Anticoagulant Therapy

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The following course content

Introduction   

Anticoagulants are a class of medications that prevent and treat blood clots, or venous thromboembolism (VTE).  

The Centers for Disease Control and Prevention (CDC) estimates that around 900,000 people in the United States are affected by some form of venous thrombosis every year. Furthermore, the CDC estimates around 60,000 to 100,000 Americans die from some form of venous thromboembolism each year.  

They further state that sudden death is the first symptom that occurs in about 25% of people who have a pulmonary embolism [4]. Thus, healthcare providers must be knowledgeable of the signs and symptoms of venous thromboembolism and the available anticoagulants for prevention and treatment.  

Understanding the different pharmacokinetics of anticoagulant medication is essential during drug selection. This course outlines anticoagulant pharmacology and addresses pharmacokinetics, including mechanism of action, side effects, usage, and contraindications. 

Definitions 

Anticoagulants - medications used to prevent and treat blood clot formation, commonly referred to as “blood thinners” [5]. 

Venous Thromboembolism - a condition where a blood clot forms in a vein, including deep vein thrombosis and pulmonary embolism, and appears during periods of hemostasis [5].

Medications Overview 

Anticoagulant medications are used for the prevention and treatment of venous thromboembolism in both inpatient and outpatient settings.  

The major anticoagulant medication classes include: 

• Unfractionated Heparin 
• Low Molecular Weight Heparin 
• Vitamin K Dependent Antagonists 
• Direct Oral Anticoagulants 

• Direct Thrombin Inhibitors 
• Direct Factor Xa Inhibitors [14] 

Unlike anticoagulants, antiplatelets act on platelet formation. Although commonly mistaken as an anticoagulant, they are not a part of this class [14].  

Depending on the type of anticoagulant, they have other indications for use, such as: 
 

• Atrial Fibrillation stroke prevention 
• Left Ventricular Thrombus 
• Left Ventricular Aneurysm 
• Prosthetic Heart Valve 
• Venous Thromboembolism treatment 
• VTE prevention in people with cancer 
• Pulmonary Embolism 
• Pregnancy 
• Heparin-Induced Thrombocytopenia 

Pharmacokinetics 

Unfractionated Heparin 

Unfractionated heparin, also known as heparin, is a medication used to prevent excess blood coagulation. It’s used to prevent and treat thrombotic events like deep vein thrombosis (DVT) and pulmonary embolism (PE).  

Heparin is also used in patients with atrial fibrillation to prevent blood clot formation and during medical procedures, like dialysis, continuous renal replacement therapy, extracorporeal circulation, and heart catheterizations and surgeries. It’s also used for various off-label indications and usually in inpatient settings, such as acute coronary syndrome, percutaneous coronary intervention (PCI), or as a bridge medication when converting to oral anticoagulants [15]. 

Heparin works by binding to an antithrombin that inactivates thrombin and thus, blocks the clotting cascade. More specifically, by inactivating thrombin factor IIa and factor Xa, fibrinogen is not converted to fibrin, and in turn, prevents clot formation [15]. 

Heparin is available via intravenous (IV) and subcutaneous (SQ) forms. Intravenous heparin is infused via continuous infusion until therapeutic levels are achieved, while the SQ form is administered intermittently for VTE prophylaxis. Starting dosages of IV heparin usually begin with a bolus of 80 units per kilogram (kg), and then a continuous infusion rate of 18 units/kg/hour. However, this is dependent on the underlying medical condition being treated and is titrated to achieve therapeutic levels.  

In hospital settings, heparin flushes are available to lock and maintain IV-line patency. Additionally, subcutaneous dosages of heparin are weight-based and dependent on the medical condition [15].  

Common side effects of heparin include: 

• Bleeding 
• Thrombocytopenia 
• Injection site reactions 
• Hyperkalemia  

[15] 

As bleeding is a common side effect, nurses and healthcare providers must monitor patients for evidence of bleeding. Some signs or symptoms of bleeding can include petechiae, bruising, nosebleeds, hematuria, and bright red or dark, tarry stools. Moreover, heparin-induced thrombocytopenia (HIT) usually occurs within five days of initiating heparin therapy, causing serious adverse effects, like myocardial infarction, stroke, DVT, PE, and even death [15]. 

Before ordering this medication, healthcare providers should be aware of this anticoagulant’s contraindications. Heparin is contraindicated in individuals who have a platelet count of less than 100,000/mm or they have an active, uncontrolled bleed except if they have disseminated intravascular coagulation (DIC). It should also be avoided in patients with a history of HIT or who cannot have routine blood monitoring of heparin therapeutic levels.  

Monitoring the patient’s hemoglobin, hematocrit, and vital signs is also essential to detecting a possible hemorrhage [15]. 

As heparin affects clotting time, healthcare providers must order therapeutic monitoring for activated partial thromboplastin time (aPTT) and activated clotting time (ACT). Prior to patients being initiated on a heparin infusion, a baseline aPTT level is drawn and then subsequently monitored every 6 hours until a therapeutic aPTT level is achieved. After there are two or more aPTT therapeutic results, then an aPTT is drawn every 24 hours.  

The therapeutic range of heparin is typically 1.5 to 2 times the normal range, and titration algorithms are dependent on the healthcare facility’s protocols. ACT monitoring is less specific than aPTT and is typically reserved for PCI or cardiac bypass [15]. 

Low Molecular Weight Heparin 

Another medication used to prevent excess blood coagulation is low molecular weight heparin (LMWH). This medication is used to prevent venous thromboembolic disease in hospitalized patients and is also used to treat DVT and PE. Low molecular weight heparin is also approved for use and treatment of medical conditions such as ST-elevation myocardial infarction (STEMI), unstable angina, and extracorporeal clot prevention.  

Common names of LMWH include enoxaparin and dalteparin [13]. 

Low molecular weight heparin’s mechanism of action works on the body’s clotting cascade by activating antithrombin III. Once antithrombin III is activated, it binds to factor Xa, which inhibits thrombin activation. Therefore, clot formation is prevented since fibrinogen is not converted to fibrin. This medication’s mechanism of action slightly differs from heparin, as LMWH inhibits factor Xa only, while heparin acts on factor IIa and factor Xa [13]. 

Low molecular weight heparin is available via subcutaneous injection. Dosages of this medication are typically calculated by body weight and are dependent on whether it’s being used for prevention or treatment. LMWH is typically administered once or twice daily and is safe to administer during pregnancy.  

Some adverse effects of LMWH include:  

• Bleeding 
• Heparin-induced Thrombocytopenia 
• Injection site reactions 
• Osteoporosis [13]. 

Some other side effects are spontaneous fracture, hyperaldosteronism, and hypersensitivity reactions. Before prescribing this medication, healthcare providers must be knowledgeable of LMWH contraindications. It’s contraindicated in patients with hemorrhagic disorders, peptic ulcer disease, cerebral hemorrhage, trauma, and recent eye or nervous system surgeries.  

Additionally, healthcare providers should caution when prescribing LMWH to patients with chronic kidney disease, as it increases the risk of accumulation in their system. Lower doses may be required for these individuals. A benefit of low molecular weight heparin when compared to unfractionated heparin is that the patient’s aPTT blood levels do not need to be monitored [13]. 

Vitamin K Dependent Antagonists

Vitamin K antagonists (VKAs) are a class of anticoagulant medications used in the prevention and treatment of blood clots. Warfarin is a commonly prescribed VKA and other less common VKAs are acenocoumarol, fluindione, and phenprocoumon [7].  

Warfarin is approved for the treatment and prevention of pulmonary embolism, venous thrombosis, and thromboembolic complications of heart valve replacement and atrial fibrillation. It’s also used to reduce mortality risk after a myocardial infarction or stroke. Prevention of transient ischemic attack and stroke are additional off-label indications [11]. 

Vitamin K antagonists act by inhibiting the liver’s vitamin K epoxide reductase complex 1 (VKORC1). This reduces the amount of vitamin K reserves and therefore reduces the production of the body’s clotting factors that require vitamin K. Some clotting factors that are reduced include factors II, VII, IX, and X [7]. 

Vitamin K antagonists are available in oral form and are typically taken once daily in the afternoon or evening. Warfarin is rapidly absorbed, and onset of action is about 24 to 72 hours. The medication’s therapeutic effects aren’t normally seen until five to seven days after taking the medication. The typical starting dosage is 5 mg but might be less (2.5 mg) in patients who are elderly or who have liver disease [11].  

Some common side effects of this class of medications include: 

• Bleeding or bruising 
• Nausea 
• Vomiting 
• Abdominal pain 
• Altered sense of taste [11]. 

As VKAs alter the body’s ability to clot, it can cause more serious adverse effects, such as: 

• Significant bleeding or hemorrhage 
• Purple toe syndrome 
• Warfarin-induced skin necrosis 
• Calciphylaxis [11]. 

Warfarin and other VKAs have several contraindications such as gastrointestinal bleeding, cerebral aneurysm, dissecting aortic aneurysm, or other hemorrhagic conditions. Additionally, if the patient has had a recent nervous system, eye, or trauma surgery, then this medication should not be prescribed. Threatened abortion, malignant hypertension, and regional or lumbar anesthesia blocks are contraindications as well [11]. 

When prescribing VKAs, healthcare providers must order therapeutic monitoring and assess the patient’s prothrombin (PT) or international normalized ratio (INR). INR is usually the preferred method where a baseline level is initially drawn, and then subsequent levels are drawn within a week. The therapeutic range is dependent on the underlying medication condition, where the goal can range from an INR of 2 to 3 for most patients or from 2.5 to 3 for patients with a mechanical mitral valve.  

Once the patient has reached their therapeutic goal, levels are typically drawn every four weeks unless there have been changes in their medications. Additionally, patients who take VKAs should have their hemoglobin and hematocrit levels and liver and kidney function checked at least every 6 months [11]. 

Direct Oral Anticoagulants 

Direct oral anticoagulants (DOACs) are a class of anticoagulant medications mainly used to prevent thrombosis formation. There are two main classes of DOACs, which include direction thrombin inhibitors and direct factor Xa inhibitors [6]. 

Direct Thrombin Inhibitors 

Direct thrombin inhibitors (DTIs) are used to treat and prevent thrombosis in patients with heparin-induced thrombocytopenia, acute coronary syndrome, or during percutaneous coronary intervention. Common names of direct thrombin inhibitors include argatroban, bivalirudin, fondaparinux, and dabigatran [9]. Additional off label uses may include anticoagulation during dialysis or renal replacement therapy, and it can be used as an alternative anticoagulant for patients who are resistant to heparin [10]. 

Direct thrombin inhibitors block coagulation activities that are involved in fibrin clot formation. There are two types of direct thrombin inhibitors, which are univalent DTIs that act by binding to the active site of thrombin, and bivalent DTIs that bind to two sites, the active thrombin site and exosite I.  

As the thrombin pathways are blocked and cleavage of fibrinogen to fibrin is prevented, this ultimately inhibits clot formation and coagulation [9]. Some DTIs, like argatroban, are metabolized primarily via the cytochrome P450 enzyme [10]. 

This class of anticoagulant medications is typically available in intravenous form. However, it is also available in oral form, but dabigatran is the only available oral form. Starting dosages for DTIs depend on the medical condition being treated [9].  

Some side effects of DTIs may include: 

• Bleeding 
• Gastrointestinal symptoms and bleeding 
• Hypotension 

• Dyspnea 
• Fever 
• Sepsis  

[10] 

When DTIs are used during PCI, some potential side effects are back pain, nausea, chest pain, and headache. Contraindications include increased bleeding, a history of medication hypersensitivity, lumbar puncture, and spinal anesthesia [10]. 

As most patients who are treated with DTIs have HIT, aPTT monitoring is common and the goal is 1.5 to 3 times the patient’s baseline. For patients who undergo PCI, ACT is used, and levels are obtained according to the hospital’s protocol or policy [10]. 

Direct Factor Xa Inhibitors 

Direct factor Xa inhibitors are used to prevent and treat several blood clotting disorders. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, and edoxaban and they are only available in oral form [9].  

These medications are often used to reduce the risk of stroke in patients with atrial fibrillation or other cardiac arrhythmias. Direct Xa inhibitors are also used to prevent and treat conditions like DVT or PE [1]. Rivaroxaban is approved for secondary prevention and adjunct therapy after acute coronary syndrome and peripheral artery disease [12]. 

Direct factor Xa inhibitors directly bind to factor Xa, preventing it from cleaving prothrombin to thrombin. This results in blocking the propagation phase of the coagulation cascade [9]. It is metabolized via the liver and by the CYP3A4/5 and CYP2J2 mechanisms [12]. 

Starting dosages of direct factor Xa inhibitors depend on the underlying medical condition. Rivaroxaban usually is started at 20mg daily for atrial fibrillation stroke prevention or 10mg daily for VTE prevention [12].  

Some side effects of direct factor Xa inhibitors may include: 

• Dizziness 
• Hemorrhage 
• Abdominal Pain  
• Pruritis 
• Nausea  

[1] [12] 

Direct factor Xa inhibitors have several drug interactions and thus, the healthcare provider must review any potential interactions before initiating this medication. Common drugs that have potential interactions are aspirin, ketoconazole, phenytoin, rifampin, and carbamazepine [1].  

They are also contraindicated in patients with hepatic and renal impairment, antiphospholipid syndrome, and increased bleeding risk. Most have black box warnings of increased risk of thrombotic adverse events and spinal or epidural hematoma. They should also be avoided in patients who are pregnant or breastfeeding [12]. 

Although this class of medications does not require routine blood monitoring, the healthcare provider should consider obtaining baseline aPTT, PT, and kidney and liver function.  

If the patient is scheduled for surgery with a moderately high risk of bleeding, direct factor Xa inhibitors should be held for at least 48 hours before the procedure [1]. 

Considerations for Prescribers 

This section reviews potential considerations when prescribing anticoagulants. 

When prescribing anticoagulant medications, healthcare providers must consider and review several factors. First, the route and dosage are typically determined by the setting, inpatient versus outpatient, if it’s being used for prevention or treatment, and the underlying medical condition.  

Additionally, healthcare providers should strive to follow current guidelines, approved uses, and hospital protocols when initiating or adjusting these medications. Healthcare providers must review the patient’s medical history, baseline lab values, contraindications, and recommended therapeutic medication range as discussed above.  

Low molecular weight heparin is often considered safe during pregnancy [13]. Certain anticoagulants, especially warfarin, should be avoided in patients who are elderly, prone to falls, or have reduced kidney function [11]. Oftentimes, anticoagulants are combined with antiplatelet medications to produce better therapeutic results in certain medical conditions [8]. 

Healthcare providers should also review the potential common and adverse side effects of anticoagulants with patients. Additionally, as bleeding is a serious adverse effect, they should review potential signs of bleeding, such as dizziness, uncontrolled bleeding to the skin, blood in the stool or urine, and other symptoms [15]. Patients should be instructed to seek immediate medical treatment if they experience any of these symptoms, fall at home, or have another traumatic injury.  

In addition, they should be instructed on how to control bleeding when cuts occur to the skin [11]. A common side effect of LMWH is pain and bruising around the injection site. Therefore, patients should understand the importance of rotating injection sites and if side effects become a concern, then an oral alternative should be considered [13]. 

As periodic blood monitoring is required for many anticoagulants, such as INR, PT, or aPPT, the healthcare provider must review the importance of completing these labs and coming to their scheduled visits [15, 11]. If the patient is non-compliant with laboratory monitoring, then the healthcare provider should consider other alternatives, such are direct oral anticoagulants that do not require routine bloodwork or DTIs that have a wider therapeutic range [6] [9]. 

In addition, the healthcare provider must be knowledgeable about the potential drug interactions for each medication and dietary concern. For example, patients on vitamin K antagonists should reduce their intake of foods high in vitamin K since it counteracts the therapeutic effects of the medication. They should avoid foods rich in vitamin K, such as spinach, kale, and broccoli [7]. Co-administration of other anticoagulants, aspirin, and non-steroidal anti-inflammatory medications also increases bleeding risk [11]. 

Most anticoagulant medications can potentially cause toxicity and patients should seek emergency medical treatment. Therefore, healthcare providers must be aware of the signs and symptoms of toxicity and the reversal agent, or antidote, for each medication.  

Protamine sulfate is the reversal agent for heparin and low molecular weight heparin. Protamine sulfate is administered via IV push and if administered too rapidly can lead to pulmonary edema, vasoconstriction, and pulmonary hypertension [15]. Vitamin K is the antidote for vitamin K antagonists [11]. Andexanet alfa is the reversal agent for direct factor Xa inhibitors and idarucizumab is approved for the reversal of dabigatran specifically [12].

Upcoming Research 

This section reviews upcoming research and medications for anticoagulant treatment. 

There have been many new anticoagulant medications introduced over the past several years and research continues to evolve for this type of medication. More recently, a newer class of anticoagulant medications called anti-factor XI and Xia inhibitors, affect the factor XI pathway for clot formation. However, it’s still being researched and there are ongoing clinical trials [3].  

Moreover, in November 2023, the American Heart Association released promising information about abelacimab, a monoclonal antibody that acts as a factor XI inhibitor, which has been shown to reduce stroke risk in patients with atrial fibrillation. The same report stated that bleeding risk was reduced by more than 60% while taking this medication [2].  

Potential factor VII and VIII inhibitors are also being researched [16]. 

Conclusion

Anticoagulants are typically indicated for the prevention and treatment of blood clotting conditions, including deep vein thrombosis and pulmonary embolism. However, they have several additional approved and off-label uses. Healthcare providers should understand the pharmacokinetics, potential side effects, and contraindications when selecting an anticoagulant. They should also follow current clinical guidelines and their facility’s protocols for a more evidence-based approach. 

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