Coagulation Cascade and Major Classes of Anticoagulants
Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood. As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart-lung machines, and dialysis equipment. One of the first anticoagulants, warfarin, was initially approved as a rodenticide.
Anticoagulants are closely related to antiplatelet drugs and thrombolytic drugs by manipulating the various pathways of blood coagulation. Specifically, antiplatelet drugs inhibit platelet aggregation (clumping together), whereas anticoagulants inhibit specific pathways of the coagulation cascade, which happens after the initial platelet aggregation and ultimately leads to formation of fibrin and stable aggregated platelet products.
The use of anticoagulants is a decision based upon the risks and benefits of anticoagulation. The biggest risk of anticoagulation therapy is the increased risk of bleeding. In otherwise healthy people, the increased risk of bleeding is minimal, but those who have had recent surgery, cerebral aneurysms, and other conditions may have too great of risk of bleeding. Generally, the benefit of anticoagulation is prevention of or reduction of progression of a thromboembolic disease. Some indications for anticoagulant therapy that are known to have benefit from therapy include:
- Atrial fibrillation — commonly forms an atrial appendage clot
- Coronary artery disease
- Deep vein thrombosis — can lead to pulmonary embolism
- Ischemic stroke
- Hypercoagulable states (e.g., Factor V Leiden) — can lead to deep vein thrombosis
- Mechanical heart valves
- Myocardial infarction
- Pulmonary embolism
- Restenosis from stents
- Cardiopulmonary bypass (or any other surgeries requiring temporary aortic occlusion)
- Heart failure
The decision to begin therapeutic anticoagulation often involves the use of multiple bleeding risk predictable outcome tools as non-invasive pre-test stratifications due to the potential for bleeds while on blood thinning agents. Among these tools are HAS-BLED, ATRIA, HEMORR2HAGES, and CHA2DS2-VASc. The risk of bleeding using the aforementioned risk assessment tools must then be weighed against thrombotic risk in order to formally determine patient's overall benefit in starting anticoagulation therapy.
The most serious and common adverse side effect associated with anticoagulant are increased risk of bleeding, both nonmajor and major bleeding events. Risk of bleeding is dependent on the class of anticoagulant agent used, patient's age, and pre-existing health conditions. Warfarin has an estimated Incidence of bleeding of 15-20% per year and life-threatening bleeding rate of 1-3% per year. Newer non-vitamin K antagonist oral anticoagulants appear to have fewer life-threatening bleeding events compared to warfarin. Additionally, patients aged 80 years or more may be especially susceptible to bleeding complications, with a rate of 13 bleeds per 100 person-years. Bleeding risk is especially important to consider in patients with renal impairment and NOAC therapy due to the fact that all NOACs, to some extent, are excreted by the kidneys. Thus, patients with renal impairment may be at higher risk of increased bleeding.
In people with cancer, a systematic review has found warfarin had no effect on death rate or the risk of blood clots. However it did increase the risk of major bleeding in 107 more people per 1000 population and minor bleeding in 167 more people in 1000 population. Apixaban had no effect on mortality, recurrence of blood clots in blood vessels or major bleeding or minor bleeding, however this finding comes only from one study.
Nonhemorrhagic adverse events are less common than hemorrhagic adverse events but should still be monitored closely. Nonhemorrhagic adverse events of warfarin include skin necrosis, limb gangrene, and purple toe syndrome. Skin necrosis and limb gangrene are most commonly observed on the third to eighth day of therapy. The exact pathogenesis of skin necrosis and limb gangrene are not completely understood but are believed to be associated with warfarin's effect on inhibiting production of protein C and protein S. Purple toe syndrome typically develops three to eight weeks after initiation of warfarin therapy. Other adverse effects of warfarin are associated with depletion of vitamin K, which can lead to inhibition of G1a proteins and growth arrest-specific gene 6, which can lead to increased risk of arterial calcification and heart valve, especially if too much Vitamin D is present. Warfarin's interference of G1a proteins have also been linked to abnormalities in fetal bone development in mothers who were treated with warfarin during pregnancy. Long-term warfarin and heparin usage have also been linked to osteoporosis.
Another potentially serious complication associated with heparin use is called heparin-induced thrombocytopenia (HIT). There are two distinct types of HIT 1) immune-mediated and 2) non-immune mediated. Immune-mediated HIT most commonly arises five to ten days after exposure to heparin. Pathogenesis of immune-mediated HIT is believed to be caused by heparin-dependent immunoglobulin antibodies binding to platelet factor 4/heparin complexes on platelets, leading to wide spread platelet activation.
Foods and food supplements with blood-thinning effects include nattokinase, lumbrokinase, beer, bilberry, celery, cranberries, fish oil, garlic, ginger, ginkgo, ginseng, green tea, horse chestnut, licorice, niacin, onion, papaya, pomegranate, red clover, soybean, St. John's wort, turmeric, wheatgrass, and willow bark. Many herbal supplements have blood-thinning properties, such as danshen and feverfew. Multivitamins that do not interact with clotting are available for patients on anticoagulants.
However, some foods and supplements encourage clotting. These include alfalfa, avocado, cat's claw, coenzyme Q10, and dark leafy greens such as spinach. Excessive intake of aforementioned food should be avoided whilst taking anticoagulants or, if coagulability is being monitored, their intake should be kept approximately constant so that anticoagulant dosage can be maintained at a level high enough to counteract this effect without fluctuations in coagulability.
Grapefruit interferes with some anticoagulant drugs, increasing the amount of time it takes for them to be metabolized out of the body, and so should be eaten with caution when on anticoagulant drugs.
Anticoagulants are often used to treat acute deep vein thrombosis. People using anticoagulants to treat this condition should avoid using bed rest as a complementary treatment because there are clinical benefits to continuing to walk and remaining mobile while using anticoagulants in this way. Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.
A number of anticoagulants are available. The traditional ones (warfarin, other coumarins and heparins) are in widespread use. Since the 2000s a number of agents have been introduced that are collectively referred to as directly acting oral anticoagulants (DOACs), novel oral anticoagulants (NOACs), or non-vitamin K antagonist oral anticoagulants. These agents include direct thrombin inhibitor (dabigatran) and factor Xa inhibitor (rivaroxaban, apixaban, betrixaban and edoxaban) and they have been shown to be as good or possibly better than the coumarins with less serious side effects. The newer anticoagulants (NOACs/DOACs), are more expensive than the traditional ones and should be used with care in patients with kidney problems.
Coumarins (vitamin K antagonists)
These oral anticoagulants are derived from coumarin, which is found in many plants. A prominent member of this class is warfarin (Coumadin) and was found to be the dominant anticoagulant prescribed in a large multispecialty practice. It takes at least 48 to 72 hours for the anticoagulant effect to develop. Where an immediate effect is required, heparin must be given concomitantly. These anticoagulants are used to treat patients with deep-vein thrombosis (DVT), pulmonary embolism (PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves. Other examples are acenocoumarol, phenprocoumon, atromentin, and phenindione.
Heparin and derivative substances
Heparin is the most widely used intravenous clinical anticoagulant worldwide. Heparin is a naturally occurring glycosaminoglycan. There are three major categories of heparin: unfractionated heparin (UFH), low molecular weight heparin (LMWH), and ultra-low-molecular weight heparin (ULMWH). Unfractionated heparin is usually derived from pig intestines and bovine lungs. UFH binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation. The activated AT then inactivates factor Xa, thrombin, and other coagulation factors. Heparin can be used in vivo (by injection), and also in vitro to prevent blood or plasma clotting in or on medical devices. In venipuncture, Vacutainer brand blood collecting tubes containing heparin usually have a green cap.
Low molecular weight heparin (LMWH)
Low molecular weight heparin (LMWH), is produced through a controlled depolymerization of unfractionated heparin. LMWH exhibits higher anti-Xa/anti-IIa activity ratio and is useful as it does not require monitoring of the APTT coagulation parameter and has fewer side effects.
Synthetic pentasaccharide inhibitors of factor Xa
- Fondaparinux is a synthetic sugar composed of the five sugars (pentasaccharide) in heparin that bind to antithrombin. It is a smaller molecule than low molecular weight heparin.
Directly acting oral
The directly acting oral anticoagulants (DOACs) were introduced on and after 2008. There are five DOACs currently on the market: dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. They were also previously referred to as "new/novel" and "non-vitamin K antagonist" oral anticoagulants (NOACs).
Compared to warfarin, DOACs have a rapid onset action and relatively short half-lives; hence, they carry out their function more rapidly and effectively and allow for drugs to quickly reduce their anticoagulation effects. Routine monitoring and dose adjustments of DOACs is less important than for warfarin, as they have better predictable anticoagulation activity.
Both DOACs and warfarin are equivalently effective but compared to warfarin, DOACs have fewer drug interactions, no known dietary interactions, wider therapeutic index, and have conventional dosing that do not require dose adjustments with constant monitoring. However, there is presently no countermeasure for most DOACs unlike in warfarin; nonetheless, the short half-lives of DOACs will result in its effects to swiftly recede. A reversal agent for dabigatran, idarucizumab, is currently available and approved for use by the FDA. Rates of adherence to DOACs are only modestly higher than adherence to warfarin among patients prescribed these drugs, and thus adherence to anticoagulation is universally poor, despite hopes that DOACs would lead to higher adherence rates.
DOACs are a lot more expensive than warfarin, after having taken into consideration the cost of frequent blood testing associated with warfarin.
Direct factor Xa inhibitors
Drugs such as rivaroxaban, apixaban and edoxaban work by inhibiting factor Xa directly (unlike the heparins and fondaparinux, which work via antithrombin activation). Also betrixaban from Portola Pharmaceuticals, darexaban (YM150) from Astellas, and more recently letaxaban (TAK-442) from Takeda and eribaxaban (PD0348292) from Pfizer. Betrixaban is significant as it is the only oral factor Xa inhibitor approved by the FDA for use in acutely medically ill patients. The development of darexaban was discontinued in September 2011: in a trial for prevention of recurrences of myocardial infarction in addition to dual antiplatelet therapy (DAPT), the drug did not demonstrate effectiveness and the risk of bleeding was increased by approximately 300%. The development of letaxaban was discontinued for acute coronary syndrome in May 2011 following negative results from a Phase II study.
Direct thrombin inhibitors
Another type of anticoagulant is the direct thrombin inhibitor. Current members of this class include the bivalent drugs hirudin, lepirudin, and bivalirudin; and the monovalent drugs argatroban and dabigatran. An oral direct thrombin inhibitor, ximelagatran (Exanta) was denied approval by the Food and Drug Administration (FDA) in September 2004 and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks. In November 2010, dabigatran etexilate was approved by the FDA to treat atrial fibrillation.
Relevance to dental treatments
As in any invasive procedures, patients on anticoagulation therapy have increased risk for bleeding and caution should be used along with local hemostasis methods to minimize bleeding risk during the operation as well as post-operatively. However, with regards to DOACs and invasive dental treatments, there has not been enough clinical evidence and experience to prove any reliable adverse-effects, relevance or interaction between these two. Further clinical prospective studies on DOACs are required to investigate the bleeding risk and haemostasis associated to surgical dental procedures.
Recommendations of modifications to usage/dosage of DOACs prior to dental treatments are made based on the balance of severity of each procedure and also the individual's bleeding risks and renal functionality. With low bleeding risk of dental procedures, it is recommended that DOAC medicine still be taken by the patient as per normal, so as to avoid increase in the risk of thromboembolic event. For dental procedures with a higher risk of bleeding complications (i.e. complex extractions, adjacent extractions leading to large wound or more than three extractions), the recommended practice is for patient to miss or delay a dose of their DOAC before such procedures so as to minimize the effect on bleeding risk.
Antithrombin protein therapeutics
The antithrombin protein itself is used as a protein therapeutic that can be purified from human plasma or produced recombinantly (for example, Atryn, which is produced in the milk of genetically modified goats.)
- Batroxobin, a toxin from a snake venom, clots platelet-rich plasma without affecting platelet functions (lyses fibrinogen).
- Hementin is an anticoagulant protease from the salivary glands of the giant Amazon leech, Haementeria ghilianii.
- Vitamin E
With the growing number of patients taking oral anticoagulation therapy, studies into reversal agents are gaining increasing interest due to major bleeding events and need for urgent anticoagulant reversal therapy. Reversal agents for warfarin are more widely studied and established guidelines for reversal exist, due to longer history of use of warfarin and the ability to get a more accurate measurement of anticoagulation effect in a patient via measuring the INR (International Normalized Ratio). In general, vitamin K is most commonly used in order to reverse the effect of warfarin in non-urgent settings. However, in urgent settings, or in settings with extremely high INR (INR >20), hemostatic reversal agents such as fresh frozen plasma (FFP), recombinant factor VIIa, and prothrombin complex concentrate (PCC) have been utilized with proven efficacy. Specifically with warfarin, four factor PCC (4F-PCC) has been shown to have superior safety and mortality benefits compared to FPP in lowering INR levels.
Although specific antidotes and reversal agents for DOACs are not as widely studied, idarucizumab (for dabigatran) and andexanet alfa (for factor Xa inhibitor) have been used in clinical settings with varying efficacy. Idarucizumab is a monoclonal antibody, approved by the US FDA in 2015, that reverses effect of dabigatran by binding to both free and thrombin-bound dabigatran. Andexanet alfa is a recombinant modified human factor Xa decoy that reverses the effect of factor Xa inhibitors by binding at the active sites of factor Xa inhibitor and making it catalytically inactive. Andexanet alfa was approved by US FDA in 2018. Another drug called ciraparantag, a potential reversal agent for direct factor Xa inhibitors, is still under investigation. Additionally, hemostatic reversal agents have also been used with varying efficacy to reverse effects of DOACs.
Coagulation inhibitor measurement
A Bethesda unit (BU) is a measure of blood coagulation inhibitor activity. It is the amount of inhibitor that will inactivate half of a coagulant during the incubation period. It is the standard measure used in the United States, and is so named because it was adopted as a standard at a conference in Bethesda, Maryland.
Laboratory instruments, blood transfusion bags, and medical and surgical equipment will get clogged up and become non-operational if blood is allowed to clot. In addition, test tubes used for laboratory blood tests will have chemicals added to stop blood clotting. Apart from heparin, most of these chemicals work by binding calcium ions, preventing the coagulation proteins from using them.
- Ethylenediaminetetraacetic acid (EDTA) strongly and irreversibly chelates (binds) calcium ions, preventing blood from clotting.
- Citrate is in liquid form in the tube and is used for coagulation tests, as well as in blood transfusion bags. It binds the calcium, but not as strongly as EDTA. Correct proportion of this anticoagulant to blood is crucial because of the dilution, and it can be reversed with the addition of calcium. It can be in the form of sodium citrate or acid-citrate-dextrose.
- Oxalate has a mechanism similar to that of citrate. It is the anticoagulant used in fluoride oxalate tubes used to determine glucose and lactate levels.
Dental considerations for long-term users
Dental practitioners play an important role in the early detection of anticoagulant overdose through oral manifestations as the patient doesn't show any symptoms. Dental treatment of patients taking anticoagulant or antiplatelet medication raises safety concerns in terms of the potential risk of bleeding complications following invasive dental procedures. Therefore, there comes the need for certain guidelines for the dental care of patients taking these drugs.
An overdose in anticoagulants usually occurs in people who have heart problems and need to take anticoagulants in a long term, in order to reduce the risk of stroke from their high blood pressure.
An International Normalised Ratio (INR) test would be recommended, to confirm the overdose so that the dosage can be adjusted to an acceptable standard. The INR test measures the time taken for a clot to form in a blood sample, relative to a standard.
An INR value of 1 indicates a level of coagulation equivalent to that of an average patient not taking warfarin and values greater than 1 indicate a longer clotting time and thus a longer bleeding time.
Assessing bleeding risk
There are 2 main parts to the assessment of bleeding risk:
- Assessment of the likely risk of bleeding associated with the required dental procedure
- Assessment of the patient's individual level bleeding risk
Managing bleeding risk
A patient who is on anticoagulants or antiplatelet medications may undergo dental treatments which are unlikely to cause bleeding such as local anaesthesia injection, basic gum charting, removal of plaque, calculus and stain above the gum level, direct or indirect fillings which are above the gingiva, root canal treatment, taking impression for denture or crown and fitting or adjustment of orthodontic appliances. For all these procedures, it is recommended for the dentist to treat the patient following the normal standard procedure and taking care to avoid any bleeding.
For a patient who needs to undergo dental treatments which is more likely to cause bleeding such as simple tooth extractions (1-3 teeth with small wound size), drainage of swelling inside the mouth, periodontal charting, root planing, direct or indirect filling which extends below the gingiva, complex filling, flap raising procedure, gingival recontouring and biopsies, the dentist needs to take extra precautions apart from the standard procedure. The recommendations are as follows:
- if the patient has another medical condition or taking other medication that may increase bleeding risk, consult the patient's general medical practitioner or specialist
- if the patient is on a short course anticoagulant or antiplatelet therapy, delay non-urgent, invasive procedure, until the medication has been discontinued
- plan treatment for early in the day and week, where possible, to allow time for the management of prolonged bleeding or re-bleeding, if it occurs
- perform the procedure as atraumatically as possible, use appropriate local measures and only discharge patient once haemostasis has been confirmed
- if travel time to emergency care is a concern, place particular emphasis at the time of the initial treatment on the use of measures to avoid complications
- advise the patient to take paracetamol, unless contraindicated, for pain relief rather than NSAIDs such as aspirin, ibuprofen, diclofenac or naproxen
- provide the patient with written post-treatment advice and emergency contact details
- follow the specific recommendations and advice given for the management of patients taking the different anticoagulants or antiplatelet drugs
There is general agreement that in most cases, treatment regimens with older anticoagulants (e.g., warfarin) and antiplatelet agents (e.g., clopidogrel, ticlopidine, prasugrel, ticagrelor, and/or aspirin) should not be altered before dental procedures. The risks of stopping or reducing these medication regimens (i.e., thromboembolism, stroke, myocardial infarction) far outweigh the consequences of prolonged bleeding, which can be controlled with local measures. In patients with other existing medical conditions that can increase the risk of prolonged bleeding after dental treatment or who are receiving other therapy that can increase bleeding risk, dental practitioners may wish to consult the patient's physician to determine whether care can safely be delivered in a primary care office. Any suggested modification to the medication regimen prior to dental surgery should be done in consultation and on advice of the patient's physician.
On the basis of limited evidence, general consensus appears to be that in most patients who are receiving the newer direct-acting oral anticoagulants (i.e., dabigatran, rivaroxaban, apixaban, or edoxaban) and undergoing dental treatment (in conjunction with usual local measures to control bleeding), no change to the anticoagulant regimen is required. In patients deemed to be at higher risk of bleeding (e.g., patients with other medical conditions or undergoing more extensive procedures associated with higher bleeding risk), consideration may be given, in consultation with and on advice of the patient's physician, to postponing the timing of the daily dose of the anticoagulant until after the procedure; timing the dental intervention as late as possible after last dose of anticoagulant; or temporarily interrupting drug therapy for 24 to 48 hours.
A substantial number of compounds is being investigated for use as anticoagulants. The most promising ones act on the contact activation system (Factor XIIa and Factor XIa); it is anticipated that this may provide agents that prevent thrombosis without conferring a risk of bleeding.
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