Correcting Coagulopathy for Image-Guided Procedures

Abstract

Patients with acquired coagulopathy often require percutaneous image-guided invasive procedures for urgent control of hemorrhage or for elective procedures. Routine preprocedural evaluation of coagulopathy previously focused on absolute prothrombin time, partial thromboplastin time, international normalized ratio, and platelet count values. Now viscoelastic testing and greater understanding of patient- and drug-specific changes in coagulation profiles can yield better coagulation profile data. More specific reversal agents and profiles combine for less generalized and more titrated transfusion or correction algorithms. This article reviews procedural and patient-specific factors for defining both hemorrhagic risk and correction strategies.

Blood coagulation is a complex physiologic interaction. For an interventional radiologist, hemostasis is the balance between procoagulant, anticoagulant, fibrinolytic, and antifibrinolytic processes to allow for a safe and effective invasive diagnostic or therapeutic procedure. Coagulopathy, or the derangement of hemostatic balance, can result in serious clinical sequelae including both iatrogenic bleeding injury and the inability to control bleeding. Critical medical or surgical illness, trauma, advanced liver or kidney disease, and anticoagulant medications contribute uniquely and variably to a patient's coagulation status.

While interventional radiologists possess a significant tool kit to treat hemorrhagic complications in medical and surgical patients by using mechanical, adhesive, liquid, and particulate embolic agents, correcting, understanding, and anticipating coagulopathy prior to intervention significantly reduces patient morbidity and mortality. Reversal strategies balance the risk of thromboembolic event, severity of bleeding, and urgency of image-guided procedures. In some cases, there may not be a necessity for complete reversal of the coagulopathy to achieve a profile for safe intervention or for control of bleeding. Specific invasive procedure types influence risk stratification and corrective strategies. Published guidelines including those from the Society of Interventional Radiology (SIR) risk stratify procedures into low risk and high risk for bleeding categories. The guidelines also offer recommendations for withholding and reinitiating anticoagulants, and antiplatelet agents to reduce hemorrhagic risk as well as guidelines for correcting specific coagulopathies. ^{1 2} This article will describe and provide context for recommendations for correcting coagulopathy risk.

General Principles of Preprocedural Evaluation

Routine Laboratory Testing

Historically, in both emergent and elective settings, a patient's “bleeding risk” is assessed using prothrombin time (PT), international normalized ratio (INR), and platelet count values. The basis for this practice is the concept that platelet-rich cross-linked fibrin clot resulting from a functioning coagulation cascade results in hemostasis. Most elective procedure and hospitalized patients undergo this routine testing. Multiple factors contributing to coagulopathy in a hospitalized patient validate the necessity for this testing. In an elective procedure setting, however, the necessity for routine laboratory testing may be unnecessary; in the absence of a bleeding history, a thorough history and physical examination should be sufficient and more cost-effective for evaluating bleeding risk. ³

Platelets

Primary hemostasis is the formation of the platelet plug at the area of vessel injury. Formation of the platelet plug is a complex event initiated with the release of von Willebrand factor (VWF) from injured endothelium, which initiates the binding and activation of circulating platelets. In turn, other pathways are activated that lead to the various responses of platelet shape change, amplification of platelet activation, endothelial cell activation, and procoagulant changes in the platelet surface membrane supporting thrombin generation and activation of α _IIb β ₃ (glycoprotein IIb/IIIa), leading to further platelet aggregation. ^{4 5 6}

A normal platelet count ranges between 150 and 450 × 10 ⁹ /L, ⁷ which is significantly greater than what is required for hemostasis. A platelet count above 50 × 10 ⁹ /L is assumed to be adequate for reducing bleeding risk during most image-guided procedures, and by consensus is typically adopted for image-guided interventions based on studies involving cancer patients undergoing more invasive procedures. ⁸ A large retrospective study of 18,204 patients that included 2,060 patients with a platelet count of 100 × 10 ^9/ L demonstrated that prophylactic platelet transfusions did not reduce bleeding or improve clinical outcomes when utilized for patients with counts greater than 50 × 10 ^9/ L. Prophylactic platelet transfusions did not reduce the frequency of RBC transfusion. Patients who did receive transfusion in this study were more likely to have a hematologic malignancy, lower baseline platelet count, and increased incidence of emergency procedures. ⁹

Platelet count alone does not linearly correlate with the likelihood of bleeding. Studies have demonstrated that low counts from increased consumption is less often associated with bleeding because these platelets tend to be hyperfunctioning despite being low in number. ^{1 10} Platelet function assays are important in patients using antiplatelet medications that inhibit adenosine receptors necessary for initiation of platelet aggregation. Clopidogrel, ticlopidine, ticagrelor, and prasugrel are examples of such agents. These assays are often used to determine effectiveness of antiplatelet medications including aspirin, and may have some value in evaluating bleeding risks.

Prothrombin and Partial Thromboplastin Time

The PT and partial thromboplastin time (PTT) values assess the extrinsic and intrinsic coagulation pathways, respectively. These multistep pathways converge to form a stable fibrin clot. The INR was established to account for the variability in PT reagent testing. Prolongation of PT and elevation of INR assess deficiency or ineffective common or extrinsic pathway factors (factors I, II, V, VII, X). These factors are synthesized by the liver, and acute or chronic liver injury can result in INR/PT abnormalities. Other patient-specific factors encountered in the hospital setting that can prolong the PT and increase the INR including disseminated intravascular coagulopathy (DIC), malnutrition, malabsorption, vitamin K deficiency, and anticoagulation therapy. ^{1 11}

The PTT evaluates the intrinsic pathway; deficiency in factors VIII, VIV, XI, and XII can prolong the PTT. Similar patient-specific factors including vitamin K deficiency, DIC, liver disease, and anticoagulation can prolong the PTT. Most commonly in the hospitalized patient, PTT elevation occurs in patients on unfractionated heparin.

Beyond Routine Testing

Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are point-of-care tests that assess clot formation, strength of clot, and resolution of clot providing more global and specific information about a patient's risk for bleeding than what is possible using data from standard coagulation tests. TEG testing has been validated and used in the surgical and trauma settings to reduce unnecessary transfusion and to guide appropriate transfusion requirements. ^{8 12}

Procedure-Associated Bleeding Risks

Specific invasive procedures influence risk stratification and corrective strategies. The Society of Interventional Radiology guidelines risk stratify procedures for bleeding into low risk and high risk. ¹ Based on the defined risk category for procedure type, the patient may require full or partial correction of a coagulopathy. The use of an access closure device may decrease the need for correcting a necessary coagulopathy during arteriography. Certain embolic agents such as n-butyl cyanoacrylate (n-BCA) adhesive, Onyx (Medtronic, Inc., Minneapolis, MN), and mechanical agents are effective in causing mechanical occlusion without the need for superimposed thrombosis, which may be particularly advantageous in patients with a coagulopathy. In many circumstances, however, for effective embolization, correction of coagulopathy is necessary. Coagulopathy reversal strategies balance the risk of thromboembolic event, severity of bleeding, and urgency of image-guided procedures. For low-risk procedures, the Society of Interventional Radiology guidelines suggest INR correction to 2.0 to 3.0 or less, and to consider platelet transfusion if platelet counts are less than 20 × 10 ⁹ /L. Low bleeding risk procedures are defined in the guidelines and include diagnostic arteriography/venography with intervention, thoracentesis, paracentesis, transjugular liver biopsy, dialysis access, tunneled and nontunneled access, and superficial drain placement.

Correction thresholds differ for high-risk procedures, with recommendations for INR correction to ≤1.5 to 1.8 and platelet transfusion if less than 50 × 10 ⁹ /L. High-risk procedures include deep organ drainages/biopsies, gastrostomy placement, TIPS, ablations, and urinary tract interventions.

Correcting Coagulopathy

Anticoagulant-Associated Coagulopathy

Warfarin

In an elective setting, simply holding warfarin for 5 days is recommended to reverse coagulopathy. This is based on the biologic half-life of warfarin of 36 to 42 hours. The PT/INR values return to normal in 4 to 6 days after discontinuation. ¹³

In the semiurgent setting when correction is required within 1 or 2 days, 2.5 to 5 mg of oral or intravenous (IV) vitamin K is added for faster correction of the coagulopathy. Urgent or emergent situations require correction with vitamin K, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC). ^{14 15}

Vitamin K

Vitamin K can be administered as an oral, subcutaneous, or IV dose. The desired clinical effect usually occurs within 6 to 8 hours after administering an IV dose of 5 to 10 mg. The dose is given slowly over a 30-minute period to decrease the risk of an anaphylactic reaction. An oral dose of 1 to 5 mg will take approximately 24 hours for an equal effect. ¹⁶ Vitamin K use results in a sustained INR correction and may reduce effectiveness of warfarin reintroduction.

Fresh Frozen Plasma

FFP contains all the necessary vitamin K–dependent coagulation factors; therefore, correction is effective immediately upon administration. FFP contains 1 IU/mL of all clotting factors; so, correcting coagulopathy may require 10 to 15 mL/kg leading to clinically significant volume overload. Factor VII has a 4- to 6-hour half-life and hemostatic efficacy is reduced after time. Once thawed, FFP can be kept at 1 to 6 °C for up to 24 hours without significant loss of clotting factors. ¹⁷

Prothrombin Complex Concentrates

PCC, a highly purified concentrate, contains four vitamin K–dependent clotting factors (II [prothrombin], VII, IX, and X). Four-factor PCC (Kcentra; CSL Behring, King of Prussia, PN) is dosed on the amount of factor IX with each vial containing approximately 500 units. A vial of PCC also contains proteins C and S, antithrombin III, and a small amount of heparin to reduce the risk of thrombotic events. ¹⁸

PCC administration does not require a blood cross-match and can be administered quickly without a thawing period and in small volumes of fluid. PCC is leukocyte free and less likely to cause transfusion reaction or transfusion-related acute lung injury (TRALI). ^{19 20 21}

A randomized clinical trial comparing PCC and plasma for urgent vitamin K antagonists (VKA) reversal in patients with major bleeding met the coprimary end points; four-factor-PCC was noninferior to plasma for hemostatic efficacy and for rapid INR reduction. ²² A meta-analysis assessing five randomized trials and eight observational studies compared PCC and FFP for warfarin reversal in the setting of major bleeding or need for emergent surgery found equivalent hemostasis, but there was a significantly greater reduction of all-cause mortality and more rapid correction in patients receiving PCC. ²³

Vitamin K–dependent factors achieve hemostatic values within 30 minutes of appropriate dose PCC infusion ( Table 1 ).

Table 1. Prothrombin complex concentrate (human) (Kcentra) use.

Mechanism	Dose of Kcentra	Maximum dose	Monitoring
• Four-factor unactivated PCC • Prothrombin complex concentrate provides an increase in the levels of the vitamin K–dependent coagulation factors (II, VII, IX, and X) with the addition of protein C and protein S	Individualize dosing based on current pre-dose INR. Dosage is expressed in units of factor IX activity. Administer with vitamin K concurrently. Repeat dosing is not recommended		• INR (baseline and at 30 min post dose) • Clinical response during and after treatment • Signs of thromboembolism and hypersensitivity reactions
	Pretreatment INR 2 to <4: 25 unit/kg	2,500 units
	Pretreatment INR 4–6: 35 unit/kg	3,500 units
	Pretreatment INR > 6: 50 unit/kg	5,000 units
	INR unavailable:	3,000 units
	“Dose rounding (to utilize fewest number of vials)” Doses can be rounded up to 10% over the original dose or 5% lower than the original dose. Round down if you are approaching the max dose. Do not exceed maximum doses when rounding

Abbreviations: INR, international normalized ratio; PCC, prothrombin concentrate.

Direct Oral Anticoagulants

There are two main classes of direct oral anticoagulants (DOACs): oral direct factor Xa inhibitors (i.e., rivaroxaban, apixaban, edoxaban, and betrixaban) and direct thrombin IIa inhibitors (i.e., dabigatran). These agents have many advantages over VKAs including fewer monitoring requirements, fewer drug and food interactions, more immediate drug onset, and quicker and well-defined offset effects. ²⁴ Patient-specific comorbidities that limit the use of these agents include chronic kidney disease, hepatic impairment, and extremes of body weight. ²⁵ DOACs are eliminated by the kidneys to varying degrees; so, alterations in renal clearance affect therapeutic levels and therefore risks of bleeding. Dabigatran is the most renally eliminated, followed in decreasing order by edoxaban, rivaroxaban, apixaban, and betrixaban. ^{26 27} All DOACs are contraindicated in patients with severe hepatic disease, so warfarin is the recommended anticoagulant in this patient population. Dabigatran, apixaban, and edoxaban may be used in patients with moderate hepatic impairment without dose adjustment. ²⁶

Fixed drug doses may lead to decreased drug availability in obese patients and increased drug availability in underweight patients. There are no FDA-approved methods for monitoring the anticoagulant effect of DOACs; PTT, PT, and thrombin time do not assess the degree of anticoagulant effect as seen with INR monitoring of VKA therapy.

Before elective invasive procedures, DOAC therapy is discontinued based on the half-life of the drug, with the understanding that renal/hepatic function can affect elimination. Before a high-risk invasive procedure, the concentration of the DOAC should be lower than 30 ng/mL to avoid bleeding risk. Urgent and emergent correction strategies are summarized in Table 2 .

Table 2. Direct oral anticoagulants (DOACs)—reversal.

	Apixaban (Eliquis)	Dabigatran (Pradaxa)	Edoxaban (Savaysa)	Rivaroxaban (Xarelto)
Classification	Selective direct Xa inhibitor	Selective thrombin inhibitor	Selective direct Xa inhibitor	Selective direct Xa inhibitor
Metabolism	25% renal, 75% biliary	80% renal, 20% biliary	50% renal, 50% biliary	66% renal, 33% biliary
Half-life	8–15 h	12–17 h 14–17 h (elderly)	10–14 h	5–9 h 9–12 h (elderly)
Recommendations for bleeding besides blood products	Kcentra 5,000 units Non-ICH bleeding or need for urgent/emergent invasive procedure: Kcentra 50 unit/kg (max. 5,000 units)	• Only DOAC with antidote: Idarucizumab (Praxbind) • Only DOAC that can be moderately reversed by dialysis	Kcentra 5,000 units	Kcentra 5,000 units Non-ICH bleeding or need for urgent/emergent invasive procedure: Kcentra 50 unit/kg (max. 5,000 units)

Abbreviation: ICH, intracranial hemorrhage.

Heparins

The half-life of heparin is 30 to 60 minutes and drug elimination occurs in 7.5 to 10 hours. Measurement of PTT and anti-Xa assays can be used to determine coagulopathy during heparin therapy. In a nonurgent clinical setting after about 4 to 5 hours (five half-lives), the heparin effect is neutralized. Urgent heparin reversal is achieved with IV protamine administration. Dosing guidelines are guided by the amount of heparin administered and by calculation or estimation of heparin remaining in plasma based on half-life. A dose of 1 mg protamine per 100 units of heparin is usually effective. When timing of last heparin dose or bolus is unknown, empiric treatment with a 25- to 50-mg dose is warranted. Protamine should be given with a slow IV push to prevent hypotension.

Protamine is also used to treat low-molecular-weight (LMW) heparin coagulopathy. Antifactor Xa activity is not completely reversed, but protamine can neutralize the higher molecular weight fractions of heparin that are typically responsible for bleeding. The dosing is different from that with unfractionated heparin. Table 3 provides reversal and withholding recommendations for heparins.

Table 3. Reversal and withholding of heparins.

Heparin	Protamine dose	Withhold time	Comments
Unfractionated heparin	1 mg per 100 units of heparin	n/a	Full-dose (50 mg) protamine indicated in patients needing reversal <60 min after heparin bolus administration
Enoxaparin	≤ 8 h: 1 mg for every 1 mg of enoxaparin; >8 h: 0.5 mg for every 1 mg of enoxaparin	Withhold 1 dose if prophylactic dose used; withhold 2 doses if therapeutic dose used	Reversal may not be necessary for >12–24 h since last enoxaparin dose in normal renal function
Dalteparin	≤ 8 h: 1 mg of protamine for every 100 units of dalteparin; > 8 h: 0.5 mg for every 100 units of dalteparin	Withhold 1 dose before high-risk procedure	Reversal may not be necessary for >12–24 h since last dalteparin dose in normal renal function

Anaphylactic reactions to protamine have been reported in patients with previous exposure to protamine or with fish allergy. Diabetic patients receiving protamine containing insulin may be at risk.

Pentasaccharide Anticoagulants

The mechanism of action of the synthetic pentasaccharide fondaparinux (Arixtra, GSK) is indirect inhibition of factor Xa, so there are no thrombin or antiplatelet effects. The plasma half-life is 15 to 17 hours and peak serum concentrations occur at 1.7 hours after subcutaneous injection. Half maximal concentration occurs at 25 minutes. In patients with normal renal function, the therapeutic effect is present for 2 to 4 days after the last administration. There is no approved reversal agent specific for fondaparinux. Andexanet alfa, used for the reversal of apixaban and rivaroxaban, may have some reversal efficacy.

Prior to invasive procedures, fondaparinux is withheld for 2 to 3 days in patients with normal renal function, and for 3 to 5 days for patients with a creatinine clearance of less than 50 mL/minutes.

Parenteral Direct Thrombin Inhibitors

Parenteral direct thrombin inhibitors include bivalirudin and argatroban. As the classification implies, these agents directly bind thrombin thereby preventing it from cleaving fibrinogen to fibrin. The mechanism of action differs from that of heparin, which acts by enhancing the activity of antithrombin.

Bivalirudin and argatroban are administered as a bolus followed by continuous infusion with an immediate anticoagulant effect. The anticoagulant effects of bivalirudin and argatroban are monitored with the activated clotting time (ACT) and PTT, with a goal of 1.5 to 2.5 times normal for bivalirudin and 1.5 to 3 times normal for argatroban. Argatroban also prolongs the PT/INR value.

For high-risk procedures, SIR guidelines recommend withholding bivalirudin and argatroban for 2 to 4 hours before procedures, with a subsequent PTT check. For low-risk procedures, withholding is not recommended. Due to the short half-life of these agents (argatroban 40–50 minutes; bivalirudin 25 minutes), supportive management and interruption of treatment is used to reverse the anticoagulant effects.

Platelet-Associated Bleeding Risks from Antiplatelet Therapy

Aspirin irreversibly inhibits the enzyme cyclooxygenase-1 and thus the synthesis of thromboxane A ₂ . Clopidogrel, prasugrel, and ticagrelor inhibit the P2Y ₁₂ platelet receptor for adenosine diphosphonate. The decision to withhold antiplatelet therapy prior to elective procedures should be based on the specific indication for antiplatelet therapy. Studies of bleeding risk in general surgery patients on antiplatelet therapy report mixed results, and no clear recommendation other than operator discretion is advised. ²⁸ Similarly, the SIR guidelines do not endorse withholding these agents for low-risk category procedures. For high-risk procedures, the elimination half-life can guide discontinuation.

Patients receiving dual-agent antiplatelet therapy for significant coronary artery disease or after coronary artery stent procedures often have greater thrombotic risk than patients using prevention monotherapy. Elimination half-lives and duration of antiplatelet effects after discontinuing therapy can guide decision making. See Table 4 for current recommendations regarding time periods for withholding antiplatelet therapies.

Table 4. Antiplatelet agents.

Agent	Time to maximum antiplatelet effect	Half-life	Comments
Aspirin	30 min	15–30 min	Antiplatelet effect appears within 1 h and persists for at least 4 d after last dose
Clopidogrel	3–7 d	8 h	More rapid inhibition of platelet function can be achieved with loading dose; antiplatelet effect lasts up to 10 d after last dose
Prasugrel	30 min	7 h	Antiplatelet effect lasts 5–7 d after last dose
Ticagrelor	1.5 h	7 h	Residual antiplatelet effect decreased to 30% after ∼2.5 d
Ticlopidine	1–3 h	24–36 h	Antiplatelet effect lasts for 5–7 d after last dose

There are reported differences in bleeding risk associated with the various antiplatelet drugs. For example, the bleeding risk from clopidogrel is lower than that with the new P2Y ₁₂ receptor inhibitors, prasugrel and ticagrelor, with greater risk in patients prescribed dual therapy (aspirin + P2Y ₁₂ inhibitor) than with aspirin alone. ²⁹

Aspirin, clopidogrel, and prasugrel have an irreversible effect on circulating platelets; new circulating platelets are therefore necessary for platelet function recovery after drug discontinuation. Simply stopping the medication is not sufficient.

Platelet function assays including bleeding time, aggregometry, PFA-100 (Siemens, Malvern, PA), VerifyNow (Werfen, Bedford, MA), and TEG–platelet mapping (TEG-PM) have been used clinically to assess platelet function. These tests have limitations and may not be readily available when needed. More generalized, although controversial, strategies to overcome the effects of antiplatelet medications are to transfuse 5 to 10 units of platelets in patients with bleeding on antiplatelet therapy. ^{30 31 32}

Trauma-Induced Coagulopathy

Trauma-induced coagulopathy is defined as an intrinsic coagulopathy occurring in patients in the acute phase of traumatic injury. The mechanism is thought to be coagulation activation, hyper-fibrinogenolysis, and consumption coagulopathy. ³³ The management priority in this patient population is bleeding source control, with the specific goal of directed blood product resuscitation. Defining all coagulation defects using viscoelastic tests, TEG and ROTEM, in addition to standard INR platelet analysis is essential for successful targeted therapy. ^{34 35} Fibrinogen levels are rapidly depleted in this population, so close monitoring and maintenance of high normal levels (200 mg/dL) is critical. Goal-directed hemostatic therapy is primarily based on coagulation factor concentrates such as fibrinogen concentrate or PCC, and early hemostatic intervention is also critical for better outcome.

Liver Disease–Associated Coagulopathy

Patients with chronic stable cirrhosis often have abnormal standard coagulation tests including thrombocytopenia and abnormal PT/INR; yet, the risk for spontaneous or elective procedure-related bleeding may not be significantly different from that of noncirrhotic patients with normal standard coagulation assays. The mechanism for thrombocytopenia is multifactorial, but platelet sequestration in the spleen and decreased production of thrombopoietin in the liver are likely major causes. ³⁶

Platelets and VWF are responsible for formation of the platelet plug in primary hemostasis. Fortunately, patients with liver disease have increased levels of VWF which results in increased platelet adhesion. Similarly, a stable prolonged INR from reduced hepatic coagulation factor synthesis is balanced by decreased synthesis of inhibitors and compensatory antifibrinolytic abnormalities resulting in a balanced hemostasis. The American Association for the Study of Liver Diseases (AASLD) guidelines specifically recommend against FFP transfusion in this population. ³⁷ In this patient population, increased intravascular volume, which occurs as a result of FFP administration, worsens portosystemic hemodynamics. Studies have demonstrated that an elevated INR in a patient with chronic liver disease is not associated with increased bleeding risk during routine IR procedures, including liver and renal biopsies. ³⁸

Patients with acute-on-chronic liver failure are more complicated as increased bleeding risks may be caused by the more acute event (i.e., multisystem organ failure, renal dysfunction, and hyperfibrinolysis). Hyperfibrinolysis from a severe unregulated systemic inflammatory response goes unregulated with disastrous clinical sequelae. Viscoelastic assays in this population, as well as patients with simple chronic liver disease, are extremely valuable to gauge the resultant bleeding risk and to guide repletion strategies using fibrinogen concentrates, platelets, and cryoprecipitate before invasive procedures. Desmopressin (DDAVP) and amino caproic acid (Amicar) also have a role in balancing hemostasis in these patients who often additionally have platelet dysfunction and hyperfibrinolysis. ³⁷

Acute liver failure (ALF) patients with viral, drug-induced, autoimmune etiologies behave similar to chronic liver disease patients with management guidelines suggesting preserved hemostasis. A study evaluating coagulation abnormalities in an ALF cohort demonstrated grossly deranged PT values with TEG tracings normal in 45% and hypercoagulable in 35%. The authors suggested that while abnormalities in INR may reflect the degree of liver dysfunction, coagulation balance is a more complicated multifactorial state that is effected by a reduction in fibrinolysis, reduced functional fibrinogen, and increased platelet function effects. ³⁹ Other studies have reported that TEG profiles in these patients can show no increased bleeding risks despite mean INR values greater than 3.0, suggesting that bleeding risk in liver patients is heterogeneous and complex. ⁴⁰

The authors use TEG parameters (reaction time [ R ] > 15 minutes) as an indication for platelet transfusion. A maximum amplitude (MA) less than 40 mm is considered an indication for platelet transfusion.

Conclusion

Bleeding and periprocedural coagulopathy are encountered on a daily basis in interventional radiology practice. Patient-specific nuances including critical illness, drug therapy, and organ dysfunction can affect bleeding risk. Generalized correction strategies and laboratory tests may be of benefit in some patients, but not be useful in others. Understanding and mitigating risks has evolved with more specific understanding of bleeding risks and the introduction of newer anticoagulant and reversal agents.

Funding Statement

Funding No funding source was applied to this paper.