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Haemostasis
The document discusses the physiology of hemostasis, including: - The essential components of hemostasis including platelet plug formation, coagulation pathways, and fibrinolysis. - Conditions that can increase the risk of uncontrolled bleeding during surgery such as patient comorbidities, anticoagulant medications, hypothermia and acidosis. - How achieving optimal hemostasis requires balancing procoagulant, anticoagulant, fibrinolytic and antifibrinolytic factors.
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Haemostasis
- 1. The Physiology ofHemostasis Ira A. Shulman, MD Professor and Vice Chair of Pathology Keck School of Medicine of USC Medical Director of Transfusion Service USC Norris Cancer Hospital Los Angeles, California
- 2. 2 Activity Goals In thispresentation, you will learn about: • Essential scientific components of hemostasis • The causes of and approximate frequencies of excessive surgical bleeding • How surgical complications, regardless of surgery type, can be attributed to bleeding and clotting • The importance of determining which patients are at greatest risk for surgical coagulopathy • How achieving optimal hemostasis can be viewed as a “balancing act”
- 3. 3 Prevalence of UncontrolledBleeding 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 1. Despotis GJ, et al. Anesth Analg. 1996;82:13-21. 2. Erol DD, et al. Internet J Anesth. 2005;9:2. 3. 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;329:1370-1376. 6. Leclerc JR, et al. Ann Intern Med. 1996;124:619-626. 7. Strebel N, et al. Arch Intern Med. 2002;162:1451-1455. 8. Daniels PR. Nat Clin Pract Urol. 2005;2:343-350. 9.Rosevear HM, et al. J Urol. 2006;176:1458- 1462. 10. Holcomb JB. Crit Care. 2004;8(suppl 2):S57-S60. 11. Sauaia A, et al. J Trauma. 1995;38:185-193. TURP=transurethral prostatic resection.
- 4. 4 Definition of Hemostasis Hemostasis:“The arrest of bleeding” Stedman’s Medical Dictionary Hemostasis: “Life in the balance” Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. • Trauma • Major surgery • Hemophilia • Stroke • Myocardial infarction (MI) • Thrombosis Bleeding to Death Clotting to Death
- 5. 5 Definition of SignificantBleeding • >2 L blood loss in an adult within first 24 post-op hours1 Volume of acute blood loss/patient weight >30 mL/kg Volume of acute blood loss >40%-50% total blood volume • 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) 1. Despotis GJ, et al. Ann Thorac Surg. 2000;70(suppl 2):S20-S32. 2. Vincent J-L, et al. Crit Care. 2006;10:1-12.
- 6. 6 Reasons for UncontrolledBleeding Patient-related • Advanced age • Small body size • Gender • Pre-op anemia (low RBC volume) • Antiplatelet or antithrombotic drugs • Hypothermia • Acidosis • Systemic inflammatory response syndrome (SIRS) • 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 Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86. RBC=red blood cell; CABG=coronary artery bypass graft.
- 7. 7 Surgery Post-op Recovery Thrombosis Clotting Bleeding Hemorrhage Can WePredict Who Will Bleed? Adapted from 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? There Is a Difference Between Who Is at Risk and Who Will Bleed
- 8. 8 Patients at Riskfor Surgical Bleeding Certain patients are at higher risk for surgical bleeding, including: • Patients taking Long-acting anticoagulant therapy Clopidogrel • Patients undergoing Repeat surgical procedures Oncologic surgery Aortic surgery Cardiac surgery Neurologic procedures or neurosurgery Radical prostatectomy • Dialysis patients • Trauma patients Ferraris VA, et al.. Ann Thorac Surg. 2007;83:S27–S86; Disorders of Hemostasis. In: Harrison’s Internal Medicine. New York, NY: Mc-Graw Hill; 2007. Available at: http://www.accessmedicine.com/resourceToc.aspx?resourceID=4. Tanaka KA, et al. Anesthesiology. 2003;98:1513-1515.
- 9. 9 Conditions Associated WithCoagulopathy • Hemophilia • Platelet disorders • Liver disease • Uremia • Disseminated intravascular coagulation (DIC) • Dilutional coagulopathy • Anticoagulant treatment • Acidosis • Hypothermia • Extracorporeal circuits Ferraris VA, et al.. Ann Thorac Surg. 2007;83:S27–S86. Disorders of Hemostasis. In: Harrison’s Internal Medicine. New York, NY: Mc-Graw Hill; 2007. Available at: http://www. accessmedicine.com/resourceToc.aspx?resourceID=4.
- 10. 10 Thienopyridines Such asClopidogrel and Postoperative Bleeding • Evidence is more compelling than for aspirin1 11 studies of clopidogrel and CABG All studies show increased bleeding when clopidogrel given within 5 days of CABG — some with increased mortality • ACC/AHA and STS/SCA guidelines recommend stopping clopidogrel for 5 days before surgery (if possible)1,2 1. Ferraris VA, et al. Ann Thorac Surg. 2005;79:1454-1461. 2. Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374. CABG=coronary artery bypass graft.
- 11. 11 Traditional Model ofHemostasis Intrinsic Pathway Extrinsic Pathway factor XII HMK PK factor XI factor XIa factor IX factor IXa factor VIIIa PL, Ca+2 factor X factor Xa factor Va PL, Ca+2 prothrombin thrombin fibrinogen fibrin factor VIIa tissue factor PL, Ca+2 factor X Adapted from Hoffman M, et al. Thromb Haemost. 2001;85:958-965.
- 12. 12 Vascular Spasm Currie D.Available at: http://faculty.etsu.edu/currie/hemostasis.htm. Accessed May 6, 2008. Blood vessel Vascular spasm Region of trauma
- 13. 13 Platelet Plug Formation—PrimaryHemostasis Reprinted with permission from Rinder C. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 8. ©2005 Lippincott Williams & Wilkins http://lww.com Platelet adhesion to subendothelial vWF vWF=von Willebrand factor; GP=glycoprotein.
- 14. 14 Platelet Plug Formation—PrimaryHemostasis Reprinted with permission from Rinder C. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 8. ©2005 Lippincott Williams & Wilkins http://lww.com
- 15. 15 Vascular Endothelium ServesAs a “Front Line” Defense Against Pathologic Thrombosis This figure was published in Semin Hematol, Vol 41(suppl 1), Lawson JH, et al, “Challenges for Providing Effective Hemostasis,” pp 55-64, ©Elsevier 2004.
- 16. 16Hoffman M, etal. Blood Coag Fibrinol. 1998;9(suppl 1):S61-S65. TF-Bearing Cell Activated Platelet Platelet TF VIIIa Va VIIIa Va Va VIIa TF VIIa Xa X II IIa IX V Va II VIII/vWF VIIIa II IXa X IX X IXa IXa VIIa Xa IIa IIa Xa Evolving Model of Hemostasis TF=tissue factor; vWF=von Willebrand factor.
- 17. 17 Fibrinolysis tPA=tissue plasminogen activator;PAI-1=plasminogen activator inhibitor 1; AP=anti-plasmin; PAP=plasmin-anti-plasmin complexes. Reprinted with permission from Chandler WL. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 7. ©2005 Lippincott Williams & Wilkins http://lww.com Endothelium Endothelium tPA PAI-1 tPA-PAI-1 PAP AP D-dimerPlasmintPA + Plasminogen
- 18. 18 Putting It AllTogether Reprinted with permission from Chandler WL. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 7. ©2005 Lippincott Williams & Wilkins http://lww.com Wound: collagen and tissue factor exposure Fibrin formation, clot stabilization Platelet binding and coagulation initiation Platelet contraction, wound healing, fibrin removal Platelet aggregation Wound healed
- 19. 19 Normal Hemostasis Isa Balance Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. • Trauma • Major surgery • Hemophilia • Stroke • MI • Thrombosis Bleeding to Death Clotting to Death • Blood coagulation • Anticoagulation • Fibrinolysis • Antifibrinolysis • Vascular tone and blood flow • Endothelial cells and platelets
- 20. 20 “Keeping on Center”:Moving Toward Normal Hemostasis Normal Hemostasis Procoagulant Activity Anticoagulant Activity Fibrinolytic Activity Antifibrinolytic Activity Bleeding Clotting Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.
- 21. 21 “Keeping on Center”(cont) Topical Hemostatics Purified Factors, FFP, Cryo, PLTs Aminocaproic acid Tranexamic acid Heparin, Warfarin LMWH, Argatroban t-PA, SK, UPA Normal Hemostasis Bleeding Clotting FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase; UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin. Procoagulant Activity Anticoagulant Activity Fibrinolytic Activity Antifibrinolytic Activity Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.
- 22. 22Adapted from ReedRL, et al. Circ Shock. 1990;32:141-152. ** ** ** ** **P<.0001 vs clotting time at 37o C. Temperature (o C) Temperature (o C) ** ** ** * * **P<.0001 vs clotting time at 37o C. 20 22 24 26 28 30 32 23 25 27 29 31 33 35 37 ThrombinTime(sec) Temperature (o C) **P<.0001 vs clotting time at 37o C. *F<.005 vs clotting time at 37o C. ** ** * Effect of Temperature on Test Results of aPTT, TT, and PT aPTT=activated partial thromboplastin time; PT=prothrombin time; TT=thrombin time. 25 30 35 40 45 50 55 60 65 70 23 25 27 29 31 33 35 37 39 aPTT(sec) 10 12 14 16 18 20 22 24 26 23 25 27 29 31 33 35 37 39 ProthrombinTime(sec) * *
- 23. 29 volunteers had2 U RBC removed by apheresis (re-infusion of PRP) 11 received back autologous RBC 18 did not receive back their RBC Valeri et al. Transfusion 2001;41:977-83. Effect of 2-unit RBC apheresis or plateletspheresis on bleeding time 0 1 2 3 4 5 6 7 8 9 RBCs Platelets BTat35°C Apheresis Hct: 41 35 (15%)↓ 40 40 Platelet count: 220 200 (9%)↓ 238 163 (32%)↓ Apheresis Return of RBCs Apheresis Return of RBCs Does Anemia Induce Reversible Platelet Dysfunction? Before apheresis 0.50 1.00 1.50 2.00 1 Hour TX1 TX2 1 DAY 2 DAY 3 DAY 7 DAY TemplateBT(ratioafter:beforeapheresis) 0.70 0.80 0.90 1.00 1.10 Before apheresis 1 Hour TX1 TX2 1 DAY 2 DAY 3 DAY 7 DAY PeripheralVenousHct (ratioafter:beforeapheresis)
- 24. 24 • During room-temperaturestorage in the blood bank, platelets express a number of glycoprotein ligands, making them prothrombotic1-3 • Platelets excrete granules containing cell signaling compounds that are capable of triggering reactions in WBCs, endothelial cells, and other native platelets3,4 • This complex activation biology is recognized as part of the platelet storage lesion4 • In certain circumstances, platelet transfusions might increase risk of stroke or death5 1. Spiess BD. Transfusion. 2007;47:354–356; 2. Seghatchian MJ, et al. Transfus Sci. 1997;18:103-107; 3. Van der Planken MG, et al. Ann Hematol. 1999;78:1-7; 4. Seghatchian J, et al. Transfus Med Rev. 1997;11:130-144; 5. Spiess BD, et al. Transfusion. 2004;44:1143-1148. The Platelet “Storage Lesion” and the Potential Prothrombotic Effect of Platelets
- 25. 25 Thrombosis Clotting Bleeding Hemorrhage Physiology and GoodSurgery Topical Hemostatic Agents Systemic Biologic Therapies Achieving Optimal Operative Hemostasis Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.
- 26. 26 Hemostasis: Final Thoughts •Many surgical complications, regardless of surgery type, can be attributed to bleeding and clotting • It is important to determine which patients are at greatest risk for surgical coagulopathy • Achieving optimal hemostasis involves a balancing act, whereby patients must be kept from bleeding or clotting to death through transfusional and nontransfusional therapies
Editor's Notes
- #2 The speaker, Dr. Ira A. Shulman, is active in various professional organizations, including the American Association of Blood Banks (AABB), the American Society for Clinical Pathology (ASCP), the College of American Pathologists (CAP), the Society for the Advancement of Blood Management (SABM), and the California Blood Bank Society (CBBS). He has served as chair of several national organizations’ committees, including the AABB Clinical Transfusion Medicine Committee, the Transfusion Medicine Resource Committee of the CAP, and the Council on Transfusion Medicine for the ASCP. He has served on the board of directors of AABB, SABM, and CBBS. He is currently the Editor and Moderator of an internationally subscribed transfusion medicine discussion group called the e-Network Forum that is considered the premier educational program for distance learning (and networking) in transfusion medicine. There are nearly 550 visitors per day to the archive of information at http://cbbsweb.org/enetcommun.html with over 2500 page views per day and more than 50 megabytes of information transferred per day. Education: University of California at Los Angeles (UCLA), BA, l967-l97l where he was a University of California Regents Scholar and graduated Phi Beta Kappa, UCLA, elected in l97l and Summa Cum Laude University of Southern California (USC) School of Medicine, Los Angeles, CA, MD, l97l-1975 where he elected to Alpha Omega Alpha Medical Honor Society, USC Post-doctoral training: LAC+USC Medical Center, Los Angeles, CA in AP/CP Pathology, l975-l979 and Blood Banking/Transfusion Medicine 1979-1980 Board Certification: Anatomic and Clinical Pathology November, l979 Special Competence in Blood Banking, May, l98l
- #3 After this presentation, participants should be better able to: Explain the essential aspects of hemostasis, including the roles played by vascular endothelium, platelets, red cells, white cells, plasma coagulation and anticoagulation factors, as well as other plasma and/or tissue factors List the causes of and approximate frequencies of excessive surgical bleeding, including nonsurgical factors Explain why many surgical complications, regardless of surgery type, can be attributed to bleeding and clotting Indicate why it is important to determine which patients are at greatest risk for surgical coagulopathy Explain why achieving optimal hemostasis involves a balancing act, whereby patients must be kept from bleeding or clotting to death through transfusional and nontransfusional therapies
- #4 Bleeding is a major complication of surgery, and although overall mortality for a planned, nonemergency surgical procedure is very low at about 0.1%,1 subcategories of surgery may show much higher rates. Excessive bleeding (&gt;2 L or &gt;30 mL/kg) after cardiac surgery is encountered in 5% to 7% of patients2 and necessitates re-exploration 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% drop in hematocrit between admission and the postpartum period or a need for red cell transfusions. 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 transurethral prostatic resection (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 References Shander A. Surgery. 2007;142(4 suppl):S20-S25. 2. Despotis GJ, et al. Anesth Analg. 1996;82:13-21. 3. Dacey LJ, et al. Arch Surg. 1998;133:442-447. 4. Moulton MJ, et al. J Thorac Cardiovasc Surg. 1996;111:1037-1046. 5. Erol DD, et al. Internet J Anesth. 2005;9:2. 6. Combs CA, et al. Obstet Gynecol. 1991;77:69-76. 7. Combs CA, et al. Obstet Gynecol. 1991;77:77-82. 8. Hull R, et al. N Engl J Med. 1993;329:1370-1376. 9. Leclerc JR, et al. Ann Intern Med. 1996;124:619-626.10. Strebel N, et al. Arch Intern Med. 2002;162:1451-1455. 11. Daniels PR. Nat Clin Pract Urol. 2005;2:343-350. 12. Rosevear HM, et al. J Urol. 2006;176:1458-1462. 13. Holcomb JB. Crit Care. 2004;8(suppl 2):S57-S60. 14. Sauaia A, et al. J Trauma. 1995;38:185-193.
- #5 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…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 (MI), 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.
- #6 Excessive, or significant, bleeding may be characterized as surgical or nonsurgical. Surgical bleeding results from failure to control bleeding from the operative site. Signs include expanding hematoma and saturated dressings. Nonsurgical bleeding is caused by failure of hemostatic pathways. It is often manifested as generalized oozing. Approximately 75% to 90% of bleeding has a surgical component1,2; it is caused by local surgical or vessel interruption. Ten percent to 25% of bleeding has a nonsurgical component, and is caused by either acquired or congenital coagulopathy.1,2 The frequency of excessive bleeding is variable and can depend on the patient, type of procedure, and specific institutional protocols. It also can depend on the definition used. Excessive bleeding has various definitions. Investigators such as Despotis et al define excessive bleeding after cardiac surgery as bleeding that is &gt;2 L of blood loss within the first 24 postoperative hours.3 This equates to a total blood volume lost divided by patient weight of &gt;30 mL/kg or a &gt;40% blood volume lost. Investigators found excessive bleeding in 5% to 7% of patients. Such bleeding can result in re-exploration and prolonged hospitalization.3 Vincent and colleagues report that massive hemorrhage is often characterized by a surgical or vascular component and a coagulopathic component.4 The former can be corrected by surgical intervention or embolization.4 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 (hypothermia or acidosis), which can affect the coagulation process.4 References Adams GL, et al. Hematol Oncol Clin North Am. 2007;21:13-24. Shander A. Surgery. 2007;142(suppl 4):S20-S25. Despotis GJ, et al. Ann Thorac Surg. 2000;70(suppl 2):S20-S32. Vincent J-L, et al. Crit Care. 2006;10:1-12.
- #7 Certain factors may predispose to uncontrolled bleeding. Among these are patient-related factors, such as advanced age, smaller body size, and preoperative anemia. Older, smaller patients have a smaller red cell mass, smaller platelet mass, and other issues that may predispose them to poorly tolerated uncontrolled bleeding. Other factors include hypothermia, acidosis, and anemia, which can induce a reversible platelet function defect. Other important factors include use of antiplatelet or antithrombotic drugs; cardiovascular and metabolic comorbidities may also 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. Acidosis and hypothermia can contribute to bleeding by their inhibitory effects on platelet functionality and on coagulation factor activity. References Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86. Valeri CR, et al. Transfusion. 2007;47:206S-248S.
- #8 In surgery, we still don’t know who is likely to bleed or clot too much. We often are not sure how to optimize the physiology of the patient. Often we are not sure which topical hemostatic agents are effective, and when it comes to systemic biologic therapies, we are 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.
- #9 The most recently published guidelines of the Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists outline important indicators of risk for surgical bleeding, including preoperative anticoagulant therapy, reoperative procedures, and types of surgery, including aortic and cardiac surgery as well as radical prostatectomy.1 In the latter example, such patients may be at risk for thrombosis secondary to tissue thromboplastins but also hemorrhage secondary to fibrinolysis. Dialysis and trauma also are indicators of surgical bleeding risk.2 References 1. Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86. 2. Disorders of Hemostasis. In: Fauci AS, et al, eds. Harrison’s Internal Medicine. New York, NY: McGraw-Hill; 2007. Available at: http://www.accessmedicine.com/resourceToc.aspx?resourceID=4. Accessed January 28, 2008.
- #10 Coagulopathy can prevent normal hemostatic mechanisms from functioning, including hemophilia, where there are extremely low levels of factors VIII or IX. Also, inherited or acquired platelet disorders can occur following the use of antiplatelet agents such as clopidogrel, abciximab, tirofiban, and GP IIb-IIIa antagonists. The coagulopathy that occurs in patients with liver disease is of major concern because of the key role the liver plays in producing the vitamin Kdependent factors II, VII, IX, and X. The coagulopathy of liver disease is quite complex and often very difficult to treat. Disseminated intravascular coagulation (DIC) is responsible for bleeding problems associated with complex bleeding disorders. Anticoagulation treatment with warfarin derivatives (coumadin and coumarin) produces a marked inhibition of II, VII, IX, and X disorders. Severe acidosis and hypothermia can impair platelet function and the activity of coagulation factors. Extracorporeal circuits can cause platelet activation, thrombin generation, and “exhausted platelet syndromes.” References Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27–S86. Disorders of Hemostasis. In: Fauci AS, et al, eds. Harrison’s Internal Medicine. New York, NY: Mc-Graw Hill; 2007. Available at: http://www.accessmedicine.com/resourceToc.aspx?resourceID=4. Accessed January 28, 2008.
- #11 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 coronary artery bypass graft (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 Regarding preoperative aspirin use, the STS/SCA guidelines state that it is reasonable to discontinue use of low-intensity antiplatelet drugs such as aspirin for 2 to 3 days prior to surgery in elective patients without acute coronary syndromes.3 References Ferraris VA, et al. Ann Thorac Surg. 2005;79:1454-1461. Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374. Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.
- #12 We have reviewed how hemostasis is defined. Now, let’s look at a graphic depiction of the physiology that drives the process. This slide illustrates 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.1,2 Hoffman and Monroe3 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 phospholipid, 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 However, depending on clinical circumstances, neither the PT nor the aPTT may accurately reflect a patient’s true in vivo hemostatic status. While the cascade model is a useful concept, the hemostasic process is much more complicated. It is a highly adaptative process that controls blood fluidity, but can rapidly induce a hemostatic plug after vascular injury in order to stop or limit bleeding. After an initial triggering event sequential steps occur, including a complex cascade of platelet and clotting factor activation. Red blood cells, leukocytes, and endothelial cells are involved in the propagation and the regulation of a hemostatic plug. There are 4 distinct phases of the hemostatic process: 1) vascular spasm; 2) platelet plug formation (platelet response/reaction) or primary hemostasis; 3) coagulation;and 4) fibrinolysis. All 4 of these phases are closely linked to each other and all are tightly coordinated in order to efficiently close the vessel wound, promote vascular healing, and maintain vessel patency. References McFarlane RG. Nature. 1964;202:498-499. Davie EW, et al. Science. 1964;145:1310-1312. Hoffman M, et al. Thromb Haemost. 2001;85:958-965.
- #13 Vascular &quot;spasm&quot; refers to a local vasoconstrictive mechanism. That is, trauma to the vessel wall causes vasoconstriction in both directions along the traumatized vessel. The region of vasoconstriction of the traumatized vessel extends several centimeters in each direction from the area of trauma. Vascular spasm reduces blood flow through the traumatized vessel and, thus, reduces blood loss. Of course, vascular spasm is only seen in those blood vessels with smooth muscle, which means arteries, veins, and arterioles. Venules have very limited amounts of smooth muscle at their venous end, and capillaries have no smooth muscle at all. Vascular spasm is most effective in the arterioles, because they are small enough, but with enough muscle to nearly or completely close. Reference Currie D. The hemostasis and coagulation page. Available at: http://faculty.etsu.edu/currie/hemostasis.htm. Accessed May 6, 2008.
- #14 Primary hemostasis results from complex interactions between the vascular wall, platelets, and adhesive proteins, which lead to closure of a damaged vessel wall by a white platelet-rich clot. Hemodynamic forces enrich platelets in a fluid boundary layer adjacent to the vessel wall where they flow along the endothelium scanning it for defects. Once a platelet detects an injury, it immediately adheres―a process beginning with initial deceleration and attachment via GPIb receptor-binding to immobilized von Willebrand factor (vWF), which leads to platelet activation.1 For example, when vascular injury disrupts endothelial cells lining an arterial wall, multimeric vWF is exposed and undergoes elongation due to high wall shear forces. Platelets bind via GP1b receptors to sites on the exposed vWF. The binding causes the platelets to activate and change shape. The activating platelets show an altered membrane phospholipid orientation and metabolic biochemistry, and the exposure of glycoprotein IIb/IIIa receptor sites. If dislodged from the damaged endothelium, activated platelets can reattach more avidly.1 Activation and adhesion are followed by secretion of substances that drive the hemostatic process by stimulating additional platelets to adhere, aggregate, and secrete. When activation and primary adhesion have been achieved, platelets commence discharge of granule contents. Granule contents include ADP, adenosine triphosphate (ATP), serotonin, calcium, vWF, factor V, and fibrinogen. The secreted substances further promote formation of the platelet plug by means of stimulating other platelets to adhere, aggregate, and secrete.2 Such aggregates present a large mass of procoagulant membranes, the surface of which serves for activation of clotting factors and fibrin polymerization is accelerated many fold. References Reininger AJ. Coagulation activity of platelets. Hamostaseologie. 2007 Sep;27(4):247-50. Lasne D, et al. Can J Anesth. 2006;53(suppl 6):S2–S11. Rinder C. Figure 8.3 in Chapter 8: Platelet physiology: Cellular and Protein Interactions. In: Perioperative Transfusion Medicine 2nd Edition. Speiss, Spence, and Shander (eds).
- #15 One of the biochemical changes that occur within the platelet is an increase in internal calcium levels. When these levels reach a threshold, a change in the shape of the platelet occurs. The activated platelet is transformed from a disc-shaped cell to a sphere with pseudopods. This change in shape results in an increase in the surface area available for biochemical reactions and increased chance of contact with other platelets. As they change shape, platelets spread over the surface of the collagen to which they adhere, filling in the spaces between pseudopods. The next step is for the primary hemostatic plug formed by platelets to be strengthened and stabilized by the deposition of insoluble strands of fibrin. Fibrin deposition occurs through a series of complex biochemical reactions during which soluble plasma coagulation factors associate with both the platelet plug and the injured vessel wall. Platelet activation causes a change in the platelet membrane surface which enables fibrin-forming proteins (coagulation factors) to bind to the membrane.
- #16 The vascular wall is lined by a continuous monolayer of endothelial cells, which play an active role in the regulation of vessel patency. In the absence of vascular injury, hemostatic activation must be blocked to prevent pathologic thrombus formation and vascular occlusion. The “front line” in prevention of thrombosis is the vascular endothelial cell, which lines the blood vessels. The luminal surface of normal endothelial cells exhibits antithrombotic properties by blocking platelet activation and inhibiting coagulation activity. For example, these cells express negatively charged heparin-like glycosaminoglycans in the external layer of the cell membrane and promote synthesis, exposure, or secretion of platelet inhibitors (prostacyclin, nitric oxide), coagulation inhibitors (thrombomodulin, protein S, tissue factor pathway inhibitor), and secrete fibrinolysis activators (tissue plasminogen activator [tPA]).1,2 Activation of endothelial cells due to injury, infection (bacterial, viral, rickettsial), inflammation, or other causes can convert the endothelial cell to a procoagulant status. When activated, the endothelial cell is characterized by expression of anionic phospholipids on the outer leaflet of the cell membrane, secretion of platelet activating agents (platelet activating factor), expression of coagulation factor receptors (tissue factor [TF], FIX and FX receptors) or cofactors V, and secretion of inhibitors of fibrinolysis (plasminogen activator inhibitor 1 [PAI-1]). 1,2 The subendothelial layer contains highly thrombogenic components such as collagen, vWF, and other molecules involved in platelet adhesion. 2 Reference Lawson JH, Murphy MP. Semin Hematol. 2004;41(suppl 1):55-64. Lasne D, et al. Can J Anesth. 2006;53(suppl 6):S2–S11.
- #17 Hoffman and colleagues have developed a cell-based model of hemostasis that is represented in this slide. This slide represents a schematic model of normal hemostasis, which requires activation of both FX and FIX. The initiating event for coagulation activation is the exposure of TF to FVII and circulating trace amounts of FVIIa. TF exposure to flowing blood can derive from wound exposing TF expressing cells, or from aberrant TF expression by activated monocytes or endothelial cells (under septic or inflammatory stimulation). The TF-FVIIa-complex activates FIX and FX generating low amounts of FXa (initiation phase). FVIIa/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. Although the trace amounts of thrombin that are generated is not sufficient for fibrinogen cleavage, it is critical for hemostasis, since it can activate platelets, back activate and release FVIII from vWF, and back activate plasma FV. On the other hand, 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 Amounts of FXa sufficient to sustain clot formation occur in the presence of anionic phospholipids (provided by activated platelets) and calcium, and FVIIIa (propagation phase). Thus, antihemophilic factors (FVIII and FIX) are necessary to generate sufficient amounts of FXa and normal hemostasis. 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 describes the fibrinolytic system. References Hoffman M, et al. Blood Coag Fibrinol. 1998;9(suppl 1):S61-S65. Karkouti K, et al. Can J Anaesth. 2006;53:1260-1262.
- #18 The fibrinolytic system regulates the size of the thrombus and prevents widespread fibrin accumulation in the vascular system. Fibrinolysis is initiated by the release of tPA from endothelial cells. tPA binds along with plasminogen to fibrin, where it converts plasminogen into plasmin, which in turn cleaves fibrin. tPA activity in plasma is controlled by PAI-1 which binds to and inhibits tPA forming inactive tPA-PAI-1 complexes. PAI-1 is present in large excess in the flowing blood, and prevents inappropriate plasmin generation by forming an inactive covalent complex with tPA. PAI-1 plasma levels are increased in inflammatory states, insulin resistance syndromes and obesity. Plasmin activity in plasma is controlled by antiplasmin (AP) that binds to and inhibits plasmin forming in active plasmin-antiplasmin complexes (PAP). Proteolysis of fibrin by plasmin induces generation of fibrin degradation products, the most specific of the stabilized fibrin degradation products being D-dimers. Elevated plasma levels of D-dimers are a marker for increased thrombin formation and fibrin degradation turnover. The fibrinolytic system is not only able to proteolyze fibrin clots, but also plays a critical role in vessel wound repair and the remodeling processes, and in angiogenesis, through degradation of the extracellular matrix. Reference Lasne D, et al. Can J Anesth. 2006;53(suppl 6):S2–S11.
- #20 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.” Pathological situations needing surgery and anesthesia, as well as surgery or invasive procedures, can acutely trigger the hemostatic system. This is why the perioperative period is especially risky for deleterious prohemorrhagic and prothrombotic abnormalities. References 1. Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. 2. Karkouti K, et al. Can J Anaesth. 2006;53:1260-1262.
- #21 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.
- #22 What are some of the tools that enable clinicians to keep patients on center? Procoagulants: Topical hemostatics, a host of purified factors, such as FVII, FVIII, and FIX; fresh frozen plasma and cryoprecipitate; and systemic delivery of platelets. Antifibrinolytics: Aminocaproic acid and tranexamic acid. Fibrinolytics: t-PA, streptokinase (SK), and urinary-type plasminogen activator (UPA). Anticoagulants: Heparin, low-molecular-weight-heparin (LMWH), warfarin, and argatroban. Other anticoagulants are currently in development.
- #23 One challenge to keeping on center is that clinical laboratory tests may not accurately guide therapy. Hypothermic patients may develop coagulopathy in part due to suppression of the enzymatic activity of activated clotting factors. However, when prothrombin time (PT) and activated partial thromboplastin time (APTT) testing is done for such patients (or for rats as part of an experiment) the results of testing may not accurately reflect the true severity of the in vivo effects of hypothermia on the subject’s coagulation process, because the lab is testing the samples after they are warmed to 37˚C. Thus, there may be a disparity between clinically evident hypothermic coagulopathy and the results of clotting studies done in the lab after the samples are warmed up.1,2 References 1. Reed RL et al. Circ Shock. 1990;32:141-152. 2. Reed RL et al. J Trauma. 1992 Sep;33(3):465-70.
- #24 To assess the relative effect of RBCs and platelets on the bleeding time (BT), 22 healthy male and 7 healthy female volunteers were subjected to the removal of 2 units of RBCs by apheresis (360 mL), followed by the return of the platelet-rich plasma (PRP) from both units and the infusion of 1000 mL of 0.9-percent NaCl. Four of the men and all seven women received their RBCs back 1 hour after their removal. Shed blood levels of thromboxane B(2) (TXB(2)), 6-keto prostaglandin F(1 alpha), and peripheral venous Hct were measured. BTs were measured in 15 men and 13 women before and after a plateletpheresis procedure to collect 3.6 x 10(11) platelets per unit. The 2-unit RBC apheresis procedure produced a 60% increase in the BT associated with a 15-percent reduction in the peripheral venous Hct and a 9-percent reduction in the platelet count. The plateletpheresis procedure produced a 32% decrease in the platelet count, no change in peripheral venous Hct, and no change in the BT. After the removal of 2 units of RBCs, the shed blood TXB(2) level decreased significantly. Reinfusion of 2 units of RBCs restored the BT and restored the TXB(2) level to the baseline levels. Thus, acute reduction in Hct produced reversible platelet dysfunction manifested by an increase in BT and decrease in shed blood TXB2 level at the template BT site. Return of RBCs restored both BT and shed blood TXB2 level to normal. The platelet dysfunction observed with the reduction in Hct was due in part to a reduction in shed blood TXB(2) and other, unknown mechanisms.
- #25 Platelet transfusions may also present a challenge to keeping the patient on center. Platelet concentrates are harvested either as a byproduct of whole blood donation or through plateletpheresis. The units are stored for up to 5 days in the blood banks at room temperature on platelet rockers.1 If the white cells that were collected along with the platelets are not removed from the product, changes inside the storage bags are profound and platelets conjugate with the white cells as well as undergo activation and expression of many cellular ligands.2,3 Cytokine levels can rise as high as 1000 fold compared to the levels seen in normal healthy humans. So the platelet infusion itself is proinflammatory and very prothrombotic.4 While it may be desirable for platelets to be prothrombotic and stop bleeding, some studies suggest that in coronary artery bypass grafting surgery (CABG) the transfusion of non-leukocyte reduced platelets may increase risk of stroke and death.5 Platelet-WBC conjugates and cytokines amplify cellular prothrombotic changes. Leukoreduction may reduce the risk of platelets, but this step probably does not necessarily make platelets stored at room temperature for 5 days quiescent or normal.4 References Seghatchian J, Krailadsiri P. Transfus Med Rev. 1997;11:130-144. Hartwig D, et al. Vox Sang. 2002; 2:182-90. Chaudhary R, et al. Indian J Med Res. 2006 Oct;124(4):427-30. Spiess BD. Transfusion. 2007;47(2):354–356. Spiess BD, et al. Transfusion. 2004;44:1143-1148.
- #26 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 coagulopathic bleeding is encountered, there is a potential use and a role now for systemic biologic therapies, which may help avoid a severe and hemorrhagic outcome. Reference Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.
- #27 In Summary, many surgical complications, regardless of surgery type, can be attributed to bleeding and clotting. It is important to determine which patients are at greatest risk for surgical coagulopathy. Achieving optimal hemostasis involves a balancing act, whereby patients must be kept from bleeding or clotting to death through transfusional and nontransfusional therapies.