Achieving optimal surgical hemostasis often requires a multidisciplinary approach. The goal of maintaining the balance between bleeding and clotting provides.

Strategies for Preventing and Treating Uncontrolled Perioperative Bleeding

Achieving optimal surgical hemostasis often requires a multidisciplinary approach. The goal of maintaining the balance between bleeding and clotting provides a clinical challenge when patients have preoperative risk for acquired coagulopathy.

Strategies for Preventing and Treating Uncontrolled Perioperative Bleeding
CE/CME Visiting Faculty Series Faculty includes renowned surgeons, anesthesiologists, blood banking specialists, and other experts in operative hemostasis and transfusion management Combination of didactic, specialty-specific case evaluations and your interactivity Part of a multicomponent educational initiative that can be accessed via This visiting faculty educational series is part of a comprehensive initiative focusing on operative hemostasis and transfusion medicine. For more CE/CME educational events and activities, please log on to

Learning Objectives Upon completion of this activity, participants should be better able to: Discuss specific patient types who may be at increased risk for perioperative bleeding and complications from acquired coagulopathy Explain the essentials of surgical hemostasis and current guidelines for achieving balance between bleeding and clotting Explain the benefits and risks of blood products as a therapeutic modality Explain the therapeutic benefits and risks of alternative hemostatic treatment modalities Explain how to initiate appropriate strategies for achieving optimal operative hemostasis

Bleeding Is a Complication of Many Types of Surgery
Surgery is the most common cause of major blood loss in a medical setting1 and can increase both morbidity and mortality2,3 Unexpected perioperative bleeding is largely caused by impaired inherited or drug-induced primary hemostasis4 In a medical setting, surgery is the most common cause of major blood loss, defined as a loss of 20% or more of total blood volume,1 and can increase both morbidity and mortality in certain procedures, such as open heart surgery.2 For example, D’Amico and associates reported that, in patients with liver disease, severe upper gastrointestinal bleeding is fatal in approximately 20% of cases.3 Unexpected bleeding in the perioperative period is largely caused by impaired inherited or drug-induced primary hemostasis.4 However, before we discuss uncontrolled bleeding, let’s quickly review hemostasis. References Mannucci PM, et al. N Engl J Med. 2007;56: Hall TS, et al. Ann Thorac Cardiovasc Surg. 2001;7: D’Amico G, et al. Hepatology. 2003;38: 4. Pfanner G, et al. Anaesthesist. 2007;56: 1. Mannucci PM, et al. N Engl J Med ;56: ; 2. Hall TS, et al. Ann Thorac Cardiovasc Surg. 2001;7: ; 3. D’Amico G, et al. Hepatology. 2003;38: ; 4. Pfanner G, et al. Anaesthesist. 2007;56:

Definition of Hemostasis
Hemostasis: “The Arrest of Bleeding” Stedman’s Medical Dictionary Bleeding to Death Clotting to Death Trauma Major Surgery Hemophilia Stroke MI Thrombosis Stedman’s Medical Dictionary defines hemostasis as “the arrest of bleeding.” However, it is arguably more than that. Lawson et al, for instance, report that, in surgery, hemostasis is about bleeding…but it’s also about clotting, timing, and balance. What do we mean by hemostasis and balance? On one side of the center point, patients can die of bleeding to death; this can be caused by trauma, major surgery and its complications, or from biochemical abnormalities such as hemophilia. But an equal and severe complication can be due to stroke, myocardial infarction, deep vein thrombosis, or pulmonary embolism that can occur in the postoperative period. The hemostatic response to injury—traumatic or surgical—is a complex series of regulatory events that requires the interaction of both cellular elements and blood plasma proteins.1 We will explore hemostasis and its management further after we review some basics of uncontrolled bleeding. Reference Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. Hemostasis: “Life in the Balance” Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.

Definition of Significant Bleeding
>2 L within the first 24 post-op hours1 Surgical or vascular component: corrected by surgical intervention or embolization2 Coagulopathic component: more difficult to control due to several interrelated mechanisms2 Consumption of coagulation factors and platelets Dilution of coagulation factors Metabolic disorders (eg, hypothermia, acidosis) The frequency of excessive bleeding is variable and can depend on the patient, type of procedure, and specific institutional protocols (such as those developed by Parkland Hospital, University of Southern California, and others). Our perspective also depends on the definition used. For instance, Despotis et al1 define excessive bleeding after cardiac surgery as bleeding that is greater than 2 L of blood loss within the first 24 postoperative hours. Investigators found excessive bleeding in 5% to 7% of patients. Such bleeding can result in reexploration and prolonged hospitalization.1 Vincent and colleagues2 report that massive hemorrhage is often characterized by a surgical or vascular component and a coagulopathic component. The former can be corrected by surgical intervention or embolization.2 Coagulopathic bleeding, however, is more difficult to control. Coagulopathy arises through several interrelated mechanisms, including the consumption of coagulation factors and platelets through repeated attempts to form clots during massive hemorrhage, the dilution of coagulation factors as a result of fluid resuscitation, and metabolic disorders (hyperthermia or acidosis), which can affect the coagulation process.2 References Despotis GJ, et al. Ann Thorac Surg. 2000;70(2 suppl):S20-S32. 2. Vincent J-L, et al. Crit Care. 2006;10:1-12. 1. Despotis GJ, et al. Ann Thorac Surg. 2000;70(2 suppl):S20-S32; Vincent J-L, et al. Crit Care. 2006;10:1-12.

Prevalence of Uncontrolled Bleeding
Surgical Discipline Uncontrolled Bleeding Rate Cardiovascular 5%-7% Post-op1 General 1.9% Laparoscopic cholecystectomy2 Obstetric 3.9% (vaginal); 6.4% (cesarean)3,4 Orthopedic 2%-6.3% Hip/knee arthroplasty5-7 Urologic 4%-8% TURP8; 3.3%-9.9% URL9 Trauma 30%-40%10,11 Bleeding is a major complication of surgery, and although overall mortality for both elective and urgent surgery is very low, at about 0.1%,1 subcategories of elective surgery may show much higher rates. Excessive bleeding (>2 L) after cardiac surgery is encountered in 5% to 7% of patients2 and necessitates reexploration in 3.6% of patients3,4 The most dangerous complication of laparoscopy is large-vessel damage and bleeding. The incidence is less than 0.1%,5 but most of the deaths related to laparoscopic cholecystectomy are from bleeding due to vessel damage. In the postoperative period, hidden bleeding due to vascular damage causes a decrease in hematocrit values, hematoma formation, and extreme pain. Uncontrolled bleeding occurs in 1.9% of laparoscopic cholecystectomy procedures5 Excessive blood loss may be difficult to define clinically, because the diagnosis is usually based on subjective observations. Postpartum hemorrhage has been defined as either a 10% change in hematocrit between admission and the postpartum period or a need for erythrocyte transfusion. Based on these definitions, vaginal delivery has been associated with a 3.9% incidence and cesarean delivery has been associated with a 6.4% incidence in postpartum hemorrhage6,7 Patients undergoing hip and knee arthroplasty often receive low-dose warfarin therapy, which is associated with a bleeding rate of 2% to 3%.8,9 Strebel and colleagues reported that the bleeding rate among patients on low-molecular-weight heparin (LMWH) in elective hip surgery ranged from 1.4% (preoperative group) to 6.3% (perioperative group) to 2.5% (postoperative group)10 Bleeding complications occur relatively frequently with the most commonly performed urologic procedures, especially in patients taking long-term anticoagulant therapy. For example, the rates of postoperative transfusion after TURP have been reported to range from 4% to 8%.11 Rosevear and colleagues retrospectively reviewed 911 upper retroperitoneal laparoscopic surgeries. Postoperative hemorrhage occurred in 3.3% of nephrectomy cases; 9.9% of partial nephrectomy cases, and 5.4% of adrenalectomy cases12 Traumatic injury is the leading cause of death worldwide among persons between 5 and 44 years of age13; uncontrolled bleeding contributes to 30%- 40% of trauma-related deaths and is the leading cause of potentially preventable early in-hospital deaths14 1. Despotis GJ, et al. Anesth Analg. 1996;82:13-21; 2. Erol DD, et al. The Internet Journal of Anesthesiology. 2005;9:2; Combs CA, et al. Obstet Gynecol. 1991;77:69-76; 4.Combs CA, et al. Obstet Gynecol. 1991;77:77-82; 5. Hull R, et al. N Engl J Med. 1993;329: ; 6. Leclerc JR, et al. Ann Intern Med. 1996;124: ; 7. Strebel N, et al. Arch Intern Med. 2002;162: ; 8. Daniels PR. Nat Clin Pract Urol. 2005;2: ; 9.Rosevear HM, et al. J Urol. 2006;176: ; 10. Holcomb JB. Crit Care. 2004;8(suppl 2):S57-S60; 11. Sauaia A, et al. J Trauma. 1995;38:

Prevalence of Uncontrolled Bleeding (cont)
Surgical Discipline Uncontrolled Bleeding Rate Cardiovascular 5%-7% Post-op1 General 1.9% Laparoscopic cholecystectomy2 Obstetric 3.9% (vaginal); 6.4% (cesarean)3,4 Orthopedic 2%-6.3% Hip/knee arthroplasty5-7 Urologic 4%-8% TURP8; 3.3%-9.9% URL9 Trauma 30%-40%10,11 References Shander A. Surgery. 2007;142(4 suppl):S20-S25. Despotis GJ, et al. Anesth Analg. 1996;82:13-21. 3. Dacey LJ, et al. Arch Surg. 1998;133: Moulton MJ, et al. J Thorac Cardiovasc Surg. 1996;111: Erol DD, et al. The Internet Journal of Anesthesiology. 2005;9:2. Combs CA, et al. Obstet Gynecol. 1991;77:69-76. Combs CA, et al. Obstet Gynecol. 1991;77:77-82. Hull R, et al. N Engl J Med. 1993;329: Leclerc JR, et al. Ann Intern Med. 1996;124: Strebel N, et al. Arch Intern Med. 2002;162: Daniels PR. Nat Clin Pract Urol. 2005;2: Rosevear HM, et al. J Urol. 2006;176: Holcomb JB. Crit Care. 2004;8(suppl 2):S57-S60. 14. Sauaia A, et al. J Trauma. 1995;38: 1. Despotis GJ, et al. Anesth Analg. 1996;82:13-21; 2. Erol DD, et al. The Internet Journal of Anesthesiology. 2005;9:2; Combs CA, et al. Obstet Gynecol. 1991;77:69-76; 4.Combs CA, et al. Obstet Gynecol. 1991;77:77-82; 5. Hull R, et al. N Engl J Med. 1993;329: ; 6. Leclerc JR, et al. Ann Intern Med. 1996;124: ; 7. Strebel N, et al. Arch Intern Med. 2002;162: ; 8. Daniels PR. Nat Clin Pract Urol. 2005;2: ; 9.Rosevear HM, et al. J Urol. 2006;176: ; 10. Holcomb JB. Crit Care. 2004;8(suppl 2):S57-S60; 11. Sauaia A, et al. J Trauma. 1995;38:

Reasons for Uncontrolled Bleeding
Patient-related Advanced age Small body size Pre-op anemia (low RBC volume) Antiplatelet or antithrombotic drugs Comorbidities: Congestive heart failure Hypertension Chronic obstructive pulmonary disease Peripheral vascular disease Diabetes mellitus Renal failure Procedure-related Prolonged operation CABG Emergency/trauma Surgical-site bleeding Surgical skill Certain factors may cause bleeding. Among these are patient-related factors, such as advanced age (older patients are at risk for bleeding and may require more transfusions); patients with small body size or preoperative anemia have a smaller red cell mass, platelet mass, and other issues that may contribute to bleeding or result from dilutional coagulation changes. Other important factors include use of antiplatelet or antithrombotic drugs; cardiovascular and metabolic comorbidities also may play a role. Furthermore, long surgical procedures, especially long cardiopulmonary bypass time, have a high correlation with bleeding. Emergency and trauma surgery, surgical-site bleeding, and the skill of the surgeon are additional factors that may contribute to perioperative bleeding. Reference Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86. RBC=red blood cell; CABG=coronary artery bypass graft. Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.

Types of Uncontrolled Bleeding
Surgical bleeding results from failure to control bleeding from the operative site; signs include expanding hematoma and saturated dressings (75%-90%)1,2 Nonsurgical bleeding is caused by failure of hemostatic pathways; often manifested as generalized oozing (10%-25%)1,2 Postoperative hemorrhage and thrombosis is a significant problem during the perioperative period. Understanding the complex and dynamic interplay of factors, proteins, and enzymes during coagulation is imperative to maintain balance between hemostasis and thrombosis.1 Most of this bleeding (75% to 90%, on average) is caused by the local surgical interruption or vessel interruption, and 10% to 25% is caused by acquired or congenital coagulopathy.2 References Adams GL, et al. Hematol Oncol Clin North Am. 2007;21:13-24. 2. Shander A. Surgery. 2007;142(4 suppl):S20-S25. 1. Adams GL, et al. Hematol Oncol Clin North Am. 2007;21:13-24; 2. Shander A. Surgery. 2007;142(4 suppl):S20-S25.

Costs of Uncontrolled Bleeding
Estimating blood costs is a complex undertaking1,2 Blood costs increase due to shrinking donor availability and precautions to minimize transfusion risks1 Great variation among institutions in reoperation and return-to-operating-room rates2 Total cost per unit is >$4002 “Clinical costs” of sustained bleeding3: Consumption of coagulation factors Hemodilution, hypothermia, and acidosis Compound factor consumption More bleeding Sophisticated knowledge about transfusion medicine is key to understanding and assessing the true costs of blood transfusion and blood products. Clinical and administrative healthcare sectors worldwide are realizing the impact of these costs. Improved outcomes depend on optimization of blood usage and better control of expenditures to direct resources toward other diagnostic, therapeutic, and technologic initiatives.1 There is much variation among institutions relating to reoperation or return-to-operating-room rates. These are not only costly but are associated with a tremendous use of clinical and staff resources. In addition, patients who need reoperation or return to the OR have an increased risk of major blood loss—a key indicator of mortality.2 Sustained bleeding carries hidden costs as well. These include consumption of coagulation factors; hemodilution, hypothermia and acidosis, consumption of various coagulation factors, and further bleeding.3 References Shander A, et al. Best Pract Res Clin Anaesthesiol. 2007;21: Shander A. Surgery. 2007;142(4 suppl):S20-S25. 3. Armand R, et al. Transfus Med Rev. 2003;17: 1. Shander A, et al. Best Pract Res Clin Anaesthesiol. 2007;21: ; 2. Shander A. Surgery. 2007;142:S20-S25; 3. Armand R, et al. Transfus Med Rev. 2003;17:

Outcomes of Uncontrolled Bleeding
Clinical Massive blood loss is associated with mortality Transfusion itself may have independent detrimental effects Financial Death Average LOS is 2X to 2.5X Cost of blood Costs of transfusion Costs of adverse outcomes Shander1 reports that massive blood loss is associated with mortality, which is not only intuitive but demonstrable in large observational studies.2,3 Many researchers have begun to ask whether transfusion itself in these massively bleeding patients may have independent detrimental effects.4 Several financial implications of transfusions exist. Death, of course, imposes its own costs, but length of hospital stay, on average, is 2 to 2.5 times longer in those who require transfusions, along with the associated increase in use of resources. The cost of 1 unit of blood essentially has quadrupled over the past 20 years, initially because of the step-wise addition of increasing numbers of more sophisticated tests for transfusion-transmitted infections and, most recently, with the move toward universal leukoreduction, resulting in a 30% jump in price. This increase is before the costs of transfusion are added, even without any adverse effects. When the costs of adverse outcomes, including litigation and lost income, and the cost of organizing and maintaining a national blood system are added, one begins to approach a true notion of the actual costs of transfusion.1 References Shander A. Surgery. 2007;142(4 suppl):S20-S25. Karkouti K, et al. Transfusion. 2004;44: Como JJ, et al. Transfusion. 2004;44: 4. Moore FA, et al. Arch Surg. 1997;132: LOS=length of stay. Adapted from Shander A. Surgery. 2007;142(4 suppl):S20-S25.

Can We Predict Who Will Bleed?
There Is a Difference Between Who Is At Risk and Who Will Bleed Surgery Post-op Recovery Thrombosis Clotting Bleeding Hemorrhage In surgery, we still don’t know who is likely to bleed or clot too much. We often aren’t sure how to optimize the physiology of the patient. Often we’re not sure which topical hemostatic agents are effective, and when it comes to systemic biologic therapies, we’re still not sure when to give, how much to give, and how not to overshoot or give too much of a potent procoagulant drug in the setting of the inflammatory state of surgery. Thus, the challenge of providing effective hemostasis in surgery is to be able to recognize the unique situation of each patient undergoing hematologic stress and to maintain his or her physiology between the delicate balance of bleeding or clotting to death. The problem of perioperative hemorrhage or thrombosis is exacerbated by the fact that a given patient may swing from one extreme to the other during the course of the operative and postoperative period. Reference Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. Who is likely to bleed or clot too much? How do we optimize the patient’s physiology? Which topical agents are effective? Which biologic agents are effective? Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.

Who Bleeds Without Warning?
STS Guidelines: Aspirin…the Dilemma Aspirin causes increased bleeding Amount of bleeding is small (0.5-1 U/patient) Aspirin important for better outcome in acute coronary syndromes Nothing more important than aspirin, including heparin, thrombolytics, IIb/IIIa, and PCI STS recommendation: Stop aspirin for a few days in very-low- risk patients; continue in all others If you discuss intraoperative bleeding with the patient’s cardiologist and suggest that aspirin causes bleeding during operation, the cardiologist would tell you that there is no more important intervention that he or she can provide for patients with acute coronary syndromes than to give an aspirin tablet, and this includes such agents as heparin, thrombolytics, clopidogrel, and glycoprotein 2b/3a inhibitors. Treatment guidelines1 recommended stopping aspirin for a few days before operation only in totally elective patients – such as the kind of patient we never see anymore – probably much less than 20% of the total population who present for operation. Everyone else should have aspirin continued throughout the entire operative period.1 Reference Ferraris VA, et al. Ann Thorac Surg. 2005;79: STS=Society of Thoracic Surgeons; PCI=percutaneous coronary intervention. Ferraris VA, et al. Ann Thorac Surg. 2005;79:

Who Bleeds Without Warning? (cont)
Do Thienopyridines Cause Post-op Bleeding? Evidence is more compelling than for aspirin1 11 studies with clopidogrel and CABG1 All studies show increased bleeding when clopidogrel given within 5 days of CABGsome with increased mortality1 AHA/ACC and STS guidelines recommend stopping clopidogrel for 5 days before operation, if possible2 What about clopidogrel? Well, here the facts are much more compelling, but with much less evidence. We found 11 studies that addressed the question of whether clopidogrel, given within 5 to 7 days before CABG, causes increased bleeding and blood transfusion. Every study showed increased bleeding associated with clopidogrel. Importantly, 2 of the studies showed increased mortality associated with clopidogrel. Unfortunately none of these studies were randomized controlled trials. But this information was enough to cause the AHA and the STS to recommend discontinuation of clopidogrel 5 to 7 days before operation.1,2 References Ferraris VA, et al. Ann Thorac Surg. 2005;79: 2. Braunwald E, et al. J Am Coll Cardiol. 2002;40: AHA=American Heart Association; ACC=American College of Cardiology. 1. Ferraris VA, et al. Ann Thorac Surg. 2005;79: ; 2. Braunwald E, et al. J Am Coll Cardiol. 2002;40:

“Cascade” Model of Hemostasis
Intrinsic Pathway Extrinsic Pathway factor XII HMK PK factor XI factor XIa factor IXa factor VIIIa PL, Ca+2 factor VIIa tissue factor PL, Ca+2 factor IX factor Xa factor Va PL, Ca+2 factor X factor X Now, let’s look at the “traditional” model of hemostasis. Many clinicians learned about the “cascade” or “waterfall” model of hemostasis while in training, and it has been refined to the scheme that is shown here. Hoffman and Monroe1 report that the cascade model accurately represents the overall structure of the coagulation process as a series of proteolytic reactions. Each protease cleaves and activates the subsequent protease in the series. This model also includes the recognition that anionic phosopholipid, especially phosphatidylserine, is required for the assembly and optimal function of most of the coagulation complexes. This information is absolutely critical to understanding the coagulation reactions. However, the viewpoint that is implicit in this concept of coagulation is that the role of cells, especially platelets, is primarily to provide anionic phospholipid for coagulation complex assembly. In this model of coagulation, the “intrinsic” and “extrinsic” pathways are reflected in the clinical laboratory tests aPTT and PT, respectively.1 Reference Hoffman M, et al. Thromb Haemost. 2001;85: prothrombin thrombin fibrinogen fibrin Adapted from Hoffman M, et al. Thromb Haemost .2001;85:

Normal Hemostasis: Pivotal Role of TF/VIIa
X VIII/vWF TF VIIa Xa Va IIa TF-Bearing Cell VIIIa TF VIIa V Va IX Platelet II IXa X Xa IIa Hoffman and colleagues have developed a cell-based model of hemostasis that is represented in this complex slide. This slide represents a schematic model of normal hemostasis, which requires activation of both factor (F)X and FIX. FVIIa/tissue factor (TF)-activated FXa and FIXa play distinct roles in coagulation. FXa cannot move to the platelet surface because of the presence of normal plasma inhibitors, but instead remains on the TF-bearing cell and activates a small amount of thrombin. This thrombin is not sufficient for fibrinogen cleavage but is critical for hemostasis, since it can activate platelets, activate and release FVIII from von Willebrand factor (vWF), activate platelet and plasma FV, and activate FIX. FIXa moves to the platelet surface, where it forms a complex with FVIIIa and activates FX on the platelet surface. This platelet-surface FXa is relatively protected from normal plasma inhibitors and can complex with platelet-surface FVa, where it activates thrombin in quantities sufficient to provide for fibrinogen cleavage.1 Fortunately, clinicians do not need to have a comprehensive understanding of the myriad pathways and components of the hemostatic system in order to effectively manage patients with either normal or abnormal hemostasis during the perioperative period.2 The next slide is much simpler to understand and more clinically practical. References Hoffman M, et al. Blood Coag Fibrinol. 1998;9(suppl 1):S61-S65. 2. Karkouti K, et al. Can J Anaesth. 2006;53: IXa VIIIa Va Activated Platelet VIIa IXa Va VIIIa Xa IIa IX II X TF=tissue factor; vWF=von Willebrand factor. Hoffman M, et al. Blood Coag Fibrinol. 1998;9(suppl 1):S61-S65. 18

Normal Hemostasis Is a Balance
Bleeding to Death Clotting to Death Trauma Major Surgery Hemophilia Stroke MI Thrombosis Blood coagulation Anticoagulation Fibrinolysis Antifibrinolysis Vascular tone and blood flow Endothelial cells and platelets Let’s return to Lawson’s “balance” concept.1 With regard to hemostasis in surgery, one has to have a basic understanding of blood coagulation, as well as mechanisms of anticoagulation, fibrinolysis, antifibrinolysis, vascular tone and blood flow, and endothelial cells and platelets. Karkouti and Dattilo state that normal hemostasis involves a fine and complex balance between numerous anticoagulant and procoagulant components, the details of which are still not fully understood.2 From this interpretation, one can see that normal hemostasis consists of complicated biologic pathways that must be considered in managing patients. However, more than this, it is really about “keeping on center.” References Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. 2. Karkouti K, et al. Can J Anaesth. 2006;53: Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.

“Keeping On Center” Procoagulant Activity Antifibrinolytic Activity
Normal Hemostasis Bleeding Clotting Lawson and colleagues refer to this “balance” as the basic paradigm of keeping patients on center, letting neither of the procoagulant or anticoagulant, fibrinolytic or antifibrinolytic pathways push a patient off this critical and safe area called normal hemostasis. Therefore, in surgery, it is important to keep patients as close as possible to the center of this balance. Reference Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64. Fibrinolytic Activity Anticoagulant Activity Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

“Keeping On Center” (cont)
Factor V falls IIase increase Procoagulant Activity Antifibrinolytic Activity TF increase Normal Hemostasis PAI-1 increase Bleeding Clotting According to Lawson et al, one of the challenges in hemostasis is to define what the normal or center area really is. The key is to find a way to keep patients in the center or close to it. Reference Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64. Fibrinolytic Activity Anticoagulant Activity Inflammatory Cytokines Heparin falls t-PA increase t-PA=tissue-type plasminogen activator; PAI-1=plasminogen activator inhibitor-1. Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

“Keeping On Center” (cont)
Topical Hemostatics Purified Factors, FFP, Cryo, PLTs Aminocaproic acid, Tranexamic acid, Aprotinin Procoagulant Activity Antifibrinolytic Activity Normal Hemostasis Bleeding Clotting What are some of the tools that enable clinicians to keep patients on center? Procoagulants: Topical hemostatics, a host of purified factors, such as factor VII, factor VIII, and factor IX; fresh frozen plasma and cryoprecipitate; and systemic delivery of platelets. Antifibrinolytics: Aminocaproic acid, tranexamic acid, and aprotinin (marketing suspended 11/5/07). Fibrinolytics: Tissue-type plasminogen activator, streptokinase, and urinary-type plasminogen activator. Anticoagulants: Heparin, low-molecular-weight-heparin, warfarin, and argatroban. Other anticoagulants are currently in development. Fibrinolytic Activity Anticoagulant Activity t-PA, SK, UPA Heparin, Warfarin LMWH, Argatroban FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase; UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin. Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

Achieving Optimal Operative Hemostasis
Thrombosis Clotting Physiology and Good Surgery According to Lawson and colleagues, avoiding misadventures in hemostasis and thrombosis starts with good physiology and good surgery. When small problems arise, there is a long list of topical hemostatic agents that are available and very likely effective. When systemic bleeding is encountered, there is a use and a role now for systemic biologic therapies, which can help avoid a severe and hemorrhagic outcome. Let’s look now at treatment modalities. Reference Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64. Bleeding Hemorrhage Topical Hemostatic Agents Systemic Biologic Therapies Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

Treatment Modalities: Blood Products Prohemostatic Agents

Blood Products in the Treatment of Hemorrhage
Transfusion Benefits, Risks, and Trends

Postoperative Blood Transfusion
Benefits: Blood volume replacement Oxygen-carrying Clotting factors Risks: TACO TRALI Disease transmission (especially platelets) TRIM Transfusion errors Evidence: Not enough data about benefits TACO=transfusion-associated circulatory overload; TRALI=transfusion-related acute lung injury; TRIM=transfusion-related immunomodulation. Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.

Benefits of Blood Transfusion
Useful in certain situations−ASA criteria Transfuse patients on CPB with Hb ≤6 g/dL Transfusion justified when Hb ≤7 g/dL in patients older than 65 years and patients with chronic CVD or respiratory disease Benefit unclear for stable patients with Hb between 7 and 10 g/dL Transfusion recommended for patients with acute blood loss >1500 mL or >30% of blood volume Evidence of rapid blood loss without immediate control warrants transfusion Issue of “triggers”—have come a long way since “10/30” rule, but still a long way to go ASA=American Society of Anesthesiologists; CPB=cardiopulmonary bypass; Hb=hemoglobin; CVD=cardiovascular disease. Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.

Risks of Blood Transfusion
TACO Common reaction from rapid or massive transfusion of blood1 Usually occurs within several hours after start of transfusion Manifested in signs and symptoms that include: Dyspnea Orthopnea Peripheral edema Rapid increase in BP Incidence difficult to determine due to underreporting2 Patients at risk include3,4: Infants and elderly >60/years Those with chronic anemia Those with cardiac/pulmonary/renal failure Transfusion-associated circulatory overload, or TACO, is a common reaction resulting from a rapid or massive transfusion of blood.1 It usually occurs within several hours after the start of a transfusion and is manifested in signs and symptoms that include dyspnea, orthopnea, peripheral edema, and rapid increase of blood pressure. The incidence of TACO is difficult to determine because of underreporting. It has been estimated that TACO occurs approximately 1 in 100 to 1 in 10,000 transfusions.2 Certain groups of patients are at increased risk for TACO, including infants; elderly patients older than 60 years; patients with cardiac, pulmonary, or renal failure; and patients with chronic anemia.1,3 TACO can effectively be prevented through identification of patients who may be at risk for the condition and administration of small volumes of required blood components at a well-controlled rate.3 References Popovsky MA. Transfus Clin Biol. 2001;8: American Association of Blood Banks. Technical Manual. 1999: Gresens CJ, et al. In: Linden JV, Bianco C, eds. Blood Safety and Surveillance. New York, NY: Marcel Dekker, Inc; 2001:71-86. 1. Popovsky MA. Transfusion Clin Biol. 2001; 8: ; 2. American Association of Blood Banks. Technical Manual. 1999: ; 3. Gresens CJ, et al. New York, NY: Marcel Dekker, Inc; 2001:71-86; 4. Popovsky MA. Transfus Clin Biol. 2001;8:

Risks of Blood Transfusion (cont)
TRALI Rare and life-threatening complication Associated with transfusion of blood components containing RBCs, platelets, granulocytes, and cryoprecipitates1 Usually occurs within 1-2 hours after start of transfusion2 Characterized by acute respiratory distress2 Symptoms include2: Severe bilateral pulmonary edema Cyanosis Severe hypoxemia Tachycardia Hypotension Fever Incidence varies considerably from 1/5000 to 16/10,0001 Fatality rate ranges from 5% to 14%2 Transfusion-related acute lung injury, or TRALI, is a rare and life-threatening complication associated with transfusion of blood components containing plasma, such as red cells, platelets, granulocytes, and cryoprecipitates.1 TRALI usually occurs within 1 to 2 hours after the start of a transfusion and is characterized by acute respiratory distress. The symptoms of TRALI include severe bilateral pulmonary edema, cyanosis, severe hypoxemia, tachycardia, hypotension, and fever.2 TRALI is more common than we think. Incidence rates vary considerably among different studies, with a range of 1 in 5000 to 1 in 10,000 units transfused, or 4 to 16 per 10,000 recipients.1 However, it has been reported to be the third leading cause of death associated with transfusion, with a case fatality rate ranging from 5% to 14%.2 The precise mechanism of TRALI is unknown, but increasing evidence has indicated that it is an immune- mediated event initiated by pathologic antibodies from donors.1,2 The presence of human leukocyte antigen (HLA)-specific antibodies in the plasma of donors has been strongly associated with the occurrence of TRALI.1 References Kopko PM, et al. Transfusion. 2001;41: 2. Popovsky MA. Transfus Clin Biol. 2001;8: 1. Kopko PM, et al. Transfusion. 2001;41: ; 2. Popovsky MA. Transfus Clin Biol. 2001;8:

Risks of Blood Transfusion (cont)
Type Occurrence in RBC Units Transfused Infectious: Human immunodeficiency virus Hepatitis B Hepatitis C Bacterial infection 1 in x 106 1 in 58, ,000 1 in 872, x106 1 in 2,000 Immunologic Reactions: Febrile nonhemolytic transfusion reactions Anaphylactic transfusion reactions ABO mismatch Hemolysis Death Leukocyte-related target organ injury Transfusion-related acute lung injury Post-transfusion purpura 1 in 100 1 in 20,000-50,000 1 in 60,000 1 in 600,000 1 in 20 to 1 in 50 Rare Transfusion Services Error: Donor screening error (malaria, T cruzi, babesioses, Creutzfeld-Jakob disease) Transfusion services error (other) 1 in 4 x 106 1 in 14,000 As early as 1943, it was recognized that blood transfusion could spread diseases, especially hepatitis. Since that time, other problems, such as the risks associated with paid donors and concerns about disease transmission, have raised awareness of the problems associated with blood transfusion. Reference Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86. Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83 S27-S86.

How to Reduce Transfusions?
Blood conservation: general principles Devise an individual plan of care to minimize blood loss Employ multidisciplinary, multimodal treatment approach The lead clinician should provide proactive management Modify routine practices if necessary Screen for, investigate, and treat anemia before and after surgery Minimize iatrogenic blood loss, including phlebotomies Employ a restrictive transfusion strategy Reassess preoperative/postoperative use of anticoagulant and antiplatelet agents Consult transfusion experts early Establish in advance a management plan for rapid control of hemorrhage and transfusion Clinical experience with patients who refuse blood transfusions for religious reasons has provided valuable lessons and raises intriguing questions about the necessity of routine blood transfusions. Healthcare centers with bloodless medicine and surgery programs feature a novel concept of patient care aimed at improving outcomes. A one-tiered approach to minimize blood usage for all patients, regardless of religious beliefs, is successfully being adopted at an increasing number of institutions. Since most single blood conservation techniques reduce blood usage by just 1 to units, a series of integrated preoperative, intraoperative, and postoperative conservation approaches is required. These include preoperative autologous donation, erythropoietic support, acute normovolemic hemodilution, individualized assessment of anemia tolerance, implementation of conservative transfusion thresholds, meticulous surgical techniques, and judicious use of phlebotomy and pharmacologic agents for limiting blood loss. Bullets 2, 3, and 6 depict steps that should be taken immediately. Reference Shander A, et al. Curr Opin Hematol. 2006;13: Shander A, et al. Curr Opin Hematol. 2006;13:

Pharmacologic Agents in Treatment of Hemorrhage
Prohemostatic Agents Antifibrinolytics Lysine analogues Aprotinin Topical hemostatics Protamine Desmopressin (DDAVP) Recombinant factor VIIa (rVIIa)

Antifibrinolytics A Brief Review

Prothrombinase complex
Fibrinolysis Summary of the coagulation and fibrinolysis cascades a The coagulation cascade b Plasmin-mediated fibrinolysis FX Prothrombin + Tissue factor FVIIa FXa FVa + Prothrombinase complex Plasminogen tPA Thrombin + aggregated platelets – + PAI-1 Fibrinogen Fibrin Plasmin The coagulation and fibrinolysis cascades may be summarized as follows: The coagulation cascade, which favours clot formation, is initiated in vivo by tissue factor and factor VIIa (FVIIa) and leads to the conversion of prothrombin to thrombin by the prothrombinase complex (FXa and FVa). Subsequent cleavage of fibrinogen by thrombin, along with the aggregation of platelets, can result in formation of a thrombus. The fibrin clot is further stabilized by FXIII, which is also activated by thrombin, and the clotting process is magnified by other positive-feedback loops (not shown). Plasmin-mediated fibrinolysis, resulting in fibrin degradation products and clot lysis, occurs following the conversion of plasminogen to plasmin by tissue-type plasminogen activator (t-PA). Plasminogen activator inhibtor 1 (PAI-1) rapidly inhibits t-PA. a-2-Antiplasmin (a-2-AP) inactivates plasmin by forming a 1:1 inhibitory complex with circulating plasmin.Thrombin-activatable fibrinolysis inhibitor (TAFI) cleaves the C-terminal lysine residues of fibrin, preventing the co-activation of plasminogen by fibrin. Thrombus – α-2-AP TAFI + Fibrin degradation products Every rise is followed by a fall. Expert Reviews in Molecular Medicine © 2002 Cambridge University Press 34

Thrombin Thrombomodulin
Fibrinolysis (cont) Coagulation Cascade Fibrinolytic Cascade Prothrombin Plasminogen – – APC TAFIa Thrombin Plasmin PC TAFI Thrombin Thrombomodulin The coagulation cascade ultimately generates thrombin, which catalyzes the conversion of fibrinogen to the fibrin clot. The fibrinolytic cascade generates plasmin, which catalyzes solubilization of the fibrin. The thrombin-thrombomodulin complex promotes downregulation of thrombin formation by generating activated protein C (APC). It also suppresses fibrinolysis by forming TAFIa. The 2 cascades are thereby linked through the thrombin, thrombomodulin, and TAFI pathway. Reference Nesheim M. Chest. 2003;124(3 suppl):33S-39S. Fibrinogen Fibrin FDPs There is a balance between formation and degradation of fibrin. From Nesheim M. Chest. 2003;124(3 suppl):33S-39S.

Antifibrinolytic Agents
Fibrinolysis (cont) Coagulation Cascade Fibrinolytic Cascade Prothrombin Plasminogen – – APC TAFIa Thrombin Plasmin PC TAFI Thrombin Thrombomodulin Fibrinogen Fibrin FDP’s Antifibrinolytic Agents Tip the balance against fibrinolysis  More clot  Less bleeding Adapted from Nesheim M. Chest. 2003;124:33S-39S.

Antifibrinolytics As implied by the name, these agents enhance hemostasis when fibrinolysis contributes to bleeding Lysine analogues ε-Aminocaproic acid (EACA) Tranexamic acid (TXA) Aprotinin: Approved by FDA to reduce blood loss and transfusion in CABG but marketing suspended 11/5/07

Lysine Analogues Block the lysine- binding sites on plasminogen, inhibiting the formation of plasmin TXA is 6-10 times more potent than EACA This slide illustrates the mode of action of lysine analogues. Activation of plasminogen by endogenous plasminogen activators results in plasmin, which causes degradation of fibrin. Binding of plasminogen to fibrin makes this process more efficient and occurs through lysine residues in fibrin that bind to lysine-binding sites on plasminogen (Panel A). In the presence of lysine analogues, these lysine-binding sites are occupied, resulting in an inhibition of fibrin binding to plasminogen and impairment of endogenous fibrinolysis (Panel B). Reference Mannucci PM, et al. N Engl J Med. 2007;356: Mannucci PM, et al. N Engl J Med. 2007;356:

Lysine Analogues (cont)
Lysine analogues1-3: EACA and TXA Indicated for enhancing hemostasis when fibrinolysis contributes to bleeding Both competitively inhibit plasmin binding to fibrin Widely used in cardiac surgery, but data supporting safety and efficacy are limited EACA associated with increased incidence of certain neurologic deficits; concerns about rhabdomyolysis and renal dysfunction Lysine analogues such as aminocaproic acid and tranexamic acid are indicated to enhance hemostasis when fibrinolysis contributes to bleeding. Both lysine analogues attenuate fibrinolysis by inhibiting lysis of plasminogen to plasmin and, to a lesser degree, by directly inhibiting plasmin activity.1 Although the cost of lysine analogues is low, clinical efficacy and safety data in cardiac patients are limited. Effects on bleeding, transfusion rates during cardiac surgery, and graft closures have not been reported in the package inserts, and published studies in adult cardiac patients are often small and of varying designs.1 Aminocaproic acid also has been associated with an increased incidence of certain neurologic deficits, and concerns about rhabdomyolysis and renal dysfunction have been raised.1 Although Mangano et al2 report that aminocaproic acid and tranexamic acid appear to be relatively safe, the numbers of trial and study participants were much smaller for these drugs than for aprotinin. Thus confidence with regard to safety issues is not solid, especially with respect to thrombosis.3 References Levy JH. Am J Health-Syst Pharm. 2005;62(suppl 4):S15-S19. Mangano DT, et al. N Engl J Med. 2006;354: 3. Mannucci PM, et al. N Engl J Med. 2007;356: 1. Mannucci PM, et al. N Engl J Med 2007;356: ; 2. Levy JH. Am J Health-Syst Pharm. 2005;62(suppl 4):S15-S19; 3. Adams GL, et al. Hematol Oncol Clin North Am. 2007;21:13-24.

Aprotinin A small protein isolated from bovine lung
A non-specific serine protease inhibitor  inhibits trypsin, plasmin, plasma/tissue kallikrein, etc Inhibits contact phase activation of coagulation that both initiates coagulation and promotes fibrinolysis In CPB, it reduces derangements in coagulation/fibrinolysis caused by negatively charged surface of CPB circuit Indirectly preserves platelet function in extracorporeal circulation Marketing suspended on 11/5/07 following FDA Advisory 2/8/06 The negatively charged surface of the CPB circuit activates factor XII, converting prekallikrein to kallikrein, which further activates factor XII.This positive feedback loop acts to intensify the intrinsic coagulation cascade. By inhibiting plasma kallikrein, aprotinin minimizes derangements in coagulation and fibrinolysis. There is also evidence that aprotinin exerts an indirect preservative effect on platelet function during extracorporeal circulation.

Topical Hemostatic Agents
Used to augment hemostasis in surgery/trauma Available in a variety of forms (solutions, gels, granules, sprays) and used in conjunction with collagen, gelatin, cellulose matrices Local thrombin and fibrinogen levels determine the rate of clot formation at wound site Many of these topical agents have thrombin or fibrinogen as their active agent Classification: Tissue/fibrin sealants (contain thrombin, fibrin, etc) Absorbable hemostatic agents (contain matrices) Combination products (contain both groups above)

Some Topical Hemostatic Agents
Sealants and Combination Products: Agent Topical Application Instructions Major Drawbacks or Comments Bovine thrombin Dry, spray, or mixed with isotonic saline applied to bleeding or oozing surfaces; may also be used with absorbable gelatin sponge or with FloSeal NT Prion disease transmission; autoantibodies may develop to impurities, potentially resulting in coagulopathy Recombinant human thrombin To be released 2008; presumably will be similar to bovine thrombin Potentially less immunogenic than bovine thrombin FloSeal Hemostatic Matrix: bovine gelatin granules and human thrombin Reconstituted mixture is applied to bleeding or oozing surfaces Infectious disease transmission similar to that with other human blood products; bovine sensitization Virally inactivated aprotinin-free fibrin sealant (Crosseal): thrombin and fibrinogen (human) Stored frozen, then thawed and sprayed Contains no animal protein and is virally inactivated and highly purified; safety concerns minimized Voils S. Pharmacotherapy. 2007;27:69S-84S.

Some Topical Hemostatic Agents (cont)
Topical Application Instructions Major Drawbacks or Comments CoStasis: microfibrillar collagen-fibrin (bovine) Reconstituted mixture forms gel matrix Similar to other bovine preparations CoSeal Surgical Sealant: 2 synthetic polyethylene glycols Reconstituted mixture forms a hydrogel that is applied to bleeding or oozing surfaces; forms mechanical seal Swells up to 4x its volume; may cause compression of anatomic structures Aprotinin and TXA Solutions containing 1 MU of aprotinin or 2.5 g of TXA in mL of saline poured into pericardial cavity during CPB Single study with minimal effectiveness of aprotinin; TXA was less effective in reducing blood product usage Chitosan hemostatic bandage Bandage that binds electrostatically to red blood cells; considered a device; used in combat Floats off wound in severe hemorrhage Zeolite Powder applied to wounded tissue; considered a device; used in combat Local hyperthermia-induced tissue damage Voils S. Pharmacotherapy. 2007;27:69S-84S.

Some Topical Hemostatic Agents (cont)
Cellulose-, Collagen-, and Gelatin-Based Topical Hemostatic Composition Approval Date Surgicel (J&J) Regenerated oxidized cellulose October 14, 1960 Gelfoam (Pfizer) Porcine gelatin molded into a sponge Available 1945; approved July 8, 1983 Surgifoam (J&J) Porcine gelatin sponge September 30, 1999 Avitene (Davol) Bovine collagen August 26, 1976 (as a drug) October 24, 1980 (as a device) Instat (J&J/Gateway) October 10, 1985 Helistat (Integra LifeSciences) November 8, 1985 Helitene (Integra LifeSciences) Gabay M. Am J Health-Syst Pharm. 2006;63:

Indications Hemostatic Agent Labeled Indication(s) Surgicel
For use in surgical procedures when conventional methods of hemostasis, such as pressure and ligature, are ineffective; for endoscopic procedures, may be used by cutting to size. Gelfoam For use in in surgical procedures, including those that may result in calcellous bone bleeding, when conventional methods of hemostasis are ineffective or impractical. Surgifoam For use in surgical procedures, except urologic and ophthalmic procedures, when conventional methods of hemostasis are ineffective or impractical. Avitene For use in surgical procedures when conventional methods of hemostasis are ineffective or impractical. Instat For use in surgical procedures, except ophthalmic procedures, when conventional methods of hemostasis are ineffective or impractical; for endoscopic procedures, may be used by cutting to size. Helistat Gabay M. Am J Health-Syst Pharm. 2006;63:

Indications (cont) Hemostatic Agent Labeled Indication(s) Helitene
For use in surgical procedures, except urologic and ophthalmic procedures, when conventional methods of hemostasis are ineffective or impractical. CoStasis For use in surgical procedures, except neurologic,ophthalmic, and urologic procedures, when conventional methods of hemostasis are ineffective or impractical. FloSeal For use in surgical procedures, except ophthalmic procedures, when conventional methods of hemostasis are ineffective or impractical. Thrombin-JMI For use as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules are accessible; may be used in combination with absorbable gelatin sponge for hemostasis; may be used in conjunction with any other device that has been approved by FDA with a specified dosage of topical thrombin. Gabay M. Am J Health-Syst Pharm. 2006;63:

Considerations Efficacy: Few randomized controlled trialsstudies have shown beneficial effects in controlling capillary bleeding, achieving hemostasis in vascular surgery, controlling bleeding from fistula-puncture site in hemodialysis, etc Cost: No published study of cost-effectiveness Safety Good clinical data evaluating the efficacy of absorbable hemostatic agents are lacking. There are few randomized controlled clinical trials directly comparing available agents.

Adverse Events Device failure (continued bleeding observed)
Device deployment failure Infection Granuloma Abscess Foreign body reaction Allergic reaction Interference with wound healing Respiratory difficulty Bowel obstruction Hematoma Intermittent ischemia Stroke Tissue necrosis Erythema Edema As this slide illustrates, absorbable hemostatic agents are associated with numerous adverse events.

Adverse Events (cont) In 2004, FDA issued a notification on possible development of paralysis following use of absorbable hemostatic agents If agent used and left on or near a bony or neural space, when wetted, the material swelled and exerted pressure on neural structures, resulting in pain, numbness, or paralysis Recommendations: Read labels carefully If used on or near bony/neural spaces, use the minimum amount necessary to achieve hemostasis and remove as much of the agent as possible after hemostasis is achieved

Protamine Heparin antagonist indicated for heparin overdosage
Rapid onset of action Has an anticoagulant effect when used alone; in the presence of heparin, both drugs lose anticoagulant activity Too-rapid administration can cause severe hypotensive and anaphylactoid-like reactions

DDAVP Originally developed and licensed for the treatment of inherited defects of hemostasis1,2 Several reviews suggest its effect is too small to influence the need for transfusion and reoperation1,2 Most evidence of efficacy is in mild hemophilia A and von Willebrand’s disease1,2 Not indicated for use in cardiac surgery patients1,2 Meta-analysis in cardiac patients: 2-fold increase in MI, a small decrease in perioperative blood loss, and no added benefits on clinical outcomes The strongest evidence of efficacy for desmopressin is in the prevention and treatment of bleeding in patients with mild hemophilia A and von Willebrand’s disease.1 Several reviews suggest that, although desmopressin helps to reduce perioperative blood loss, its effect is too small to influence other, more clinically relevant outcomes, such as the need for transfusion and reoperation.1 Desmopressin is not indicated for use in cardiac surgery patients, but a meta-analysis in this cohort revealed that treatment with the agent resulted in a 2-fold increase in mycocardial infarction, a small decrease in perioperative blood loss, and no added benefits on clinical outcomes.2 References Mannucci PM, et al. N Engl J Med. 2007;356: 2. Levy JH. Am J Health-Syst Pharm. 2005;62(suppl 4):S15-S19. 1. Mannucci PM, et al. N Engl J Med. 2007;356: ; 2. Levy JH. Am J Health-Syst Pharm. 2005; 62(suppl 4):S15-S19.

rVIIa Vitamin K-dependent glycoprotein structurally similar to human plasma-derived factor VIIa Approved in United States for treatment of bleeding in patients with hemophilia A or B with inhibitors to factor VIII or IX Multiple reports of off-label use in cardiac surgery, trauma, liver transplantation to secure hemostasis Promotes hemostasis by activating the coagulation cascade Believed to cause local thrombin generation and platelet recruitment at sites of vascular and microvascular injury

rVIIa (cont) A central factor in coagulation
A trypsin-like serine protease (characterized by a serine residue in the active side of the enzyme) Initiates coagulation in a complex with TF Once bound to TF, it is activated (FVIIa) by different proteases Produced in liver; vitamin K–dependent (warfarin) The main role of factor VII (FVII) is to initiate the process of coagulation in conjunction with tissue factor (TF). TF is found on the outside of blood vessels, normally not exposed to the bloodstream. Upon vessel injury, TF is exposed to the blood and circulating factor VII. Once bound to TF, FVII is activated to FVIIa by different proteases, among which are thrombin (factor IIa), activated factor X and the FVIIa-TF complex itself. The most important substrates for FVIIa-TF are factor X and factor IX. The action of the factor is impeded by TF pathway inhibitor (TFPI), which is released almost immediately after initiation of coagulation. Factor VII is vitamin K–dependent; it is produced in the liver. Use of warfarin or similar anticoagulants impairs its function.

Mechanism of Action As this slide illustrates, when the vessel wall is disrupted, subendothelial TF becomes exposed to circulating blood and may bind factor VIIa (Panel A). This binding activates factor X, and activated factor X (factor Xa) generates small amounts of thrombin. The thrombin (factor IIa) in turn activates platelets and factors V and VIII. Activated platelets bind circulating factor VIIa (Panel B), resulting in further factor Xa generation as well as activation of factor IX. Activated factor IX (factor IXa) (with its cofactor VIIIa) yields additional factor Xa. The complex of factor Xa and its cofactor Va then converts prothrombin (factor II) into thrombin (factor IIa) in amounts that are sufficient to induce the conversion of fibrinogen to fibrin. Reference Mannucci PM, et al. N Engl J Med. 2007;356: Mannucci PM, et al. N Engl J Med. 2007;356:

Approved Indications and Usage
Date: March 25, 1999 Indication: Treatment of bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or factor IX Date: October 13, 2006 Indication: Treatment of bleeding episodes and for the prevention of bleeding in surgical interventions or invasive procedures in patients with acquired hemophilia

Approved Indications and Usage (cont)
rVIIa is indicated for: Treatment of bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or factor IX and in patients with acquired hemophilia Prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to factor VIII or factor IX and in patients with acquired hemophilia Treatment of bleeding episodes in patients with congenital factor VIII deficiency Prevention of bleeding in surgical interventions or invasive procedures in patients with congenital factor VIII deficiency NovoSeven [ package insert]. Princeton, NJ: Novo Nordisk Pharmaceuticals; September 1999.

Approved Indications and Usage (cont)
Remember the mechanism… IXa and VIIIa aid VIIa in activating X If IXa or VIIIa is missing (or inhibited), rVIIa can replace their function by converting more X to Xa All of the indications have something to do with missing/inhibited factors IX or VIII. Mannucci PM, et al. N Engl J Med. 2007;356:

Monitoring of Treatment
Primarily, clinical evaluation of hemostasis Lab testsNo direct correlation to achieving hemostasis: PT: Shortening to a plateau in hemophilia A/B with inhibitors aPTT: Shortens the prolonged aPTT in hemophilia A/B with inhibitors; normalization not usually observed in doses shown to induce clinical improvement; clinical improvement is associated with a shortening of aPTT of 15 to 20 seconds Plasma FVII clotting activity (FVII:C)

No. of episodes reported
Adverse Reactions Seems to be well tolerated (298 hemophilia A or B patients with inhibitors) Body System Event No. of episodes reported (n=1939 treatments) No. of unique patients (n=298) Body as a whole Fever Platelets, Bleeding, and Clotting Hemorrhage NOS Fibrinogen plasma decreased Skin and Musculoskeletal Hemarthrosis Cardiovascular Hypertension 16 15 10 14 9 13 8 5 6 NovoSeven [package insert]. Princeton, NJ: Princeton, NJ: Novo Nordisk Pharmaceuticals; September 1999.

“Off-label” Uses of rVIIa
Increasingly being considered for: Reversal of oral anticoagulation Reversal of heparin, lepirudin, and fondaparinux Thrombocytopenia and thrombocytopathy Bleeding with impaired liver function Gastrointestinal bleeding Trauma Surgery: Non-traumarelated (hepatic resection, prostatectomy, cardiac, spinal) These off-label uses are mostly based on anecdotal case reports Need better evidence

“Off-label” Uses of rVIIa (cont)
Evidence is lagging behind the rising off-label use of rVIIa Multiple case series/reports: Benefits in obstetric bleeding, trauma, perioperative bleeding Beware of perils of case reports: Subjective; no control; bias (usually only positive experiences are reported) Some concerns: Thrombotic complications (eg, myocardial/cerebral ischemia, DVT, pulmonary embolism) At a cost of $2000-$8000 per dose, annual costs of such off-label uses can easily run into millions of dollars in hospitals Only few randomized controlled trials  This is changing

Current Ongoing Global Trials
Trial Title Study Design Phase Total Enrollment Expected Completion "Salvage Use" of Recombinant Activated Factor VII After Inadequate Haemostatic Response to Conventional Therapy in Complex Cardiac Surgery Multicenter, Treatment, Randomized, Double-Blind, Placebo-Control, Parallel Assignment, Safety/Efficacy Study Phase 3 40 June 2008 Evaluation of the Quality of the NovoSeven (rFVIIa) Treatment Practice at Rigs hospital, Copenhagen University Hospital Natural History, Longitudinal, Defined Population, Retrospective/ Prospective Study ?? December 2010 Effect of Recombinant Coagulation Factor VIIa on Peri-Operative Blood Loss in Patients Undergoing Major Burn Excision and Grafting Randomized, Double-Blind (Subject, Caregiver, Investigator) Placebo-Control, Parallel Assignment, Efficacy Study 52 December 2009 Efficacy and Safety of Factor VIIa (Eptacog Alfa) on Rebleeding After Surgery for Spontaneous Supratentorial Intracerebral Hemorrhage. Randomized, Controlled, Open-Label, Investigator-Blinded Pilot Study Phase 2 30 January 2008 This and the next several slides delineate the major ongoing clinical trials examining rVIIa. Today, only a few of these trials will be discussed. US National Institutes of Health. ClinicalTrials.gov. Available at: Accessed February 10, 2008.

Current Ongoing Global Trials (cont)
Trial Title Study Design Phase Total Enrollment Expected Completion "Salvage Use" of Recombinant Activated Factor VII After Inadequate Haemostatic Response to Conventional Therapy in Complex Cardiac Surgery Multicenter, Treatment, Randomized, Double-Blind, Placebo-Control, Parallel Assignment, Safety/Efficacy Study Phase 3 40 June 2008 Effect of Recombinant Coagulation Factor VIIa on Peri-Operative Blood Loss in Patients Undergoing Major Burn Excision and Grafting Randomized, Double-Blind (Subject, Caregiver, Investigator) Placebo- Control, Parallel Assignment, Efficacy Study 52 December 2009 Efficacy and Safety of Factor VIIa on Rebleeding After Surgery for Spontaneous Intracerebral Hemorrhage (ICH) (PRE-SICH). Randomized, Controlled, Open-Label, Investigator-Blinded Pilot Study Phase 2 30 January 2008 "Salvage Use" of Recombinant Factor VIIa After Inadequate Haemostasis in Complex Cardiac Surgery Sponsored by: Austin Health This randomized, placebo-controlled study tests the hypothesis that rVIIa will improve hemostasis in patients who have an inadequate response to conventional therapy in complex cardiac surgery. Major bleeding is still of concern in complex cardiac surgery. It has been shown to be associated with poorer patient outcome and results in the consumption of resources (hospital costs, manpower and blood bank reserves). This study has the potential to provide evidence that rVIIa can reduce transfusion requirements and improve patient outcomes in a problematic aspect of complicated cardiac surgery. Reference US National Institutes of Health. ClinicalTrials.gov. Available at: Accessed February 10, 2008. US National Institutes of Health. ClinicalTrials.gov. Available at: Accessed February 10, 2008.

Current Ongoing Global Trials (cont)
Trial Title Study Design Phase Total Enrollment Expected Completion Recombinant Human Activated Factor VII as Salvage Therapy in Women With Severe Postpartum Hemorrhage Randomized, Open-Label, Active Control, Parallel Assignment, Safety/Efficacy Study Phase 4 84 December 2009 Randomized, Open, Prospective, Multicenter Pilot Study to Evaluate the Efficacy and Safety of Activated Recombinant Factor VII in Acute Intracerebral Haemorrhage in Patients Treated With Oral Anticoagulants or Antiplatelets Agents. Randomized, Single-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study Phase 2 32 September 2006 The Use of rFVIIa in Trauma Patients: A Multi-Center Case Registry Natural History, Cross-Sectional, Case Control, Retrospective/ Prospective Study ?? 1000 Not recruiting yet Assessment of rFVIIa in Controlling Bleeding in Patients With Severe Trauma Injuries Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study Phase 3 1502 Recruiting Recombinant Human Activated Factor VII as Salvage Therapy in Women With Severe Postpartum Hemorrhage Sponsors and Collaborators: Centre Hospital University of Nimes University Hospital, LilleAssistance Publique - Hôpitaux de Paris University Hospital, Montpellier University Hospital, GenevaCentre Hospitalier, Universitaire de Nice The aim of this clinical research project is to evaluate the use of rVIIa, given as a salvage therapy, in women with a dramatic postpartum hemorrhage still ongoing after all the currently available medical and surgical treatments have been used. Its early use will be compared, before elective surgery or arterial embolization, and its late use, after embolization or surgery, before salvage hysterectomy. Reference US National Institutes of Health. ClinicalTrials.gov. Available at: Accessed February 10, 2008. US National Institutes of Health. ClinicalTrials.gov. Available at: Accessed February 10, 2008.

Patient Case: Adam B. Dx: Post-op coagulopathy and uncontrolled bleeding History: 50-year-old male; had antibodies to c and E Suffered excessive bleeding during surgery and narrowly avoided transfusion of incompatible blood Ongoing chest tube drainage in the 2 weeks following surgery required transfusion of 1 U QOD Last night, he developed coagulopathy and dramatically increased bleeding Increasing clotting times not corrected by FFP HCT declined to 19% Antigen-negative PRBC were not immediately available HCT=hematocrit; PRBC=packed red blood cells.

Patient Case: Adam B. First thoughts about continuing to transfuse Adam B. What are the risks associated with additional transfusions? What Would You Do Next?

Take-Away Points “Keeping On Center”
Achieving optimal operative hemostasis means maintaining balance between bleeding and clotting Preoperative risk assessment may predict who will bleed Transfusion concerns include risks, costs, and impact on patient quality of life Look at patient’s risks for complications and think about the balance Incorporate blood conservation and prohemostatic therapy into hemostasis strategy “Keeping On Center”

For more CE/CME educational programs on the subject of operative hemostasis and transfusion medicine, including uniquely progressive learning designed for each clinical discipline, log on to:

Specialty-Specific Clinical Cases
More Opportunities to Decide … What You Would Do Next!

Patient Case: Brian C. Dx: Acute cholecystitis
History: 54-year-old male; 5’11,” 240 lb; third ED visit for same reason H/O appendectomy; mild high BP (on BP meds and baby aspirin) and borderline diabetes mellitus (no meds) Labsnormal PT and PTT; HCT 39%, platelets 410,000 Lap cholecystectomy was performed with difficult establishment of pneumoperitoneum Bleeding began at base of gall bladder Cauterization failed to arrest bleeding Pressure and topical hemostatics failed to help Consult: Agreed to switch to open procedure 2500 cc blood in abdomen on opening HCT 22%, platelets 140,000 Liver was packed; gall bladder was removed; and after U of PRBC, 1 of cryoprecipitate and 1 of FFP, patient was still bleeding What Would You Do Next?

Patient Case: Chaney D. Dx: Abdominal crush injury, fracture of both tibias, and closed head trauma History: Very fit 47-year-old male, no previous surgery, only med was baby aspirin Head-on collision, spun around, and hit head-on from rear again; air bags deployed after first hit only Exploratory lap removed spleen, and liver laceration repaired After 2 hours, 12 U PRBC, FFP, cryoprecipitate; bleeding continued from liver Damage control planned and liver tightly packed HCT 22%, platelets 85,000 Plan to re-explore the next day Bled through the packing and returned to OR HCT 16%, platelets 44,000 What Would You Do Next?

Patient Case: Deidre E. Dx: Postpartum hemorrhage
History: 38-year-old had C section for failure to progress with delivery of 8 lb, 11 oz baby with mild preeclampsia Pre-op HCT was 31% and EBL was 600 cc 2 hours postpartum, patient showed signs of volume depletion, with decreased urine output and low BP HCT was 20%, fibrinogen <100; FDP elevated and platelets 75,000 Urine was grossly bloody, glucose 60 and LFT drawn Repeat platelet count was 30,000 and blood was not clotting HELLP syndrome was diagnosed and transfusions begun What Would You Do Next?

Patient Case: Elvin F. Dx: Hip replacement from traumatic arthritis
History: 54-year-old male with mild hypertension (on meds) Labs normal; received 5000 U heparin preoperatively Began bleeding heavily; received third and forth units of blood, and cell saver used HCT 24 (37 pre-op), platelets 125,000 and fibrinogen 50 Urine blood tinged; according to patient’s wife, he was taking 1600 mg ibuprofen and possibly a baby aspirin FDP was positive and patient developed a coagulopathy Patient was warmed; acidosis and volume status corrected What Would You Do Next?

Patient Case: Fenton G. Dx: Urgent repeat on-pump CABG due to unstable angina History: 68-year-old male with prior CABG, several MIs, CHF (on lisinopril) 3-vessel disease noted with EF 25%; LMWH given in cath lab Patient had high BP (on BP meds and clopidogrel) and type 2 diabetes mellitus HCT 42%, platelets 220,000 1 g TXA given after intubation followed by 200 mg/min Heparin 10,000 U in CPB reservoir and 400 U/kg On separation from bypass, HCT 24%, with 1 L volume in reservoir Intra-aortic balloon pump placed and patient given milrinone and norepinephrine Protamine returns ACT to normal Patient oozy at closure Patient continues to bleed in PACU at rate of 200 cc per hour What Would You Do Next?

Patient Case: Gavin H. Dx: Trabeculated bladder with UA stones
History: 70-year-old male with BPH; taking finasteride and tamsulosin On BP med (amlodipine) and aspirin; PSA 1.2 Coagulation studies normal and platelets 225,000 TURP performed under general anesthesia Bleeding was encountered; attempts at cautery unsuccessful 60 cc foley placed on stretch with irrigation, which cleared but then became bloody again Bleeding increased the next day HCT was 33% (39 pre-op); resection attempts failed to arrest bleeding What Would You Do Next?

Achieving optimal surgical hemostasis often requires a multidisciplinary approach. The goal of maintaining the balance between bleeding and clotting provides.

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Presentation on theme: "Achieving optimal surgical hemostasis often requires a multidisciplinary approach. The goal of maintaining the balance between bleeding and clotting provides."— Presentation transcript:

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Achieving optimal surgical hemostasis often requires a multidisciplinary approach. The goal of maintaining the balance between bleeding and clotting provides.

Similar presentations

Presentation on theme: "Achieving optimal surgical hemostasis often requires a multidisciplinary approach. The goal of maintaining the balance between bleeding and clotting provides."— Presentation transcript:

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About project

Feedback