Procoagulants

Heparin rebound can occur after initial reversal and is generally observed 2 to 3 hours after the first dose of protamine, when the patient is in the intensive care unit.²⁴ Heparin levels at this time may range from 0.1 to 0.3 IU/mL, equivalent to circulating levels of heparin, based on a 5 L blood volume, of 500 to 1,500 units. Protamine doses of 5 to 15 mg at this time may be effective at reversing heparin rebound rather than the dose of 50 mg commonly administered.²⁵ Studies have evaluated the ROTEM (Durham, NC) assay for determining the need for additional protamine administration and note that most patients do not need additional protamine administration within 30 minutes of initial administration. The ACT is not a sensitive indicator of low heparin concentrations because platelet counts and fibrinogen levels may also affect values.

Protamine can cause adverse reactions including anaphylaxis, acute pulmonary vasoconstriction and right ventricular failure, and hypotension.²⁰ Patients at an increased risk for adverse reactions are sensitized, often from exposure to neutral protamine Hagedorn (NPH), which contains insulin and protamine.²⁰ In a study of 1,551 cardiac surgery patients, the incidence of protamine reactions was 1/50 in insulin–dependent diabetics receiving NPH-insulin and 1/501 among other patients.²⁶ A subsequent prospective study found that reactions occurred in 0.6% (1/160) of patients with NPH-insulin–dependent diabetes.²⁷ Other individuals reported at risk for protamine reactions include patients with vasectomy, multiple drug allergies, and prior protamine exposure.²⁰ Despite the potential for anaphylaxis, there are no currently available alternatives to protamine.

Desmopressin

Desmopressin (DDAVP) is the V2 analog of arginine vasopressin that stimulates the release of ultra large von Willebrand factor (vWF) multimers from endothelial cells.²⁸ vWF mediates platelet adherence to vascular subendothelium by functioning as a protein bridge between glycoprotein Ib receptors on platelets and subendothelial vascular basement membrane proteins. DDAVP shortens the bleeding time of patients with mild forms of hemophilia A or von Willebrand’s disease (VWD).²⁹ The specific surgical patients that might benefit from use of DDAVP are not clear. DDAVP is administered intravenously at a dose of 0.3 mg/kg and should be given over 15 to 30 minutes to avoid hypotension.³⁰ Most studies have not confirmed the early reported efficacy during complex cardiac surgery. There have been 18 trials of DDAVP in 1,295 patients undergoing cardiac surgery that show a small effect on perioperative blood loss (median decrease, 115 mL).^31,32 Because critically ill patients are often receiving vasopressin, which also has V2- and V1-mediated effects, there may not be a benefit to adding DDAVP to these patients.

DDAVP is also used to treat VWD; there are multiple types of this deficiency and therapy for each type varies. DDAVP is most useful in in type 3 (typically considered mild); in severe forms of types 1 and 2 VWD, DDAVP is not effective and vWF concentrates are available.³³ VWD is the most frequent inherited bleeding disorder and is due to quantitative (types 1 and 3) or qualitative (type 2) defects of vWF.³³ DDAVP is the treatment for type 1 VWD. In type 3 and in severe forms of types 1 and 2 VWD, DDAVP is not effective and virally inactivated plasma vWF concentrates should be used in bleeding, surgery, and secondary long-term prophylaxis.³³

DDAVP should be administered by slow intravenous infusion to avoid hypotension because it stimulates endothelial cells releasing vasoactive mediators in addition to vWF.^34,35 Prior reports that DDAVP reduced blood loss and transfusion needs approximately 30% during complex cardiac surgery^36–38 have not been confirmed.^30,35 There have been 18 trials of DDAVP in 1,295 patients undergoing cardiac surgery that show a small effect on perioperative blood loss (median decrease, 115 mL). Although DDAVP may stimulate release of vWF, its effect is likely minimal compared to multiple other factors involved in hemostasis. Also, DDAVP may be associated with other adverse effects as myocardial infarction was twofold higher compared to placebo with no improvement in clinical outcomes.⁶ However, in another review evaluating 16 trials of DDAVP in cardiac surgery and in other high-risk operations, the rate of thrombosis did not differ significantly between patients who received DDAVP and patients who received placebo (3.4% vs. 2.7%).³⁹

Fibrinogen

Fibrinogen is a 340-kDa plasma glycoprotein synthesized in the liver and a critical component of effective clot formation.⁴⁰ It is the substrate of three important enzymes involved in clot formation: thrombin, factor (F) XIIIa, and plasmin as previously reviewed. The half-life is ~3.7 days (range, 3.00 to 4.08 days). For clot formation, thrombin cleaves the fibrinogen molecule, producing a soluble fibrin monomer which polymerizes to form a loose network in trapping red blood cells and a clot begins to form. Cross-linking of the fibrin polymers, induced by FXIIIa, is fundamental to the coagulation process, increasing the elasticity of the clot and its resistance to fibrinolysis. Fibrinogen also acts as the binding site (ligand) for glycoprotein IIb/IIIa receptors, found on the platelet surface, which are responsible for platelet aggregation. These platelets then become enmeshed within the fibrin strands, stabilizing the growing clot, and create the ability to cross-link and expand the clot and seal the bleeding site. During major hemorrhage, hemodilution after blood loss and subsequent volume replacement leads to reduced fibrinogen levels impairing fibrin polymerization and reduces clot stability. Thus, fibrinogen supplementation to restore plasma fibrinogen is key to normalizing clotting function.

Fibrinogen is an underrecognized coagulation factor that is critical for producing effective clot in surgical patients, and data supports hypofibrinogenemia as a predictor of perioperative bleeding.^41–43 Normal fibrinogen levels are 200 to 400 mg/dL, although during the third trimester of pregnancy, fibrinogen levels are elevated to greater than 400 mg/dL. While the optimal fibrinogen level needed in a bleeding patient is not known, bleeding increases for each 100 mg/dL decrease in fibrinogen level in parturients.⁴⁴ Low fibrinogen levels can predict bleeding after prolonged CPB.^45,46 Treatment of fibrinogen deficiency is important for survival, and the amount of fibrinogen administered to trauma patients has been positively correlated with reductions in mortality.⁴⁰

A major problem with managing bleeding is that many transfusion algorithms recommend therapy only when fibrinogen levels are less than 100 mg/dL. It is important to consider that such low levels of fibrinogen can increase laboratory measures of hemostasis including prothrombin time (PT) and partial thromboplastin time (PTT) that may not be corrected with transfusing fresh frozen plasma. In this situation, cryoprecipitate or fibrinogen concentrates are a better option to restore adequate plasma levels (~200 mg/dL) and need to be considered when treating life-threatening bleeding. Fibrinogen can be repleted by cryoprecipitate; 1 unit per 10 kg increases fibrinogen by 50 to 70 mg/dL. In Europe, fibrinogen concentrates are available and cryoprecipitate is not used. A fibrinogen concentrate (RiaSTAP [CSL Behring, King of Prussia, PA]) has just been granted licensing as an orphan drug for treating bleeding in patients with congenital afibrinogenemia or hypofibrinogenemia, but not for patients with dysfibrinogenemia.

Recombinant Coagulation Products

Recombinant proteins are becoming more readily available for managing bleeding, topical hemostasis and for other therapeutic interventions.^47,48 Recombinant proteins can also be modified to alter specific characteristics that may be important in therapeutic effects or provide quantities that can be administered supraphysiologically as a therapeutic agent.^47,48 Currently, they are used to manage bleeding in hemophilia, VWD, and in patients with acquired antibodies/inhibitors.⁴⁷

Recombinant Activated Factor VIIa

Recombinant activated factor VIIa (rFVIIa; NovoSeven [Novo Nordisk, Princeton, NJ]) is most widely known and approved for hemophilia patients with inhibitors to treat bleeding but is increasingly used off-label as a prohemostatic agent for life-threatening hemorrhage.⁴⁹ Recombinant factor VIIa produces a prohemostatic effect by multiple mechanisms that include complexing with tissue factor (TF) expressed at the site of vascular injury to locally produce thrombin and amplify hemostatic activation.⁵⁰ Circulating FVIIa accounts for approximately 1% of circulating FVII and has no effect until bound with TF.⁵⁰ An increasing number of publications report the off-label use of rFVIIa in cardiac surgical patients. The therapeutic dose of rFVIIa in nonhemophilia patients has not been established.⁵¹ However, guidelines as reported by Goodnough et al.⁵¹ and Despotis et al.⁵² for off-label use in patients with life-threatening hemorrhage are listed in Table 29-1.

Controlled clinical trials report the incidence of thrombotic complications among patients who received rFVIIa was relatively low and similar to that among patients who received placebo (Table 29-2).⁵³ However, most case reports giving rFVIIa as rescue therapy include patients who have impaired coagulation, have received multiple transfusions, and are at a high risk for adverse events. The complex role that transfusion therapy has in producing adverse outcomes is emerging in the scientific literature.^54–56 A report using the FDA MedWatch database noted thromboembolic events in patients with diseases other than hemophilia in whom rFVIIa was used on an off-label basis and included 54% of the events as arterial thrombosis (e.g., stroke or acute myocardial infarction).⁵⁷ Venous thromboembolism (mostly, venous thrombosis or pulmonary embolism) occurred in 56% of patients. In 72% of the 50 reported deaths, thromboembolism was considered the probable cause. It is not clear to what extent the clinical conditions requiring the use of rFVIIa may have contributed to the risk of thrombosis.³¹ Other major issues about rFVIIa include costs and dosing. This drug has also seen widespread use in treating battlefield injuries.