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Potential Future Clinical Applications

There are millions of trauma deaths every year. Many patients do not survive long enough to reach the hospital. Hemorrhage is the leading cause of death and cost associated with trauma.

What is Hemostasis?

Hemostasis is the mechanism that leads to cessation of bleeding from a blood vessel. It is a process that involves multiple interlinked steps. This cascade culminates into the formation of a “plug” that closes up the damaged site of the blood vessel controlling the bleeding. It begins with endothelial damage or disruption of vessel wall.

STAGES

The mechanism of hemostasis can divide into four stages:

  1. Constriction of the blood vessel
  2. Formation of a temporary “platelet plug”
  3. Activation of the coagulation cascade
  4. Formation of “fibrin plug” or the final clot
STAGES

The mechanism of hemostasis can divide into four stages:

  1. Constriction of the blood vessel
  2. Formation of a temporary “platelet plug”
  3. Activation of the coagulation cascade
  4. Formation of “fibrin plug” or the final clot
PURPOSE

Hemostasis facilitates a series of enzymatic activations that lead to the formation of a clot with platelets and fibrin polymer. This clot seals the injured area, controls and prevents further bleeding while the tissue regeneration process takes place. Once the injury starts to heal, the plug is gradually dissolved with the restoration of normal circulation. 1,2

COMPLICATIONS

Acute and chronic bleeding results in anemia that must be treated to maintain an adequate oxygen-carrying capacity by the hemoglobin in the red blood cells, often requiring blood transfusion from donors. Rapid transfusion can also cause hypothermia and hypocalcemia, which lead to impaired platelet function, impaired coagulation, and ventricular dysfunction. All of these will cause further bleeding and hypotension. If bleeding is persistent and prolonged, it may lead to tissue hypoxemia, severe acidosis, multiorgan dysfunction, or death.3

CAUSES

There are multiple causes of bleeding, that can range from the relatively benign and easy to control conditions to scenarios of life-threatening massive hemorrhage, defined as blood loss in excess of one circulating volume within a 24-hour period, that is a major cause of death after trauma or surgery. The pathophysiology of massive blood loss can be complex, comprising a wide range of physiologic derangements arising from tissue injury to intravascular volume loss, resulting in the activation of several systems, including the autonomic nervous system, the coagulation and fibrinolytic systems, the complement system, as well as the systemic inflammatory response. Hyperfibrinolysis conditions erodes stabilized blood clots, and antifibrinolytic agents may be also required to preserve hemostasis for a longer period.

TREATMENTS

Regarding hemorrhage control, the location of the bleeding is critically important, as it will influence the ability to mechanically stop the bleeding by direct compression of the wound or by packing non-compressible sites. Several medications can also be given to patients aiming to promote and enhance their ability to form clots. Tranexamic acid (TXA) is a synthetic lysine derivative that blocks the activation of plasmin. Plasmin breaks down fibrin clots thereby inhibiting hemostasis. TXA has demonstrated improved mortality and decreased blood product requirements among trauma patients when given in the first 3 hours after injury.5 However, the use of TXA in urban areas with advanced prehospital and trauma systems has been questioned by several studies showing decreased efficacy.6-8 Since fibrinogen is one of the first clotting factors depleted following hemorrhage, several studies have focused on its use in the trauma patient. While it has shown decreased mortality in the short term, the 30-day mortality was not significantly different9 and more studies have been encouraged. Recombinant factor VIIa is another possible treatment for severe hemorrhage; however, it is not considered a first-line treatment and it is associated with a high rate of thrombosis. It is approved for use pre-operatively in patients with factor VII deficiency or hemophilia. Prothrombin complex concentrate (PCC) is another medication that deserves further study for hemorrhaging patients. Four-factor PCC consists of factors II, VII, IX, and X and is used to reverse vitamin K antagonists as well as treat congenital coagulation disorders.4

CONCLUSION

Be able to better control severe and potentially life-threatening bleeding events is still a huge unmet needs in the current medical practice.

REFERENCES
  1. LaPelusa A, Dave HD. Physiology, Hemostasis. [Updated 2020 Jul 10]. StatPearls Publishing; 2021 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545263/ 
  2. Smith SA, Travers RJ, Morrissey JH. How it all starts: Initiation of the clotting cascade. Crit Rev Biochem Mol Biol. 2015;50(4):326-36.
  3. Keeyapaj W. Bleeding and Coagulation Catastrophes in the Operating Room. Medscape (Aug 22, 2019) https://emedicine.medscape.com/article/2500074-overview 
  4. Donley ER, Loyd JW. Hemorrhage Control. [Updated 2020 Jul 20]. StatPearls Publishing; 2021 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535393/
  5. The CRASH-2 Collaborators, Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23-32.
  6. Valle EJ, Allen CJ, Van Haren RM, Jouria JM, Li H, Livingstone AS, et al. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg 2014;76:1373–8.
  7. Harvin JA, Peirce CA, Mims MM, Hudson JA, Podbielski JM, Wade CE, et al. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg 2015;78:905–9; discussion 909-11.
  8. Cole E, Davenport R, Willett K, Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg 2015;261:390–4.
  9. Use of fibrinogen concentrate for trauma-related bleeding: A systematic-review and meta-analysis. Stabler SN, Li SS, Karpov A, Vu EN. J Trauma Acute Care Surg. 2020 Dec;89(6):1212-1224.

SURGERY

Approximately 313 million surgical procedures are performed worldwide each year,1 with at least 4.2 million people dying within 30 days from surgery, accounting for 7.7% of all deaths globally.2 Postoperative complications and morbidity remain very high3,4 with perioperative bleeding playing a major risk during and after surgery, being associated with a high rate of postoperative morbidity, infectious complications, increased hospital length of stay, early and late mortality5–7 as well as an increased healthcare resource use, with an annual expenditure on blood and transfusion-related activities range from $1.62M to $6.03M per hospital.8–9

Approximately 10% of all cardiac surgery patients suffer from severe or massive blood loss, and up to about 5% of them require emergent re-exploration in an attempt to correct ongoing bleeding and establish adequate hemostasis.10,11 Cardiac surgery is the single largest consumer of allogenic blood products, with approximately 30% of patients treated.12,13

The principal causes of non-vascular sources of hemostatic perioperative bleeding are a preexisting undetected bleeding disorder, the nature of the operation itself, or acquired coagulation abnormalities secondary to hemorrhage, hemodilution, or hemostatic factor consumption.14

Multiple factors contribute to the complex causes of bleeding in surgical patients that include blood loss, hemodilution, acquired platelet dysfunction, coagulation factor consumption in extracorporeal circuits, activation of fibrinolytic, fibrinogenolytic and inflammatory pathways, and hypothermia.15,16 Delayed hemostasis can also result from prescribed oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, edoxaban) and platelet inhibitors (P2Y12 receptor inhibitors-clopidogrel, prasugrel, or ticagrelor), or by injected heparins (UFH and LMWH: enoxaparin, dalteparin, tinzaparin). Despite the availability of antidotes for some of them, the management of bleeding related to these medications remain a concern for a patient approaching the surgical table. Thus, bleeding during and after surgery includes both pre-existing and/or acquired defects in hemostasis.

Approximately 313 million surgical procedures are performed worldwide each year,1 with at least 4.2 million people dying within 30 days from surgery, accounting for 7.7% of all deaths globally.2 Postoperative complications and morbidity remain very high3,4 with perioperative bleeding playing a major risk during and after surgery, being associated with a high rate of postoperative morbidity, infectious complications, increased hospital length of stay, early and late mortality5–7 as well as an increased healthcare resource use, with an annual expenditure on blood and transfusion-related activities range from $1.62M to $6.03M per hospital.8–9

Approximately 10% of all cardiac surgery patients suffer from severe or massive blood loss, and up to about 5% of them require emergent re-exploration in an attempt to correct ongoing bleeding and establish adequate hemostasis.10,11 Cardiac surgery is the single largest consumer of allogenic blood products, with approximately 30% of patients treated.12,13

The principal causes of non-vascular sources of hemostatic perioperative bleeding are a preexisting undetected bleeding disorder, the nature of the operation itself, or acquired coagulation abnormalities secondary to hemorrhage, hemodilution, or hemostatic factor consumption.14

Multiple factors contribute to the complex causes of bleeding in surgical patients that include blood loss, hemodilution, acquired platelet dysfunction, coagulation factor consumption in extracorporeal circuits, activation of fibrinolytic, fibrinogenolytic and inflammatory pathways, and hypothermia.15,16 Delayed hemostasis can also result from prescribed oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, edoxaban) and platelet inhibitors (P2Y12 receptor inhibitors-clopidogrel, prasugrel, or ticagrelor), or by injected heparins (UFH and LMWH: enoxaparin, dalteparin, tinzaparin). Despite the availability of antidotes for some of them, the management of bleeding related to these medications remain a concern for a patient approaching the surgical table. Thus, bleeding during and after surgery includes both pre-existing and/or acquired defects in hemostasis.

REFERENCES
  1. Meara JG, Leather AJ, Hagander L, Aikire BC, Alonson N, Ameh EA et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Surgery 2015; 158:3–6.
  2. Nepogodiev D, Martin J, Biccard B, Makupe A, Bhangu A. National Institute for Health Research Global Health Research Unit on Global Surgery. Global burden of postoperative death. Lancet 2019; 393: 401.
  3. International Surgical Outcomes Study. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth2016; 117: 601–609.
  4. Biccard BM, Madiba TE, Kluyts HL, Munlemvo DM, Madzimbamuto FD, Basenero A et al. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-dayprospective observational cohort study. Lancet 2018; 391:1589–1598.
  5. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010; 252: 11–17.
  6. Smilowitz NR, Oberweis BS, Nukala S, Rosenberg A, Zhao S, Xu J et al. Association between anemia, bleeding, and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: 315–323.e2.
  7. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth 2012; 26: 46–51.
  8. Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res 2011; 11:135.
  9. Shander A., Van Aken H., Colomina MJ., et al. Patient blood management in Europe. British Journal of Anaesthesia 2012. 109 (1): 55–68.
  10. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
  11. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
  12. Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
  13. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
  14. Ghadimi K et al. Perioperative management of the bleeding patient. British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016). doi: 10.1093/bja/aew358
  15. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33
  16. Despotis GJ, Avidan MS, Hogue CW. Jr., Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72: S1821–31
REFERENCES
  1. Meara JG, Leather AJ, Hagander L, Aikire BC, Alonson N, Ameh EA et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Surgery 2015; 158:3–6.
  2. Nepogodiev D, Martin J, Biccard B, Makupe A, Bhangu A. National Institute for Health Research Global Health Research Unit on Global Surgery. Global burden of postoperative death. Lancet 2019; 393: 401.
  3. International Surgical Outcomes Study. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth2016; 117: 601–609.
  4. Biccard BM, Madiba TE, Kluyts HL, Munlemvo DM, Madzimbamuto FD, Basenero A et al. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-dayprospective observational cohort study. Lancet 2018; 391:1589–1598.
  5. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010; 252: 11–17.
  6. Smilowitz NR, Oberweis BS, Nukala S, Rosenberg A, Zhao S, Xu J et al. Association between anemia, bleeding, and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: 315–323.e2.
  7. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth 2012; 26: 46–51.
  8. Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res 2011; 11:135.
  9. Shander A., Van Aken H., Colomina MJ., et al. Patient blood management in Europe. British Journal of Anaesthesia 2012. 109 (1): 55–68.
  10. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
  11. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
  12. Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
  13. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
  14. Ghadimi K et al. Perioperative management of the bleeding patient. British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016). doi: 10.1093/bja/aew358
  15. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33
  16. Despotis GJ, Avidan MS, Hogue CW. Jr., Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72: S1821–31


TRAUMA (1)

Accidents

One in ten deaths are due to severe trauma, a major global public health issue, resulting in more than 5.8 million lost lives annually worldwide.1-3 Road traffic accidents is among the three leading causes of injury and violence-related deaths according to WHO, with over 16,000 people dying daily.4 More recently, bombing assaults are responsible for mass casualties, resulting in hundreds of severely injured and bleeding patients suddenly posing a huge challenges for the local A&E healthcare systems.5-7 Uncontrolled post-traumatic bleeding is still the leading cause of potentially preventable death among injured patients.8-10

The National Trauma Institute estimated in 2015 that severe bleeding accounts for greater than 35% of pre-hospital deaths and nearly 40% of deaths within the first 24 hours of injury in the civilian areas.11 Coagulopathy affects 25% of these injured patients, resulting from multiple conditions, as such hemorrhage, hemodilution, hypothermia, and acidosis.12

In 2003, injuries have been listed as the third leading cause of overall death in US and the leading cause of death for those between the ages of 1 and 46, representing 30% of the years of potential life lost before age 65 and accounted for almost 10% of the national expenditure on healthcare. Despite advances in medicine and prehospital care, these numbers have not improved significantly. Hemorrhage secondary to traumatic injury is the leading cause of death of Americans from one to 46 years of age.11 The Stop the Bleed campaign, first launched in 2013, aims to reduce the morbidity and mortality associated with hemorrhage secondary to traumatic injury.13 Significant improvements in clinical outcomes can be made by transferring knowledge from the military to civilian medicine.14,15

REFERENCES
  1. Meara JG, Leather AJ, Hagander L, Aikire BC, Alonson N, Ameh EA et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Surgery 2015; 158:3–6.
  2. Nepogodiev D, Martin J, Biccard B, Makupe A, Bhangu A. National Institute for Health Research Global Health Research Unit on Global Surgery. Global burden of postoperative death. Lancet 2019; 393: 401.
  3. International Surgical Outcomes Study. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth2016; 117: 601–609.
  4. Biccard BM, Madiba TE, Kluyts HL, Munlemvo DM, Madzimbamuto FD, Basenero A et al. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-dayprospective observational cohort study. Lancet 2018; 391:1589–1598.
  5. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010; 252: 11–17.
  6. Smilowitz NR, Oberweis BS, Nukala S, Rosenberg A, Zhao S, Xu J et al. Association between anemia, bleeding, and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: 315–323.e2.
  7. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth 2012; 26: 46–51.
  8. Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res 2011; 11:135.
  9. Shander A., Van Aken H., Colomina MJ., et al. Patient blood management in Europe. British Journal of Anaesthesia 2012. 109 (1): 55–68.
  10. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
  11. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
  12. Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
  13. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
  14. Ghadimi K et al. Perioperative management of the bleeding patient. British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016). doi: 10.1093/bja/aew358
  15. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33
  16. Despotis GJ, Avidan MS, Hogue CW. Jr., Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72: S1821–31
REFERENCES
  1. Donley ER, Loyd JW. Hemorrhage Control. [Updated 2020 Jul 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535393/
  2. G. B. D. Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1151–210.
  3. World Health Organization (ed.): Injuries and violence: the facts 2014, Publication edn. On line: World Health Organization; 2014: https://www.who.int/violence_injury_prevention/media/news/2015/Injury_violence_facts_2014/en/. Accessed 22 Feb 2019.
  4. World Health Organization (ed.): The global burden of disease: 2004 update. Online: World Health Organization; 2008: https://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/. Accessed 22 Feb 2019.
  5. Craigie RJ, Farrelly PJ, Santos R, Smith SR, Pollard JS, Jones DJ. Manchester Arena bombing: lessons learnt from a mass casualty incident. J R Army Med Corps. 2018; https://doi.org/10.1136/jramc-2018-000930.
  6. Gates JD, Arabian S, Biddinger P, Blansfield J, Burke P, Chung S, Fischer J, Friedman F, Gervasini A, Goralnick E, et al. The initial response to the Boston marathon bombing: lessons learned to prepare for the next disaster. Ann Surg. 2014;260(6):960–6.
  7. Hirsch M, Carli P, Nizard R, Riou B, Baroudjian B, Baubet T, Chhor V, Chollet-Xemard C, Dantchev N, Fleury N, et al. The medical response to multisite terrorist attacks in Paris. Lancet. 2015;386(10012):2535–8.
  8. Cothren CC, Moore EE, Hedegaard HB, Meng K. Epidemiology of urban trauma deaths: a comprehensive reassessment 10 years later. World J Surg. 2007;31(7):1507–11.
  9. Davenport RA, Guerreiro M, Frith D, Rourke C, Platton S, Cohen M, Pearse R, Thiemermann C, Brohi K. Activated protein C drives the hyperfibrinolysis of acute traumatic coagulopathy. Anesthesiology. 2017;126(1):115–27.
  10. Cause-specific mortality and morbidity. http://www.who.int/whosis/whostat/EN_WHS09_Table2.pdf . Accessed 21 Feb 2019.
  11. Chambers JA, Seastedt K, Krell R, Caterson E, Levy M, Turner N. “Stop the Bleed”: A U.S. Military Installation’s Model for Implementation of a Rapid Hemorrhage Control Program. Mil Med. 2019 Mar 01;184(3-4):67-71.
  12. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006 Jun;60(6 Suppl):S3-11.
  13. The CRASH-2 Collaborators, Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23-32.
  14. Spahn DR, Bouillon B, Cerny V, Duranteau J, Filipescu D, Hunt BJ, Komadina R, Maegele M, Nardi G, Riddez L, Samama CM, Vincent JL, Rossaint R. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019 Mar 27;23(1):98.
  15. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E, Filipescu D, Hunt BJ, Komadina R, Maegele M, Nardi G, Neugebauer E, Ozier Y, Riddez L, Schultz A, Vincent JL, Spahn DR., STOP Bleeding Campaign. The STOP the Bleeding Campaign. Crit Care. 2013 Apr 26;17(2):136.


TRAUMA (2)

Military battle-field

Hemorrhage due to trauma is the leading preventable cause of death in the military setting1, accounting up tot to 90% of potentially preventable deaths.1-3 In the civilian setting, trauma is the second most leading cause of death in trauma patients, reported between 26% and 40 %, and head injury considered more lethal.4,5 In the military battle field, 87% of the combat-related mortality caused by traumatic hemorrhage occurs before reaching a definitive care facility, as compared to 56% in the civilian setting.3,6,7 Prehospital early strategies to control hemorrhage became fundamental to allow the bridging to definitive surgical care, impacting the overall outcomes that are strictly time dependent in the context of a life-threatening hemorrhage in which the duration of ongoing bleeding may lead to either death or, in case of initial survival and subsequent massive transfusion, to possible sepsis and/or multi-organ failure.8-10

The coagulopathy of trauma is a complex pathophysiologic state that results in diffuse, microvascular bleeding. Approximately 40% of trauma-related mortality is associated with profound coagulopathy. Hypothermia, acidosis, and resuscitative hemodilution have been considered as the significant contributors to coagulation dysfunction after trauma. Over the past decade, clinical observations around the globe have independently shown that coagulopathy may be present as early as hospital admission in some trauma patients. The hemostatic manifestation is associated with increased blood transfusion requirements, about in 10% of military patients11,12, longer hospital stay, and higher mortality. The recognition of this early coagulopathy leads to the use of new terminology and proposed hypotheses.13,14

REFERENCES
  1. Meara JG, Leather AJ, Hagander L, Aikire BC, Alonson N, Ameh EA et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Surgery 2015; 158:3–6.
  2. Nepogodiev D, Martin J, Biccard B, Makupe A, Bhangu A. National Institute for Health Research Global Health Research Unit on Global Surgery. Global burden of postoperative death. Lancet 2019; 393: 401.
  3. International Surgical Outcomes Study. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth2016; 117: 601–609.
  4. Biccard BM, Madiba TE, Kluyts HL, Munlemvo DM, Madzimbamuto FD, Basenero A et al. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-dayprospective observational cohort study. Lancet 2018; 391:1589–1598.
  5. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010; 252: 11–17.
  6. Smilowitz NR, Oberweis BS, Nukala S, Rosenberg A, Zhao S, Xu J et al. Association between anemia, bleeding, and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: 315–323.e2.
  7. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth 2012; 26: 46–51.
  8. Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res 2011; 11:135.
  9. Shander A., Van Aken H., Colomina MJ., et al. Patient blood management in Europe. British Journal of Anaesthesia 2012. 109 (1): 55–68.
  10. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
  11. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
  12. Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
  13. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
  14. Ghadimi K et al. Perioperative management of the bleeding patient. British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016). doi: 10.1093/bja/aew358
  15. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33
  16. Despotis GJ, Avidan MS, Hogue CW. Jr., Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72: S1821–31
REFERENCES
  1. Van Oostendorp SE, Tan ECTH, Geeraedts Jr LMG. Prehospital control of life-threatening truncal and junctional haemorrhage is the ultimate challenge in optimizing trauma care; a review of treatment options and their applicability in the civilian trauma setting. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine (2016) 24:110
  2. Bellamy RF. The causes of death in conventional land warfare: implications for combat casualty care research. Mil Med. 1984;149:55–62.
  3. Eastridge BJ, Mabry RL, Seguin P, Cantrell J, Tops T, Uribe P, et al. Death on the battlefield (2001–2011): implications for the future of combat casualty care. J Trauma Acute Care Surg. 2012;73:S431–7.
  4. Tien HC, Spencer F, Tremblay LN, Rizoli SB, Brenneman FD. Preventable deaths from hemorrhage at a level I Canadian trauma center. J Trauma. 2007;62:142–6.
  5. Teixeira PGR, Inaba K, Hadjizacharia P, Brown C, Salim A, Rhee P, et al. Preventable or potentially preventable mortality at a mature trauma center. J Trauma. 2007;63:1338–46.
  6. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, et al. Epidemiology of trauma deaths: a reassessment. J Trauma. 1995;38:185–93.
  7. Chaudery M, Clark J, Wilson MH, Bew D, Yang GZ, Darzi A. Traumatic intra-abdominal hemorrhage control: has current technology tipped the balance toward a role for prehospital intervention? J Trauma Acute Care Surg. 2015;78:153–63.
  8. Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma. 2003;54:898–905.
  9. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006;60:S3–11.
  10. Geeraedts LMGJ, Kaasjager HAH, van Vugt AB, Frolke JPM. Exsanguination in trauma: a review of diagnostics and treatment options. Injury. 2009;40:11–20.
  11.  Cap AP, Beckett A, Avi Benov A, et al. Whole blood transufion. Military medicine 2018. 183;10:44.
  12. Gurney  JM, Spinella PC. Blood transfusion management in the severely bleeding military patient. Curr Opin Anaesthesiol. 2018 Apr;31(2):207-214.
  13. Martini WZ. Coagulation complications following trauma. Military Medical Research 2016. 3:35.
  14. Gonzalez E, Moore EE, Moore HB, Chapman MP, Silliman CC, Banerjee A. Trauma-induced coagulopathy: an institution’s 35 year perspective on practice and research. Scand J Surg. 2014;103(2):89–103.


INTRACEREBRAL HEMORRHAGE (ICH)

ICH is a devastating disease. The overall incidence of spontaneous ICH worldwide is 24.6 per 100,000 person-years with approximately 40,000 to 67,000 cases per year in the United States.1-3 ICH is the cause of up to 20% of all strokes, yet accounts for nearly half of all stroke deaths worldwide, with a survival rate that has not changed for several decades,2 and the only intervention that improves functional outcome is early intensive blood pressure lowering.4-6 30-day mortality rate ranges from 35% to 52% with only 20% of survivors expected to have full functional recovery at 6 months.7 Approximately half of this mortality occurs within the first 24 hours8, highlighting the critical importance of early and effective treatment in the Emergency Department (ED). Around a quarter of ICH are complicated by hematoma expansion, which most often occurs within the first few hours, up to 24 h, and is associated with very poor outcomes.9-11 It is also interesting to consider that ICH may be a devastating complication associated with oral anticoagulants.

 

REFERENCES
  1. Meara JG, Leather AJ, Hagander L, Aikire BC, Alonson N, Ameh EA et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Surgery 2015; 158:3–6.
  2. Nepogodiev D, Martin J, Biccard B, Makupe A, Bhangu A. National Institute for Health Research Global Health Research Unit on Global Surgery. Global burden of postoperative death. Lancet 2019; 393: 401.
  3. International Surgical Outcomes Study. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth2016; 117: 601–609.
  4. Biccard BM, Madiba TE, Kluyts HL, Munlemvo DM, Madzimbamuto FD, Basenero A et al. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-dayprospective observational cohort study. Lancet 2018; 391:1589–1598.
  5. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010; 252: 11–17.
  6. Smilowitz NR, Oberweis BS, Nukala S, Rosenberg A, Zhao S, Xu J et al. Association between anemia, bleeding, and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: 315–323.e2.
  7. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth 2012; 26: 46–51.
  8. Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res 2011; 11:135.
  9. Shander A., Van Aken H., Colomina MJ., et al. Patient blood management in Europe. British Journal of Anaesthesia 2012. 109 (1): 55–68.
  10. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
  11. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
  12. Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
  13. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
  14. Ghadimi K et al. Perioperative management of the bleeding patient. British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016). doi: 10.1093/bja/aew358
  15. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33
  16. Despotis GJ, Avidan MS, Hogue CW. Jr., Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72: S1821–31
REFERENCES
  1. J. Alfredo Caceres JA and Goldstein JN. Intracranial Hemorrhage. Emerg Med Clin North Am. 2012 Aug; 30(3): 771–794. doi: 10.1016/j.emc.2012.06.003
  2. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9: 167–76.
  3. Aguilar MI, Freeman WD. Spontaneous intracerebral hemorrhage. Semin Neurol. 2010;30(5):555–64
  4. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368: 2355–65.
  5. Al-Shahi Salman R, Law ZK, Bath PM, Steiner T, Sprigg N. Haemostatic therapies for acute spontaneous intracerebral haemorrhage. Cochrane Database Syst Rev 2018; 4: CD005951.
  6. Steiner T, Bösel J. Options to restrict hematoma expansion after spontaneous intracerebral hemorrhage. Stroke 2010; 41: 402–09.
  7. Broderick J, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults. Stroke. 2007;38(6):2001–2023.
  8. Elliott J, Smith M. The Acute Management of Intracerebral Hemorrhage: A Clinical Review. Anesthesia & Analgesia. 2010;110(5):1419–1427
  9. Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997; 28: 1–5.
  10. Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke 1996; 27: 1783–87.
  11. Dowlatshahi D, Demchuk AM, Flaherty ML, et al. Defining hematoma expansion in intracerebral hemorrhage relationship with patient outcomes. Neurology 2011; 76: 1238–44.


GYNECOLOGY (1)

 Heavy menstrual bleeding (HMB)

HMB is defined as excessive menstrual blood loss which interferes with a woman’s physical, social, emotional, and/or material quality of life. It can occur alone or in combination with other symptoms.1 The objective definition of a total menstrual blood loss exceeding 80 mL per menstruation not always correlate with women’s perception of how this bleeding condition heavily impact their lives.2,3 Reported HMB prevalence in women varies between 27.2% and 54.0%, making it a common disorder.4 About 1 in 20 women aged 30–49 years consult their general practitioner each year for HMB, which is the second highest-ranked reason for a hospital referral and accounts for 12% of all gynecologic referrals.5 Overall, from 85 to nearly 39% of women experience HMB based on subjective assessments.6-8 HMB has been associated with lower quality of life and increased health care expenses.2,9 There are a number of factors that are known to be associated with HMB.7

The cause of HBM can be fibroids and polyps, adenomyosis, irregular ovulation, bleeding disorders, hyperfibrinolysis, drugs, cancer and other etiologic factors.10 HMB has been shown to have negative effects on the psychological state, energy, work productivity, social relationships, family life and sexual functions of women,2,11,12 and the excessive blood loss during the menstrual period can cause also physical health problems such as iron deficiency anemia and intense fatigue.13-16

REFERENCES
  1. Meara JG, Leather AJ, Hagander L, Aikire BC, Alonson N, Ameh EA et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Surgery 2015; 158:3–6.
  2. Nepogodiev D, Martin J, Biccard B, Makupe A, Bhangu A. National Institute for Health Research Global Health Research Unit on Global Surgery. Global burden of postoperative death. Lancet 2019; 393: 401.
  3. International Surgical Outcomes Study. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth2016; 117: 601–609.
  4. Biccard BM, Madiba TE, Kluyts HL, Munlemvo DM, Madzimbamuto FD, Basenero A et al. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-dayprospective observational cohort study. Lancet 2018; 391:1589–1598.
  5. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010; 252: 11–17.
  6. Smilowitz NR, Oberweis BS, Nukala S, Rosenberg A, Zhao S, Xu J et al. Association between anemia, bleeding, and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: 315–323.e2.
  7. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth 2012; 26: 46–51.
  8. Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res 2011; 11:135.
  9. Shander A., Van Aken H., Colomina MJ., et al. Patient blood management in Europe. British Journal of Anaesthesia 2012. 109 (1): 55–68.
  10. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
  11. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
  12. Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
  13. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
  14. Ghadimi K et al. Perioperative management of the bleeding patient. British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016). doi: 10.1093/bja/aew358
  15. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33
  16. Despotis GJ, Avidan MS, Hogue CW. Jr., Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72: S1821–31
REFERENCES
  1. National Institute for Health and Care Excellence. Heavy menstrual bleeding: assessment and management (NICE guideline [NG88]). 2018. https://www.nice.org.uk/guidance/ng88. Accessed 20 Jun 2018.
  2. Karlsson TS, Marions LB, Edlund MG. Heavy menstrual bleeding significantly affects quality of life. Acta Obstet Gynecol Scand. 2014;93(1):52–7.
  3. Habiba M, Julian S, Taub N, Clark M, Rashid A, Baker R, et al. Limited role of multi-attribute utility scale and SF-36 in predicting management outcome of heavy menstrual bleeding. Eur J Obstet Gynecol Reprod Biol. 2010;148(1):81–5.
  4. Kocaoz S, Cirpan R and Degirmencioglu AZ. The prevalence and impacts heavy menstrual bleeding on anemia, fatigue and quality of life in women of reproductive age. Pak J Med Sci. 2019 Mar-Apr; 35(2): 365–370.
  5. Lee BS, Ling X, Asif S, Kraemer P, Hanisch JU, Inki P, et al. Therapy of heavy menstrual bleeding in Korea: subanalysis and results from a multinational clinical trial in the Asian region investigating the levonorgestrel-releasing intrauterine system versus conventional therapy. Obstet Gynecol Sci. 2015;58(2):162–70.
  6. Harlow SD, Campbell OM. Epidemiology of menstrual disorders in developing countries: a systematic review. BJOG. 2004;111(1):6–16.
  7. Marsh EE, Brocks ME, Ghant MS, Recht HS, Simon M. Prevalence and knowledge of heavy menstrual bleeding among African American women. Int J Gynecol Obstet. 2014;125(1):56–9.
  8. Santos IS, Minten GC, Valle NCJ, Tuerlinckx GC, Silva AB, Pereira GA, et al. Menstrual bleeding patterns: a community-based cross-sectional study among women aged 18-45 years in southern Brazil. BMC Womens Health. 2011;11(1):26.
  9. Jensen JT, Lefebvre P, Laliberte F, Sarda SP, Law A, Pocoski J, et al. Cost burden and treatment patterns associated with management of heavy menstrual bleeding. J Women’s Health (Larchmt). 2012;21(5):539–47.
  10. The American College of Obstetricians and Gynecologist (2016). Heavy menstrual bleeding. Available from: www.acog.org/-/media/For-Patients/faq193.pdf?dmc=1&ts=20171024T1826016029 (accessed 2017 October 24).
  11. Matteson KA, Clark MA. Questioning our questions: do frequently asked questions adequately cover the aspects of women’s lives most affected by abnormal uterine bleeding? Opinions of women with abnormal uterine bleeding participating in focus group discussions. Women Health. 2010;50:195e211.
  12. Liu Z, Doan QV, Blumenthal P, Dubois RW. A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health. 2007;10:183-194.
  13. Knol HM, Mulder AB, Bogchelman DH, Kluin-Nelemans HC, van der Zee AG, Meijer K. The prevalence of underlying bleeding disorders in patients with heavy menstrual bleeding with and without gynecologic abnormalities. Am J Obstet Gynecol. 2013;209:202.e1-e7.
  14. Wang W, Bourgeois T, Klima J, Berlan ED, Fisher AN, O’Brien SH. Iron deficiency and fatigue in adolescent females with heavy menstrual bleeding. Haemophilia. 2013;19:225-230.
  15. Bruinvels G, Burden R, Brown N, Richards T, Pedlar C. The prevalence and impact of heavy menstrual bleeding (menorrhagia) in elite and non-elite athletes. PLoS One. 2016;11:e0149881.
  16. Szczepaniak P, Zabczyk M, Undas A Increased plasma clot permeability and susceptibility to lysis are associated with heavy menstrual bleeding of unknown cause: a case-control study. .PLoS One. 2015 24;10):e0125069.


GYNECOLOGY (2)

Post-partum hemorrhage (PPH)

Postpartum hemorrhage is a major cause of death during pregnancy and early motherhood, accounting for 25% of maternal deaths worldwide,1 and is the second leading direct cause of maternal deaths in the UK.2 The pregnancy-related mortality ratio in the United States was 17.3 deaths per 100,000 live births in 2013. National statistics suggest that approximately 11.4% of these deaths are caused by PPH.3 In industrialized countries, PPH usually ranks in the top 3 causes of maternal mortality, and in the developing world maternal mortality rates goes easily in excess of 1000 women per 100,000 live births, with an estimated 60% of maternal deaths, accounting for more than 100,000 maternal deaths per year, according to the WHO.4 The American College of Obstetricians and Gynecologists places the estimate at 140,000 maternal deaths per year or 1 woman every 4 minutes.5 The rate of PPH increased from 1.5% in 1999 to 4.1% in 2009, and the rate of atonic PPH rose from 1% in 1999 to 3.4% in 2009. The risk of PPH with a morbidly adherent placenta is markedly higher.6 It is defined as blood loss of more than 500 mL from the genital tract after delivery (or >1000 mL after a caesarean section), the hemorrhage might occur within the first 24 hours of delivery or, less commonly, between 24 hours and 12 weeks.7 For every maternal death due to postpartum hemorrhage, there are at least 10 “near-misses”. Serious maternal morbidities include multiorgan failure, multiple blood transfusion, and peripartum hysterectomy.7 There have been recent advances in the management of postpartum hemorrhage secondary to coagulopathy and abnormal invasion of the placenta.7,8 Hyperfibrinolysis is an important pathophysiological mechanism underlying PPH and TXA reduces death due to bleeding in women with PPH.9

REFERENCES
  1. Meara JG, Leather AJ, Hagander L, Aikire BC, Alonson N, Ameh EA et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Surgery 2015; 158:3–6.
  2. Nepogodiev D, Martin J, Biccard B, Makupe A, Bhangu A. National Institute for Health Research Global Health Research Unit on Global Surgery. Global burden of postoperative death. Lancet 2019; 393: 401.
  3. International Surgical Outcomes Study. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth2016; 117: 601–609.
  4. Biccard BM, Madiba TE, Kluyts HL, Munlemvo DM, Madzimbamuto FD, Basenero A et al. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-dayprospective observational cohort study. Lancet 2018; 391:1589–1598.
  5. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010; 252: 11–17.
  6. Smilowitz NR, Oberweis BS, Nukala S, Rosenberg A, Zhao S, Xu J et al. Association between anemia, bleeding, and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: 315–323.e2.
  7. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth 2012; 26: 46–51.
  8. Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res 2011; 11:135.
  9. Shander A., Van Aken H., Colomina MJ., et al. Patient blood management in Europe. British Journal of Anaesthesia 2012. 109 (1): 55–68.
  10. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
  11. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
  12. Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
  13. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
  14. Ghadimi K et al. Perioperative management of the bleeding patient. British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016). doi: 10.1093/bja/aew358
  15. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33
  16. Despotis GJ, Avidan MS, Hogue CW. Jr., Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72: S1821–31
REFERENCES
  1. World Health Organization. WHO recommendations for the prevention and treatment of postpartum haemorrhage. WHO, 2012. http://apps.who.int/iris/bitstream/10665/75411/1/9789241548502_eng.pdf
  2. Knight M, Tuffnell D, Kenyon S, Shakespeare J, Gray R, Kurinczuk JJ (eds) on behalf of MBRRACE-UK. Saving lives, improving mothers’ care: Surveillance of maternal deaths in the UK 2011-13 and lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009-13. National Perinatal Epidemiology Unit, 2015.
  3. Centers for Disease Control and Prevention. Reproductive Health: Pregnancy Mortality Surveillance System. Available at https://www.cdc.gov/reproductivehealth/maternalinfanthealth/pmss.html. June 29, 2017; Accessed: July 21, 2017.
  4. WHO. Reducing the Global Burden: Postpartum Haemorrhage. Making Pregnancy Safer. 2007.
  5. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 76, October 2006: postpartum hemorrhage. Obstet Gynecol. 2006 Oct. 108(4):1039-47.
  6. Lutomski J, Byrne B, Devane D, Greene R. Increasing trends in atonic postpartum haemorrhage in Ireland: an 11-year population-based cohort study. BJOG. 2012 Feb. 119(3):306-14.
  7. Chandraharan E and Krishna A. Diagnosis and management of postpartum haemorrhage. BMJ 2017;358:j3875 doi: 10.1136/bmj.j3875.
  8. Chandraharan E, Arulkumaran S. Massive postpartum haemorrhage and management of coagulopathy. Obstetrics, Gynaecol Reprod Med 2007;17:119-22.
  9. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. WOMAN Trial Collaborators. Lancet. 2017;389(10084):2105-2116


RARE DISEASES

Several hemorrhagic rare diseases could potentially benefit from compounds able to limit bleeding by modulating fibrinolysis and maintain a more efficient hemostasis.

Hemophilia

Hemophilia is a rare, inherited bleeding disorder due to factor VIII or IX deficiency in which blood cannot clot normally at the site of a wound or injury. The disorder occurs because those blood clotting factors are missing or do not work properly. Because a clot does not form, extensive bleeding can be caused from a cut or wound. In addition, the formation of clots are vulnerable to fibrinolysis.1,2 This is called external bleeding. Bleeding inside the body, called internal bleeding, can occur as well, especially in muscles and in joints like the hips and knees. Hemophilia affects males almost exclusively, but there are rare circumstances when a female can be affected with the disorder.

Hemophilia can occur in all races and ethnic groups. Hemophilia A affects 1 in 5,000 to 10,000 males. Hemophilia B is less common, affecting 1 in 25,000 to 30,000 males.1

Osler-Weber-Rendu syndrome (HHT – hereditary hemorrhagic telangiectasia)

HHT is a rare autosomal dominant genetic disorder leading to abnormal vascular formation in different organs, that can complicate with acute and chronic bleeding events, that might require blood transfusion in severe cases. Medical (incluidng TXA) and surgical treatments, are aimed at decreasing the amount of hemorrhage and minimizing the sequelae of arteriovenous malformations. It occurs in about one in 5,000–8,000 people in North America.3,4

Hereditary cerebral hemorrhage with amyloidosis (HCHWA)

Hereditary cerebral hemorrhage with amyloidosis (HCHWA)
HCHWA is a rare inherited autosomal dominant neurological condition in which an abnormal protein (amyloid) builds up and deposit in the walls of the arteries of the brain (and less frequently, veins), which can lead to hemorrhagic strokes, seizures, neurological deficits, cognitive decline, and dementia. Symptoms usually present before the 5th decade of life.3 There is no cure for HCHWA, and antihypertensive therapy is typically recommended.5,6

REFERENCES
  1. Meara JG, Leather AJ, Hagander L, Aikire BC, Alonson N, Ameh EA et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Surgery 2015; 158:3–6.
  2. Nepogodiev D, Martin J, Biccard B, Makupe A, Bhangu A. National Institute for Health Research Global Health Research Unit on Global Surgery. Global burden of postoperative death. Lancet 2019; 393: 401.
  3. International Surgical Outcomes Study. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth2016; 117: 601–609.
  4. Biccard BM, Madiba TE, Kluyts HL, Munlemvo DM, Madzimbamuto FD, Basenero A et al. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-dayprospective observational cohort study. Lancet 2018; 391:1589–1598.
  5. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010; 252: 11–17.
  6. Smilowitz NR, Oberweis BS, Nukala S, Rosenberg A, Zhao S, Xu J et al. Association between anemia, bleeding, and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: 315–323.e2.
  7. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth 2012; 26: 46–51.
  8. Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res 2011; 11:135.
  9. Shander A., Van Aken H., Colomina MJ., et al. Patient blood management in Europe. British Journal of Anaesthesia 2012. 109 (1): 55–68.
  10. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
  11. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
  12. Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
  13. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
  14. Ghadimi K et al. Perioperative management of the bleeding patient. British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016). doi: 10.1093/bja/aew358
  15. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33
  16. Despotis GJ, Avidan MS, Hogue CW. Jr., Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72: S1821–31
REFERENCES
  1. Cleveland Clinic – Health Library – Disease & Conditions / Hemophilia. https://my.clevelandclinic.org/health/diseases/14083-hemophilia
  2. Janbain M, Enjolras N, Bordet JC, Bolbos R, Brevet M, Leissinger C, Dargaud Y Hemostatic effect of tranexamic acid combined with factor VIII concentrate in prophylactic setting in severe hemophilia A: A preclinical study. .J Thromb Haemost. 2020 Mar;18(3):584-59.
  3. Govani FS, Shovlin CL (July 2009). “Hereditary haemorrhagic telangiectasia: a clinical and scientific review”. European Journal of Human Genetics. 17(7): 860–71. doi:10.1038/ejhg.2009.35.
  4. Dupuis-Girod S, Bailly S, Plauchu H (March 2010). “Hereditary hemorrhagic telangiectasia (HHT): from molecular biology to patient care”. J. Thromb. Haemost. 8 (7): 1447–56. doi:10.1111/j.1538-7836.2010.03860.x.
  5. HAAN J., TERWINDT G.M.. Hereditary cerebral hemorrhage with amyloidosis. Orphanet. February 2013; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=85458 .
  6. Menon RS. Cerebral Amyloid Angiopathy. Medscape. April 25, 2016; http://emedicine.medscape.com/article/1162720-overview.


GASTROINTESTINAL BLEEDING

Acute gastrointestinal (GI) bleeding is a potentially life-threatening emergency and common cause of hospitalization.1-3 The incidence of Upper GI bleeding (UGIB) is about 100 cases per 100,000 population per year.4 Bleeding from the upper GI tract is approximately 4 times more common than bleeding from the lower GI tract and is a major cause of morbidity and mortality, in part due to a hyperfibrinolytic state.4 Mortality rates from UGIB are 6%-10% overall.4,5 Variceal hemorrhage is a common condition associated with Cirrhosis.6 Esophagogastroduodenoscopy allows the identification and often treatment of these conditions, unless there is a need for surgical intervention.7

In patients with UGIB, comorbid illness, rather than actual bleeding, is the major cause of death. Comorbid illness has been noted in 50.9% of patients, with similar occurrences in males (48.7%) and females (55.4%). One or more comorbid illnesses have been noted in 98.3% of mortalities in UGIB; in 72.3% of patients, comorbid illnesses have been noted as the primary cause of death.8,9

Peptic ulcer disease (PUD) remains the most common cause of UGIB. In a literature review involving more than 10,000 patients with UGIB, PUD was responsible for 27%-40% of all bleeding episodes.10 High-risk patient populations at risk for PUD include those with a history of alcohol abuse, chronic renal failure, and/or nonsteroidal anti-inflammatory drug (NSAID) use.11

REFERENCES
  1. Meara JG, Leather AJ, Hagander L, Aikire BC, Alonson N, Ameh EA et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Surgery 2015; 158:3–6.
  2. Nepogodiev D, Martin J, Biccard B, Makupe A, Bhangu A. National Institute for Health Research Global Health Research Unit on Global Surgery. Global burden of postoperative death. Lancet 2019; 393: 401.
  3. International Surgical Outcomes Study. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth2016; 117: 601–609.
  4. Biccard BM, Madiba TE, Kluyts HL, Munlemvo DM, Madzimbamuto FD, Basenero A et al. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-dayprospective observational cohort study. Lancet 2018; 391:1589–1598.
  5. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010; 252: 11–17.
  6. Smilowitz NR, Oberweis BS, Nukala S, Rosenberg A, Zhao S, Xu J et al. Association between anemia, bleeding, and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: 315–323.e2.
  7. Christensen MC, Dziewior F, Kempel A, von Heymann C. Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth 2012; 26: 46–51.
  8. Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res 2011; 11:135.
  9. Shander A., Van Aken H., Colomina MJ., et al. Patient blood management in Europe. British Journal of Anaesthesia 2012. 109 (1): 55–68.
  10. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
  11. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
  12. Murphy GJ, Pike K, Rogers CA, et al; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
  13. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
  14. Ghadimi K et al. Perioperative management of the bleeding patient. British Journal of Anaesthesia, 117 (S3): iii18–iii30 (2016). doi: 10.1093/bja/aew358
  15. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011; 113: 1319–33
  16. Despotis GJ, Avidan MS, Hogue CW. Jr., Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001; 72: S1821–31
REFERENCES
  1. Bennie Ray Upchurch, III, Upper Gastrointestinal Bleeding (UGIB): Practice Essentials, Medscape.com, updated: Aug 12, 2019
  2. Lam KL, Wong JC, Lau JY. Pharmacological treatment in upper gastrointestinal bleeding. Curr Treat Options Gastroenterol. 2015 Dec. 13(4):369-76.
  3. Curdia-Goncalves T, Rosa B, Cotter J. New insights on an old medical emergency: non-portal hypertension related upper gastrointestinal bleeding. Rev Esp Enferm Dig. 2016 Oct. 108(10):648-56.
  4. Violi F, Ferro D, Basili S, Quintarelli C, Saliola M, Alessandri C, Cordova C, Balsano F. Hyperfibrinolysis increases the risk of gastrointestinal hemorrhage in patients with advanced cirrosis. Hepatology 1992;15:672-6. 
  5. Fallah MA, Prakash C, Edmundowicz S. Acute gastrointestinal bleeding. Med Clin North Am. 2000 Sep. 84(5):1183-208.
  6. O’Brien J, Triantos C, Burroughs AK. Management of varices in patients with cirrhosis. Nat Rev Gastroenterol Hepatol. 2013 Jul;10(7):402-12. doi: 10.1038/nrgastro.2013.51. Epub 2013 Apr 2. PMID: 23545523.
  7. Pongprasobchai S, Nimitvilai S, Chasawat J, Manatsathit S. Upper gastrointestinal bleeding etiology score for predicting variceal and non-variceal bleeding. World J Gastroenterol. 2009 Mar 7. 15(9):1099-104.
  8. Straube S, Tramer MR, Moore RA, Derry S, McQuay HJ. Mortality with upper gastrointestinal bleeding and perforation: effects of time and NSAID use. BMC Gastroenterol. 2009 Jun 5. 9:41.
  9. Yavorski RT, Wong RK, Maydonovitch C, Battin LS, Furnia A, Amundson DE. Analysis of 3,294 cases of upper gastrointestinal bleeding in military medical facilities. Am J Gastroenterol. 1995 Apr. 90(4):568-73.
  10. Stabile BE, Stamos MJ. Surgical management of gastrointestinal bleeding. Gastroenterol Clin North Am. 2000 Mar. 29(1):189-222.
  11. Cheung FK, Lau JY. Management of massive peptic ulcer bleeding. Gastroenterol Clin North Am. 2009 Jun. 38(2):231-43.

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