Las Vegas—When choosing the best treatment for trauma- or surgery-related bleeding, clinicians should know their pathophysiology and the pros and cons of each agent, according to a presentation at the American Society of Health-System Pharmacists 2012 Midyear Clinical Meeting.

“It amazes me how frequently I bring up the topic during rounds and find clinicians are unfamiliar with many of the causes, mechanisms and treatments for massive bleeding,” said presenter Rob MacLaren, PharmD, an associate professor at the University of Colorado School of Pharmacy, in Aurora.

The primary goal of treating trauma-related bleeding is to prevent the depletion of thrombin, Dr. MacLaren explained. “Trauma and shock lead to a release of large amounts of thrombin, which then binds to thrombomodulin, which is actually an anticoagulant,” he said. “On top of this, trauma patients often receive large volumes of resuscitative fluids that further dilute endogenous clotting factors and increase bleeding.”

Given this and other risks associated with large volumes of resuscitative fluids, Dr. MacLaren recommended administering 2 L of crystalloid fluids “as soon as you can” and observing the patient’s response. If their vital signs do not quickly return to normal, he recommended adding more crystalloid fluid and considering the patient for transfusion and surgery.

Before administering blood products or drugs, clinicians should ensure that other risk factors for mortality are under control. Most critically, minimize the risk for hypothermia, acidosis and dilution, he said. Because patients with this “lethal triad” have a 95% risk for death (Crit Care 2006;10:222), trying to control these should be a priority, Dr. MacLaren said.

Blood Products Are ‘Not Benign’

Once these risk factors are evaluated and, ideally, controlled, clinicians can consider transfusion of a blood product (Table 1). However, Dr. MacLaren said this decision should not be made lightly. “All blood products are associated with a risk of acute lung injury, infections and organ failure and are, therefore, not benign,” he said.

Table 1. Blood Products Used in Patients With Hemorrhage
Product Contents Indication(s) and Dose(s) Concernsa
Platelets Thrombocytes in plasma Bleeding: Platelet <50 × 109/L Prevention: Platelet <20; x; 109/L Stored at 20°-24°C Bacterial contamination ~1/2,000-1/3,000 units Worsens immune reactions
Fresh frozen plasma Coagulation factors and fibrinogen in variable amounts INR 1.5: 15 mL/kg (~30% factor replacement) Requires thawing Hypervolemia
Prothrombin complex concentrates (Bebulin, Baxter; Profilnine, Grifols) Factors II, VII, IX, X and prothrombin, proteins C, S, Z in variable amounts INR 1.5: 25-50 IU/kg (based on factor IX) Variable amounts of factors May contain heparin Numerous donors Costly
Cryoprecipitate Factors VIII, XIII, vWF, fibrinogen, fibronectin fibrinogen <100 mg/dL: 1 unit will ↑ fibrinogen ~5-10; mg/dL
vWF deficiency
Variable amounts of fibrinogen Costly
Cryosupernatant Not factor VIII, vWF, and minimal fibrinogen TTP Costly
INR, International normalized ratio; TRALI, transfusion-related acute lung injury; TRIM, transfusion-related immunomodulation; TTP, thrombotic thrombocytopenia purpura; vWF, von Willebrand factor
a All products are associated with thrombotic events, TRALI, TRIM, infection transmission and febrile reactions.
Based on Pharmacotherapy 2007;27(9 Pt 2):57s-68s and Pharmacotherapy 2007;27(9 Pt 2):69s-84s.

Bearing these complications in mind, each blood product has its advantages and limitations, Dr. MacLaren said. For example, cryoprecipitate increases fibrinogen levels but does not reduce a patient’s international normalized ratio (INR); platelets and red blood cells can worsen the immune response; and prothrombin complex concentrates and fresh frozen plasma (FFP) can lower INR levels but not below the goal of 1.5 prothrombin time. “Furthermore, large amounts of FFP may contribute to the development of encephalopathy and cerebral edema,” he noted.

Dr. MacLaren discussed the features of several of the newer pharmacologic agents that have joined the mainstays for treatment of hemorrhage (Table 2). “Recombinant factors VIIa [rFVIIa] and VIIIa [rFVIIIa] are appealing because they work downstream and cause a thrombin burst,” he explained. “Therefore, they are more specific to the site of injury, and they don’t involve all the systemic activity of clotting factors and platelets that the procoagulant blood products need.”

Table 2. Pharmacologic Agents Used in Patients With Hemorrhage
Product Contents/Mechanism of Action Indications and Dose Concerns
Local hemostatics Cellulose-based fibrin (human or bovine) ± fibrinolytic inhibitor ± aprotonin ± thrombin Thrombin (human or bovine) Zeolite causes exothermic reaction Chitason (chitin) activates platelets and electrophysiologic endothelial attraction of RBCs To control or prevent oozing of blood at surgical site: Dose depends on product May not adhere
Immune reaction,
infection transmission, aprotinin
Immune reaction
Heat-induced tissue damage
May not adhere
Vitamin K Cofactor for activation of factors II, VII, IX, K INR 1.5: 0.5-20 mg Slow-acting Variable SQ absorption IV requires slow administration
Recombinant factor VIIa (NovoSeven, NovoNordisk) Activates platelets to augment thrombin burst Refractory hemorrhage (surgery, trauma):
10-90 mcg/kg IV
Short-acting Thrombosis (<10%) Costly
Recombinant factor VIIIa (Advate, Baxter; Helixate FS, CSL Behring; Kogenate, Bayer; Recombinate, Baxter; ReFacto, Wyeth) Promotes fibrin crosslinking Extremely refractory hemorrhage (surgery, trauma):
10-40 units/kg IV
Short-acting Thrombosis Costly Requires refridgeration
Desmopressin Selective V2 agonist to release factor VIII, vWF, and tPA Platelet dysfunction: 0.3 mcg/kg IV Short-acting Tachyphylaxis and ↑  bleeding risk with repeat doses
Conjugated estrogen ↓ antithrombin and protein S,
↑ factors VII, VIII, IX, X, prothrombin
Platelet dysfunction: 25-50 mg IV Slow-acting Slow-offset
Inhibit plasminogen proteases and plasmin (aprotonin) and some anti-inflammation Prevention of surgical blood loss, refractory hemorrhage:
EACA: 150 mg/kg
(10,000 mg), then
15 mg/kg/h (2,000 mg/h)
TA: 10-30 mg/kg,
then 1-16 mg/kg/h (<400 mg/h)
Thrombosis, hypotension (TA)
EACA, ε-aminocaproic acid; INR, International normalized ratio; RBC, red blood cell; SQ, subcutaneous; TA, tranexamic acid; tPA, tissue plasminogen activator; vWF, von Willebrand factor
Based on N Engl J Med 2007;356(2):2301-2311, Pharmacotherapy 2007;27(9 Pt 2):93s-102s and Pharmacotherapy 2007;27(9Pt2):69s-84s.

Although rFVIIa reduces the use of blood products and lowers the risk for acute respiratory distress syndrome, possibly a result of the reduced use of blood products, Dr. MacLaren noted, it does not actually reduce the incidence of mortality (Ann Intern Med 2011;154:529-540). Similarly, in the cardiac surgery setting, rFVIIa does not reduce mortality rates but increases the rate of thromboembolic events. “This agent should only be used for refractory bleeding,” he said.

Among the antifibrinolytics, tranexamic acid (TA) is a promising agent, he said, and data indicate that it significantly reduces the risk for trauma-related death (Lancet 2010;376:23-32; Lancet 2011;377:1096-1100). However, to prevent one death, 120 patients need to be treated, Dr. MacLaren said. He noted that TA might have greater utility in the surgical setting, where it and ×-aminocaproic acid (EACA) can be used interchangeably to prevent and treat massive blood loss.

The myriad considerations involved in choosing a treatment for these types of bleeds make the task a tricky one, commented Asad Patanwala, PharmD, an assistant professor at the University of Arizona’s College of Pharmacy, in Tucson. However, he said advances in thromboelastography (TEG)—a method of testing clotting efficiency that is used primarily in the surgery setting—may yield better decision making. “TEG-directed therapy may allow for specific coagulation abnormalities to be targeted,” Dr. Patanwala told Pharmacy Practice News. “It could allow clinicians to tailor therapies, rather than using a one-size-fits-all approach, but better evidence is needed before it can be routinely used in settings such as trauma.”

Drs. MacLaren and Patanwala reported no relevant financial conflicts of interest.