Introduction and bleeding mechanisms
The hemostatic system limits hemorrhage when vascular integrity is compromised and includes several major components such as platelets, von Willebrand factor (VWF), coagulation and fibrinolytic factors and the blood vessel wall. A substantial percentage of patients undergoing cardiac surgical procedures are at risk for development of bleeding that may result in hemodynamic consequences necessitating volume/vasopressor resuscitation along with transfusion support. Accordingly, many studies have examined the role of interventions designed to optimize the management of this clinical problem (e.g. point-of-care diagnostics).
Excessive microvascular bleeding after cardiac surgery can result in re-exploration, which has been shown to be associated with a variety of negative outcomes such as a 3- to 4-fold increase in mortality, renal failure, sepsis, atrial arrhythmias, prolonged mechanical ventilation and longer length of stay . Moulton et al.  demonstrated that excessive bleeding is the most likely cause of increased mortality, as mortality was increased 3-fold when patients, who were not re-explored, bled more than 2 L within the first 24 h after surgery. Patients with excessive bleeding and who require transfusion support are predisposed to target organ injury, the result of one or more potential mechanisms. These may include ischemic injury as related to bleeding with hypotension/hypo-perfusion or anemia, microemboli or microthrombi [i.e. as related to cardiopulmonary bypass (CPB) or transfusion] or aggravation of ischemic injury by white-cell priming lipids within transfusion. This is supported by several recent studies that have demonstrated that transfusion of non-leuko-reduced units may potentially increase the incidence of multi-organ system failure (MOSF). Stroke, short-term or long-term mortality may be increased in cardiac surgical patients who receive transfusion .
Mechanisms for excessive bleeding after cardiac surgery
Although excessive bleeding during and after surgery may be related to isolated defects within the hemostatic system, excessive bleeding is probably more likely related to a series of events or ‘multiple hits’. The incidence of bleeding complications and/or the severity of a specific bleeding event can be related to the number of defects or ‘hits’ as well as the degree or severity of the individual or multiple defects. Potential defects that can influence the incidence and severity of bleeding after cardiac surgery include pre-existing inherited or preoperatively acquired (e.g. pharmacologic agents, other co-existing disorders that affect the hemostatic system) defects as well as those acquired defects that are secondary to the use of extracorporeal circulation. Hereditary deficiencies in either coagulation factors or platelets may lead to excessive bleeding, however, these are uncommon causes of bleeding after cardiac surgery relative to the incidence of acquired defects (Table 1) . Pre-existing preoperative disseminated intravascular coagulation (DIC), significant hepatic or renal impairment, or connective tissue disorders (e.g. Ehlers-Danlos syndrome) may also predispose patients to excessive bleeding after surgery.
|Source of hemostatic defect (S)||Prevalence/incidence|
|Platelet disorders (e.g. abnormal adhesion or aggregation receptors, storage defects)||One hundred and thirty cases described in the literature 0.4% of general population and 8% of pts with history of bleeding/abnormal screening tests|
|Severe bleeding (i.e. as related to adhesion or aggregation defects)||<1:1 000 000|
|Mild bleeding (storage pool defects, signal transduction defects)||Incidence unknown, less common than von Willebrand disease|
|Coagulation factor deficiency|
|Factor VIII||1:5000–10 000|
|Factor IX||1:30 000|
|Factor XI||1:1 000 000 or 1:50 (Ashkenazi Jewish births)|
|Factor VII||1:500 000|
|Factor V, X||1:1 000 000|
|Afibrinogenemia, Dysfibringenemia||1:1 000 000|
|Factor XIII||1:2 000 000|
|Factor II (prothrombin deficiency)||1:2 000 000|
|von Willebrand disease (75% Type 1)||1.5%– 1:10 000|
|Acquired with extracorporeal circulation|
|<50 000 μL−1||6%|
|<100 000 μL−1||60%|
|Qualitative platelet abnormalities|
|Reduced TRAP-mediated activation in PRP||10%|
|Reduced PAF-mediated activation in whole blood||33%|
|Coagulation factor deficiency (<20% activity)||30%|
|Hypofibrinogenemia (fibrinogen < 100 mg dL−1)||9%|
Patients undergoing cardiac surgery with CPB are at increased risk for microvascular bleeding secondary to acquired hemostatic system abnormalities as related to use of extracorporeal circulation which include: (i) Hemodilution secondary to volume resuscitation or loss (i.e. via bleeding or use of cell salvage) of platelets and coagulation factors; (ii) The type of solution used to replenish the intravascular space (e.g. Use of large doses of Hespan may lead to specific abnormalities in coagulation factors and platelet adhesion/function; (iii) The effects of hypothermia on both plasma coagulation factors and platelet function; (iv) Consumption or a ‘DIC-like’ state secondary to tissue injury, contact activation and most importantly, as related to transfusion of shed pericardial blood; (v) Excessive fibrinolysis as either a primary or more likely a secondary process (i.e. as related to thrombin-mediated activation); and (vi) Residual heparin or ‘heparin’ rebound .
Activation of both intrinsic and extrinsic pathways results in excessive thrombin generation and fibrinolytic activity which can lead to consumption of platelets and labile coagulation factors. The risk of excessive, non-surgical bleeding is influenced by the type of procedure , the duration of CPB  and other patient-related factors (age, gender, body surface area or BSA, co-existing disease, preoperative hematocrit etc.). These mechanisms ultimately can lead to multiple abnormalities involving either coagulation factors and/or platelets as summarized in Table 2. Although excessive bleeding after cardiac surgery can be related to reduced circulating levels of coagulation factors  and other abnormalities such as heparin rebound, hypothermia and/or acidosis , platelet-related abnormalities listed in Table 2 are considered the most important hemostatic abnormality in this setting.
|Disseminated intravascular coagulation (DIC)|
|Excessive fibrinolysis because of either primary or secondary fibrinolysis (i.e. as related to CPB-mediated DIC and/or reduced fibrinolysis inhibitors such as PAI1, α-2 antiplasmin)|
|Decreased or denatured coagulation factors|
|Prolonged bleeding time|
|Decreased platelet reactivity to one or more platelet agonists|
|Loss of platelet glycoprotein receptors|
|Fibrinogen (Gp IIb/IIIa)|
|von Willebrand Factor receptor (Gp Ib)|
|Platelet Degranulation (i.e. as demonstrated by release of BTG, PF4, ADP)|
|Changes in platelet signaling/adhesion molecule expression|
|Protamine-related platelet dysfunction|
Although the use of aspirin and non-steroidal anti-inflammatory agents can lead to bleeding in a subset of patients who display evidence of an exaggerated response to these agents (i.e. hyper-responders), the majority of patients do not bleed excessively because the majority of patients manifest a normal response to aspirin (i.e. mild platelet inhibition) . Similarly, although patients on preoperative warfarin may bleed after cardiac surgery, two studies have demonstrated an inverse relationship between postoperative International Normalized Ratio (INR) and blood loss, which may be secondary to warfarin-mediated hemostatic system-preservation during CPB. The introduction and use of lower molecular-weight heparin compounds, direct inhibitors of thrombin (e.g. hirudin, argatroban, bivalirudin, dermatan, Orgaran), and platelets (e.g. abciximab, eptifibatide, tirofiban and most importantly long-acting adenosine diphosphate (ADP) antagonists such as clopidogrel ) as well as fibrinolytic agents (e.g. recombinant tissue plasminogen activator) can potentially increase bleeding and complicate clinical management. The risk of bleeding related to these agents depends on their relative potency, pharmacodynamic half-life, time-interval from most recent dose before surgery, and whether or not a reversal agent is available. Although, the exact association between these agents and either the severity of bleeding or transfusion requirements in patients undergoing cardiac surgical procedures is evolving, several reports have demonstrated severe, intractable bleeding with use of either the direct thrombin inhibitors for anticoagulation with CPB or with preoperative use of clopidogrel .