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 high^3,4 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 mortality^5–7 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.

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

Hemorrhage due to trauma is the leading preventable cause of death in the military setting¹, accounting up 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 patients^11,12, longer hospital stay, and higher mortality. The recognition of this early coagulopathy leads to the use of new terminology and proposed hypotheses.^13,14

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.

 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

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

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

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