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JP-7854662-B2 - Methods to reduce the incidence of thrombosis or thromboembolism

JP7854662B2JP 7854662 B2JP7854662 B2JP 7854662B2JP-7854662-B2

Inventors

  • ジェシカ・シー・カルデナス
  • チャールズ・イー・ウェイド
  • ヤオ－ウェイ・ワン
  • ブライアン・エー・コットン
  • クリストン・オズボーン

Assignees

  • ザ ボード オブ リージェンツ オブ ザ ユニバーシティー オブ テキサス システム
  • グリフォルス・シェアド・サービシズ・ノース・アメリカ・インコーポレイテッド

Dates

Publication Date
20260507
Application Date
20210112
Priority Date
20200404

Claims (17)

  1. A composition for reducing the occurrence of thrombosis or thromboembolism in patients identified as being at risk, comprising an anticoagulant selected from the group consisting of unfractionated heparin, low molecular weight heparin, heparinoids, fondaparinux, hydraparinux, and combinations thereof, and antithrombin (ATIII), wherein ATIII is administered at a concentration that increases the patient's ATIII level to greater than 1.2 IU/mL , and the patients identified as being at risk are patients with blunt physical trauma .
  2. The composition according to claim 1, wherein the thrombosis is venous thrombosis.
  3. The composition according to claim 1 or 2, wherein the thromboembolism is venous thromboembolism (VTE).
  4. The composition according to claim 1, wherein ATIII is administered at a concentration that increases the patient's ATIII level to more than 1.3 IU/mL.
  5. The composition according to claim 1, wherein ATIII is administered at a concentration that increases the patient's ATIII level to more than 1.4 IU/mL.
  6. The composition according to claim 1, wherein ATIII is administered at a concentration that increases the patient's ATIII level to more than 1.5 IU/mL.
  7. The composition according to claim 1, wherein ATIII is administered at a concentration that increases the patient's ATIII level to a range of 1.5 IU/mL to 2.5 IU/mL.
  8. The composition according to claim 1, wherein ATIII is administered at a concentration that increases the patient's ATIII level to a range of 1.5 IU/mL to 2.0 IU/mL.
  9. The composition according to claim 1, wherein ATIII is derived from plasma or is a recombinant.
  10. The composition according to claim 1, wherein the low molecular weight heparin is selected from the group consisting of bemiparin, sertoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin, combinations thereof, and pharmaceutically acceptable salts thereof.
  11. The composition according to claim 1, wherein the heparinoid is selected from the group consisting of danaparoids, dermatan sulfate, throdoxides, combinations thereof, and pharmaceutically acceptable salts thereof.
  12. The composition according to claim 1, wherein the anticoagulant is low molecular weight heparin.
  13. The composition according to claim 12 , wherein the low molecular weight heparin is enoxaparin or a pharmaceutically acceptable salt thereof.
  14. The composition according to claim 1, wherein the therapeutically effective dose of low molecular weight heparin is 20 mg to 180 mg per day.
  15. The composition according to claim 14 , wherein the therapeutically effective amount of low molecular weight heparin is 20 mg to 40 mg per day.
  16. The composition according to claim 1, wherein the therapeutically effective dose of low molecular weight heparin is 0.1 to 2.5 mg/kg.
  17. The composition according to claim 16 , wherein the therapeutically effective amount of low molecular weight heparin is 0.5 to 1.5 mg/kg.

Description

Article 30, Paragraph 2 of the Patent Act applies. The academic paper titled "Supplementation with antithrombin III ex vivo optimizations enoxaparin responses in critically injured patients" (Thromb Res., 2020 Mar., Vol. 187, pp. 131-138) is published on the website (https://www.thrombosisresearch.com/article/S0049-3848(20)30013-X/fulltext). This disclosure relates to the field of pharmaceutical products. Certain embodiments of this specification relate to methods and compositions for reducing the incidence of thrombosis or thromboembolism in patients identified as being at risk, the methods comprising the step of administering to a patient a therapeutically effective dose of one or more anticoagulants and antithrombin III (ATIII). Related Technical Description Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in patients with multiple traumatic injuries. Despite thorough preventive efforts to reduce risk, VTE remains one of the most common preventable causes of in-hospital death in this population [1,2]. Depending largely on the urgency of the patient and the level of monitoring, up to 30% of probationed patients experience VTE during hospitalization. These events result in aggressive intervention, prolonged hospitalization, and increased healthcare costs [2,3]. Three months after discharge, the VTE rate in surviving trauma patients still exceeds 10% [4], and 30% of thromboembolic events in the entire trauma population occur after discharge [5]. These are not clinically insignificant events. In fact, Drake et al. recently showed that 10.8% of preventable or potentially preventable deaths after discharge are attributable to extensive PE [6]. The precise pathophysiology of VTE in trauma patients is not fully understood, but it is undoubtedly multifactorial and is thought to occur secondary to a combination of risk factors including abnormal coagulation activation, endothelial dysfunction, persistent inflammation, prolonged immobility, massive transfusion, and mechanical ventilation [2]. Several studies have reported elevated post-traumatic thrombin production, a strong predictor of VTE in trauma patients [7–11]. Therefore, restoring hemostatic homeostasis by limiting thrombin production after bleeding control is achieved is critically important in preventing thromboembolic complications in recovering trauma patients. To address this, the American Academy of Chest Physicians has established standard treatment recommendations for aggressive VTE prophylaxis in trauma patients, including protocolized anticoagulation.[12] One of the most commonly used prophylactic anticoagulants is enoxaparin (Lovenox), a low molecular weight heparin that can be monitored in hospital by measuring anti-FXa levels. Enoxaparin acts by enhancing the activity of antithrombin III (AT), a circulating anticoagulant. Enoxaparin binds to AT, inhibiting FXa and thrombin and thus increasing their activity to downmodulate coagulation. Despite increasingly aggressive institutional thromboprophylaxis protocols, 50–70% of trauma patients do not achieve the recommended anti-FXa target range (0.1–0.4 IU/mL), which indicates a change in responsiveness to enoxaparin anticoagulation.[13,14] Such unresponsiveness has been associated with an increased risk of VTE. For example, Malinoski et al. showed an increased incidence of DVT in trauma and surgical patients who did not achieve the recommended anti-FXa range [15]. Since adjusting the enoxaparin dose in response to low anti-FXa levels does not change the incidence of VTE, escalating the heparinoid dose appears ineffective [16]. Sabbagh et al. first introduced the use of fresh frozen plasma (FFP) in the mid-1980s to reverse heparin resistance in patients undergoing cardiopulmonary bypass [17]. This diagram shows the flow of admitted and registered patients in the study of the present invention. PE = pulmonary embolism.This figure shows antithrombin (AT) levels in trauma patient plasma at baseline and after treatment with fresh frozen plasma (FFP) or AT concentrate. AT is shown as an activity percentage. FFP treatment was 30% by volume. AT was supplemented to final concentrations of 120, 150, 180, or 200%. Data are shown as mean with standard deviation. The dotted line represents the detection limit. * indicates p<0.05 compared to baseline after one-way ANOVA with Bonferroni correction.This figure shows the levels of anti-FXa and thrombin after enoxaparin treatment. Anti-FXa levels (A) and changes in peak thrombin (B) were measured in trauma patients after treatment of their plasma with enoxaparin, with or without FFP or AT supplementation. The delta peak represents the percentage change in thrombin in treated plasma compared to baseline untreated plasma. Data are shown as mean with standard deviation. * indicates p<0.05 compared to enoxaparin alone after one-way ANOVA with Bonferroni correction.This figure shows the levels of anti-