Surgical Critical Care

Being Fluid

Be as fluid as water, do not give your enemies anything solid to attack.

Robert Greene

Trauma-Induced Coagulopathy (TIC) doesn’t have a standard definition. It “simply” refers to an abnormal coagulation capacity attributable to trauma. TIC can manifest as a spectrum of phenotypes from hypocoagulation to hypercoagulation.  This is why for this post we won’t actually follow our normal format, but we tried to summarise information from different articles, reviews and guidelines to create a point of knowledge about TIC, aka “what do we know so far?”

Introduction

From the literature, we distinguish 2 types of TICs: an Early and a Late TIC. Early TIC (generally within 6 hours from the index injury) is characterized by the inability to achieve haemostasis, which may lead to uncontrolled haemorrhage and protracted shock. On the other hand, late TIC (usually >24 hours after injury) is represented by a hypercoagulable state, which may result in excessive macro-clotting and micro-clotting leading to thromboembolic events (e.g. deep venous thrombosis (DVT) and pulmonary embolism) or acute respiratory distress syndrome (ARDS) and multiple organ failure. 

Early and late TICs are not mutually exclusive: patients may develop early TIC due to massive blood loss, but die of extensive microvascular occlusion recognized as an irreversible shock. Furthermore, the transition from hypocoagulability to hypercoagulability may occur within minutes, hours or it may be delayed for days.

Notably, disseminated intravascular coagulation (DIC) is a syndrome related to but distinct from TIC. DIC is defined as “an acquired syndrome characterized by the intravascular activation of coagulation with a loss of localization arising from different causes”. Do you see the differences?

Early TIC is dominated by acute blood loss with associated shock, impaired clot formation and hyperfibrinolysis. Late TIC mirrors certain phenotypes of DIC due to the late systemic prothrombotic-antifibrinolytic processes.

Yes, ok… This post smells like an internal medicine/haematologist class… As Acute Care People, why do we have to know these things?

Uncontrolled bleeding has been reported to cause 25% of all injury-related deaths and 40-80% of potentially preventable deaths! TIC incidence in severely injured patients is extremely frequent! 

The remaining ongoing quagmire is the inability to distinguish between patients with exsanguinating injuries whose TIC is the result of metabolic failure (i.e. who are bleeding because they are dying) from patients whose TIC is the cause of the ongoing blood loss (i.e. who are dying because they are bleeding). Furthermore, not all patients with abnormalities in laboratory coagulation tests are bleeding! Can you smell the chaos coming out of the oven? 

Studies in civilian and military populations have indicated that TIC is more severe when both severe tissue injury and shock are present. Metabolic acidosis and penetrating injury are commonly reported risk factors for TIC. Long pre-hospital times and pre-hospital treatment with crystalloid solutions worsen TIC. The severity of TIC correlates with the severity of TBI, but studies have suggested that hypoperfusion is an important cofactor. An often-neglected factor is hypocalcaemia, caused by both shock and blood products containing citrate (especially plasma and platelets). Citrate has a well known anticoagulant effect by chelating calcium ions. For this reason, it has been suggested that the ‘lethal triad’ should include hypocalcaemia and become the ‘lethal diamond’ (The Art of Alchemy – Part 3). Of note, it is important to recognize that although TIC is common in severely injured individuals, many patients with laboratory-based TIC do not have substantial bleeding.

Physiological haemostasis is terminated when the area of injury is surrounded by a platelet–fibrin clot that stops the bleeding. This clot forms a physical barrier to the diffusion of activated factors and provides a provisional scaffold for healing processes.

Coagulopathy occurs not only when procoagulants are consumed or diluted, but also when one or more of the control mechanisms are disrupted. Cells have an active role in regulating and localizing the coagulation reactions, especially platelets and endothelial cells. Platelets adhere at a site of injury and provide the surface on which procoagulants reactions occur. Impaired cell-mediated regulation of haemostasis can lead to hemostasis failure even when the levels of protein components are normal. In the cell-based model of haemostasis, the overlapping events of initiation, amplification and propagation of large-scale thrombin generation are regulated by cell surfaces rather than by the protein components alone. 

The lethal triad is also composed of acidosis and hypothermia: indeed a pH drop from 7.4 to 7.2 reduces the activity of each of the coagulation proteases by more than half and hypothermia remains a marker for poor a prognosis after haemorrhage, probably representing metabolic dysfunction again.

Most trauma patients with high ISS are in haemorrhagic shock, how does it affect coagulation?

The pathophysiology of haemorrhagic shock is fundamentally blood volume depletion with diminished oxygen delivery to the microcirculation, ultimately resulting in metabolic acidosis. Although isolated transient haemorrhagic shock may be tolerated, when it is compounded by tissue injury, haemodilution and coagulation factor abnormalities, it is a major driver of TIC. It is important to distinguish early hypocoagulable TIC from iatrogenic coagulopathy secondary to inappropriate resuscitation with large volumes of cold fluids and blood products.

Hypocalcemia is another mechanism by which haemorrhagic shock can impair coagulation. Calcium has an important role in the formation and stabilization of fibrin polymerization sites and, consequently, it affects all platelet-dependent functions. Hypocalcaemia is prevalent after haemorrhage, owing to resuscitation with citrated blood products, low hepatic clearance of citrate due to defective hepatic perfusion, and other still poorly understood shock-related mechanisms.

As haemorrhagic shock progresses, hypercoagulability ensues, owing to prothrombotic changes and fibrinolysis shutdown that promote organ damage by generating thrombi and occluding the microvascular circulation, leading ultimately to organ failure. 

And the extent of tissue injury? 

Tissue injury promotes both early hypocoagulability and later hypercoagulability. Tissue damage with endothelial disruption activates the coagulation system at the injury site via TF, a transmembrane protein expressed within the sub-endothelium that becomes exposed. The development of TIC is typically associated with the severity and extent of tissue injury. 

It is also possible that the specific organ(s) affected by tissue damage contribute to TIC. For example, TBI creates a hypocoagulable state that has been suggested to be partially attributable to the cerebral tissue releasing high concentrations of potent procoagulant molecules. Apparently, damage to organs with high contents of tissue plasminogen factor (tPA; which is profibrinolytic), such as the pancreas, lungs and urogenital system, may also compromise haemostasis via fibrinolytic activation. However, the exact contribution of these organ injuries is unknown. In addition, tissue injury has also been directly correlated with fibrinolysis shutdown through the release of cellular by-products of injury, as well as mechanical trauma to red blood cells (RBCs) and platelets, leading to the release of their contents. 

How are platelets involved?

Platelets are biologically dynamic in coordinating haemostasis, endothelial health and immune function. Interest in the role of platelets in TIC intensified following the description of the cell-based model of haemostasis in 2001.

Most patients with TIC have preserved platelet counts and evidence of circulating populations of activated platelets, yet paradoxically impaired ex vivo aggregation responses. This phenomenon is described as ‘platelet exhaustion’, due to injury and shock, and it is driven by the endothelial release of TF, platelet-activating factor and vWF that activates platelets beyond what is needed for primary haemostasis at the local sites of injury. This thereby creates a pool of activated circulating platelets that are ‘spent’ or exhausted following the release of their procoagulant and anticoagulant factors. Importantly, these acquired platelet dysfunctions of TIC may not be reversed by transfusion of platelets stored at room temperature, perhaps owing to injury-induced and shock-induced circulating platelet inhibitors. Recent work suggests cold-stored platelets may be more effective in restoring platelet contribution to haemostasis.

Still, many question marks are unsolved…

Could also an inappropriate thrombin generation have a role?

In the initial phases of bleeding, thrombin generation may be insufficient, whereas later excessive thrombin generation may contribute to adverse thrombotic events. Insufficient thrombin concentration results in clots composed of thick fibrin fibres with diminished stability, which are more prone to fibrinolysis. Depletion of endogenous inhibitors after the injury can offset a decrease in procoagulants and increase the risk of thromboembolic complications. Thrombin generation can be altered by dilution of coagulation factors following fluid therapy, rapid coagulation factor consumption immediately after injury, shock-related systemic acidosis and hypothermia.

Importantly, standard coagulation assays do not reflect the activity of the anticoagulant systems. Thus, a slightly prolonged prothrombin time (PT), international normalized ratio (INR) or activated partial thromboplastin time (aPTT) could reflect a modest depletion of procoagulants, which is not necessarily accompanied by diminished thrombin generation and a bleeding tendency in vivo, as it is offset by depletion of anticoagulants. 

Concerning late TIC, thrombin is at the cross-road of coagulation and inflammation, and excessive thrombin generation may have an important role in delayed hypercoagulability in injured patients.

Is fibrinogen depletion important?

Fibrinogen is the most abundant coagulation factor in the blood, with circulating levels in the range of 2–4 g/L in a healthy adult and a circulating half-life of about 4 days. Conversion of fibrinogen to fibrin occurs via thrombin-mediated cleavage at two sites, exposing binding sites for other fibrin molecules, thereby giving rise to spontaneous polymerization. Circulating fibrinogen levels increase up to 20-fold in the acute phase response, mediated by IL-6 release following tissue injury, infection and inflammation. Despite its high circulating concentrations, fibrinogen is the first coagulation factor to reach critically low levels in severe bleeding events.

In major trauma, key contributors to hypofibrinogenaemia include haemodilution (due to fluid resuscitation), blood loss, consumption in clot formation at the wound sites, hypothermia (which impairs fibrinogen synthesis), fibrinogenolysis and increased degradation due to acidosis. Low fibrinogen levels upon admission are independently associated with an increase in injury severity and shock. Moreover, the fibrinogen level upon admission is an independent predictor of the need for transfusion and 24-hour and 28-day mortality.

What about dysregulated fibrinolysis?

Fibrinolysis activation following severe injury has been documented for over half a century. Although the exact pathophysiology remains unclear, hyperfibrinolysis is exacerbated by the loss of fibrinolytic inhibitors, including α2 antiplasmin and platelet dysfunction.

Hyperfibrinolysis is suppressed in most patients with traumatic injury by a surge of PAI-1 that initiates at 2 hours from injury and results in shutdown of fibrinolytic activity in the majority of patients by 12 hours.

The precise mechanism of acute fibrinolysis shutdown remains unclear. There is some evidence that the plasminogen-binding protein, S100-A10, is shed into the circulation and may associate with tPA, thereby impeding fibrinolysis. Resuscitation promotes PAI-1 elevation in most injured patients, and the increase is pathological if sustained beyond 24 hours.

Patients with low fibrinolytic activity, measured by viscoelastic activity tests and elevated D-dimer or plasmin–antiplasmin levels, have increased mortality compared to patients with balanced fibrinolytic activity, with significantly less blood product utilization than patients with hyperfibrinolysis. Patients with fibrinolysis shutdown tend to have delayed mortality from brain injury and organ failure, whereas patients with hyperfibrinolysis die early from haemorrhage.

Patients with a traumatic injury who retain low fibrinolytic activity beyond 24 hours (both adults and children) exhibit increased mortality. This phenomenon could be attributed to elevated PAI-1, which is associated with poor outcomes in sepsis. However, this event requires further investigation in trauma.

Now that we have some sort of basis let’s try to move on…

Clinical trials have demonstrated challenges in identifying patients at risk of major bleeding, and, therefore, clinically relevant TIC. First, there is controversy over the definition of massive transfusion. 

When we speak of Early TIC, the conventional tests include a platelet count, Clauss assay to measure fibrinogen level, PT and aPTT. Major limiting factors with these assays are the time to obtaining results from multiple tests and the inability to identify hyperfibrinolysis. The alternative currently is VHAs (viscoelastic haemostatic assays), which provide several measurements in a single readout. Up to now, the exact definition of TIC based on conventional coagulation assays remains a topic of debate as investigators argue over the PT or INR and aPTT thresholds. Of note, PT or INR reflect only the contribution of plasma proteins to clot formation, without regard for the central role of platelets. Consequently, VHAs have been adopted for the diagnosis of TIC in many countries, owing to their assessment of whole-blood clot formation and degradation in real-time, although there has been criticism regarding assay reproducibility of older versions of VHA devices. Viscoelastic evidence of decreased clot strength has repeatedly been associated with massive transfusion and increased mortality in trauma, although there is disagreement on specific thresholds defining hyperfibrinolysis. 

Trying to define TIC with a single laboratory measurement is imprecise. TIC is a complex process that involves the endothelium, platelets, circulating coagulation factors and the immune system, and no single assay or set of assays available to date can effectively integrate the measurements of the crucial coordinated events involved in vascular homeostasis to provide a comprehensive evaluation. Even in the setting of an abnormal laboratory test result, the clinical status of the patient ultimately drives decision making; abnormal laboratory results should not be corrected with blood products in a patient with no clinical signs of coagulopathy and requiring no surgical or interventional haemostasis.

In Late TIC, shock is the dominant risk factor in early TIC, whereas tissue injury is more influential in late TIC. The specific laboratory definition of late hypercoagulable TIC remains elusive. However, several studies have identified increased clot strength and fibrinolysis shutdown following resuscitation, as measured by VHAs, as risk factors for VTE and stroke. Effective prevention of thromboembolic complications requires a better understanding of the underlying mechanisms, which seem likely to be at the crossroads of inflammation and coagulation extending beyond Virchow’s triad (i.e. hypercoagulability, stasis, endothelial damage).

Finally, we can try to speak of the management!

The priorities in the management of the patient at risk for life-threatening bleeding are:

  1. mechanically stopping the bleeding, which is fundamentally limited to tourniquets and direct pressure on bleeding sites in the field and rapid access to a capable trauma surgeon;
  2. reversing hypovolaemic shock, largely through the restoration of circulating blood volume;
  3. restoring clotting homeostasis through administering the right blood products to the right patient at the right time;
  4. damage control resuscitation and damage control surgery are further measures in patients at high risk of TIC.

The European guidelines on the management of major bleeding and coagulopathy following trauma strongly emphasize fibrinogen replacement to overcome the rapid depletion of fibrinogen in patients with a traumatic injury. This approach varies from a largely ‘plasma and platelets first’ approach to haemostatic resuscitation in the United States. Further complicating this issue is the lack of stored blood in many under-resourced settings, making recommendations for management regionally dependent.

Here is a suggestion about how to organize a massive transfusion protocol. Remember, this is just one suggestion, please check if in your institution there is already one or you need to create one in concert among surgeons, anaesthetists and blood banks.

A short recap?

“Perhaps the most conspicuous gaps to be addressed in the management of TIC are a clinical definition and the ability to further distinguish between the dynamic early hypocoagulable state and the late hypercoagulable state on the basis of mechanistic foundations. The initial proposal to use PT or INR to define early TIC was subsequently questioned, and these measurements are rather considered biomarkers of injury. Clinical coagulation scoring systems have been developed but are relatively insensitive unless based on body cavity exposure in the operating room. Definitions of massive transfusion do not capture the effect of TIC on TBI. Additionally, multiple TIC phenotypes exist, and these need to be defined to optimize goal-directed therapy. Finally, in patients with refractory early TIC, we are unable to distinguish those who are dying because they are bleeding from those bleeding because they are dying.”

As you can understand this is something where a lot of effort is pushed to understand the pathophysiology of TIC and then the proper treatment.

We hope these lines are of some help!

See you next time!

Namasté…

References
  1. Spahn DR, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care 2019;23:98; DOI: 10.1186/s13054-019-2347-3.
  2. Moore EE, et al. Trauma-induced coagulopathy. Nat Rev Dis Primers 2021;7:30. DOI: 10.1038/s41572-021-00264-3.
  3. European Resuscitation Council and European Society for Trauma and Emergency Surgery. European Trauma Course.
  4. Boffard KD. Manual of Definitive Surgical Trauma Care. 5th Ed. Boca Raton, FL: CRC Press; 2019.
How to Cite This Post

Marrano E, Bellio G. Being Fluid. Surgical Pizza. Published on September 13, 2021. Accessed on September 18, 2021. Available at [https://surgicalpizza.org/critical-care/being-fluid/].

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