Case Study: Intraoperative Heparin Resistance


Video Transcript +

  • Hereditary antithrombin deficiency is very rare in the population, but it is animportant topic to discuss because there is an increased risk of VTE in thesepatients.
  • So what is hereditary antithrombin deficiency? It is a hereditary autosomaldominant disorder that typically reduces functional antithrombin levels to 40% to 60% of normal.
    • The overall incidence of hereditary antithrombin deficiency in thegeneral population is very low, between 0.02% and 0.2%.
    • However, patients with hereditary antithrombin deficiency are about 20 times more likely to have a VTE compared with the general population, which means that up to 3% of patients with thrombotic events may have hereditary antithrombin deficiency.
    • The risk of VTE is much higher in hereditary antithrombin-deficient patients than it is in patients with other thrombophilias like factor VLeiden or prothrombin gene mutation.
    • As proceduralists, we need to be concerned about hereditary antithrombin deficiency because these patients have an increased risk of VTE during procedures and deliveries.
  • For example, up to 70% of pregnant women with hereditary antithrombin deficiency without thromboprophylaxis may experience thromboembolic complications during pregnancy.
  • Patients with antithrombin deficiency also have an increased riskof VTE when undergoing surgeries, including vascular,orthopedic, bariatric, and cardiac surgeries.
    • Because of this, patients who experience heparin response issues need awork-up to determine the cause. Some centers may even consider antithrombin level testing in certain patients prior to a procedure.
  • Hereditary antithrombin deficiency can be the reason why surgical patients don't have the expected response to heparin anticoagulation.
  • So what do we do when we encounter someone with hereditary antithrombin deficiency?
    • We know that they may have about half the level of antithrombinactivity compared with people in the general population, which carrieswith it the risk of VTE.
    • It also means that we need to consider using FFP or antithrombin concentrate during the procedure to improve heparin responsiveness
  • We also know that recurrent thrombosis and occasional fatal thromboembolism are possible in patients with hereditary antithrombin deficiency, so patients with a history of thrombosis should be maintained on anticoagulant therapy.
  • We have to understand that these patients, while they require very specificp rophylactic therapy to prevent DVT or PE periprocedurally, are also very likely to have low-heparin response if they have a procedure that requires anticoagulation with heparin.
  • Patients with hereditary antithrombin deficiency are at the highest risk for bloodclots in certain situations such as surgery, the use of oral contraceptives,pregnancy, childbirth, and when they already have had a blood clot in the past.
  • Before surgeries involving heparinization, patients with hereditary antithrombin deficiency require careful perioperative management necessary to preventthrombosis.
  • One way to do that is with antithrombin concentrate.
  • THROMBATE III is an antithrombin concentrate that temporarily replaces themissing antithrombin in patients with hereditary antithrombin deficiency.
  • It is simple to use, with one dosing formula, and provides for convenient storageand reconstitution. It can also be used before, during, and after surgery.
  • So, what about when a patient with hereditary antithrombin deficiency comes tothe operating room for a procedure that is going to require heparin?
  • Let's take a look at Frederick, a 52-year-old male with peripheral vascular disease and lower-extremity claudication requiring surgical intervention.
    • He has a medical history of hypertension, hyperlipidemia, and long-termanticoagulation with apixaban after recurrent DVTs in his early 40s. Hewas diagnosed at this time with hereditary antithrombin deficiency.
    • He also had family members who died from thrombotic-related diseaseand they very likely had hereditary antithrombin deficiency as well.
  • Following a previous procedure, Frederick's postoperative antithrombin activity level was 27%, and at the 6-week follow-up, his level was still persistently low at35%.
  • He continued on long-term anticoagulation due to his history of recurrent DVTs.
  • Frederick is now going to have a lower extremity vascular procedure and is going to need anticoagulation at the time of the procedure.
    • Because we know that, on average, antithrombin deficient patients arewalking around every day with about half of the normal antithrombin level, we can presume that Fredrick will not respond normally toheparin.
  • What most people suggest for a person like Frederick is that at the time of hisprocedure, he should be given FFP or antithrombin concentrate to return his antithrombin to a more normal level
  • With Frederick's antithrombin level around 35%, a massive amount of plasma would be required in an effort to return his antithrombin to a more normal level.
  • Administration of antithrombin concentrate periprocedurally is an option that would alleviate this volume concern. Unlike plasma, a concentrate can beprepared relatively quickly with no need for thawing.
  • One such antithrombin concentrate is THROMBATE III. THROMBATE III 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.
  • Please refer to the Important Safety Information that will be presented at the end of this video.
  • After receiving THROMBATE III for his procedure, Frederick should continue to receive THROMBATE III daily for the remainder of hospitalization until he can restart his long-term anticoagulation with apixaban.
  • Coagulation tests should be performed to avoid excessive or insufficient anticoagulation, and Frederick should be monitored for bleeding or thrombosis.
  • Functional plasma AT levels should be measured with amidolytic or clottingassays; immunoassays should not be used.
  • Physicians may be reluctant to restart anticoagulation periprocedurally, but incases likeFrederick's, it's important that his antithrombin levels are raised tonormal with supplementation or that he is returned to his apixabananticoagulation.
  • Right after the surgery, you wouldn't use a full-strength anticoagulant. Instead,you would use an antithrombin concentrate, such as THROMBATE III.
  • In clinical studies with THROMBATE III, the most common adverse reactions thatoccurred in ≥5% of subjects were dizziness, chest discomfort, nausea, dysgeusia,and pain (cramps).
  • In the future, if more procedures requiring discontinuation of Frederick's long-termanticoagulation are necessary, THROMBATE III can be used to reduceclotting risks.
 
 

Patient History

  • Frederick is a 52-year-old male with peripheral vascular disease and lower-extremity claudication requiring surgical intervention
  • Medical history of hypertension, hyperlipidemia, and long-term anticoagulation with apixaban after recurrent DVTs in his early 40s
  • Father had pulmonary embolism, sibling with sudden death
 
 
 

Surgical Course

  • Apixaban is held for 4 days prior to elective femoral-popliteal bypass
  • Intraoperatively, patient receives 5000 IU IV heparin during vascular anastomosis
  • After the incision is closed, distal pulses are not evident by palpitation or Doppler ultrasound examination
  • The bypass is re-explored and found to be full of clot
  • Additional heparin 10,000 IU given and thrombectomy performed
  • New clots form in surgical field
  • Activated clotting time (ACT) is checked and found to be low—only 180 seconds
  • A total of 20,000 IU additional heparin is given to achieve target ACT of 250 seconds, and procedure is finally completed successfully
 

Postoperative Evaluation and Management

  • Postoperative antithrombin activity level found to be 27%
  • At 6-week follow-up, patient found to have persistently low antithrombin level of 35%
  • Diagnosis of hATd made and patient continued on lifetime anticoagulation
 

Treatment Plan/Management

  • In the future, when stopping his long-term anticoagulation is required, Frederick can be protected from clotting risk with THROMBATE III at the time of the procedure
  • Many surgical procedures require cessation of long-term anticoagulation to prevent hemorrhage during surgery, exposing Frederick to risk of VTE
  • Preoperatively, THROMBATE III daily dosing should be started when apixaban is stopped
  • THROMBATE III can be continued until the postoperative risk of bleeding allows resumption of long-term anticoagulation
 

hATd, hereditary antithrombin deficiency; DVT, deep vein thrombosis; IU, international units; IV, intravenous; VTE, venous thromboembolism.

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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.

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