Anticoagulants in the Management of Pulmonary Embolism

*Ladan Panahi, George Udeani, Michael Horseman, Jaye Weston, Nephy Samuel, Merlyn Joseph, Andrea Mora, Daniela Bazan and Pooja Patel*

### **Abstract**

Pulmonary embolism management has typically been accomplished with anticoagulant treatment that includes parenteral heparins and oral vitamin K antagonists. Even though heparins and oral vitamin K antagonists continue to play a role in pulmonary embolism management, other newer available options have somewhat reduced the role of heparins and vitamin K antagonists in pulmonary embolism management. This reduction in utilization involves their toxicity profile, clearance limitations, and many drug and nutrient interactions. New direct oral anticoagulation therapies have led to more available options in the management of pulmonary embolism in the inpatient and outpatient settings. More evidence and research are now available about reversal agents and monitoring parameters regarding these newer agents, leading to more interest in administering them for safe and effective pulmonary embolism management. Current research and literature have also helped direct the selection of appropriate use of pharmacological management of pulmonary embolism based on the specific population such as patients with liver failure, renal failure, malignancy, and COVID-19.

**Keywords:** pulmonary embolism (PE), venous thromboembolism (VTE), anticoagulants, direct oral anticoagulants (DOAC), heparin, vitamin K antagonist (VKA)

### **1. Introduction**

Pulmonary embolism (PE) is a type of venous thromboembolism (VTE) that is potentially fatal but can be treated with different types of therapy. PE is an obstruction of the pulmonary arteries that can be caused by a clot, tumor, fat, or air. PE occurs when a portion of a blood clot breaks off and travels until it lodges in the pulmonary arteries [1]. Most deep vein thrombosis will develop in the lower extremities, but up to half can lead to PE [2]. PE is a significant health issue in the US, since there is an increased prevalence of this condition in the elderly. Other risk factors include obesity, heart failure, and cancer [3].

Current anticoagulation management guidelines prefer direct oral anticoagulants (DOAC) such as dabigatran, rivaroxaban, apixaban, and edoxaban for initial and long-term therapy for treating PE [4]. DOACs are preferred over vitamin K antagonist (VKA) therapy. This is due to the similar risk reduction for recurrent VTE, reduced risk of bleeding, and improved patient and provider convenience over the intensive monitoring associated with VKA therapy [4]. Each of the DOACs has demonstrated similar efficacy outcomes compared to VKA therapy with recurrent embolism [4]. In contrast, the risk of bleeding differs with the DOACs, which demonstrate less risk when compared to warfarin [4]. One possible exception to this, however, is that gastrointestinal bleeding may be higher with dabigatran, rivaroxaban, and edoxaban compared to warfarin. This has been observed in patients treated with atrial fibrillation [4]. Treatment recommendations differ when managing PE in special populations such as cancer, pregnancy, obesity, elderly, renal dysfunction, hepatic dysfunction, and COVID-19. Low-molecular-weight heparin (LMWH) is recommended over VKA therapy in cancer-associated thrombosis. Evidence suggests that LMWH is more effective in reducing recurrent embolism in this population and is more reliable in patients who have difficulty tolerating oral intake. It further removed the need for frequent monitoring of the international normalized ratio (INR) [4]. The prevention of PE in hospitalized patients includes either LMWH, low-dose unfractionated heparin (UFH) administered twice or three times daily, or fondaparinux [5]. Bleeding remains a concern with anticoagulation therapy. With the availability of reversal agents, clinicians have been able to push the boundaries of PE management with confidence in both the inpatient and outpatient settings.

The duration of anticoagulant therapy for PE is 3 months, at minimum, which may be extended or indefinite in selected circumstances [4]. In patients with a PE provoked by surgery or a nonsurgical transient risk factor, the recommended duration of anticoagulation is 3 months [4]. In patients with an unprovoked PE, bleeding risk determines the duration, but in patients with high bleeding risk, the duration remains at 3 months. In low to moderate bleeding risk, the duration of therapy becomes indefinite [4].

### **2. Unfractionated heparin (UFH)**

UFH is a parenteral anticoagulant that works by inactivating thrombin (IIa) and factor Xa *via* antithrombin. It is derived from porcine or bovine tissue. UFH is the anticoagulant of choice in patients with PE who have a high bleeding risk, critical illness, or need a surgical/invasive procedure. This is due to its short halflife that ranges from 0.5 to 1.5 h, leading to the anticoagulant effect's rapid onset and offset within hours of IV discontinuation [6]. Furthermore, due to its unique metabolism and clearance through the reticuloendothelial system, it is a desirable option for patients with poor and/or unstable renal function (creatinine clearance (CrCL) < 30 mL/min) [1]. Lastly, UFH lacks cytochrome P450 enzyme activity in the liver, and hence, drug interactions are predominantly limited to increased bleeding risk with concurrent anticoagulant and antiplatelet therapy. This makes it a favorable agent in patients with concerns of drug–drug interactions [7].

The IV route is the preferred mode of administration in shock and/or hypotension due to the absorption variability from subcutaneous tissues secondary to UFH plasma protein binding [6]. Dosing and special considerations for UFH are discussed in **Table 1**.

Some adverse drug reactions of concern are thrombocytopenia and major bleeding, such as intracranial and gastrointestinal bleeds. Heparin-associated thrombocytopenia can present in two forms. There is an early, benign, reversible nonimmune thrombocytopenia form and a late, more serious immunoglobulin G



### **Table 1.**

*Anticoagulant dosing and special considerations.*

(IgG)-mediated immune thrombocytopenia type, referred to as heparin-induced thrombocytopenia (HIT). HIT poses a concern with UFH use in the treatment of PE, with the overall incidence being reported to be up to 7% in patients with a mortality of 20–30% and varies depending on factors such as patient population (surgical vs. medicine), duration of heparin use, and the type of heparin administered [17, 18]. UFH has a threefold higher risk of HIT compared to LMWH and serious limb-threatening and life-threatening complications [19]. The mechanism of HIT stems from IgG formation against the heparin/PF4 complex on platelets. Once IgG binds to the heparin/PF4 complex on platelets, the platelets become activated, resulting in venous and arterial thrombi formation [19, 20]. Monitoring platelets every 2–4 days or more frequently in higher-risk patients is recommended in patients on treatment doses of heparin [20]. Another side effect of concern is the significant reduction in bone density reported in about 30% of adult patients and the symptomatic bone fractures that occur in 2–3% of adult patients receiving heparin for at least 1 month or more [21].

A complete outline of first line and alternate reversal agents utilized for anticoagulants for PE management is outlined in **Table 2**. Protamine sulfate is a reversal agent indicated for the reversal of UFH- and LMWH-associated bleeds. This agent is administered by a slow IV infusion at doses <5 mg/min due to the concerns of anaphylaxis, hypotension, bradycardia, and respiratory toxicity associated with the rapid infusion [8]. Due to UFH's short half-life, a reversal agent may not be necessary for most cases, as the UFH effect will normalize due to its rapid clearance [8].


*2 LMWH: low molecular weight heparin.*

*3 VKA: vitamin K antagonist.*

*4 4F-PCC: 4-factor prothrombin complex concentrate.*

*5 FFP: fresh-frozen plasma.*

*6 PCC: prothrombin complex concentrate.*

*7 aPCC: activated prothrombin complex concentrate.*

**Table 2.**

*Recommended reversal agents for anticoagulant therapy.*
