Patients with decreasing AT levels are at greater risk of experiencing a thrombotic episode, which underscores the importance of finding the balance between VTE risk and AT levels20

Even plasma levels that are considered normal (between 86 and 100 IU/dL) pose a significant risk for VTE21

The risk of VTE, when stratified for unprovoked VTE,* is 6 times higher for those with AT levels between 61% and 75%21

  • 85% of patients with hereditary AT deficiency will have at least 1 thrombotic episode by age 507
  • Nearly 70% of these patients will have an event before the age of 357
  • Risk of unprovoked VTE* increases with decreasing AT levels

Risk of unprovoked VTE* increases with decreasing AT levels

Data reflect events that occurred in the absence of transient risk factors (ie, surgery, trauma, prolonged bed rest [>1 week], pregnancy/puerperium, and combined oral contraceptive use). Risk assessed in comparison to patients with normal AT levels (or levels >100 IU/dL).

Including those with cancer, liver disease, and nephrotic syndrome.

Odds ratio adjusted for sex, age, body mass index, and thrombophilia (all defects except that under study). From a case-controlled study of 1401 patients with a first objectively documented VTE and 1847 healthy controls to assess the risk of VTE associated with varying plasma levels of AT, protein C (PC), and protein S (PS). Patients with surgery- or pregnancy-related VTE were tested for AT, PC, and PS at least 3 months after operation or delivery, in order to avoid changes in plasma levels of the naturally occurring anticoagulants related to these conditions.

AT III deficiency and pregnancy

Pregnancy with hATd and History of Pulmonary Embolism (PE)

Patient History

  • Laura is a 37-year-old who is at ~5 weeks’ gestation
  • African-American female diagnosed with hereditary antithrombin deficiency
  • Asymptomatic until age 27, when she experienced a massive PE requiring lytic therapy
  • Younger sibling died of massive PE at age 18

BID, twice daily; DVT, deep vein thrombosis; hATd, hereditary antithrombin deficiency; PE, pulmonary embolism.
* Therapeutic range is >0.5 to <1.2 IU/mL.

Hypothetical case profile is not intended to convey clinical diagnostic or therapeutic recommendations.

Initial Evaluation and Management

  • Maintained on warfarin since PE
  • Transitioned to enoxaparin 40 mg daily
  • Baseline pregnancy-related coagulation studies were obtained and were normal
  • Monitoring planned every 8–10 weeks
  • Labs included antithrombin level, anti-Xa, factors VII and VIII, and fibrinogen

Pregnancy Complications and Management

  • At 8 weeks, Laura developed a DVT despite no evidence of increased coagulation system activation
  • Enoxaparin increased to 80 mg BID to offset the hypermetabolic state
  • Anti-Xa level was in good therapeutic range at 0.8 IU/mL*
  • Antithrombin level (51%) had not decreased significantly, so no antithrombin supplementation was given

Delivery Plan

  • Meetings with maternal-fetal medicine specialist to discuss delivery options given history
  • Elective induction at 38 weeks was recommended
  • Plan was to bring patient into hospital 2 days in advance to give THROMBATE III to raise antithrombin level to 100% and check decay rate every 12 hours
  • Pharmacy was alerted to ensure adequate stocks as patient would need THROMBATE III for several days
  • Labs showed no abnormal increase in coagulation studies compared with normal pregnancy

Delivery Outcome

  • Patient went into spontaneous labor 2 days before scheduled induction
  • Patient was informed that she was not a candidate for epidural because there was no time to discontinue enoxaparin before delivery
  • AT level on admission was 38%
  • Patient was given 3000 units of THROMBATE III and antithrombin level increased to 112%
  • Patient delivered vaginally without issue
  • Post-delivery antithrombin level was 71%

Postpartum Management

  • Patient was maintained on 2000 units of THROMBATE III daily for 2 days postpartum
  • Peak antithrombin levels at 1-hour post dose were 108% and 116%
  • Trough antithrombin levels drawn before next dose were 44% and 59%, respectively
  • Patient was given 3000 units of THROMBATE III on day of discharge and continued on enoxaparin 80 mg BID

Postpartum Outcome

  • No significant post-delivery complications were noted
  • Mother and baby did well
  • Patient was transitioned back to warfarin after 6 weeks
Thrombate III in surgical procedures

Case Study: Intraoperative Heparin Resistance

Video Transcript

  • Hereditary antithrombin deficiency is very rare in the population, but it is an important topic to discuss because there is an increased risk of VTE in the sepatients
  • 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 the general 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 specific prophylactic 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 prevent thrombosis
  • 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 at 35%
  • 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 are walking around every day with about half of the normal antithrombin level, we can presume that Fredrick will not respond normally to heparin
  • What most people suggest for a person like Frederick is that at the time of his procedure, 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 peri procedurally is an option that would alleviate this volume concern. Unlike plasma, a concentrate can be prepared 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 a pixaban
  • 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 clotting assays; immunoassays should not be used
  • Physicians may be reluctant to restart anticoagulation peri procedurally, 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 that occurred 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 reduce clotting 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

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

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

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.

When an infusion of THROMBATE III is indicated for a patient with hereditary deficiency to control an acute thrombotic episode or prevent thrombosis during or following surgical or obstetrical procedures, raise the AT level to normal and maintain this level for 2 to 8 days, depending on the indication for treatment, type and extent of surgery, patient’s medical condition, past history and physician’s judgment. Base the concomitant administration of heparin in each of these situations on the medical judgment of the physician.

 

Hypothetical case profile is not intended to convey clinical diagnostic or therapeutic recommendations.

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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.