break it in half easily to adjust your dose as your doctor instructed.

https://my.clevelandclinic.org/health/drugs_devices_supplements/hic_Understanding_Coumadin

Today, on the basis of 4 clinical trials involving over 9,000 patients, PRADAXA is approved to treat blood clots in the veins of your legs(deep vein thrombosis, or DVT) or lungs (pulmonary embolism, or PE)in patients who have been treated with blood thinner injections, and to reduce the risk of them occurring again.

In these trials, PRADAXA was compared to warfarin or to placebo (sugar pills) for the treatment of DVT and PE patients.

https://www.pradaxa.com/pradaxa-vs-warfarin?gclid=CMaRq7al9ssCFUxZhgodZuoC5w

Warfarin (NB-which goes by the brand name Coumadin, see link in here) reduces the risk of stroke in patients with atrial fibrillation (NB- atrial fibrillation (also called AFib or AF) is a quivering or irregular heartbeat (arrhythmia) that can lead to blood clots, stroke, heart failure and other heart-related complications. Some people refer to AF as a quivering heart, see link here) but increases the risk of hemorrhage and is difficult to use.

Dabigatran is a new oral direct thrombin inhibitor (NB-direct thrombin inhibitors are a class of medication that act as anticoagulants by directly inhibiting the enzyme thrombin). Some are in clinical use, while others are undergoing clinical development), see link in here.

Some international large clinical trials, see link in here,  show results for patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.

Picture below shows a deep vein thrombosis which is a blood clot that forms inside a vein, usually deep within the leg. About half a million Americans every year get one, and up to 100,000 die because of it. The danger is that part of the clot can break off and travel through your bloodstream. It could get stuck in your lungs and block blood flow, causing organ damage or death, see link in here.

Blod Clot

Image SOURCE: http://www.webmd.com/heart-disease/guide/warfarin-other-blood-thinners

The behaviour of blood thinning drugs is dependent on their physico-chemical properties and since a significant proportion of drugs contain ionisable centers a knowledge of their pKa (NB-pKa was introduced as an index to express the acidity of weak acids, where pKa is defined as follows. For example, the Ka constant for acetic acid (CH3C00H) is 0.0000158 (= 10-4.8), but the pKa constant is 4.8, which is a simpler expression. In addition, the smaller the pKa value, the stronger the acid, see link in here ) is essential, see link in here. The pKa is defined as the negative log of the dissociation constant, see link in here:

pka=-log10(Ka)              (1)

where the dissociation constant is defined thus:

Ka=[A][H+]/[AH]

Most drugs have pKa in the range 0-12, and whilst it is possible to calculate pKa it is desirable to experimentally measure the value for representative examples. There are a number of instruments that are capable of measuring pKa utilising Sirius T3 instrument, see link in here .

Table 1 below shows the pka values for warfarin, see link in here  and dabigatran, see link in here.

Table 1

==========================

Anticoagulant           pka          

warfarin                     4.99

dabigatran                 4.24        11.51*

==========================

* dabigatran possess both acidic and basic functionality.

Both groups are at ionized at blood pH and exist as zwitterionic

structures, see link in here.

Adding physico-chemical features of anticoagulants utilized in “dissolving” blood clots is important for better understanding the de-blocking process within the veins utilizing anticoagulants.

SOURCE

http://theochem.chem.rug.nl/publications/PDF/ft683.pdf

http://www.rsc.org/chemical-sciences-repository/articles/article/dr000000003197?doi=10.1039/c5ra04680g

http://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra11623f#!divAbstract

http://www.cambridgemedchemconsulting.com/resources/physiochem/pka.html

http://www.webmd.com/heart-disease/guide/warfarin-other-blood-thinners

https://www.google.com/#q=define+atrial+fibrillation

https://www.researchgate.net/profile/Lars_Wallentin/publication/26777612_Dabigatran_versus_Warfarin_in_Patients_with_Atrial_Fibrillation/links/02bfe50c8c2fa639c0000000.pdf

http://www.webmd.com/heart-disease/guide/warfarin-other-blood-thinners

 

Other related articles published in this Open Access Online Scientific Journal, include the following:

Coagulation N=69

https://pharmaceuticalintelligence.com/?s=Coagulation

Peripheral Arterial Disease N=43

https://pharmaceuticalintelligence.com/?s=Peripheral

Antiarrhythmic drugs

https://pharmaceuticalintelligence.com/?s=Antiarrhythmic+drugs

A-Fib

https://pharmaceuticalintelligence.com/?s=a-fib

Electrophysiology N = 80

https://pharmaceuticalintelligence.com/?s=Electrophysiology

 

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