Antithrombin deficiency is the most common cause of low heparin response7,9

  • Hi. I'm Dr. Stephen Bader, a cardiac anesthesiologist in a busy community hospital, but I used to work in a large, academic, university hospital. 
  • Obviously, during an operative procedure, we need to balance the risk of bleeding with that of thromboembolic events for each individual patient. 
  • My experience using heparin for various procedures is that it can be very unpredictable. 
  • Whether I'm doing a vascular surgery with an interventional radiologist or a cardiac surgery that requires large doses of heparin, it is important not only to prevent clotting and other thromboembolic complications during the procedure but also to not have significant bleeding at the end of the procedure.
    • Heparin resistance, or responsiveness issues, can occur in heparin-requiring surgeries, and it is a problem that some may be worried about and uncomfortable dealing with should it arise because administering additional heparin to overcome resistance could lead to bleeding at the end of the procedure. 
  • So let's take a few minutes to talk about how heparin works, how we deal with heparin response issues, and how we might consider them before they are encountered during a procedure.  
  • What is low heparin response?
    • While there isn't a consistent definition, low heparin response is commonly defined as needing a daily dose in excess of 35,000 units/day.
  • As we'll talk about a bit later, low heparin response is often caused by antithrombin deficiency. 
  • Antithrombin is a thromboprotective protein that inhibits the coagulation enzymes in a slow, progressive manner when heparin is absent. These enzymes include factor Xa and thrombin, and to a lesser extent, factors IXa, XIa, XIIa, and VIIa.
  • However, when heparin is present, the action of antithrombin is enhanced by at least 1000-fold. 
  • Thus, antithrombin plays a key role in anticoagulation by preventing the activation of coagulation-promoting proteins except at the site of injury. 
  • In this way, antithrombin participates in a feedback loop in which blood can clot rapidly when needed but does not clot all of the time.
  • Now, let's talk about the interaction between antithrombin and heparin.
  • Heparin exerts its anticoagulant effects based on its interaction with the cofactor antithrombin. Heparin and antithrombin work together to provide a continuous anticoagulant effect. 
  • This allows antithrombin, which is a relatively slow inhibitor of the anticoagulation cascade, to become a more potent anticoagulant. 
  • Now that we know a little more about how antithrombin and heparin work, how does heparin response affect what we do before, during, and after surgery? 
 
Before
 
  • Before a procedure, I consider a patient's risk of bleeding, including:
    • The invasiveness of the surgery
    • The consequences of bleeding
    • The patient's medical history, with special attention to comorbidities that may have an impact on hemostasis or coagulation. 
  • I may notice that the patient has other risk factors, such as being elderly or having illnesses such as renal diseases or a history of bleeding or anemia.
  • If I see that a patient has been receiving heparin therapy for a few days prior to the surgery, in the back of my mind, I'm already considering whether the patient will respond to heparin as expected and I'm anticipating the ACT as well as PTT levels. 
 
During
 
  • During the procedure, I'm reacting to the patient's response to heparin and titrating to effect—giving heparin, checking ACT levels, and titrating heparin based on that response.
    • When I suspect low heparin response, the options to diagnose it in the operating room are limited, but I utilize interventions aimed at achieving the targeted ACT and providing an adequate buffer of safety for anticoagulation.
    • Most of the time, we give another dose of heparin. If a patient doesn't respond, I may think about antithrombin deficiency, which can be either acquired or hereditary. Antithrombin deficiency is the most common cause of low heparin response, and as you know, there are various ways to replenish antithrombin.
    • Other mechanisms affecting heparin response are less common than antithrombin deficiency, such as increased heparin clearance, high factor VIII levels, and dosing or administration errors. Some patients may have underlying thrombocytosis, causing neutralization of heparin.
 
After
 
  • After the surgery, physicians may consider hematologic workup to make sure that a patient with low heparin response doesn't have hereditary antithrombin deficiency, which is rare but puts patients at high risk of thrombosis. These patients need to be identified for appropriate management postoperatively and during future surgeries and life events, such as childbirth, which further increase their risk of thrombosis.
  • For these patients, the risks of hereditary antithrombin deficiency can be mitigated with functional evaluation of antithrombin activity, including laboratory testing, as well as with long-term management to address and reduce risks during future procedures or other high-risk life events.
 
 

 

Dr. Stephen Bader discusses important considerations for before, during, and after surgery

  • Heparin resistance, or responsiveness issues, can occur in heparin-requiring surgeries, and administering additional heparin to overcome resistance could lead to bleeding at the end of the procedure
  • Low heparin response is commonly defined as needing a daily dose in excess of 35,000 units/day
  • Options to diagnose low heparin response in the operating room are limited, but interventions should be utilized to achieve the targeted ACT 
  • After the surgery, physicians may consider hematologic workup to make sure that a patient with low heparin response does not have hereditary antithrombin deficiency
  • Patients with hereditary antithrombin deficiency need to be identified for appropriate management postoperatively and during future surgeries and life events, such as childbirth, which further increase their risk of thrombosis
 

Mitigating VTE Risk: Functional Evaluation of AT

  • The risks of hereditary antithrombin deficiency can be mitigated with functional evaluation of antithrombin activity, including laboratory testing, as well as with long-term management to address and reduce risks during future procedures or other high-risk life events5

 

Whom to Test12

 

  • Unexplained VTE at a younger age (<50 years)
  • Recurrent spontaneous or unusually extensive spontaneous VTE
  • Unexplained arterial thromboembolism in a younger patient
  • Unexplained VTE at an unusual site
  • Recurrence of VTE while adequatedly anticoagulated
  • Family history of spontaneous VTE
  • Family history of known thrombophilia, even if patient is asymptomatic
 

How to Test: Functional Antithrombin Assays

 

  • Functional anththrombin assays are most commonly used and are recommended for initial testing for antithrombin deficiency7
  • Initial testing should be completed a few weeks after thrombotic event—heparin use may decrease antithrombin levels by 30%12
  • High specificity and sensitivity; positive predictive value = 96%7
 

Management12

 

  • Asymptomatic individuals with antithrombin deficiency typically are not started on long-term anticoagulation; however they need to receive DVT prophylaxis in high-risk situations, such as surgery, pregnancy, or childbirth
  • Patients with antithrombin deficiency who have had a VTE event should be considered for long-term anticoagulation
 
 

 

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References: 1. THROMBATE III [Prescribing Information]. Research Triangle Park, NC: Grifols Therapeutics LLC. 2. Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis, and treatment options. Drugs. 2007;67(10):1429-1440. 3. Li W, Johnson DJ, Esmon CT, Huntington JA. Nat Struct Mol Biol. 2004;11(9):857-862. 4. James AH, Konkle BA, Bauer KA. Prevention and treatment of venous thromboembolism in pregnancy and patients with hereditary antithrombin deficiency. Int J Womens Health. 2013;5:233-241. 5. Wolberg AS. Blood Rev. 2007;21(3):131-142. 6. Davi G, Patrono C. N Engl J Med. 2007;357(24):2482-2494. 7. Kottke-Marchant K, Duncan A. Antithrombin deficiency: issues in laboratory diagnosis. Arch Pathol Lab Med. 2002;126(11):1326-1336. 8. Mitton BA, Steineck A. Antithrombin deficiency. eMedicine from WebMD. http://emedicine.medscape.com/article/198573-overview. Updated August 22, 2019. Accessed September 4, 2020. 9. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia. 2008;14(6):1229-1239.10. Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III protein C, or protein S deficiency. Arteroscler Thromb Vasc Biol. 1996;16(6):742-748. 11. Ranucci M. Antithrombin III: key factor in extracorporeal circulation. Minerva Anestesiol. 2002;68(5):454-457. 12. Foy P, Moll S. Thrombophilia: 2009 update. Curr Treat Options Cardiovasc Med. 2009;11(2):114-128. 13. AABB, American Red Cross, America's Blood Centers, Armed Services Blood Program. Circular of information for the use of human blood and blood components. October 2017. http://www.aabb.org/tm/coi/Documents/coi1017.pdf. Accessed September 4, 2020. 14. Wells PS, Blajchman MA, Henderson P, et al. Am J Hematol. 1994;45:321-324. 15. US Census Bureau, Population Division. US and World Population Clock. http://www.census.gov/ popclock/. Accessed February 13, 2020. 16. Khawar H, Kelley W,Guzman N. Fresh frozen plasma. In: StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK513347/. Updated October 7, 2019. Accessed February 10, 2020. 17. Hellgren M, Tengborn T, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest. 1982;14:127-141. 18. Franchini M, Veneri D, Salvagno GL, Manzato F, Lippi G. Inherited thrombophilia. Crit Rev Clin Lab Sci. 2006;43(3):249-290. 19. Rodgers GM. Role of antithrombin concentrate in hereditary antithrombin deficiency: an update. Thromb Haemost. 2009;101(5):806-812. 20. Di Minno MND, Dentali F, Lupoli R, Ageno W. Mild antithrombin deficiency and risk of recurrent venous thromboembolism. Circulation. 2014;129(4):497-503. 21. Bucciarelli P, Passamonti SM, Biguzzi E, et al. Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboembolism. J Thromb Haemost. 2012;10(9):1783-1791. 22. Centers for Disease Control and Prevention. Venous thromboembolism in adult hospitalizations – United States, 2007-2009. MMWR Morb Mortal Wkly Rep. 2012;61(22):401-404. 23. Finley A, Greenberg C. Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass. Anesth Analg. 2013;116(6):1210-1222. 24. Kovács B, Bereczky Z, Oláh Z, et al. The superiority of anti-FXa assay over anti-FIIa assay in detecting heparin-binding site antithrombin deficiency. Am J Clin Pathol. 2013;140(5):675-679. 25. Olson E, Whitney M, Friedman B et al. In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity, Integrative Biology, 2012;4(6):595–605. 26. Lloyd-Jones D, Adams RJ, Brown TM, et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2010;121:e46-e215.

IMPORTANT SAFETY INFORMATION


THROMBATE III® (antithrombin III [human]) is indicated in patients with hereditary antithrombin deficiency for treatment and prevention of thromboembolism and for prevention of perioperative and peripartum thromboembolism.

Hypersensitivity reactions may occur. Should evidence of an acute hypersensitivity reaction be observed, promptly interrupt the infusion and begin appropriate treatment.

Because THROMBATE III is made from human blood, it may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in the product.

Perform coagulation tests to avoid excessive or insufficient anticoagulation and monitor for bleeding or thrombosis. Measure functional plasma AT levels with amidolytic or clotting assays; do not use immunoassays.

In clinical studies, the most common adverse reactions (≥ 5% of subjects) were dizziness, chest discomfort, nausea, dysgeusia, and pain (cramps).

The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary AT deficiency. Thus, in order to avoid bleeding, the dosage of heparin (or low molecular weight heparin) may need to be reduced during treatment with THROMBATE III.

Please see full Prescribing Information for THROMBATE III.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch, or call 1-800-FDA-1088.