Management of Acute Hemorrhage

Micah J. Mooberry

Rommel P. Lu

Nigel S. Key

Evaluation and management of the acutely bleeding patient is a common encounter for the hematologist and is often fraught with innumerable challenges. It can additionally involve a wide variety of clinical scenarios, including pediatric, obstetric, surgical, and medical patients. These challenges are often further compounded by a paucity of clinical and laboratory information on which to base decisions. With these factors in mind, this chapter briefly discusses an approach to the initial evaluation of the acutely bleeding patient, including both clinical and laboratory assessments, followed by a discussion of specific therapeutic agents available for the treatment of acute hemorrhage. It concludes with a discussion of several specific bleeding situations and management of complications of antithrombotic therapy.

INITIAL EVALUATION

Clinical Approach

In the ideal setting, the evaluation of acute hemorrhage should be a multistep process beginning with a complete clinical history, followed by a focused physical examination and a directed laboratory evaluation. However, with the advent and now ubiquitous presence of more sophisticated medical diagnostic testing, the interview and examination of the patient often play a secondary role in the medical evaluation. Despite this trend, the clinical evaluation of the acutely bleeding patient is paramount and should be the foundation for further decision making regarding diagnostic testing, as well as possible intervention strategies. Contrary to outpatient bleeding evaluations, adherence to this algorithm may not always be possible in the setting of significant acute hemorrhage, and an abbreviated workup that focuses on pertinent exam and laboratory findings may be all that time allows.

When possible, a detailed history should be obtained, with particular attention paid to prior bleeding episodes, if present. The goal should be to answer several questions with reasonable certainty: (a) Is a bleeding disorder present? (b) If so, is it a disorder of primary or secondary hemostasis? (c) Is it acquired or hereditary in nature? To help make these determinations, the severity and nature (mucocutaneous, intramuscular, intra-articular, etc.) of each prior bleeding episode, as well as the number of bleeding episodes, should be assessed. Specific inquiries should also be made regarding menorrhagia, the presence of bleeding episodes during infancy and childhood, bleeding associated with dental procedures, peripartum hemorrhage, and excessive or unprovoked bruising.

A history of provoked versus spontaneous hemorrhage can offer additional insight. Bleeding events after a hemostatic challenge, such as trauma or surgery, could be indicative of an underlying mild bleeding disorder that had not manifested previously with spontaneous bleeding.¹ Conversely, the absence of bleeding despite the hemostatic challenge of multiple surgeries may suggest the absence of a longstanding bleeding disorder. Timing of bleeding with respect to the hemostatic challenge can also provide clues to whether there is a defect in primary or secondary hemostasis (e.g., immediate bleeding with disorders of primary hemostasis vs. delayed bleeding with disorders of secondary hemostasis) (see Table 76.1).

A thorough family history of bleeding symptoms should also be obtained, querying similar symptoms as those posed to the patient. It should be noted, however, that the absence of a family history of bleeding does not exclude the presence of a congenital bleeding disorder, as there may be no affected family members in the setting of spontaneous mutations or autosomal recessive disorders.²^,³ Obtaining a list of all comorbidities is also worthwhile, as numerous medical conditions are associated with specific coagulation disorders, which may or may not be realized by the patient. Finally, a full review of all current medications can aid in patient management, both from a diagnostic and a therapeutic perspective. This should include an inquiry into nonprescription compounds as well. Obvious culprits in the setting of acute hemorrhage include anticoagulants and antiplatelet agents; however, numerous over-the-counter medications contain nonsteroidal agents that exert antiplatelet effects and are often not considered “medications” by patients unless specifically addressed. Several herbal and nutritional supplements have also been implicated in hemorrhagic events and should be investigated, although they are unlikely to be the sole cause of bleeding complications.⁴

A focused physical examination is also prudent, as this can provide substantial insight into possible pathologic mechanisms and help guide management decisions. Bruises, petechiae, mucocutaneous bleeding, and menorrhagia are often seen in patients with platelet defects, von Willebrand disease (vWD), and other defects in primary hemostasis. In comparison, bleeding into muscles and joints is more characteristic of disorders of secondary hemostasis, such as hemophilia A and B and certain other coagulation factor deficiencies. The exam can also potentially lead to the discovery of previously undiagnosed comorbid conditions that may contribute to a patient’s bleeding. Examples include gum hypertrophy in acute myelogenous leukemia (AML) (types M4 and M5); macroglossia, periorbital ecchymoses, and carpal tunnel syndrome in amyloidosis⁵^,⁶; harsh systolic murmur in severe valvular disease; and jaundice,
icterus, spider angiomata, and splenomegaly in severe liver disease, among others (see Table 76.2).

Table 76.1 Classification of bleeding disorders

Disorders of Primary Hemostasis	Disorders of Secondary Hemostasis
von Willebrand disease	Hemophilia A
Platelet function disorders Inherited Acquired Drug induced	Hemophilia B Other factor deficiencies: II, V, VII, X, XI, XIII Factor inhibitors
Thrombocytopenia Inherited Acquired Drug induced Immune mediated	Fibrinogen abnormalities	Hyperfibrinolysis Inherited deficiencies Acquired Connective tissue disorders

After the clinical assessment of the patient is complete, one should formulate a pretest probability as to whether a bleeding disorder exists or not, and if so, what type. Given the frequency with which “normal” subjects report bleeding symptoms, however, the ability to identify mild bleeding disorders can be challenging.⁷^,⁸^,⁹^,¹⁰^,¹¹ To that end, several attempts have been made to develop standardized screening tools that predict the presence of a bleeding disorder.¹²^,¹³^,¹⁴^,¹⁵ To date, however, no prospectively validated clinical tool exists to predict the presence of a bleeding disorder. Notably, the International Society on Thrombosis and Hemostasis recently proposed a Bleeding Assessment Tool consisting of a standardized questionnaire and well-defined interpretation grid to be used in any future studies aimed at description of bleeding symptoms or diagnosing bleeding disorders,¹⁶ but this will need to be validated before it is adopted into clinical use.

Table 76.2 Comorbid conditions and bleeding

Disease	Cause of Bleeding	Other Findings/Manifestations
Acute leukemia	Thrombocytopenia, hyperfibrinolysis in acute promyelocytic leukemia	Pallor, petechiae, gum hypertrophy
Amyloidosis	Acquired FX deficiency, other factor deficiencies (II, V, VII, VIII, IX), hyperfibrinolysis	Macroglossia, periorbital ecchymoses, carpal tunnel syndrome
Ehlers Danlos syndrome	Defect in collagen synthesis	Joint laxity, skin hyperelasticity
Hereditary hemorrhagic telangiectasia	Arteriovenous malformations of multiple sites, GI telangiectasias	Recurrent epistaxis, oral telangiectasias
Hypothyroidism	Acquired vWD	Thin hair, obesity, cold intolerance, dry skin
Liver disease/cirrhosis	Thrombocytopenia, factor deficiencies, hyperfibrinolysis	Hepatosplenomegaly, icterus, jaundice, spider angiomata
Scurvy	Defect in collagen synthesis	Corkscrew hairs, petechiae, perifollicular purpura
Severe valvular disease	Acquired vWD, thrombocytopenia	Harsh murmur
Wilms tumor	Acquired vWD	Flank mass

Laboratory Evaluation

Evidence has shown that indiscriminate coagulation testing in patients undergoing surgery or other invasive procedures does not help predict risk of bleeding and is therefore not recommended.¹⁷^,¹⁸^,¹⁹ In the setting of acute hemorrhage, however, laboratory testing is vital and should be pursued for several reasons: confirmation of a clinically suspected bleeding disorder, clearly defining the defect if present, and guiding treatment/intervention strategies.

Screening tests of coagulation that evaluate for both primary and secondary hemostatic abnormalities should be performed in all patients with acute hemorrhage. These include a complete blood count (CBC) and platelet count, peripheral blood smear, activated partial thromboplastin time (aPTT), and prothrombin time (PT). These tests are available in most settings, and due to their automated nature, provide reproducible results in a timely manner. In general, these basic tests in conjunction with the clinical assessment should be able to direct further evaluation toward defects of primary or secondary hemostasis. The details of the laboratory evaluation will not be fully covered here (see Chapter 50); however, it should be mentioned that preanalytical variables can have a profound effect on test results and therefore attention should be paid to proper collection and handling of specimens.²⁰^,²¹

If all testing for hemostatic defects returns normal, it should be remembered that up to 40% to 50% of suspected bleeding disorders yield a normal laboratory screening evaluation, particularly mild bleeding disorders that probably include heterogeneous platelet function defects.²²^,²³ Additionally, abnormalities on coagulation tests, particularly in the acutely ill patient, may
not be indicative of a primary coagulation defect, but instead be epiphenomena or the result of another acute medical process. Therefore, a suspected primary coagulation disorder should always be confirmed after the acute situation has resolved. In the event that exhaustive laboratory testing does not provide definitive answers as to the cause of the acute bleeding episode, empiric treatment based upon clinical findings and sound medical judgment is a reasonable choice and may be the only course of action available.

THERAPEUTIC APPROACH

Blood Component Therapy

Conservative approach to transfusion therapy has become the standard of care in most situations. In contrast to whole blood, which is utilized primarily in military settings,²⁴^,²⁵ red cell units contain negligible amounts of platelets and coagulation factors and are used to provide increased oxygen-carrying capacity. Plasma-containing blood products, including platelets, are conversely administered to correct hemostatic defects. The primary advantage of blood component therapy is the ability to allocate resources according to individual needs (see Table 76.3). The clinical decision to transfuse should be individualized and not simply based on a given blood count. The underlying mechanism causing the cytopenia or coagulopathy and its clinical risks must be considered as well. However, despite the potential transfusion-associated infectious, metabolic, and immunologic risks, it is important not to withhold blood products to anybody with a life-threatening hemorrhage. The management strategy for transfusion therapy that follows generally refers to adult patients. Guidelines for pediatric transfusion may differ.

Table 76.3 Blood component therapy

Component	Description	Volume	Dosing
Red cells	Prepared by removing plasma from whole blood or apheresis Transfused red cells have a halflife of ˜30 d in the absence of processes that would result in red cell loss or premature removal.	200-350 mL	In average-sized adults, one unit of compatible red cells will increase hemoglobin by 1 g/dL and hematocrit by 3%, provided there is no ongoing hemolysis or bleeding. In neonates and older children, a transfusion dose of 10-15 mL/kg is generally given and results in hemoglobin rise of 2-3 g/dL.
Platelets	Collected as RDP or SDP RDPs are derived from whole blood and six units of RDPs constitute one adult dose. SDPs are apheresed platelets and are full adult doses.	One adult dose is 250-300 mL	In adults, expect an increment of approximately 30,000-60,000/µL for each SDP or pooled six units of RDP. In neonates and older children, a dose of 5-10 mL/kg generally results in 50,000/µL increment.
Plasma (FFP, FP24, thawed plasma)	Consists of non-cellular portion of blood. May be prepared from whole blood or collected by apheresis	150-300 mL	10-15 mL/kg (equivalent to 3-4 U in adult)
Cryoprecipitate	Prepared from plasma Each unit contains at least 80 IU of factor VIII:C and 150 mg of fibrinogen in 15 mL plasma.	One adult dose is ˜150 mL	One dose (10 U in adult or 1 U per 10 kg body weight in neonates and older children) increases fibrinogen level by 0.5 g/L in the absence of continued consumption or bleeding
Modified from Brecher M, ed. Technical manual, 15th ed. Bethesda, MD: AABB press, 2005; Mintz P, ed. Transfusion therapy: clinical principles and practice, 2nd ed. Bethesda, MD: AABB Press, 2005.

Red Cell Transfusion

The decision to transfuse red cells requires a detailed analysis of clinical factors, with the primary goal of restoring tissue perfusion and reversing the effects of shock if already present. Generally, this decision is made on the basis of hemoglobin and hematocrit values in conjunction with the patient’s physiologic response to anemia and coexisting medical condition. The administration of red cell transfusions in an actively bleeding patient is often lifesaving, but recommendations about when and how much to transfuse are unclear.²⁶ For many years, most clinical practices used a hemoglobin/hematocrit threshold of <10 g/dL/30% as transfusion trigger in numerous clinical settings. More recently, however, a pivotal controlled study evaluating transfusion strategies in critically ill patients provided new evidence to guide transfusion practices. This trial demonstrated that a restrictive transfusion approach (i.e., transfusing patients only with a hemoglobin <7 g/dL) was as effective as a liberal strategy (i.e., transfusing patients with a hemoglobin <10 g/dL) and had a lower in-hospital 30-day mortality, cardiac complication rate, and organ dysfunction.²⁷ However, patients with
ongoing hemorrhage were excluded from the study. Thus, it is important to realize the possible limitations of restrictive transfusion strategy in acute settings.

The urgent need for transfusion is uniquely apparent in the operative and trauma settings. Significant hypotension occurs once more than 30% of blood volume is lost and is a late sign of internal hemorrhage. Frequently, red cells are transfused to improve blood pressure, hemoglobin concentration, or both before the cause of bleeding is identified. In the acute trauma setting, the rapidity and amount of blood loss may be inaccurately estimated by the hemoglobin/hematocrit values, thereby making it difficult to exclusively rely on these tests to determine the relationship between blood loss and transfusion requirement. A number of factors must be considered besides hemoglobin level, such as vital signs, oxygenation, and clinical status, to ensure tissue demands for oxygen are met. This is especially applicable in patients with limited cardiac reserve or significant atherosclerotic vascular disease, in whom the heart may be unable to increase total body oxygen delivery in the face of anemia, without risk of myocardial ischemia. A transfusion study in elderly patients with acute myocardial infarction showed a lower short-term mortality when patients were transfused to achieve a hemoglobin as high as 10 g/dL. Evidently, transfusion trigger for red cells must be customized to defined patient groups, and the decision to transfuse must be made on the basis of individual patient characteristics.²⁸

Two of the recommendations of the American Society of Anesthesiologists Task Force with practical applications in the management of acute hemorrhage are:

Transfusion is rarely indicated when the hemoglobin level is above 10 g/dL and is almost always indicated when the hemoglobin level is below 6 g/dL.
The determination of transfusion in patients whose hemoglobin level is 6 to 10 g/dL should be based on ongoing indication of organ ischemia, rate and magnitude of any potential or actual bleeding, patient’s intravascular volume status, and risk of complications due to inadequate oxygenation.²⁹

Blood Substitutes

Biomedical advances have made the development of hemoglobin-based oxygen carriers (i.e., blood substitutes) possible, but due to safety concerns about increased rate of myocardial infarction, stroke, hypertension, and renal dysfunction in patients who have received them in clinical trials, they are still under development.³⁰^,³¹^,³²

Platelet Transfusion

Platelet transfusion is used to treat or prevent bleeding due to defect in platelet number or function. In general, most patients do not experience spontaneous bleeding at platelet counts of 40,000 to 50,000/µL unless there is a coexisting platelet dysfunction or other hemostatic defect. Studies indicate that achieving a platelet count of 40,000 to 50,000/µL with platelet transfusion in patients with severe thrombocytopenia might be sufficient to allow an invasive procedure to be safely performed. A threshold of 80,000/µL has been proposed for spinal epidural anesthesia. In those situations in which no excessive bleeding can be tolerated, such as central nervous system or retinal procedures, a platelet count of 100,000/µL is often used. In patients who are severely thrombocytopenic, such as those receiving myeloablative chemotherapy, it is a common practice to maintain a platelet count >10,000/µL in stable nonbleeding patients, and >20,000/µL in febrile nonbleeding patients, based on the observations that serious spontaneous bleeding is unlikely to occur at platelet counts >10,000/µL. When known platelet dysfunction results in microvascular bleeding or before anticipated major surgery, platelet transfusion may be required despite having a seemingly adequate platelet count. However, prophylactic platelet transfusion in patients with immune thrombocytopenic purpura based on platelet count alone in the absence of spontaneous bleeding is discouraged since bleeding is less frequent at equivalent platelet counts, and platelet transfusions are often ineffective. Similarly, prophylactic platelet transfusion practice is discouraged in cases of thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT), unless there is life-threatening bleeding or in anticipation of major surgery. However, the reluctance to transfuse platelets in TTP and HIT may have been overemphasized, and it remains a controversial topic. In the presence of active bleeding, maintaining a platelet count of 50,000 to 100,000/µL with platelet transfusion support is often practiced. A platelet count threshold of 100,000/µL is often used in patients with severe, noncompressible bleeding such as in the gastrointestinal (GI) tract, intracranial, or intrathoracic areas, while a lower platelet count threshold is used in less severe bleeding. Overall, these guidelines tend to be based on expert recommendations rather than level I evidence.²⁹^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸

Practical issues regarding platelet transfusion include:

Response to platelet transfusion is adversely affected by the presence of fever, sepsis, splenomegaly, severe bleeding, consumptive coagulopathy, human leukocyte antigens (HLA) alloimmunization, and treatment with certain drugs (e.g., amphotericin B).³³^,³⁹^,⁴⁰
Rh (D)-negative patients, especially women of childbearing age, should receive platelets from Rh (D)-negative instead of Rh (D)-positive donors because of the risk of alloimmunization and development of a clinically significant antibody to Rh (D) antigen, which can cause a hemolytic transfusion reaction from subsequent Rh (D) mismatched transfusions. However, this is not practically feasible at all times because of limited platelet inventory. If platelets from Rh (D)-positive donors are transfused to Rh (D)-negative recipients (especially women of childbearing age), consideration should be given to administering prophylactic Rh (D) immune globulin to prevent sensitization.⁴¹^,⁴²

Plasma Transfusion

Fresh frozen plasma (FFP) contains coagulation proteins involved in the maintenance of vascular integrity, anticoagulation proteins, and proteins involved in fibrinolysis. FFP is frozen at ?18°C or colder within 6 to 8 hours of collection and contains functional quantities of all coagulation factors. Plasma frozen within 24 hours (FP24) and thawed plasma may contain variably reduced levels of factors V and VIII. Despite these processing differences, FP24, thawed plasma, and FFP are generally used for the same indications.⁴³

Current published guidelines by multiple organizations consider plasma transfusion appropriate only under specific circumstances. The definitive indications for FFP transfusion are replacement of coagulation factor deficiency in the event of
bleeding with certain coagulopathies (including patients with liver disease, isolated factor V deficiency, disseminated intravascular coagulopathy [DIC], or while on a vitamin K antagonist [VKA]) or TTP. Conditional uses of FFP include prophylactic use in patients with certain coagulopathies prior to invasive procedures, those undergoing cardiopulmonary bypass surgery, or children on extracorporeal membrane oxygenation.

When used to correct multiple coagulation factor deficiencies, the response to plasma transfusion should be closely monitored by follow-up laboratory tests and clinical assessment. A PT and/or aPTT >1.5 times the normal range are typically the recommended triggers for plasma transfusion, although this cutoff is being challenged by several groups.²⁹^,⁴⁴^,⁴⁵^,⁴⁶ Despite these guidelines, requests for FFP are the most frequent inappropriate orders received by the blood bank. The most frequent reason for these inappropriate orders is for correction of a prolonged international normalized ratio (INR) in the absence of bleeding. In clinical practice, prophylactic plasma transfusion prior to invasive procedures including neurosurgical interventions has become routine. It is suggested that inappropriate FFP orders occur because of three assumptions: (a) Elevation of the PT/INR will predict bleeding in the setting of a procedure. (b) Preprocedure administration of FFP will correct the prolonged clotting time results. (c) Prophylactic transfusion results in fewer bleeding events. However, these three assumptions about the relationship of FFP transfusion and decrease in INR, especially in patients with mildly prolonged INRs, are unproven. Studies in patients undergoing liver biopsies, bronchoscopic biopsies, renal biopsies, central line vein cannulation, thoracentesis, and angiography have repeatedly demonstrated that the PT and aPTT are not predictive of hemorrhage. Furthermore, plasma transfusion prior to an invasive procedure to correct a mild to moderately abnormal INR neither corrects the INR nor reduces the perceived bleeding risk.⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵² Therefore, transfusion for patients not meeting current FFP guidelines does not reliably reduce the INR and exposes patients to unnecessary transfusion risk.

Practical issues regarding plasma transfusion include:

A significant degree of change in the INR following FFP transfusion may not be seen until the INR is >1.7, largely because the INR of donor plasma itself ranges between 1.0 and 1.3. Thus, the difference in coagulation activity between donor plasma and patient plasma is so small that plasma transfusions produce minimal demonstrable effect on the patient’s INR.⁵¹ Administering vitamin K may be a therapeutic option to consider in patients who have a presumed coexisting vitamin K deficiency.
If plasma is to be transfused, its timing should be carefully considered. If correction of a markedly abnormal PT or aPTT is required before surgery, FFP is better given just before the patient is called to the operating room, and not the night before. Several coagulation factors have very short half-lives, and if FFP is given 8 hours preoperatively, those factors will be cleared from the circulation by the time surgery begins.⁵³
Many transfusion protocols suggest administering plasma after the patient has received 4 to 6 U of red cells, but recent studies in trauma are challenging this practice and are suggesting earlier rather than later plasma administration⁵⁴^,⁵⁵ (see section “Massive Transfusion Therapy”).

Cryoprecipitate Transfusion

Cryoprecipitate is the precipitable protein fraction derived from frozen plasma thawed at 1°C to 6°C. It contains concentrated levels of fibrinogen, von Willebrand factor (vWF), factor VIII, factor XIII, and fibronectin in a small volume, but it is generally administered as a source of fibrinogen. Patients with hemophilia A or vWD disease should only be treated with cryoprecipitate when appropriate factor VIII concentrates or factor VIII concentrates containing FVIII: vWF are not available.⁵⁶

Since FFP contains all coagulation factors, FFP transfusion should supply the depleted hemostatic proteins, although a large volume of plasma is usually required to fully replete significant deficiencies. This becomes a challenge in patients who are unable to tolerate larger intravascular volumes, such as those with significant cardiac, pulmonary, renal, and/or hepatic disease. In patients with ongoing bleeding with a fibrinogen level <0.8 to 1.0 g/L, cryoprecipitate transfusion is recommended.²⁹

Massive Transfusion Therapy

Massive transfusion has been defined differently across studies, but in general it refers to transfusion of at least 10 U of red cells in the first 24 hours after trauma.³⁰ In lethal hemorrhagic shock, transfusion of blood products is performed empirically and is not guided by laboratory tests but is based on clinical parameters.⁵⁷ Hemorrhagic shock is a severe and life-threatening condition. Over 30% of military casualties receive blood transfusion and about 6% require massive transfusion.⁵⁸ In patients with severe traumatic injury, there is an association between rising transfusion requirements and increased risk of multiorgan failure and worsened clinical outcomes.⁵⁹^,⁶⁰^,⁶¹ The increase in mortality is correlated with the number of red cell units transfused (22%, 30%, 50%, and 59% mortality in the groups receiving 1 to 10 U, 11 to 20 U, 21 to 40 U, and >40 U, respectively).⁶⁰ In the absence of timely and robust tests of coagulation during acute trauma, massive transfusion protocols were designed to provide rapid delivery of blood products to patients with lifethreatening hemorrhage.

In the setting of exsanguinating hemorrhage, transfusion therapy is usually based on the number of red cell units administered and expressed as plasma to red cells (P:RBC) and platelets to red cells (PLT:RBC) ratios. Retrospective studies of trauma resuscitation protocols, especially from military experiences, indicate that traditional transfusion protocols do not achieve normal hemostasis and are designed to treat dilution, while earlier and aggressive treatment of coagulopathy with a P:RBC ratio of 1:1 to 1:2 and a PLT:RBC ratio of 1:1 (using random donor platelets [RDPs]) or 1:6 (using single donor platelets [SDPs]) have indicated a possible survival advantage compared to recommendations in existing transfusion guidelines. Currently, there is no standardized massive transfusion protocol in the United States but many trauma centers have their own protocols, with early use of blood type “O” Rh (D)-negative red cells and “AB” plasma in anticipation of further transfusion needs. These observations of RBC:P:PLT ratios of 1:1:1 (1 U red cell, 1 U plasma and 1 U RDPs), practically expressed as 6:6:1 (6 U red cells, 6 U plasma and 1 U single donor apheresed platelets), albeit retrospective, are paving the way to a changing paradigm of transfusion therapy in the military environment and are beginning to receive attention in the
civilian trauma setting.⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶ Whether this high ratio of plasma to red cells would decrease mortality in nonmassively transfused patients is unknown.

Trauma-Induced Coagulopathy

The presence of a coagulopathy occurring early after traumatic injury is a well-recognized independent predictor of mortality.⁶⁷ The factors underlying the development of coagulopathy are multiple and traditionally were thought to include dilution of coagulation factors and platelets, compromise of the coagulation system by infusion of crystalloids and colloids, increased fibrinolysis and hypocalcemia.⁶⁸^,⁶⁹ The interplay between hypothermia, acidosis, and coagulopathy has been referred to as the “lethal triad.” In patients who are already acidotic, massive transfusion of red cells increases acid load.⁶⁸^,⁷⁰ Trauma patients receiving large volumes of plasma may develop hypocalcemia due to the chelating citrate anticoagulant present in plasma. Liberal red cell transfusion, although improving oxygen transport, does not replace coagulation factors and platelets. All these factors, which may occur simultaneously, can potentially contribute to coagulopathic bleeding.⁷¹

Recent observational studies have described a distinct coagulopathy in trauma referred to as trauma-induced coagulopathy (TIC), Acute Traumatic Coagulopathy, or Acute Coagulopathy of Trauma Shock. TIC is a syndrome of “nonsurgical bleeding.” The classic model of trauma coagulopathy occurring during resuscitation has been challenged by recent clinical observations, specifically studies showing that TIC may be present in 20% to 30% of patients upon arrival at the emergency room. This coagulopathy is present even prior to massive transfusion, fluid resuscitation therapy, or the development of hypothermia, and is independently associated with a four- to fivefold increase in mortality compared to patients who do not have coagulopathy upon initial presentation.⁶⁷^,⁷²^,⁷³ A combination of massive tissue injury and shock is believed to underlie the pathogenesis of TIC.⁷⁴ This situation is in contrast to the traditional understanding of posttraumatic coagulopathy in resuscitated patients that develops as a consequence of medical intervention. TIC is characterized by systemic anticoagulation and hyperfibrinolysis that manifests as a bleeding phenotype with mild prolongation of the INR (>1.3) and aPTT (>1.5 times normal) with preservation of fibrinogen levels and platelet counts.⁷⁵ Its mechanism is unclear but it does not appear to be a consumptive coagulopathy; instead, widespread activation of the protein C pathway has been implicated.⁷⁶ Recognition of this coagulopathy has stimulated revision of massive transfusion protocols. Early use of plasma, platelets, and cryoprecipitate together with red cells is advocated to reduce overall blood product use and potentially avoidable deaths from hemorrhage after trauma. This development in modern trauma care emphasizes the concept that not all bleeding can be controlled surgically.⁷⁴^,⁷⁷^,⁷⁸

Pharmacologic Therapy

Prothrombin Complex Concentrates

Prothrombin complex concentrates (PCCs), otherwise known as intermediate purity FIX concentrates, were initially used primarily for the treatment of hemophilia B; however, they are rarely used for that indication now due to the availability of newer FIX preparations. Derived from pooled human plasma, these virally inactivated agents contain the vitamin K-dependent factors II, VII, IX, and × in varying amounts. Earlier preparations had considerable variability in their compositions;⁷⁹ however, this limitation has improved over the past 15 years with newer forms, and current composition is in line with levels listed by the manufacturer.⁸⁰ Due to increased thrombogenicity and risk of DIC seen with earlier forms, most agents now also contain varying levels of anticoagulants, including protein C, protein S, antithrombin, and heparin.⁸¹ Earlier forms also contained variable amounts of activated factors,⁸² particularly FVIIa and FIXa, which have been greatly reduced or eliminated in current preparations.⁸⁰ Although most current concentrates contain sufficient levels of all four vitamin K-dependent factors, several so-called three factor PCCs, which contain relatively low FVII levels, are also marketed, and are the only agents currently available in the United States.⁸³

Although not licensed as such in the United States, the principal indication for PCCs currently is reversal of the effects of oral anticoagulation with VKAs (see section “Complications of Antithrombotic Therapy”). PCCs are also occasionally used as replacement therapy in patients with congenital or acquired deficiencies of FII or FX.⁸⁴^,⁸⁵ Although not licensed for this indication, PCCs have additionally been used in treatment of severe hemorrhage requiring massive transfusion,⁸⁶ but this practice is only widespread in certain European countries.⁸⁷^,⁸⁸ Other reported uses include treatment of bleeding due to vitamin K deficiency, severe liver disease⁸⁹^,⁹⁰ or after liver transplantation. In the latter two conditions, these agents are commonly used when volume status is of concern and the use of FFP risks volume overload. It should be noted, though, that PCCs do not contain all coagulation factors that are deficient in liver dysfunction, most notably FV and fibrinogen, and supplementation with FFP and/or cryoprecipitate may be needed to adequately treat active hemorrhage.

Potency labeling and dosing recommendations for PCCs are based on International Units (IUs) of FIX.⁹¹ One IU of PCC per kg body weight generally increases the plasma activity of FIX by approximately 1 IU/dL. Doses are subsequently calculated based upon the goal FIX level, or in the case of VKA overdose, by INR. Typical doses are 25 to 50 IU/kg and can be repeated every 24 hours as needed. The most feared complication of PCC administration is thromboembolism, which has been reported in numerous case series.⁹²^,⁹³ With recent advances in preparation of these agents, including addition of anticoagulants and minimization of activated factors, it appears that thromboembolic events are relatively uncommon.⁸⁹^,⁹⁴ Despite this trend, however, PCCs should still be used with caution when the risk for thromboembolism is deemed to be high, such as in the setting of severe liver disease. PCC use is relatively contraindicated in the context of DIC due to thrombotic risk; however, this is less of a problem with the newer preparations that may be used in hemorrhagic forms of DIC when volume limitations preclude the use of FFP. Other adverse events reported include allergic, and even anaphylactic, reactions, although both are rare.⁸⁷

Recombinant Factor VIIa

Recombinant factor VIIa (rFVIIa) was first introduced in the 1980s as a hemostatic agent for patients with hemophilia A and B with known inhibitors, and was approved for this indication in most countries by the late 1990s.⁹⁵ Since that time, its off-label use has become increasingly widespread, particularly in the setting of acute massive or life-threatening hemorrhage.
Its mechanism of action is thought to be related to enhanced platelet-surface thrombin generation.⁹⁶^,⁹⁷

Recombinant FVIIa is currently approved for the prevention and treatment of bleeding in congenital hemophilia A and B with inhibitors, acquired hemophilia, and congenital FVII deficiency. Additional approved uses in Europe include bleeding in Glanzmann’s thrombasthenia in the presence of antibodies to glycoprotein (GP) IIb-IIIa and/or HLA, with past or present refractoriness to platelet transfusions.⁹⁷ As mentioned above, off-label use of rFVIIa is widespread despite lack of definitive evidence regarding efficacy in most settings. Reported uses include bleeding due to anticoagulation, intracerebral hemorrhage, surgical bleeding, postpartum or obstetric hemorrhage, FXI deficiency, and liver disease, among others. Large-scale trials in these areas are limited, and additionally, results of existing trials have often resulted in conflicting data. In general, however, rFVIIa use is deemed appropriate by most experts when uncontrollable hemorrhage is encountered. Consensus panels in numerous countries have additionally made recommendations on appropriate use of rFVIIa, which are congruous with this approach.⁹⁸^,⁹⁹^,¹⁰⁰

Another area of interest regarding the use of rFVIIa has been in the setting of civilian and military trauma, where uncontrolled massive bleeding contributes to up to 40% of early in-hospital deaths.¹⁰¹^,¹⁰² Several early phase trials appeared to demonstrate efficacy of rFVIIa in reducing bleeding and transfusion requirements.¹⁰³^,¹⁰⁴^,¹⁰⁵^,¹⁰⁶^,¹⁰⁷ This effect appeared to be more significant with blunt trauma, as opposed to penetrating trauma.¹⁰⁸ Data on mortality benefit were mixed, with several trials showing benefit in both early and overall mortality¹⁰³^,¹⁰⁹^,¹¹⁰^,¹¹¹; however, a recent phase III clinical trial was terminated prematurely due to low likelihood of showing improvement in primary endpoints of morbidity and mortality.¹¹² Overall, aggressive transfusion therapy remains the standard of care in trauma (see section “Blood Component Therapy”); however, rFVIIa continues to be used in cases where hemorrhage continues despite these measures. At this time, more trials are needed to further assess its efficacy in the setting of trauma.

Dosing regimens reported for rFVIIa in off-label uses vary tremendously by study, making interpretation of efficacy data difficult. Reported doses range from 5 to 200 µg/kg. In the setting of hemophilia, dosing regimens are more standard. Typical doses for bleeding in hemophilia are 90 µg/kg every 2 to 3 hours × three doses, however recent studies in hemophilia have shown that a single dose of 270 µg/kg is equally effective.¹¹³^,¹¹⁴ With no clear dosing guidelines in off-label uses, a reasonable starting point is 90 µg/kg, repeating doses every 2 to 3 hours if bleeding persists. Lower doses may be considered where there is heightened concern for thrombotic events. Of note, newer bioengineered forms of rFVIIa with greater potency and/or more rapid onset of action are in clinical development.¹¹⁵^,¹¹⁶^,¹¹⁷^,¹¹⁸

Adverse events related to use of rFVIIa are mostly restricted to thrombotic events, including stroke and myocardial infarction. A recent review of safety data reported an incidence of <1% of serious thromboembolism in hemophilia patients treated with rFVIIa.¹¹⁹ Thrombotic events have been reported with off-label use of rFVIIa as well; however, most placebo-controlled trials have not been powered to demonstrate a significant increase in thrombosis. To address this issue, a recent review evaluated 35 randomized, placebo-controlled trials where rFVIIa was used off-label to treat life-threatening hemorrhage. Results showed no difference in rates of venous thromboembolism; however, there was an increased rate of arterial events associated with rFVIIa use (5.5% vs. 3.2%). This effect was more pronounced in patients 65 years or older (9.0% vs. 3.8%), with particularly high rates seen in individuals 75 years or older (10.8% vs. 4.1%).¹²⁰ Thus, given the risk of thrombosis, caution should be taken when using rFVIIa in older patients or persons with known or high risk of atherosclerotic disease.

Antifibrinolytics

Antifibrinolytic agents include the synthetic lysine analogues ε-aminocaproic acid (EACA) and tranexamic acid (TXA), as well as the bovine-derived serine protease inhibitor aprotinin. The former two agents exert their pharmacologic effect by blocking the interaction between fibrin and plasminogen through reversibly binding to the lysine-binding site of plasminogen, subsequently preventing its activation and transformation to plasmin.¹²¹^,¹²²^,¹²³^,¹²⁴ Aprotinin, on the other hand, is a nonspecific serine protease inhibitor of multiple enzymes, including trypsin, chymotrypsin, kallikrein, activated protein C, thrombin, and plasmin, and has effects on both coagulation and inflammation.¹²⁵^,¹²⁶

Aprotinin has been primarily used in the setting of cardiac surgery, where it was initially shown to decrease blood loss and transfusion requirements with coronary artery bypass grafting.¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹^,¹³²^,¹³³ Other perioperative uses have included prevention of blood loss in liver transplantation¹³⁴^,¹³⁵^,¹³⁶^,¹³⁷ and in orthopedic surgeries,¹³⁸ although both have been less well studied. Concerns about the use of aprotinin in cardiac surgery due to associated adverse events, including renal failure, myocardial infarction, stroke, and death, were raised after publication of results from several observational and cohort studies.¹³⁹^,¹⁴⁰^,¹⁴¹^,¹⁴² Subsequently, a large scale, prospective, blinded, randomized, controlled trial confirmed an increased risk of death with aprotinin as compared to EACA and TXA, and the study was prematurely terminated.¹⁴³ Based upon these results, aprotinin has now been removed from the market and is no longer available for clinical use.

The lysine analogues, EACA and TXA, are also used for prevention of blood loss in cardiovascular surgeries; however, they have been much less extensively studied.¹⁴⁴ Most studies have shown a reduction in perioperative blood loss with both agents, with mixed results regarding reduction in transfusion requirements and need for reoperation. Use of these agents has not been clearly associated with an increased risk of adverse events, including thrombotic events¹⁴⁵^,¹⁴⁶; however, most of the studies have not been adequately powered to address this question conclusively. At this point, larger studies are needed to thoroughly assess their safety profiles in this setting. Both agents have also been evaluated in orthopedic and liver transplant surgeries and have been shown to reduce bleeding and transfusion requirements, albeit again with somewhat variable results.

In the setting of acute hemorrhage, lysine analogues have been used in a variety of situations to control bleeding. Both agents have long been used as adjuncts for the treatment of bleeding in patients with hemophilia and vWD undergoing dental extractions, in which setting they reduce the amount of coagulation factor replacement required.¹⁴⁷^,¹⁴⁸^,¹⁴⁹^,¹⁵⁰^,¹⁵¹ In conditions associated with hyperfibrinolysis, such as liver disease, acute promyelocytic leukemia, and α₂-antiplasmin deficiency, they have also proven effective.¹⁵²^,¹⁵³^,¹⁵⁴ Other situations in which these agents are used include bleeding associated with
thrombocytopenia,¹⁵⁵^,¹⁵⁶^,¹⁵⁷ prevention of bleeding with oral surgery while on anticoagulation,¹⁵⁸^,¹⁵⁹^,¹⁶⁰^,¹⁶¹ traumatic hyphema,¹⁶²^,¹⁶³^,¹⁶⁴^,¹⁶⁵ menorrhagia,¹⁶⁶^,¹⁶⁷^,¹⁶⁸^,¹⁶⁹^,¹⁷⁰ and postpartum hemorrhage (PPH).¹⁷¹^,¹⁷²^,¹⁷³ Regarding the latter two indications, TXA has recently been Food and Drug Administration (FDA) approved for use in menorrhagia.¹⁷⁴ While data on the use of lysine analogues for PPH are relatively sparse at this time, efforts are currently underway to perform a large-scale, international, randomized, controlled trial assessing TXA in obstetric hemorrhage, particularly in low and middle income countries.¹⁷⁵

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