Acquired Coagulation Defects and How to Manage Them

Educational Objectives

The goal of this program is to improve management of acquired coagulation disorders. After hearing and assimilating this program, the clinician will be better able to:

1. Select drugs for reversal of anticoagulant therapies.
2. Identify patients with acquired hemophilia.
3. Differentiate vitamin K deficiency from liver disease.

Summary

Warfarin: warfarin may cause headache and slurred speech suggestive of subdural hematoma; warfarin should be stopped and preparations containing vitamin K administered intravenously; oral preparations may be used in cases in which the bleeding is not life threatening; University of North Carolina healthcare guidelines recommend the use of prothrombin complex concentrates (PCCs [eg, Balfaxar, Kcentra]) for life threatening bleeding in patients on warfarin; PCCs are plasma-derived mixtures of vitamin K-dependent clotting factors, some of which contain four factors (ie, II, VII, IX, X) and not the three (ie, II, IX, X) found in initial preparations; the administration of recombinant VIIa improves international normalized ratio (INR); activated prothrombin complex concentrates are prothrombotic; 4-factor prothrombin complex concentrate (4F-PCC) is approved for warfarin reversal and is superior to plasma; 4F-PCC may be used at 50 units/kg in cases of INR >6 and is contraindicated in patients with heparin-induced thrombocytopenia; 4F-PCC may be administered quickly, has low volume, and is lyophilized; the risk for transfusion reactions or congestive heart failure is low with 4F-PCC; 30 mL/kg of fresh frozen plasma (FFP) would be required to correct factor levels by 30% (in patients with, eg, an INR of 3); FFP for correction of INR is not recommended; factor VII is labile; factor VII wears off quickly after administration with FFP

Acquired hemophilia: patients may present with multiple bruises, reduced hemoglobin and prolonged partial thromboplastin time (PTT); a hematology consultation is recommended; patients may have acquired factor VIII inhibitors or acquired hemophilia; factor VIII levels should be checked; acquired hemophilia is a rare autoimmune condition in which patients produce autoantibodies to their own factor VIII; administration of factor VIII, FFP or cryoprecipitate is not advisable because it is functionally inhibited by antibodies

Diagnosis: associated with older age; patients have no prior history of bleeding, normal prothrombin time (PT), and prolonged PTT; patients with lupus inhibitors do not have bleeding; patients with acquired hemophilia present with mucocutaneous bleeding from multiple sites (gastrointestinal, nasal, genitourinary)

Management: hemostasis must be achieved with use of bypassing agents, eg, recombinant factor VIIa (eg, NovoSeven), recombinant porcine factor VIII, immunosuppressive agents which counteract autoantibodies; transfer to a tertiary center should be prioritized

Carcinoma and end-stage liver disease: lower gastrointestinal bleeding is common; an increase in heart rate and decrease in blood pressure may be observed; PT and PTT are markedly high; cryoprecipitate is the replacement of choice for patients with cirrhotic liver disease; cryoprecipitate has fibrinogen which helps manage bleeding; administration of platelets and FFP is not recommended; patients have hyperfibrinolysis; red blood cell administration helps recruit platelets against the blood vessel wall to arrest bleeding; fibrinogen levels and all clotting factors except factor VIII are decreased in patients with cirrhosis; factor VIII is increased because it is produced by the endothelial cells of the liver (not by hepatocytes), and because production of the protein which helps in clearance of factor VIII is decreased in liver disease; factor VII levels are low because of its short half-life; factor V levels are used to differentiate liver disease from vitamin K deficiency; factor V is normal in patients with vitamin K deficiency; cryoprecipitate helps correct platelet dysfunction; antifibrinolytics (eg, tranexamic acid, aminocaproic acid) are recommended for correction of hyperfibrinolysis; consumption of all clotting factors occurs in patients with disseminated intravascular coagulation (ie, low factor V, VII, and pseudo-normalized or low factor VIII); human leukocyte antigen matched platelets may correct bleeding; desmopressin and tranexamic acid improve platelet function

Nonalcoholic steatohepatitis (NASH): splenomegaly in patients with NASH may reduce platelet counts; platelet correction immediately prior to surgery is not effective; splenectomy is not recommended; thrombopoietin (TPO) receptor agonists are beneficial

Epidemiology and pathogenesis: the incidence of thrombocytopenia in chronic liver disease is 6%; incidence in cirrhosis is ≤70%; splenic sequestration is combined with decreased production of platelets because of decreased thrombopoietin in patients with liver disease

TPO agonists: increase platelet counts by stimulating the thrombopoietin receptor and improve platelet function; include romiplostim, eltrombopag, and avatrombopag; eltrombopag and avatrombopag are oral agents used for short term increase in platelet counts in patients with cirrhosis undergoing surgery; lusutrombopag is approved for use by the Food and Drug Administration; TPO agonists are used before surgery and 2 to 3 wk after surgery for recovery

Anticoagulants in patients with intracranial hemorrhage: patients on dabigatran (eg, Pradaxa, Pradax, Prazaxa) have prolonged thrombin time; anti-factor Xa levels are analyzed to detect use of rivaroxaban, apixaban, and edoxaban; levels of heparin or low molecular weight heparin should be obtained; emergent evacuation and stabilization is required for patients with intracranial hemorrhage; two doses of idarucizumab (eg, Praxbind) of 2.5 g reverses the effects of dabigatran; idarucizumab has a duration of action long enough for surgery to be completed; andexanet is decoy factor Xa used for the reversal of rivaroxaban, apixaban, and edoxaban; information on the type and duration of factor Xa inhibitor use must be obtained; not recommended for patients undergoing surgery because of its short half-life; should be reserved for cases of life threatening bleeding and given at doses of 400 to 800 mg, with follow-up infusion

Readings

Ghanima W, Cooper N, Rodeghiero F, et al. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019;104(6):1112-1123. doi:10.3324/haematol.2018.212845; Giannandrea D, Mengoni A, Carluccio E, et al. Practical considerations on anticoagulation reversal: spotlight on the reversal of dabigatran. Vasc Health Risk Manag. 2019;15:139-142. Published 2019 May 23. doi:10.2147/VHRM.S181806; Kustos SA, Fasinu PS. Direct-acting oral anticoagulants and their reversal agents-an update. Medicines (Basel). 2019;6(4):103. Published 2019 Oct 15. doi:10.3390/medicines6040103; López-Trujillo MA, Olivares-Gazca JM, Cantero-Fortiz Y, et al. Nonalcoholic fatty liver disease and thrombocytopenia III: its association with insulin resistance. Clin Appl Thromb Hemost. 2019;25:1076029619888694. doi:10.1177/1076029619888694; Marchili MR, Santoro E, Marchesi A, Bianchi S, Rotondi Aufiero L, Villani A. Vitamin K deficiency: a case report and review of current guidelines. Ital J Pediatr. 2018;44(1):36. Published 2018 Mar 14. doi:10.1186/s13052-018-0474-0; Miatech JL, Kantamani D, Stagg MP. Management of acquired factor VIII inhibitors with NovoSeven and Obizur. Cureus. 2021;13(10):e19145. Published 2021 Oct 30. doi:10.7759/cureus.19145; Rassi AB, d'Amico EA, Tripodi A, et al. Fresh frozen plasma transfusion in patients with cirrhosis and coagulopathy: effect on conventional coagulation tests and thrombomodulin-modified thrombin generation. J Hepatol. 2020;72(1):85-94. doi:10.1016/j.jhep.2019.09.008; Refaai MA, Bajcic P, McNeill R, et al. Retrospective analysis of the real-world utilization of 4-factor prothrombin complex concentrate and plasma in oral anticoagulant-associated bleeding in US hospitals. Clin Appl Thromb Hemost. 2023;29:10760296231179682. doi:10.1177/10760296231179682; Zanon E. Acquired hemophilia A: An update on the etiopathogenesis, diagnosis, and treatment. Diagnostics (Basel). 2023;13(3):420. Published 2023 Jan 23. doi:10.3390/diagnostics13030420.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Ma's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Ma was recorded at the Carolina Refresher Course 2023: 34th Annual Update in Anesthesiology, Pain, and Critical Care Medicine, held June 18-22, 2023, on Kiawah Island, SC, and presented by the University of North Carolina at Chapel Hill, School of Medicine. For information about upcoming CME activities from this presenter, please visit med.unc.edu/cpd. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

AN654301

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.