Anticoagulants and Their Monitoring

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Abbreviations

aPTT

activated partial thromboplastin time

CTP

Child‐Turcotte‐Pugh

DOAC

direct‐acting oral agent

INR

international normalized ratio

LMWH

low‐molecular‐weight heparin

UFH

unfractionated heparin

VKA

vitamin K antagonist

Currently available anticoagulants include: (1) heparin, unfractionated heparin (UFH) and low‐molecular‐weight heparin (LMWH); (2) vitamin K antagonist (VKA) or warfarin; and (3) direct‐acting oral agents (DOACs). It is important to understand the mechanism of action of various anticoagulants to choose the right agent in a given clinical setting and monitor their use in routine practice. Use of anticoagulants and their monitoring is particularly challenging in patients with cirrhosis, with changes of procoagulation/anticoagulation factors prevalent due to underlying hepatic dysfunction. In general, choice of anticoagulant for initiation of anticoagulation and maintenance of anticoagulation are different.

Initiation of Anticoagulation

Heparin, including UFH and LMWH, are used to initiate anticoagulation, and both of these agents are safe for use in patients with cirrhosis. ¹ , ² UFH is preferred for patients with severe renal dysfunction. Due to its short half‐life, UFH is also useful in situations that potentially require interruption of anticoagulation, such as hemodynamic instability and potential need for invasive procedures. ³ Activated partial thromboplastin time (aPTT) has traditionally been used to monitor UFH therapy; however, its prolongation at baseline in patients with cirrhosis may confound and complicate this monitoring. ⁴ , ⁵ Lately, anti‐Xa level has been recommended to monitor heparin therapy, and these levels correlate well with antithrombin levels. The level of anti‐thrombin III is 10% to 23% lower in patients with cirrhosis compared with healthy individuals, confounding their use for monitoring of anticoagulation in patients with cirrhosis. ¹ , ⁶ Data also show discrepancy between anti‐Xa and aPTT values among patients with cirrhosis, which may predispose to adverse events. ⁷ The overdose and higher anticoagulant effect of these agents can be overcome using the specific antidote of protamine sulfate (Table 1). Although not validated in patients with cirrhosis, target APTT on heparin is 1.5 to 2.5 times upper limit of normal or anti‐Xa level of 0.3 to 0.7 U/mL. No monitoring is required for patients receiving LMWH.

Table 1.

Advantages and Disadvantages of Various Anticoagulants

	UFH	LMWH	VKA	DOAC
Mechanism of action	Binding anti‐thrombin III	Binding anti‐thrombin III	Inhibits vitamin K–dependent clotting factors II, VII, IX, and X	Direct thrombin or Xa inhibitor
Route and frequency of administration	Intravenous infusion	Subcutaneous injection of 1‐2 daily doses	Oral with once‐daily dose	Oral with 1‐2 daily doses
Mean plasma half‐life	Minutes to 1‐2 hours	6‐12 hours	40 hours	12‐14 hours
Monitoring of efficacy	aPTT or Xa (0.3‐0.7 U/mL), but poor measure in cirrhosis	None required	INR target range of 1.5 to 2.5*	None required
Role	Initiation of anticoagulation	Initiation or maintenance of anticoagulation	Maintenance of anticoagulation	Maintenance of anticoagulation
Use in pregnancy	Recommended at delivery given rapid reversibility	Recommended throughout pregnancy except at delivery	Contraindicated	Not studied in pregnancy and not recommended
Advantages	Unaffected by hepatic or renal function	Good safety profile in liver disease	Ease of administration	No need for monitoring
	Rapidly reversible effect	Better efficacy in malignancy	Cheap and widely available	Antidote available
	Antidote available	Antidote available	Antidote available
Disadvantages	Heparin‐induced thrombocytopenia	Cannot use with severe renal dysfunction	Drug‐drug interaction	Cannot use with severe liver disease (CTP class B or C)
	Need for hospitalization	Subcutaneous route	Drug‐food interaction	Expensive and limited experience
			Requires regular monitoring	Absorption may be affected from bowel edema in PHT
			Absorption may be affected from bowel edema in PHT

^*Target INR 1.0 higher than baseline if baseline INR is above 1.5.

Abbreviation: PHT, portal hypertension.

Maintenance of Anticoagulation

Traditionally, VKA or warfarin has been the drug of choice for long‐term anticoagulation management. VKA inhibits the functional levels of the vitamin K–dependent procoagulant factors VII, IX, X, and II. These drugs also reduce functional levels of the anticoagulant proteins C and S. ⁸ For dose adjustment of VKA administration, international normalized ratio (INR) is used for monitoring, with therapeutic level maintained between 2 and 3. However, the baseline INR is often elevated among patients with cirrhosis, making their use difficult in these patients. Further, INR testing is based on the plasma from normal individuals and not from patients with cirrhosis, making INR an incompletely reliable test for monitoring VKA therapy in patients with cirrhosis. ⁹ , ¹⁰ , ¹¹ Current evidence does not support the use of INR as a predictor of bleeding or to monitor the effectiveness of hemostasis‐modifying therapy in patients with cirrhosis. ¹² In this regard, thrombin generation tests (thrombin clotting time or ecarin clotting time) or thromboelastography may perform better compared with the INR for predicting bleeding risk, but is used for monitoring anticoagulant therapy in routine clinical practice. ¹³ , ¹⁴ In general, target INR for patients with cirrhosis is a goal INR of 1.0 higher than baseline, if the baseline INR is >1.5. Vitamin K, prothrombin complex concentrates, and fresh frozen plasma can be used to reverse bleeding in patients receiving warfarin. LMWH can be used for maintenance of anticoagulation when INR levels cannot be optimally maintained on VKA, and may also be recommended for patients with associated hepatocellular carcinoma or extrahepatic malignancy.

DOACs include direct thrombin inhibitor, such as dabigatran, and direct factor Xa inhibitors, such as rivaroxaban, apixaban, edoxaban, and betrixaban. Data on their use in patients with cirrhosis and liver disease are limited, because the randomized trials of DOAC have routinely excluded these patients. Although traditionally routine monitoring is not needed when these agents are used, there is a safety concern in patients with cirrhosis due to increased drug levels among patients with severely reduced hepatic function ¹⁵ and potential of drug‐induced liver injury associated with these drugs. ¹⁶ , ¹⁷ In general, DOACs are not recommended for use among patients with advanced cirrhosis with Child‐Turcotte‐Pugh (CTP) class B or C. Compared with traditional anticoagulation with warfarin, use of DOAC is associated with similar or lower risk for bleeding in patients with cirrhosis. ¹⁸ , ¹⁹ , ²⁰ , ²¹ Reversal agents for DOAC overdose are available for use in routine practice.

Conclusion

Of the various anticoagulants available, the choice of their use depends on the indication (initiation or maintenance) and on the clinical situation with pros and cons of these agents (Table 1). Their use in patients with cirrhosis remains challenging as a result of altered procoagulants and anticoagulant factors with elevated INR and aPTT with decreased anti‐Xa levels. Clearly, there is an unmet clinical need of randomized clinical trials on the use of DOACs among patients with cirrhosis before routinely using them, especially in patients with poor hepatic reserve. Until then, the use of anticoagulants and management of thrombosis in patients with cirrhosis will continue based on standard guidelines for their use and monitoring in patients without cirrhosis. ²²