(and a few interesting facts about clotting mechanisms)

First of all, the 10mL of fluid is not saline. In fact, two decades of research tells us that aggressive crystalloid resuscitation is harmful.^[1]

Saline presents many challenges when used to resuscitate hypotensive patients:

• It’s acidic nature causes the body to use and deplete its natural buffers which leads to increased acidosis
• It is pro-inflammatory and is associated with poor outcomes
• It dilutes clotting factors
• It is often cold and contributes to hypothermia

All of this increases mortality by exposing the patient all three aspects of the Trauma Triad of Death:

• Hypothermia
• Coagulopathy
• Metabolic Acidosis

This triad of factors refers to the conditions which increase mortality in the trauma patient. Uncontrolled bleeding causes hypothermia which leads to reduced clotting or ‘Coagulopathy’. Uncontrolled bleeding also leads to hypoxia in tissues which causes metabolic acidosis and decreased myocardial pumping, this leads to further acidosis and increased hypothermia and reduced clotting. This condition continues to spiral out of control unless blood pressure is stabilized, hypothermia is corrected and acidosis reversed.

Early control of bleeding and avoiding hypothermia are the most important aspects of trauma management.

Hypothermia is easily correctable but paramedics often under-appreciate how harmful it is. Clotting is three times longer at +22 degrees C than at +37 degrees C.^[2]

But there is a relatively new therapy that can save lives

Tranexamic Acid or TXA is gaining popularity worldwide for its effectiveness in controlling internal bleeding.

Most of the evidence comes from two major studies. The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage or ‘CRASH 2’^[3] study and the ‘Matters’^[4] study. The CRASH 2 Study predicted a 32 percent reduction in death due to uncontrolled hemorrhage if TXA was given within one hour. The Journal of Intensive Care had this to say about the CRASH 2 study results:

So how does it work?

Drug action

When the body is subjected to hypotensive episodes, changes to the inner lining of our blood vessels secrete substances that break down clots and promote bleeding. This is referred to as ‘Acute Traumatic Coagulopathy’. Acute Traumatic Coagulopathy is present on admission in 25% of trauma patients and associated with a 5-fold increase in mortality.^[6]

Tissue and endothelial blood vessel damage lead to release of tissue plasminogen activator (t-PA). tPA combines with plasminogen to make plasmin. Plasmin breaks down clots. This is the body’s way of re-establishing circulation after the occlusion of a blood vessel as seen in myocardial infarction.

Clearly, tPA is helpful if you suffer from vessel occlusion due to clotting. But In cases of traumatic coagulopathy, the situation is reversed and tPA secretion works against survival.

Bleeding due to trauma is one of those situations where paramedics can help the body to adapt to abnormal situations. In this case TXA is helpful because TXA binds to the same receptor as tPA but instead of stimulating clot breakdown, TXA occupies the receptor and effectively blocks other molecules from breaking down the clot. This results in clot formation and reduction of life threatening hemorrhage.

So…to summarize, if I’m having a heart attack, clot breakdown is as welcome as a cold beverage on a sunny day.

But if I’m bleeding out because my spleen has ruptured, clot breakdown is as welcome as a Donald Trump Tweet during the Cuban Missile Crisis. Therefore, I want my paramedic to give me TXA and a blanket!

Interesting Facts

An intriguing feature is the circadian variation in t-PA that has been observed. Free t-PA levels are lowest in the morning and increase during the day to reach their peak activity level in the late afternoon.  It has been suggested that the high incidence of myocardial infarction and cerebral thrombosis in the morning hours, may be connected to the circadian rhythm of fibrinolytic activity.

Mortality statistics in Greenland show that Eskimos have a low prevalence of myocardial infarction. This has been related to their diet, although it may also be due to the observation that Eskimos have a rapid increase in t-PA activity in the morning compared to Caucasians.^[7]

Alcohol

Most reports on alcohol and fibrinolysis show an increase in plasma PAI-1 levels following alcohol consumption. PAI causes an acute decrease in t-PA activity. In a recent study of moderate alcohol consumption in a group of healthy men, it was observed that t-PA activity falls sharply after alcohol intake for the first 5 hours, although it then rises and becomes significantly higher after 13 hours. Moderate alcohol consumption may therefore be associated with a lower risk of coronary heart disease ‘the day after’.

Exercise

A rise in the fibrinolytic activity after exercise has been reported by many authors and attributed mainly to the acute release of t-PA from the vascular endothelium. The increase in t-PA activity is related to both the intensity and the duration of exercise and may reach 30 times the normal after a marathon race. When comparing physically active and inactive men, it was found that t-PA activity increases more in active men.

Insect venom

The release of t-PA from the endothelium may be involved in the pathogenesis of anaphylactic shock induced by insect venom. Levels have been found to increase about 10-fold following a controlled insect-sting challenge in subjects with a previous history of insect-sting induced anaphylactic reaction.

Venous occlusion

The venous occlusion test is often used to test subjects for their capacity to release t-PA from the occluded venous segment. A test takes 5-20 minutes and involves a blood pressure cuff on the upper arm, inflated midway between the systolic and diastolic blood pressure. The t-PA activity rises 3-12 times.

Smoking

Chronic smoking induces higher baseline levels of t-PA and PAI-1 antigen and lower t-PA activity. In addition, the release of t-PA after a venous occlusion is impaired in chronic smokers.^[8]

<sup>1. ROC Hypotensive Resuscitation Field Trial of Hypotensive versus Standard Resuscitation in Patients with Hypotension after Trauma. 2014
2. Crit Care Med. 1995 Apr;23(4):698-704. Effects of temperature on bleeding time and clotting time in normal male and female volunteers. Valeri CR1, MacGregor H, Cassidy G, Tinney R, Pompei F.
3. 32 % reduction in bleeding related death if given within 1 hour of trauma event CRASH 2 study, March 2011 (the Lancet) http://www.thelancet.com/crash-2
4. MATTERS, Morrison et all. October 2011 http://www.medschool.lsuhsc.edu/emergency_medicine/docs/archsurg.tranexemic%20acid.pdf
5. Tranexamic acid and trauma-induced coagulopathy Takeshi Nishida, Takahiro Kinoshita and Kazuma YamakawaEmail authorView ORCID ID profile Journal of Intensive Care20175:5 https://doi.org/10.1186/s40560-016-0201-0
6. Brohi K, Singh J, Heron M et al. Acute traumatic coagulopathy. J Trauma 2003; 54:1127–1130.
7. https://diapharma.com/tissue-plasminogen-activator-tpa/
8. https://diapharma.com/tissue-plasminogen-activator-tpa/</sup>