Abstract
Hemostasis occurs through a complex process that involves numerous different blood clotting proteins. These blood clotting proteins interact in the initiation, amplification, and propagation phases of the coagulation cascade. Platelets also function to stop bleeding by creating platelet plugs at the site of injury. Furthermore, von Willebrand factor (VWF) binds to factor VIII, platelet surface glycoproteins, and connective tissue to assist in hemostasis. When the coagulation cascade is initiated, fibrinolysis will also occur simultaneously. Fibrinolysis is the physiological mechanism that dissolves clots and maintains vessel patency. Hemorrhage occurs when the clotting cascade is interrupted through a deficiency or malfunction in one or more of these clotting proteins or when there is a disorder of fibrinolysis. In addition, a qualitative or quantitative defect in platelets or VWF can also lead to a bleeding event. The etiology of bleeding events in patients may be multifaceted, and managing these bleeding patients can be complex and difficult at times. Treatment is generally aimed at replacing the missing or defective blood clotting protein or platelets. This chapter highlights various medications, both recombinant and human derived, that are utilized in the management of bleeding patients. Medication uses listed in this chapter are both based on manufacturer-approved indications and also on unlabeled indications, which have been reported in case reports, case series, and more rigorous studies.
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Keywords
- Bleeding
- Hemorrhage
- Management
- Adult
- Pediatric
- Tranexamic acid
- Aminocaproic acid
- Fibrinogen concentrate
- Recombinant factor VIIa
- Desmopressin
- Antihemophilic factor/von Willebrand factor complex (human)
- Phytonadione
- Four-factor prothrombin complex concentrate
- Thrombin powder
- Protamine
- Anti-inhibitor coagulant complex
Hemostatic Agents Used to Stop Bleeding
Tranexamic Acid
Brand Names (USA): Lysteda™, Cyklokapron™
Description: Tranexamic acid is a synthetic amino acid that is classified as antifibrinolytic. It is a competitive inhibitor of plasminogen activation, which becomes a noncompetitive inhibitor at higher concentrations. Tranexamic acid displaces plasminogen from fibrin and resu lts in the inhibition of fibrinolysis. Tranexamic acid is approximately ten times more potent than aminocaproic acid, and its elimination half-life is 2–11 h [1, 2]. Tranexamic acid is available in an intravenous solution and an oral tablet. In addition, an oral solution may be compounded. If 10 mL of the compounded oral 5 % solution is swallowed, this provides 500 mg of tranexamic acid orally [3]. However, this oral solution is mostly studied for topical use.
Adult Use: Tranexamic acid can be used for menorrhagia [2], blood loss reduction during elective cesarean section [4], blood loss reduction during hip fracture surgery [5], blood loss reduction in orthognathic surgery [6], blood loss reduction in dental procedure patients on oral anticoagulant therapy [7], prevention of perioperative bleeding associated with cardiac and spinal surgery [8–11], blood loss reduction during total hip and total knee replacement surgery [12–18], and trauma-associated hemorrhage [19].
Pediatric Use: In the pediatric setting, tranexamic acid can be used for the prevention of bleeding associated with extracorporeal membrane oxygenation (ECMO) during surgery for congenital diaphragmatic hernia (CDH) repair [20, 21], prevention of perioperative bleeding associated with cardiac surgery [22–24], menorrhagia [2], blood loss reduction in hemophilia patients undergoing tooth extraction [25], treatment of hemoptysis in cystic fibrosis patients [26–28], and prevention of perioperative bleeding associated with spinal surgery and craniosynostosis surgery [29–32].
Adverse Effects and Monitoring Parameters: Orally administered tranexamic acid can cause gastrointestinal upset, headache, abdominal pain, muscle pain, and thrombosis (Table 34.1). Visual defects may occur; thus, patients should undergo routine ophthalmologist examinations. Intravenous tranexamic acid can also cause hypotension with rapid administration [33]. The dose and frequency of tranexamic acid should be adjusted in patients with renal dysfunction (see Table 34.2). Importantly, tranexamic acid should not be used when there is evidence of active intravascular thrombosis [1, 2]. Caution is advised if antifibrinolytics are used together with prothrombin complex concentrates (PCC) or activated prothrombin complex concentrates (APCC) because of the risk of thrombosis. If treatment with both agents is deemed necessary, it is recommended to wait 4–6 h after the last dose of PCC or APCC before administering antifibrinolytic s [34].
Aminocaproic Acid
Brand Name (USA): Amicar™
Description: Aminocaproic acid is an antifibrinolytic that binds competitively to plasminogen, which reduces the conversion of plasminogen to plasmin, resulting in the inhibition of fibrin degradation. The main difference between aminocaproic acid and tranexamic acid is that tranexamic binds more strongly to plasminogen; thus, aminocaproic acid is less potent than tranexamic acid. Aminocaproic acid has an elimination half-life of 2 h and may accumulate in patients with renal dysfunction. Thus, a reduced dose may be necessary in anephric patients or those with renal dysfunction. Aminocaproic acid is available as an intravenous solution, oral solution, and oral tablet [35, 36].
Adult Use: Aminocaproic acid can be used to enhance hemostasis when fibrinolysis contributes to bleeding [35], control of acute bleeding [35], control of bleeding with severe thrombocytopenia [37, 38], control of bleeding in congenital and acquired coagulation disorder [39], blood loss reduction in patients on oral anticoagulant therapy undergoing dental procedures [40], and prevention of perioperative bleeding associated with cardiac surgery [41, 42].
Pediatric Use: Aminocaproic acid can be used in children for the prevention of perioperative bleeding associated with cardiac and spinal surgery [42–44] and prevention of bleeding associated with ECMO [45–47].
Adverse Effects and Monitoring Parameters: The most common adverse effect of aminocaproic acid is gastrointestinal upset (Table 34.3). Other adverse effects include thrombosis and an increase in blood urea nitrogen (BUN) and skeletal muscle weakness. Aminocaproic acid can also cause skeletal muscle weakness; therefore, creatine phosphokinase (CPK) should be monitored, and treatment should be discontinued with a significant rise in CPK. Other monitoring parameters include fibrinogen, BUN, and creatinine. Importantly, aminocaproic acid should not be used when there is evidence of active intravascular thrombosis [ 35].
Fibrinogen Concentrate (Human)
Brand Name (USA): RiaSTAP™
Description: Fibrinogen concentrate (coagulation factor I) is generated from pooled human plasma and is a physiological substrate of thrombin, factor XIIIa, and plasmin. Soluble fibrinogen is converte d to insoluble fibrin. Fibrin is stabilized by factor XIIIa, which induces cross-linking of fibrin polymers to provide strength and stability to the blood clot. The cross-linked fibrin is the end result of the coagulation cascade. Human fibrinogen concentration has a fairly long elimination half-life of 61–97 h; however, this half-life may be decreased in children and adolescents. Fibrinogen concentrate is available as intravenous powder, for reconstitution [48].
Adult Use: Fibrinogen concentrate can be used in the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency (afibrinogenemia and hypofibrinogenemia) [48], supportive therapy in trauma patients who are bleeding [49–53], blood loss reduction in cardiovascular surgery [49, 54, 55], blood loss reduction in postpartum hemorrhage [56], and improvement in clot firmness after orthopedic surgery [57].
Pediatric Use: Fibrinogen concentrate can be used in children for the treatment of congenital fibrinogen deficiency [58, 59] and reduction of blood loss after surgical craniosynostosis repair [60].
Adverse Effects and Monitoring Parameters: Fibrinogen concentrate may cause hypersensitivity reactions, thrombosis, and headache (Table 34.4). Similar to all plasma-derived factor products, fibrinogen concentrate may also transmit disease, since the product is derived from human plasma. Monitoring parameters include fibrinogen levels and signs/symptoms of thrombosis and hypersensitivity. A target fibrinogen level of 100 mg/dL should be maintained until hemostasis occurs and wound healing is complete. The reference range for normal fibrinogen is 200–450 m g/dL [48].
Factor VIIa (Recombinant)
Brand Name (USA): NovoSeven™ RT
Description: Recombinant factor VIIa is a vitamin K-dependent glycoprotein that promotes hemostasis by activating the extrinsic pathway of the coagulation cascade. Factor VII complexes with tissue factor and activates coagulation factors IX and X. When complexed with other factors, coagulation factor Xa converts prothrombin to thrombin, a key step in the formatio n of a fibrin-platelet hemostatic plug. Recombinant factor VIIa has a short terminal half-life of 2.6–3.1 h, thus a need for frequent dosing. Recombinant factor VIIa is available as an intravenous solution [61].
Adult Use: Recombinant factor VIIa is indicated for use in patients with hemophilia A or B with inhibitors [61], congenital factor VII deficiency [61], acquired hemophilia [61], and Glanzmann’s thrombasthenia [61]. There have been numerous studies and reports on the unlabeled use of recombinant factor VIIa in bleeding patients. The paragraph below is not an exhaustive list but rather a general summary of the use of this product in different patient populations. Recombinant factor VIIa has been reported to be used in patients with warfarin-related intracerebral hemorrhage (ICH) [62, 63], refractory bleeding after cardiac or liver surgery in nonhemophilic patients [63–67], anticoagulation reversal [68–70], blood loss reduction after cardiac surgery [71], coagulopathy reversal in isolated traumatic brain injury (TBI) [72], diffuse alveolar hemorrhage in bone marrow transplant (BMT) patients [73], bridge to transplant in end-stage liver disease patients [73], trauma-related coagulopathy [73], refractory perioperative bleeding in noncardiac patients [73], life-threatening refractory hemorrhage of any cause in severely coagulopathic patients [63, 73], blood loss reduction in abdominal trauma patients [74], and esophageal varices [63].
Pediatric Use: Recombinant factor VIIa can also be utilized in the pediatric population for reduction in blood loss and requirement for blood products after cardiac surgery [75, 76], coagulopathies [77], treatment of severe bleeding associated with dengue hemorrhagic fever [78], liver impairment [79, 80], and nonhemophilic hemorrhages [81].
Adverse Effects and Monitoring Parameters: Recombinant factor VIIa may cause antibody formation, hypersensitive reactions, thromboembolic events, and hyper- or hypotension (Table 34.5). Monitoring parameters include evidence of hemostasis. The prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (PTT), and factor VII may also be useful as adjunct tests to evaluate efficacy [61].
Desmopressin
Brand Names (USA): DDAVP™, Stimate™
Description: Desmopressin is a synthetic analogue of vasopressin, but the molecular structure is modified from vasopressin to reduce its vasoactive actions; vasopressin activates both V1 and V2 receptors where desmopressin only stimulates V2 receptors. Desmopressin incr eases plasma levels of von Willebrand factor (VWF), factor VIII (FVIII), and tissue plasminogen activator (t-PA) contributing to a shortened PTT and bleeding time. These effects are likely due to stimulating the release of VWF from endothelial storage sites; however, this mechanism is not fully understood, and several hypotheses exist [82–86]. The secreted t-PA is inactivated by plasminogen activator inhibitor and thus does not seem to promote fibrinolysis or bleeding. Most patients with type 1 von Willebrand disease (VWD) and FVIII/VWF levels greater than 10 units/mL will respond to desmopressin, but patients with type 2 VWD have a more variable response. Prior to utilizing desmopressin for therapy, a therapeutic trial should be conducted to determine a patient’s response. To test responsiveness, blood samples are taken 30–60 min and 4 h after an intravenous injection of desmopressin to obtain a reliable figure on recovery and clearance of FVIII and VWF [87]. Desmopressin has an elimination half-life of 2–4 h; however, the half-life is prolonged to 9 h in patients with renal impairment (See Table 34.7) [35].
Formulations: Desmopressin is available as a 4 mcg/mL injection and a 1.5 mg/mL nasal solution. The nasal formulation is ~2.75 times less potent than the injection formulation. Therefore, the nasal solution is often used for minor bleeding, while the intravenous injection is preferred for surgical bleeding prophylaxis and major bleeding. Desmopressin is also available as an oral tablet and a rhinal tube [83].
Adult Use: Desmopressin is utilized in the treatment and prevention of bleeding episodes in mild-to-moderate hemophilia A and mild-to-moderate VWD type 1 patients who respond to a desmopressin challenge [34, 88, 89], uremia associated with acute or chronic renal failure [90], prevention of surgical bleeding in patients with uremia [91], stabilization of platelet function in intracranial hemorrhage [92], blood loss reduction after cardiac surgery [93, 94], blood loss reduction in dental procedures [83], and blood loss reduction in patients with liver cirrhosis [95–98]. It is recommended to utilize VWF in addition to desmopressin if the postsurgical treatment is necessary for more than three days [83].
Pediatric Use: In the pediatric setting, desmopressin is utilized for heavy menstrual bleeding in adolescent females [99, 100], congenital VWD in patients who respond to a desmopressin challenge [82], congenital platelet defect disorders in patients who respond to a desmopressin challenge [82], circumcision in combined factor V and VIII deficiency [101], tonsillectomy and adenoidectomy [83], and otologic surgery [83]. Studies have shown that desmopressin administered as a one-time dose after cardiopulmonary bypass failed to reduce blood loss after cardiovascular surgery in pediatrics [102–104]. Of note, children under two years of age tend to have a lower response to desmopressin in comparison to older children [83].
Adverse Effects and Monitoring Parameters: Desmopressin may cause flushing, hypo- or hypertension, headache, fatigue, hyponatremia, abdominal pain, abnormal lacrimation (intranasal formulation), conjunctivitis (intranasal formulation), and ocular edema (intranasal formulation) (Tables 34.6 and 34.7). Monitoring parameters include fluid intake, urine volume, and signs/symptoms of hyponatremia [83]. Young children may be at an increased risk for hyponatremia-induced seizures when the intravenous formulation is utilized; fluid restriction and careful monitoring of serum sodium levels and urine output are warranted [105–109]. Due to the risk of hyponatremia, some institutions adopt sodium limits associated with desmopressin administration, i.e., avoid desmopressin if sodium is less than 130 meq/L. Tachyphylaxis can occur with consecutive dosing of desmopressin; thus, it is recommended to use specific factor concentrates or platelet transfusions, depending on the underlying disease, if hemostasis after major trauma or surgery is desired [110].
Antihemophilic Factor/von Willebrand Factor Complex (Human)
Brand Name (USA): Humate-P™
Description: Humate-P™ is a factor product that is derived from human plasma and contains FVIII, VWF, and small amounts of fibrinogen and albumin [111]. Its use is primarily to replace endogenous factor VIII and VWF in patients with hemophilia A or VWD. Factor VIII in conjunction with activated factor IX activates factor X which converts prothrombin to thrombin and fibrinogen to fibrin. VWF promotes platelet aggregation and adhesion to damaged vasculature and acts as a carrier protein for factor VIII. Circulating levels of functional VWF are measured as ristocetin cofactor (VWF:RCo) activity. The average ratio of VWF:RCo to FVIII in Humate-P™ is 2.4:1, which is more similar to the ratio in normal human plasma in comparison to other VWF/FVIII products. The elimination hale-life of VWF:RCo in Humate-P™ has a wide range of 3–34 h in patients with VWD. Humate-p™ is available as an intravenous powder for reconstitution [112].
Adult Use: Humate-P™ is utilized in adult patients for the prevention and treatment of bleeding episodes in patients with hemophilia A [111]); treatment of spontaneous or trauma-induced bleeding and prevention of excessive bleeding during and after surgery in patients with severe VWD [111, 113, 114], including mild or moderate disease where use of desmopressin is known or suspected to be inadequate [111]); reduction of postpartum blood loss in VWD type 3 patients [115]; and development of acquired von Willebrand disease after ventricular assist device implantation [112]. When used for surgical prophylaxis, target levels of VWF:RCo should be approximately 100 units/dL and, at least for the first 3 days of treatment, a nadir of 50 units/dL VWF:RCo, as well as similar targets for FVIII [83]. Humate-P™ administered as a continuous infusion has also been reported to be successful for surgical prophylaxis [83].
Pediatric Use: Humate-P™ is utilized in pediatric patients with VWD undergoing surgery, bleeding events in VWD [116, 117], prophylaxis in VWD [116], and valproate-associated von Willebrand syndrome [117].
Adverse Effects and Monitoring Parameters: Adverse effects of Humate-P™ include antibody formation, hypersensitivity, thrombotic events, rash, dizziness, headache, and nausea/vomiting (Table 34.8). Monitoring parameters include heart rate, blood pressure, AHF levels prior to and during treatment, inhibitor development, hematocrit, signs/symptoms of intravascular hemolysis, bleeding, and VWF activity. In surgical patients, monitor VWF:RCo at baseline and after surgery and trough VWF:RCo and FVIII:C daily. Humate-P™ can also transmit infections since it’s derived from human plasma [ 111].
Antihemophilic Factor/von Willebrand Factor Complex (Human)
Brand Name (USA): Alphanate™
Description: Alphanate™ is derived from human plasma and contains FVIII, VWF, and other plasma proteins. Alphanate™ is used to replace endogenous factor VIII and VWF. The average ratio of VWF:RCo to FVIII in Alphanate™is not provided by the manufacturer but is approximately 1:1. Of note, Alphanate™ has less VWF per unit when compared with Humate-P™. The elimination half-life range for Alphanate™ is the same as Humate-P™ (3–34 h). Alphanate™ is available as an intravenous powder for reconstitution [83].
Adult Use: Alphanate™ is utilized for the prevention and treatment of hemorrhagic episodes in patients with hemophilia A [118] and prophylaxis with surgical and/or invasive procedures in patients with VWD when desmopressin is either ineffective or contraindicated [118, 119]. Alphanate™ is not indicated for surgical prophylaxis in patients with severe VWD, type 3 [83, 118].
Pediatric Use: Alphanate™ is used in pediatric patients with VWD for the treatment of bleeding episodes [120] and prophylaxis prior to surgery [118, 120].
Adverse Effects and Monitoring Parameters: Alphanate™ can cause antibody formation, hypersensitivity, thrombotic evens, rash, face edema, headache, dizziness, and nausea (Table 34.9). Alphanate™ can also cause transmission of infections since it is derived from human plasma. Monitoring parameters are the same as those listed for Humate-P™.
Phytonadione (Vitamin K)
Brand Name (USA): Mephyton™
Description: Phytonadione is a vitamin that is necessary for the liver to synthesize factors II, VII, IX, and X. These vitamin-K dependent coagulation factors are γ-carboxylated by the action of vitamin K and glutamyl carboxylase. Phytonadione is available as an intravenous aqueous colloidal solution and an oral tablet [121].
Adult Use: Phytonadione is used in the prevention and treatment of hypoprothrombinemia caused by vitamin K antagonist (VKA)-induced or other drug-induced vitamin K deficiency [121], hypoprothrombinemia due to drugs or factors limiting absorption or synthesis [121], vitamin K deficiency secondary to VKA [122–124], and preprocedural/surgical INR normalization in patients receiving warfarin [122, 125].
Pediatric Use: Phytonadione is used in pediatric patients to treat vitamin K deficiency secondary to vitamin K antagonist administration [121] and bleeding in patients with chronic cholestasis [126].
Adverse Effects and Monitoring Parameters: Phytonadione can cause hypersensitivity reactions, flushing, dizziness, and abnormal taste (Table 34.10). PT, INR, and hypersensitive reactions should be monitored following phytonadione administration [ 121].
Four-Factor Prothrombin Complex Concentrate (Human)
Brand Name (USA): Kcentra™
Description: Kcentra™ is derived from human plasma and contains factors II, VII, IX, and X proteins C and S. Coagulation factors II, IX, and X are part of the intrinsic coagulation pathway, while factor VII is part of the extrinsic coagulation pathway. Ultimately, these factors facilitate the activation of prothrombin into thrombin which converts fibrinogen into fibrin resulting in clot formation. Proteins C and S are vitamin K-dependent inhibiting enzymes involved in regulating the coagulation process. Protein S serves as a cofactor for protein C, which is converted to activated protein C (APC). APC is a serine protease that inactivates factors Va and VIIIa, limiting thrombotic formation. The elimination half-life of this product is dependent on the half-life of its individual components: factor II, 48–60 h; factor VII, 1.5–6 h; factor IX, 20–24 h; factor X, 24–48 h; protein C, 1.5–6 h; and protein S, 24–48 h. Kcentra™ is available as an intravenous powder for reconstitution [127]. Three-factor prothrombin complex concentrates (Bebulin™ and Profilnine™) differ from Kcentra in that they do not contain factor VII but only contain factors II, IX, and X (see Tables 34.12 and 34.13) [128–130].
Adult Use: Kcentra™ is indicated for VKA reversal in patients with acute major bleeding or need for an urgent surgery/invasive procedure [127]. Reports have also shown Kcentra™ to be effective in the reversal of direct factor Xa anticoagulants [131, 132], an alternative agent to fresh frozen plasma (FFP) in patients with serious/life-threatening bleeding related to vitamin K antagonist therapy [133], and in acquired, non-warfarin-related coagulopathy in major trauma and surgery [134–137].
Pediatric Use: Data supporting four-factor prothrombin complex concentrate use in pediatric patients is limited to case reports or case series. These data show prothrombin complex concentrate can be used for prophylaxis in patients with severe congenital factor X deficiency [138, 139] and in dilutional coagulopathy [140]. Prothrombin complex concentrate may also be useful in pediatric patients with limited total blood volume and high risk of volume overload; however, there have been no formal studies validating this.
Adverse Effects and Monitoring Parameters: Kcentra™ can cause hypersensitivity reactions, hypercoagulopathy, hypo- or hypertension, tachycardia, headache, and nausea/vomiting (Tables 34.11, 34.12, and 34.13). Infection can also be transmitted since Kcentra™ is derived from human plasma. The INR should be monitored at baseline and at 30 min post dose, and a patient’s clinical response should be monitored during and after treatment [127].
Thrombin Powder
Brand Name (USA): Recothrom™
Description: Thrombin is a to pical product that is made through recombinant DNA technology. Thrombin activates platelets and catalyzes the conversion of fibrinogen to fibrin to promote hemostasis. Thrombin is available as a topical powder for recon struction, topical pad, topical solution, and topical sponge [141].
Adult Use: Thrombin is utilized for hemostasis [141]; control of localized, accessible bleeding from lacerated tissues [34]; control of bleeding after dental extractions or at surgical sites [34]; and reduction of blood loss in total knee arthroplasty [142].
Pediatric Use: Thrombin powder has been studied in pediatric patients and is approved to aid in hemostasis, specifically in burn patients [141].
Adverse Effects and Monitoring Parameters: Patients who receive thrombin powder should be monitored for abnormal hemostasis (Table 34.14). Thrombin powder may also cause pruritus. Of note, this product is for topical use only [141].
Protamine Sulfate
Brand Name (USA): Not applicable
Description: Protamine is a strongly alkaline substance and is derived from the sperm of salmon and other fish species. When protamine is administered alone, it has anticoagulant effects. However, when protamine is administered in the presence of heparin, a strong acidic medication, a stable salt is formed, and the anticoagulant activity of both medications is lost. Protamine has a very rapid onset of action (5 min), and the elimination half-life is approximately 7 min. However, when protamine is administered, it neutralizes the heparin; therefore, subsequent doses are not usually required. Protamine is available as an intravenous solution [143].
Adult Use: Protamine is utilized in adults for the reversal of heparin and low molecular weight heparins [143, 144]. When heparin is given as a continuous IV infusion, only heparin given in the preceding several hours should be considered when administering protamine [145]. Protamine can also be utilized for low molecular weight heparin (LMWH) overdose, but the anti-Xa activity is never completely neutralized [146–148]. Protamine is also used to neutralize heparin in patients previously on cardiopulmonary bypass, the most effective dosing being individualized management [149], and to reduce bleeding complications after carotid endarterectomy [150].
Pediatric Use: Protamine is utilized in the pediatric patient to reverse heparin and low molecular weight heparin, to neutralize heparin from combined estimated blood volume of the patient and cardiopulmonary bypass circuit [151, 152], and to treat severe post-reperfusion coagulopathy in liver transplant patients [153].
Adverse Effects and Monitoring Parameters: Severe hypotension can occur with rapid administration of protamine; thus, protamine should be administered over at least a 10-min period (Table 34.15). Transient hypotension can still be expected within 3–4 min after administration [154]. There is also a risk for anaphylaxis with protamine administration secondary to histamine release, which has been reported mainly during cardiac surgeries [155]. Since protamine has weak anticoagulant activity, due to an interaction with platelets and proteins including fibrinogen, protamine overdose can cause bleeding. This effect should be distinguished from the rebound anticoagulation that may occur 30 min to 18 h following the reversal of heparin with protamine [143].
Anti-inhibitor Coagulant Complex (Human)
Brand Name (USA): Feiba NF™
Description: Anti-inhibitor coagulant complex is a human plasma-derived factor product and contains nonactivated factors II, IX, and X and activated factor VII. Anti-inhibitor coagulant complex also contains factor VIII bypassing activity at approximately equal unitages to the other factors and 1–6 units of factor VIII coagulant antigen per milliliter. Anti-inhibitor coagulant complex shortens the activated partial thromboplastin time of plasma containing factor VIII inhibitor. Strengths are expressed in terms of factor VIII inhibitor bypassing activity, and one unit of activity is defined as the amount of anti-inhibitor coagulant complex that shortens the PTT of a high-titer factor VIII inhibitor reference plasma to 50 % of the blank value. The elimination half-life of anti-inhibitor coagulant complex is approximately 4–7 h. Anti-inhibitor coagulant complex is available as an intravenous powder for reconstitution [156].
Adult Use: Anti-inhibitor coagulant complex is utilized in adults for control and prevention of bleeding episodes in hemophilia patients with inhibitors [156] and moderate to severe bleeding in patients with acquired hemophilia [157, 158]. Anti-inhibitor coagulant complex is also used for perioperative management in hemophilia patients with inhibitors, life-threatening bleeding associated with dabigatran use [159–165], and life-threatening bleeding associated with rivaroxaban use [166]; reversal of warfarin-related bleeding [167]; and management of refractory bleeding in cardiac surgery [168].
Pediatric Use: Anti-inhibitor coagulant complex is utilized in pediatrics for control and prevention of bleeding episodes in hemophilia patients with inhibitors [156], prevention of bleeding episodes in factor X deficiency [169], and treatment of hemothorax in children with congenital coagulopathy [170].
Adverse Effects and Monitoring Parameters: Thrombotic and thromboembolic events can occur following anti-inhibitor coagulant complex use, especially with doses ≥ 100 units/kg (Table 34.16). Therefore, caution is advised in patients with atherosclerotic disease, crush injury, septicemia, or concomitant treatment with factor VIIa or antifibrinolytics due to increased risk of developing thrombotic events from circulating tissue factor or predisposing coagulopathy. Infection can also be transmitted since anti-inhibitor coagulant complex is derived from human plasma. Monitoring parameters include signs of symptoms of DIC, hemoglobin, and hematocrit. Of note, PTT and thromboelastography (TEG) should not be utilized to monitor response; DIC can occur when practitioners attempt to normalize these values with anti-inhibitor coagulant complex [156].
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Beaty, R.S. (2016). Hemostatic Agents Used to Stop Bleeding. In: Teruya, J. (eds) Management of Bleeding Patients. Springer, Cham. https://doi.org/10.1007/978-3-319-30726-8_34
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DOI: https://doi.org/10.1007/978-3-319-30726-8_34
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