Hemorrhage Control and Thrombosis Following Severe Injury

Pathogenesis

Exsanguinating hemorrhage is second only to head trauma as the most common cause of death among injured patients who reach the hospital alive. Although disruption of the integrity of the vasculature is the proximate cause of the bleeding, the primary injury, the body's response, and therapeutic interventions can combine to produce a secondary coagulopathy that complicates efforts to control bleeding. This coagulopathy of trauma is a combination of the effects of blood loss, physiologic and therapeutic hemodilution, coagulation factor and platelet consumption, acidosis, hypothermia, and inappropriate fibrinolysis ( Fig. 40.1 ).

Loss of clotting activity occurs early in massive hemorrhage. The entire store of clotting activity for a healthy 70-kg man is 10 g of fibrinogen and 15 mL of platelets. Fully half of that fibrinogen and a third of those platelets can be lost in massive hemorrhage or hematomas even before the treatment of injury begins. Therapies aimed at increasing vascular volume or blood pressure can drive further blood loss.

Dilution of remaining blood by physiologic vascular refill and from the administration of asanguinous fluid or plasma-poor RBCs further reduces coagulation factor activity and platelet concentration. The loss of blood pressure leaves the plasma colloid osmotic pressure unopposed, and protein-poor fluid moves into the vascular space diluting coagulation factors and platelets. Administered nonblood fluids make the dilution worse. Emergency medical technicians and paramedics administer IV fluids in the field. Larger IV lines are placed upon arrival at the trauma center, and vascular access is tested with fluid boluses. Hypotension that threatened tissue perfusion was treated aggressively with volume until quite recently. In the early phases of trauma care, before a blood type was available, volume was provided with crystalloid fluids and uncrossmatched blood group O RBCs. Because blood volume is reduced, the combination of ongoing loss and dilute replacement leads to accelerated whole-body washout of coagulation activity.

Consumption of plasma coagulation factors and platelets leads to decreases in their concentrations in the circulating blood, especially after blunt trauma, ballistic wounds, and other high-energy-transfer injuries. Moderate injury can largely deplete the factor VII pool, resulting in the common finding of an isolated elevation of the PT. More severe injury can deplete the platelet pool, which in aggregate can cover only a very small fraction of the total endothelial surface. The lung capillary bed, as an example, has a surface area equivalent to half a tennis court, whereas the circulating blood contains enough platelets to cover 5 to 15 m ² . Moreover, certain injuries, such as head injury with brain tissue embolization, large bone fractures with fat embolization or amniotic fluid embolization, can cause acute disseminated intravascular coagulation (DIC) with defibrination.

Hypothermia can occur when the injured suffer exposure in the prehospital and assessment phases, are resuscitated with cold fluids, or sustain evaporative, convective, and conductive heat loss in the operating room. Hypothermia slows the rates of all the enzymatic plasma coagulation reactions but has its greatest effect on the activation of platelets. Platelet activation from torsion on the GP Ib,IX,V complex by von Willebrand factor is largely abolished at 30° C. This acquired Bernard-Soulier–like platelet dysfunction can result in platelets in the wound that do not secrete, aggregate, or provide active surfaces for coagulation factor complex assembly. At core temperatures between 32° C and 34° C, platelet activities are present but reduced.

Acidosis occurs when hypotension or anemia leads to loss of critical oxygen delivery to tissues. Acidosis interferes with plasma coagulation by reducing the activity of the vitamin K–dependent factor complexes on cell surfaces. These complexes are held together by the vitamin K–dependent γ-carboxyglutamic diacids of coagulation factors complexing calcium ions against negatively charged phospholipid rafts on activated platelet surfaces. Increased proton concentrations partially destabilize and markedly reduce the activity of these coagulation factor complexes.

Thrombolysis is activated at the same time as the coagulation cascade but is normally inhibited by plasminogen activator inhibitor type 1 (PAI-1) and the thrombin-activatable fibrinolysis inhibitor (TAFI). However, initial massive activation of thrombin can lead to massive activation of protein C with inactivation of PAI-1 and later, when thrombin activity is reduced by low concentrations of prothrombin or low activity of the activating complexes, TAFI is not released. Moreover, fibrin strands, normally thick when produced by high local activities of thrombin acting on normal concentrations of fibrinogen, are thin with high surface-to-volume ratios when laid down in the presence of reduced thrombin activity or low concentrations of fibrinogen. The high surface-to-volume ratio and reduced branching makes the fibrin strands more susceptible to enzymatic lysis.

The interactions of these pathophysiologic mechanisms are at least additive and in many cases multiplicative ( Table 40.1 ). Loss, dilution, and consumption all contribute to reduce the concentrations of plasma coagulation factors and platelets. Hypothermia and acidosis reduce the activities of those factors and platelets that remain. Uninhibited thrombolysis reduces the effect of the limited clotting activity available and contributes fibrin breakdown products, which interfere with further coagulation. The ongoing result of all of these mechanisms is the coagulopathy of trauma.

The coagulopathy of trauma bears a strong resemblance to, and is sometimes indistinguishable from, DIC. As noted previously, in the presence of brain, fat, or amniotic fluid embolization, coagulation with marked consumption of coagulation factors and platelets can occur in the intravascular space at sites remote from initial injury. This is classic DIC. However, in the usual situation in severe trauma, consumption of coagulation factors and platelets is largely restricted to sites of injury, but coagulation becomes ineffective because of the extent of injury, concurrent loss, dilution, hypothermia, acidosis, and thrombolysis.

Clinical Presentation

The disturbance in the coagulation system caused by the initial physiologic response, and the subsequent complications of hypothermia and acidosis, are demonstrated in clinical studies of patients arriving in emergency rooms in whom abnormal coagulation parameters were common and unrelated to dilution. The presence of an abnormal coagulation test upon arrival in the emergency department increased with the severity of the injury and predicted an increased mortality rate. An elevation in the PTT to greater than 1.5 times normal or a platelet count less than 50,000/µL were particularly ominous signs, associated with a 90% all-cause mortality in the profoundly injured.

The initial treatment of the severely injured, hypotensive patient results in an exacerbation of the coagulopathy in several different ways. Infusion of crystalloid or colloid solutions dilutes the clotting factors and platelets remaining within the vasculature. Although it is not intuitively obvious, massive transfusion of rapidly hemorrhaging patients, using a unit-for-unit ratio of red cells, plasma, and platelets will inevitably result in a coagulation defect, albeit less than if crystalloids and artificial colloids are used. Because the processing of 500 mL of donated blood involves the addition of 180 mL of anticoagulant and additive solutions and the loss of some of the cellular components in filters and bag transfers as the blood is processed, when recombined, the resulting product has a hematocrit of 29%, coagulation factor concentrations of approximately 60% of their normal levels, and a platelet count of 90,000/µL. Any increase in the relative amount of plasma or platelets transfused to correct the coagulopathy will decrease the effective hematocrit of the material infused further. In addition, transfusion of red cells, which are stored at 4° C, worsens hypothermia if blood is not warmed; and older red cell units have a decreased pH, which exacerbates the acidosis that may already be present.

Although considerable individual variability is seen, dilutional coagulopathy generally becomes a problem when more than 5 units of pRBC have been transfused without additional plasma. The clinical manifestations of this dilutional coagulopathy are a diffuse bleeding diathesis, with oozing from surgical incisions, mucous membranes, and venipuncture sites, as well as difficulty controlling the bleeding in the traumatized region.

Patients with injury to the brain are at particularly high risk for the development of bleeding problems. The brain is rich in tissue thromboplastin that, when exposed to circulating blood, activates the extrinsic arm of the clotting cascade. Traumatic brain injury is commonly associated with thrombocytopenia and coagulopathy, with the incidence increasing with the severity of the insult. DIC can be seen, although its incidence is variably reported and the definitions for acute coagulopathy of trauma and shock are more sensitive and specific. The incidence of abnormal coagulation tests increases in the population of patients with moderate or severe traumatic brain injury over the 3 days following the insult, so serial laboratory evaluation is warranted.