Hemorrhage and Coagulopathy Case File
Eugene C. Toy, MD, Manuel Suarez, MD, FACCP, Terrence H. Liu, MD, MPH
Case 41
A 20-year-old man is brought from the operating room to the ICU following a dam age-control operation for multiple gunshot wounds. The patient was reportedly unstable throughout the entire operation. The injuries indentified include transection of the left superficial femoral artery (SFA) and multiple small bowel perforations. During the operation, the patient had 3 small bowel segments resected and had placement of a temporary intraluminal shunt in the SFA to control the bleeding and reestablish blood flow to his leg. At the time he arrives to the ICU, his temperature is 34.6°C, pulse rate is 128 beats/minute, and blood pressure is 90/70 mm Hg. He is intubated and mechanically ventilated. The patient is bleeding externally from his wounds and multiple intravenous catheter sites.
⯈ What is the most likely diagnosis?
⯈ What are the causes of the patient's current condition?
⯈ What are the priorities in this patient's management?
ANSWER TO CASE 41:
Hemorrhage and Coagulopathy
Summary: A 20-year-old man has gunshot wounds through his abdomen and extremity. The bowel injuries have been controlled with resection, and the vascular injury has been controlled with a temporary shunt. He was noted to be unstable throughout the surgery. His presentation to the ICU is consistent with shock and coagulopathy.
- Most likely diagnosis: Hemorrhagic shock and coagulopathy.
- Causes of patient's condition: Trauma with massive blood loss and transfusion and hypothermia.
- Priorities in this patient's management: Warm the patient, resuscitate with packed red blood cells (PRBCs), fresh frozen plasma, and platelets to correct coagulopathy and acidosis.
ANALYSIS
Objectives
- To learn the principles of massive transfusion.
- To learn the conditions that contribute to coagulopathy following massive transfusions.
- To understand the limitations of laboratory studies for the evaluation of patients with this condition.
Considerations
This patient suffered significant penetrating trauma that required a damage-control operation and temporary shunting of the SFA. On admission to the ICU, he is hypotensive, tachycardic, and is bleeding from his wounds and catheter sites. His surgical bleeding site has been controlled (shunting of the SFA), but he continues to bleed from his wounds, indicating that he has a significant coagulopathy. During the operation, he has lost not only red blood cells, but also the coagulation factors that are present in his plasma. Additionally, he is hypothermic, which is common among trauma victims.
The hypothermia usually starts in the emergency department during the initial resuscitation and continues while in the operating room. Trauma patients have all of their clothes removed and are infused with normal saline and PRBCs that may not be warm. In the operating room, their chest and/or abdomen may be open, increasing their heat loss. They also may be paralyzed for intubation, which prevents shivering. All of these mechanisms can lead to profound hypothermia. The hypothermia actively slows down the coagulation process, exacerbating coagulopathy and continued nonsurgical bleeding (ie, bleeding that cannot be controlled by suture ligation). It is likely that this patient is also acidotic from incomplete resuscitation, which can also worsen the coagulopathic state. The combination of acidosis, hypothermia, and coagulopathy is often referred to as the "triad of death."
Approach To:
Hemorrhage and Coagulopathy
DEFINITIONS
HEMOSTATIC RESUSCITATION: Hemostatic resuscitation is a relatively new concept that evolved largely based on clinical observations from injuries managed during the conflicts in Iraq and Afghanistan. This begins with limitation of fluids in the field, application of tourniquets and hemostatic agents for direct bleeding control. Once victims arrive to the medical care facility, the resuscitation is directed to preserve coagulation functions rather than restoring normal vital signs.
MASSIVE TRANSFUSION: A commonly used definition is the transfusion of >10 U of PRBCs in 24 hours. Patients who require massive transfusion have suffered a large amount of blood volume losses; therefore, they require the replacement of PRBCs, fresh frozen plasma, and platelets in a short time period. These components are often given in ratios that mimic whole blood concentrations.
FACTOR VII: Coagulation factor that can be made in recombinant fashion and administered to patients who are coagulopathic.
THROMBOELASTOGRAPHY: Method for real-time measurement of coagulation status. The results report the time to clot formation and the clot strength. They can be used for goal-directed administration of blood products.
PLATELETPHERESIS: Process whereby the platelets are separated from the other blood components and the remaining components are returned to the donor. Thus, a unit of plateletpheresis consists of approximately 6-7 units of random platelet units.
CLINICAL APPROACH
Massive Transfusion Principles
Hemorrhage remains one of the leading causes of preventable deaths in trauma patients. The cause of death goes beyond just exsanguination. Up to one-third of all trauma patients who present to the hospital already have a coagulopathy due to tissue injury, hypoperfusion, and loss of clotting factors and platelets via hemorrhage. Accentuation of this initial coagulopathy may also be mediated by an increase in fibrinolysis via a protein C pathway. Surgical control of the hemorrhage is the primary therapy of ongoing bleeding. Until surgical control of hemorrhage is accomplished, the patient should be resuscitated with volume. Historically, the correction of hypovolemia caused by hemorrhage was infusion of large volumes of crystalloids. Normal saline was the crystalloid of choice, but infusion of large volumes of normal saline has untoward complications; dilutional coagulopathy, thrombocytopenia, and hyperchloremic acidosis from large crystalloid infusions increases coagulopathy. Ongoing hemorrhage affects all 3 components of the "triad of death" and increases coagulopathy.
The complications of resuscitating a patient with large volumes of crystalloid has led to a "hemostatic resuscitation" approach: resuscitating the patient with blood and blood products that will help mitigate the coagulopathy of trauma until definitive control of the bleeding is achieved.
The goal of a hemostatic resuscitation is to replace the patient with products that approximates the blood that they have lost. This hemostatic resuscitation isoften referred to as a "massive transfusion" as it includes large volumes of PRBCs, fresh frozen plasma, and platelets. There is no one single definition of what constitutes a massive transfusion, but several definitions have been proposed. These include:
1 . Replacement of 1 entire blood volume within 24 hours.
2 . Transfusion of > 10 U of PRBCs in 24 hours.
3 . Transfusion of > 20 U of PRBCs in 24 hours.
Also, there are definitions of "dynamic massive transfusion" including
1 . Transfusion of >4 U of PRBCs in 1 hour when ongoing need is foreseeable.
2. Replacement of 50% of total blood volume within 3 hours.
When patients receive a blood transfusion, they are actually receiving a transfusion of PRBCs. This is the end product of whole blood (taken from a donor) that has been centrifuged so that the heavier components (the red blood cells) can be separated from the lighter components (the plasma and platelets). The coagulation factors remain in the plasma component. When a patient is transfused, they receive red blood cells to increase oxygen-carrying capacity, but do not receive any coagulation factors. Multiple transfusions of PRBCs without addition of coagulation factors will lead to a dilutional coagulopathy. Thus, during massive transfusions, when patients are given large volumes of PRBCs, they should also be given fresh frozen plasma (FFP) to provide hemostatic factors. The exact ratio of PRBCs to FFP to provide the perfect hemostatic scenario is not known. However, most experts would agree that a 1:1:1 ratio of PRBCs:FFP:platelets is the best formula for a hemostatic resuscitation. One unit of plateletpheresis is approximately 6 to 10 random platelet concentrates, so 1 U of single donor plateletpheresis is transfused after 6 U of PRBCs and FFP.
Coagulopathy Following Massive Transfusions
Up to one-third of trauma patients with significant injury will present to the trauma bay with a coagulopathy already in progress. This is in part due to loss of coagulation factors from bleeding, as well as tissue injury and hypoperfusion. To understand the conditions that affect coagulopathy after massive transfusions, it is first important to understand the normal process of coagulation. The major physiologic events that occur during coagulation are vasoconstriction, platelet plug formation, fibrin formation, and fibrinolysis. During platelet plug formation, the coagulation factors interact with the surface of the platelets to form a fibrin lattice that provides support to the platelet plug.
During and after massive transfusion, many of the factors associated with normal coagulation are altered. Thrombocytopenia limits the amount of platelet plug that can be formed at the site of injury. Initially, this is caused by absolute loss of platelets from hemorrhage and dilution from crystalloid administration. The infusion of large volumes of crystalloid contributes to coagulopathy during massive transfusions. Therefore, crystalloid infusion should be limited during massive transfusions. Then, during the massive transfusion, PRBCs and FFP are administered, both of which contain minimal amounts of platelets. This can lead to further drop in the platelet count. Often, hospitals have a limited supply of platelets, due to their short shelf life. This can lead to a delay in the administration of platelets, even during massive transfusions given by protocol.
The storage solution for blood products contains citrate as a preservative to keep the products from clotting during storage. Citrate is a strong binder of calcium, so when large volumes of PRBCs are given, intravascular stores of calcium can be depleted. Coagulation defects can be seen when calcium levels drop below 0.7 mmol/L.
Despite administration of all blood components (RBCs, FFP, platelets), coagulopathy can still be seen in some patients during massive transfusion. It is thought that administration of specific clotting factors can help the coagulation process. Factor VII can be made in a recombinant fashion and administered intravenously. The administration of recombinant activated Factor VII (rFVII) is still controversial. In a randomized controlled trial, rFVII was shown to decrease the PRBCs use by 20% in trauma patients who required massive transfusions. The administration of rFVII contributes to a prothrombotic state, which could increase the risk of venous thromboembolic events. In recent studies, there does not appear to be an increased risk for thromboembolic events in trauma patients.
Other life-threatening problems that exacerbate coagulopathy are hypothermia and acidosis. These 3 problems combined are often referred to as the "triad of death" and each problem compounds the other. Hypothermia often begins in the trauma bay and continues to progress through the operating room and even into the ICU. Hypothermia directly affects the coagulation cascade by inhibiting the initiation of clot formation and increasing the time it takes for thrombin levels to reach normal. It is extremely important in all trauma patients to keep them warm by warming the fluids administered (including blood products) and keeping the patient covered with warm blankets or other warming devices. Acidosis is often started by hypoperfusion of tissue after blood loss, but can be exacerbated by administration of large volumes of normal saline. The chloride content of normal saline (154 mEq/L) can lead to a hyperchloremic acidosis. Acidosis impairs the ability of thrombin to participate in hemostasis and severely inhibits the activity of enzyme complexes on lipid surfaces.
Laboratory Studies
Current management of patients undergoing massive transfusions include frequent laboratory monitoring of arterial lactate to assess adequacy of resuscitation, ionized calcium, and electrolytes. The laboratory values that are used to determine the coagulation status of the patient are the prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). These tests are problematic in trauma patients in that the trauma patient's actual coagulopathic state is in constant flux as they are continuously receiving large volumes of blood, plasma, and platelets. The standard coagulation lab examinations take time to analyze, so the result reported does not necessarily reflect the patient's coagulation state when the results are returned. Also, in order to run the PT/PTT tests, the patient's blood sample is warmed to 37°C and mixed with platelet-poor plasma. Trauma patients are often hypothermic, so this analysis again does not reflect the patient's actual coagulation status, nor does it reflect the cellular interactions of clotting.
Evidence is starting to show that rotational thromboelastometry (ROTEM) or thromboelastograms (TEGs) are superior to standard coagulation measurements in trauma patients. These lab tests can be performed in a near real-time analysis and return rapid results. This allows for immediate analysis and goal-directed therapy of the coagulation disorder. The thromboelastogram (Figure 41-1) is measured on a
Figure 41-1. A sample of (elite-activated whole blood (0.4 mL) is placed into a prewarmed cuvette. A pin suspended from a torsion wire is then lowered into the cuvette. The cuvette is rotated backward and forward in a small arc. As the fibrin strands interact with the activated platelets on the surface of the pin, the rotational movement of the cuvette is transmitted to the pin. The stronger the clot, the more the pin moves.
small aliquot of whole blood and measures the clotting time (R value), clot formation (α-angle), clot strength (MA, maximum amplitude), and clot lysis (LY 30). The clotting time measures the time to onset of clot formation. An increase in the clotting time represents a deficiency of coagulation factors. The kinetics of the clot formation is represented by the α-angle. This represents the rate of fibrin build-up and cross-linking. The maximum amplitude is a measurement of the overall clot strength. The clot strength is a representation of platelet and fibrin interactivity. The use of TEG has shown to decrease the mortality rate and improve transfusion practices in patients receiving massive transfusions.
CLINICAL CASE CORRELATION
- See also Case 4 (Hemodynamic Monitoring), Case 5 (Vasoactive Drugs and Pharmacology), Case 21 (GI Bleeding), Case 26 (Fluid and Electrolyte Abnormalities), and Case 28 (Blunt Trauma).
COMPREHENSION QUESTIONS
41.1 A 20-year-old man is shot in the right upper quadrant of his abdomen. On admission to the trauma bay, the paramedics inform you that he has 2 large bore IVs and has been given 2 L of normal saline en route to the hospital. His airway is patent, he is breathing spontaneously with oxygen saturations of 99% on 2 L/min by nasal cannula. His blood pressure is 80/40 mm Hg and his heart rate is 120 beats/minute. He has a missile wound to the right upper quadrant of the abdomen. His abdomen is very tender and he is cold and diaphoretic. The best next step in treatment for this patient is:
A. Administer 500 mL of 5 % albumin.
B. Administer 2 L of lactated Ringer solution.
C. Give 2 U of type-specific blood.
D. Give 2 U of non-type-specific blood (O negative).
E. Warm the patient and send for coagulation labs.
41.2 A 37-year-old woman is brought in by paramedics after sustaining a severe crush injury of her right lower extremity. She is taken to the operation room (OR) where her lower extremity is explored, washed out, has an external fixation device placed, and a wound vacuum device placed over the open wound. The surgery takes several hours, and she is admitted to the ICU after the surgery. Her wound vacuum output is 1.5 L of frank blood over the next 4 hours. She received 2 U of PRBCs during the surgery and has received 3 more units since arriving in the ICU, and 1 more unit is being transfused now. Her heart rate is 120 beats/minute and her blood pressure is 90/60 mm Hg. Her current hemoglobin concentration is 7 g/dL and platelet count is 475,000. Her INR is 1.9. Her temperature is 35°C. The best next step in management of this patient is:
A. Transfuse platelets.
B. Transfuse FFP and recheck INR in 2 hours.
C. Take patient to OR for continued bleed from wound.
D. Decrease the wound vacuum suction.
E. Transfuse 2 more units of blood and recheck hemoglobin.
41.3 A patient is undergoing a massive transfusion during an operation for a Grade IV liver laceration. He has received 9 U of PRBCs and 8 U of FFP. The best next step in treating this patient is:
A. 4 more units of PRBCs
B. 2 L of crystalloid
C. 1 U of plateletpheresis
D. 6 U of plateletpheresis
E. 1 U of cryoprecipitate
41.4 A 63-year-old woman is undergoing colectomy for severe diverticulitis. During the operation, there is a significant amount of bleeding from an unidentified mesenteric vessel. The surgeons have stated that they are having difficulty getting control of the vessel and have called for a vascular surgeon. While the surgeons are working to get surgical control of the bleeding, she has been transfused 6 U of PRBCs in the last hour. She is still bleeding and intermittently hypotensive. The next step in management is:
A. Continue to transfuse red blood cells based on whether she is still hypotensive.
B. Continue to work on surgical control of bleeding and begin a massive transfusion protocol.
C. Check her INR and transfuse FFP only if INR >2.0.
D. Administer rFVII and normal saline intravenously
ANSWERS TO QUESTIONS
41.1 D. This patient has a gunshot wound to the right upper quadrant and is hypotensive and tachycardic. His appearance is consistent with high grade of shock. He is breathing and has normal saturations, so it is unlikely that he has an injury to his chest. His abdomen is tender and he most likely has blood in his abdomen. In this patient who has already received 2 L of normal saline before reaching the hospital and is still hypotensive, it is appropriate to start giving the patient blood. In the initial trauma setting, it is inappropriate to wait for type-specific blood. The first blood transfusions should be non-type and crossed blood (Type O). A sample of the patient's blood should be sent for analysis so that future transfusions can be cross-matched. While it is important to start warming the patient as soon as possible, immediate resuscitation with blood and blood products predicates the warming and evaluation of coagulation status.
41.2 C. This patient suffered a significant injury to her lower extremity that required an operation, fixation device, and wound vacuum placed over her open wound. After being admitted to the ICU, she continues to have several problems. Her bleeding has not stopped, she has low blood concentrations, her coagulation has elevated, and she is cold. The most concerning aspect of this patient is her continued bleeding as noted by the high output of blood in her wound vacuum. When faced with a patient who does not respond appropriately to resuscitation, it is important to consider that the cause is inadequate "source control." In this case the acute surgical bleeding must be stopped so that she can be adequately resuscitated. It is likely that she will need more blood, FFP, and possibly platelets while the bleeding is being controlled, but the first step is to control surgical bleeding.
41.3 C. During a massive transfusion, the goal is to achieve a hemostatic resuscitation. Although this is best achieved in a 1:1:1 ratio of blood products. One pack of plateletpheresis equal to 6 to 10 packs of pooled platelet packs. Thus, after 6 to 8 U of PRBCs and FFP are given, 1 U of platelets should be administered.
41.4 B. This patient has required 6 U of PRBCs in the last hour and there is anticipation that the she will have ongoing transfusion requirements. This meets the definition of a dynamic massive transfusion needs. While the surgeons are gaining surgical control of the bleeding, a massive transfusion should begin so that hemostatic resuscitation can be started to decrease the probability that the patient will become coagulopathic.
CLINICAL PEARLS
⯈ Up to one-third of all trauma patients who arrive to the emergency department are already coagulopathic.
⯈ The "triad of death" is the presence of coagulopathy, acidosis, and hypothermia. Each of these detrimental conditions exacerbates the other and should be preempted by active warming of the patient and the use of hemostatic resuscitation.
⯈ The current recommendation for massive transfusions is that it should be done in a 1:1:1 ratio of PRBCs:FFP:platelets.
⯈ The standard coagulation laboratory studies lag behind in severely injured trauma patients undergoing massive transfusions. TEG or ROTEM analysis is likely a better representation of the patient's actual coagulation status.
⯈ One unit of single pool plateletpheresis is equivalent to 6-10 units of randomly donated platelets and is given for every 6 units of packed RBC in the massive transfusion protocol.
References
Boffard KD, Riou B, Warren B, et al. Recombinant factor VIla as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials.] Tr auma. 2005;59:8-15.
Sihler KC, Napolitano LM. Complications of massive transfusion. Chest, 2010;137:209-220.
Johansson PI, Ostrowski SR, Secher NH. Management of major blood loss: an update. Acta Anaesthesia! Scand. 2010;54(9):1039-1049.
Perkins JG, Schreiber MA, Wade CE, et al. Early versus late recombinant factor VIla in combat trauma patients requiring massive transfusion.] Trauma. 2007;62(5):1095-1099; discussion 1099-1101.
Sihler KC, Napolitano LM. Massive transfusion: new insights. Chest. 2009;136(6):1654-1667.
Tieu BH, Holcomb JB, Schreiber MA. Coagulopathy: its pathophysiology and treatment in the injured patient. World ] Surg. 2007;31(5):1055-1064.
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