Thrombosis and Hemostasis in Liver Disease and Kidney Disease: A call for More Research

-Contributed by Abi Kasberg, PhD

A recent announcement made by the Research and Practice in Thrombosis and Haemostasis (RPTH) journal has caught our attention because it highlights an important clinical space that is in urgent need of more research, data, and attention. In June, RPTH offered a publication fee waiver for manuscript submissions on the topic of thrombosis and hemostasis in liver or kidney disease. By offering this publication waiver, RPTH gave a nudge to the research field to accumulate and publish data on the roles of thrombosis and hemostasis in liver and kidney diseases now. Patient outcomes are being impacted by these complications. Yet, there is insufficient knowledge surrounding the causes and mechanisms of thrombosis and bleeding during liver and kidney disease to provide the best treatment opportunities and outcomes. At DiaPharma, our interests and expertise encompass the fields of thrombosis, hemostasis, liver disease, and kidney disease. Hence, our curiosities were particularly piqued by this publication fee waiver offered by RPTH.

We want to participate in this call for research by reviewing current research questions to consider while exploring the impact of thrombosis and hemostasis in liver and kidney disease.

Hemostasis is in a delicate and dynamic equilibrium during liver and kidney diseases. Changes in hemostasis can occur rapidly between coagulation and anticoagulation. Figure adapted from Lisman et al. 2021

⇨ How do hemostatic changes manifest during acute and chronic liver and kidney disease? What are the mechanisms driving these hemostatic imbalances?

Injury to the kidneys and liver are associated with changes to hemostatic pathways that can manifest as alterations to both coagulation and bleeding. Hemostasis in liver cirrhosis, for example, is in dynamic disequilibrium. Hemostatic changes occur rapidly between procoagulant and anticoagulant conditions (Flores et al. 2017). Individuals with chronic kidney disease (CKD) are at increased risk of developing clotting and bleeding complications (Kholi et al. 2022). This has created a challenging prognostic landscape in which to predict whether a patient with liver or kidney disease is at risk for thrombosis and/or bleeding.

The mechanisms of this imbalance are not well defined. It is postulated that cirrhosis leads to decreased synthesis of anticoagulants, decreased platelet production, and changes to purinergic signaling pathways (Flores et al. 2017). Likewise, in CKD, platelet dysfunctions, anemia, increased levels of von Willebrand factor (vWF), and hypercoagulation occur which greatly impact hemostasis (Zanetto et al. 2023). CKD patients display persistent hypercoaguability despite recovered kidney function following kidney transplant (Kholi et al. 2022). Acute kidney injury (AKI) is associated with reduced platelet aggregation and decreased levels of factor XIII in mechanisms that may be mediated through endothelial dysfunction (Zanetto et al. 2023). More research is needed to better define the specific cell types and pathways involved in AKI-driven coagulopathy, CKD, and liver disease associated hemostatic imbalances.

⇨ Given that hypo and hypercoagulation have distinct characteristics, can individual hemostatic profiles be leveraged to predict risk of bleeding and thrombosis?

It has been proposed that there is a state of rebalanced hemostasis in patients with liver disease. Rebalanced hemostasis describes the neutralizing outcome of pro-hemostasis systems being simultaneously compensated for by anti-hemostatic systems (Lisman et al. 2021). However, this rebalanced hemostatic scale is delicate and susceptible to swift bias towards hypercoagulation or hypocoagulation. Because of rebalanced hemostasis, both bleeding and thrombosis can occur in this patient population (Lisman et al. 2021).

This is where individual hemostatic profiles potentially come into play. Hypocoagulation attributes can include impaired platelet function, low fibrinogen levels, and hyperfibrinolysis (Lisman et al. 2021). Hypercoagulation profiles can include elevated von Willebrand Factor (vWF), decreased ADAMTS-13 levels, increased thrombin generation, and hypofibrinolysis (Lisman et al. 2021). Can these classical hemostatic characteristics be measured and analyzed on an individual basis to predict patient-specific clotting and bleeding risk?

⇨ Better diagnostic tests and biomarkers are needed to more accurately identify and predict risk of bleeding and thrombosis in patients with liver or kidney disease.

Current diagnostic coagulation tests are poor predictors of thrombosis and bleeding risk in patients with liver or kidney disease. This can be particularly problematic during preprocedural assessments. Prolonged prothrombin time (PT) does not accurately reflect bleeding risk in acute-on-chronic liver failure (ACLF) patients. Patients with ACLF who have preserved clotting capacity can demonstrate reduced clot stability and formation (Zanetto et al. 2023).

International normalized ratio (INR) tests the function of procoagulant factors. Many clotting factors (II, VII, IX, X) are produced in the liver. Hence, upon liver injury, there are deficiencies in clotting factor levels that drive elevated (INR) (Flores et al. 2017). INR measurements fall short of accurately predicting bleeding risk, particularly in individuals with liver cirrhosis (Flores et al. 2017, Kujovich 2015). This can become further muddled by the fact that ACLF is defined in part by elevated INR. Therefore, elevated INR may indicate liver disease without accurately reflecting the state of coagulation. Better laboratory tests are needed that accurately identify patients at risk of bleeding and thrombosis while also considering and adjusting for the severity of liver or kidney disease.

⇨ How do anticoagulants impact liver health and do they contribute to liver toxicity?

The therapeutic administration of anticoagulants, such as warfarin and dabigatran, can induce the elevation of transaminases (Arora and Goldhaber 2006). Elevated transaminases, such as ALT and AST, are widely used as initial indicators of liver toxicity. This suggests that anticoagulants may contribute to liver injury. The mechanism of why this phenomenon occurs and its clinical impact is not well understood. Are anticoagulants directly toxic to the liver, and if so, through what mechanisms? Is hepatocyte injury or cell death occurring following anticoagulation use? Could it be an immune-mediated response? Perhaps it could even be considered that elevated ALT and AST levels following anticoagulation therapy are unrelated to liver health. More studies investigating this are needed.

⇨ Do abnormal liver panels during hemostatic disorders indicate liver disease?

Changes to INR during thrombophilia, bleeding events, or thrombotic events could indicate liver damage since INR is included on standard liver function panels. This could highlight a problem with hemostasis testing, particularly with the INR test itself. INR is prone to interferences and sensitivities of different reagents, especially in the presence of direct oral anticoagulants (DOACs) (Douxfils et al. 2018). INR is calculated using a standardization factor named the international sensitivity index (ISI). ISI is utilized to account for prothrombin time assay variability compared to thromboplastin standard reagent (Patel et al. 2023). Suggestions have been made to develop ISI values specific to each anticoagulant to better account for variability of prothrombin reagent response to anticoagulants (Patel et al. 2023, Tripodi et al. 2011). The use of a DOAC eliminating reagent could stop DOAC interference from coagulation panels and could be particularly useful during liver transplantation (Patel et al. 2023). As such, INR may be a better indicator of bleeding risk than of liver function, and hence better biomarkers of liver damage are needed to assess liver disease during hemostatic disorders. More studies are needed to investigate to characterize the frequency and mechanisms of liver damage during hemostatic disorders.

⇨ How is kidney disease and bleeding associated during liver cirrhosis?

Preliminary studies suggest that there may be an association between increased bleeding during decompensated cirrhosis and kidney dysfunction (Zanetto et al. 2023). Rebalanced hemostasis is vulnerable to hemorrhage when destabilizing triggers including renal failure occur in patients with liver disease (Kujovich 2015). Renal failure may cause acquired platelet dysfunction and abnormal endothelial function that facilitate bleeding (Kujovich 2015). More data is needed to confirm this association and investigate the relationship between kidney disease, cirrhosis, and abnormal bleeding.

Conclusion

Hemostasis is in a fragile, imbalanced state during liver and kidney disease, making it challenging to predict bleeding and thrombotic outcomes in these patients. More research is needed to investigate this space. Thanks to this friendly push from RPTH, more data will be published and available soon.