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Thrombocytopenia in Chronic Liver Disease

In the United States, nearly 4 million adults have chronic liver disease (CLD), which is a progressive illness. Patients with CLD have an imbalance of pro- and anti-coagulant factors and are at an increased risk for thrombosis and, paradoxically, also at risk of bleeding.1 Thrombocytopenia (TCP), defined as a decrease in platelet count below 150 X 109/L, is a common perioperative condition occurring in 76% of cirrhotic patients. In fact, it is the most common hematological complication in patients with CLD.2-3

Patients scheduled for interventional radiology (IR) procedures often present with thrombocytopenia and impaired coagulation markers, potentially increasing their risk of periprocedural bleeding. While an unequivocal linear relationship between platelet count and risk of bleeding has not been established, thrombocytopenia can prevent patients with CLD from receiving crucial diagnostic and therapeutic interventions and is associated with a poor prognosis.4 The interventional radiologist typically relies on a combination of patient hematologic history including platelet counts and prior thrombocytopenic episodes, patient medication history, etiology of the thrombocytopenia, guidelines, and his/her own experience to determine the best course of action to manage thrombocytopenia in CLD patients prior to an intervention.4

 

Common IR procedures in patients with CLD

Patients with CLD undergo various diagnostic and therapeutic procedures associated with a low to high bleeding risk as part of their ongoing care. Some of these procedures include chemoembolization, liver biopsies, paracentesis, thoracentesis, radiofrequency ablation (RFA), microwave ablation (MWA), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), transjugular intrahepatic portosystemic shunt (TIPS), cardiac catheterization/intervention (eg, transcatheter aortic valve replacement (TAVR) surgery), and tunneled central venous catheter placements. There are limited data on the safety of these procedures in patients with TCP and CLD that can guide the decision to correct/to not correct coagulation abnormalities periprocedurally. Considerations with each of these management strategies include the risk of withholding potentially life-sustaining treatments, financial costs associated with delays in procedures, the risk of carrying out unnecessary transfusions in patients, transfusion-related risks, and bleeding risks in patients without preoperative transfusion.5

 

Management of TCP in CLD

Effective management of thrombocytopenia enables patients to get medically necessary procedures without risk of bleeding complications and helps to reduce associated healthcare costs while improving patient outcomes.6 From a nursing perspective, two options exist: platelet transfusions and treatment with thrombopoietin receptor agonists (TPO-RAs).

 

Platelet transfusion

In the United States, annually, about 2.3 million platelet units are transfused into patients to reduce bleeding risk, and this procedure is considered the standard of treatment for thrombocytopenia.6-7 Typically, prophylactic or therapeutic transfusions are initiated in patients with CLD when platelet counts are below 50 X 109/L, with the Society of Interventional Radiology guidelines supporting this threshold based on procedure and/or bleeding risk.8-9 While there are obvious pros to this form of treatment including the prevention of and rapid treatment of bleeding in patients with thrombocytopenia, cons include risk of infection, alloimmunization, development of refractoriness, circulatory overload, and febrile and non-hemolytic reactions. Platelet transfusions also do not ensure a hemostatic platelet count, especially in cases where bleeding risk is high.10 Other major limitations include the short lifespan of platelets, which must be used within four days of collection as they have a limited duration of effect, and the high cost of transfusion, especially in cases of multiple transfusions.10-11 In any case, platelet transfusions are inappropriate as a long-term management option in patients with CLD, mainly due to the risk of alloimmunization which can increase the risk of rejection if a liver transplantation is required in the future.12

 

Pharmacotherapy

Thrombopoietin receptor agonists (TPO-RAs)

Impaired thrombopoietin production contributes to the development of thrombocytopenia especially in cases of advanced liver disease, thereby justifying the use of TPO receptor agonists to treat this class of patients.4 Two TPO-RAs are currently approved for use in the treatment of thrombocytopenia in patients with CLD: avatrombopag (DOPTELET®) and lusutrombopag (MULPLETA®).13-14 Avatrombopag and lusutrombopag can increase patient platelet counts following 5 days and 7 days of oral administration, compared with placebo treatment, and the platelet count peaks 10-14 days later.4 The main objective of studies with these agents involved sparing the need for platelet transfusions and achieving platelet counts of 50 X 109/L. Lusutrombopag is available as a single dose: 3mg PO for 7 days, regardless of platelet count, whereas avatrombopag is tailored based on the baseline platelet count (40 mg for platelet counts 40-50 X 109/L and 60 mg for platelet counts < 40 X 109/L).13-14 Unlike platelet transfusions, TPO-RAs cannot achieve a rapid response and are therefore suited for scheduled procedures.4

While TPO-RA treatment is associated with fewer procedure-related complications, monitoring of patient side effects including hepatotoxicity and thromboembolic events is required.

 

Complications in patients with CLD and thrombocytopenia and their impact on nursing staff

Common complications in patients with CLD include portal hypertension, variceal bleeding, ascites, and hepatic encephalopathy which often require therapeutic procedures. Conducting interventional procedures is further complicated when the patient presents with thrombocytopenia. Perioperative treatments for thrombocytopenia are associated with various responsibilities for the nursing staff. For instance, in case of platelet transfusions, nurses need to monitor the recipient closely for the first 15 minutes and periodically thereafter to ensure there are no adverse events and to stop the transfusion in case of one. The most common complications with transfusions include febrile non-hemolytic reactions and chill-rigor reactions.8 Other serious complications that are associated with high mortality rates include hemolytic reaction due to ABO incompatibility and transfusion-related acute lung injury.8 Nurses should monitor the patient for fever, chills, tachycardia, flushing, urticaria, bone/muscle/chest/abdominal pain, nausea, dyspnea, collapse, hypo/hypertension, dark urine, or general malaise, and should seek hematological advice where severe reactions occur. Jaundice, bruising, and peripheral edema are also complications that may impact a nurse’s plan of care for CLD patients.15-16.

If patients are being treated with TPO-RAs to manage thrombocytopenia, nurses need to be aware of thromboembolic and hepatic complications. Patients treated with avatrombopag and lusutrombopag must be monitored for platelet counts and thromboembolic events such as portal vein thrombosis, especially in cases where patients have known risk factors for thromboembolism, including genetic prothrombotic conditions (Factor V Leiden, prothrombin 20210A, antithrombin deficiency or Protein C or S deficiency).13-14

Summary

Currently, none of the traditional treatment options for thrombocytopenia in CLD satisfy all the requirements of an ideal therapy: efficacy in a majority of patients, orally bioavailability, activity across various disease states, fewer adverse effects, and cost-effectiveness.6 Platelet transfusions have limited empirical data that specifically outline a platelet count threshold in patients with CLD to help the physician decide on a treatment plan. Similarly, there is no consensus on the appropriate threshold values for prophylactic transfusions in patients with CLD.

The new TPO-R agonists avatrombopag and lusutrombopag check several boxes of an ideal therapeutic agent: oral availability, outpatient dosing, lesser complications in the periprocedural management of thrombocytopenia as compared with platelet transfusions. However, these are still associated with the potential for serious adverse events like portal vein thrombosis and hepatotoxicity in patients with CLD requiring careful monitoring of patient adverse events. Nurses and caregivers must maintain frequent follow-up, ensure adherence to prescribed therapies, and monitor for adverse reactions.

This article is provided in conguntion with BioCentricinc, Inc 

References

  1. Chronic Liver Disease and Cirrhosis. CDC Website. https://www.cdc.gov/nchs/fastats/liver-disease.htm. Accessed April 19, 2019.
  2. DeAngelis GA, Khot R, Haskal ZJ, et al. Bleeding risk and management in interventional procedures in chronic liver disease. J Vas Interv Radiol. 2016;27:1665-1674.
  3. Afdhal NH, Giannini EG, Tayyab G, et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. NEJM.2012;367:716-24.
  4. Nagrebetsky A, Al-Samkari H, Davis NM, et al. Perioperative thrombocytopenia: evidence, evaluation, and emerging therapies. Br J Anesthesia. 2019;122(1):19-31.
  5. Warner MA, Woodrum D, Hanson A, et al. Preprocedural platelet transfusion for thrombocytopenic patients undergoing interventional radiology procedures is not associated with reduced bleeding complications. Transfusion. 2017;57:890-898.
  6. Poordad F. Review article: Thrombocytopenia in chronic liver disease. Aliment Pharmacol Ther. 2007;26:5-11.
  7. Ellingson KD, Sapiano MRP, Haass KA, et al. Continued decline in blood collection and transfusion in the United States-2015. Transfusion. 2017;57(suppl 2):1588-1598.
  8. Blumberg N, Heal JM, Phillips GL. Platelet transfusions: trigger, dose, benefits, and risks. Medicine Reports. 2010;2:5.
  9. Patel IJ, Davidson JC, Nikolic B, et al. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Basc Interv Radiol. 2012;23:727-736.
  10. Hayashi H, Beppu T, Shirabe K, Maehara Y, Baba H. Management of thrombocytopenia due to liver cirrhosis: A review. World Journal of Gastroenterology : WJG. 2014;20:2595-2605.
  11. Brown RS. Review article: a pharmacoeconomic analysis of thrombocytopenia in chronic liver disease. Aliment Pharmacol Ther. 26(Suppl 1):41-48.
  12. Tillman HL, McHutchison JG. Use of thrombopoietic agents for the thrombocytopenia of liver disease. Semin Hematol. 2010;47:266-273.
  13. Doptelet [package insert]. Durham, NC: Dova Pharmaceuticals Inc; 2018.
  14. Mulpleta [package insert]. Florham Park, NJ: Shionogi; 2018.
  15. Bonnar J, Browne P, Cahill M, et al. Guidelines for the administration of blood and blood components. National Blood Users Group. 2004. Available at: https://www.giveblood.ie/Media/Publications/Other_Documents/Guidelines_for_the_Administration_of_Blood_and_Blood_Components.pdf.
  16. Clements A, Greenslade L. Nursing care for end-stage liver disease. Nurs Times. 2014;110(29):17-19.

 

1Ronald Gore, AD, RN, CRN

1Sonia Castillo, RN, BSN

1, 2Edward Wolfgang Lee, MD, PhD, FSIR (EdwardLee@mednet.ucla.edu)

1Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA

2Dumont-UCLA Transplant Center, Pfleger Liver Institute, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA

Address all correspondence and requests for reprints to:

Edward Wolfgang Lee, MD, PhD, FSIR

Department of Radiology and Surgery

Division of Interventional Radiology

Division of Liver and Pancreas Transplantation

Ronald Reagan Medical Center at UCLA

David Geffen School of Medicine at UCLA

757 Westwood Plaza, Suite 2125
Los Angeles, CA 90095-743730

E-mail: EdwardLee@mednet.ucla.edu

Tel: 310.267.8771

FAX: 310.267.3631

 

No conflict of interest; No financial support

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