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Massive transfusion and coagulopathy: pathophysiology and implications for clinical management

[Transfusion massive et coagulopathie : physiopathologie et implications cliniques]

Jean-François Hardy, MD FRCPC^*, Philippe de Moerloose, MD, Marc Samama, MD PhD and members of the Groupe d’intérêt en Hémostase Périopératoire

^* From the Department of Anesthesiology, Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Montréal, Québec, Canada;
The Hemostasis unit, Hôpital Universitaire de Genève, Genève, Suisse; and
The Département d’anesthésie-réanimation, Hôpital Avicenne, Bobigny, France.

Address correspondence to: Dr. Jean-François Hardy, Département d’anesthésiologie, Porte AS-1115-3, Pavillon Lachapelle, CHUM Hôpital Notre Dame, 1560 rue Sherbrooke est, Montréal, Québec H2L 4M1, Canada. E-mail: jean-francois.hardy{at}umontreal.ca

	Abstract

TOP Abstract Introduction I. Pathophysiology of... III. Management of coagulopathy... IV. Conclusions References

 
Purpose: To review the pathophysiology of coagulopathy in massively transfused, adult and previously hemostatically competent patients in both elective surgical and trauma settings, and to recommend the most appropriate treatment strategies.

Methods: Medline was searched for articles on "massive transfusion," "transfusion," "trauma," "surgery," "coagulopathy" and "hemostatic defects." A group of experts reviewed the findings.

Principal findings: Coagulopathy will result from hemodilution, hypothermia, the use of fractionated blood products and disseminated intravascular coagulation. The clinical significance of the effects of hydroxyethyl starch solutions on hemostasis remains unclear. Maintaining a normal body temperature is a first-line, effective strategy to improve hemostasis during massive transfusion. Red cells play an important role in coagulation and hematocrits higher than 30% may be required to sustain hemostasis. In elective surgery patients, a decrease in fibrinogen concentration is observed initially while thrombocytopenia is a late occurrence. In trauma patients, tissue trauma, shock, tissue anoxia and hypothermia contribute to the development of disseminated intravascular coagulation and microvascular bleeding. The use of platelets and/or fresh frozen plasma should depend on clinical judgment as well as the results of coagulation testing and should be used mainly to treat a clinical coagulopathy.

Conclusions: Coagulopathy associated with massive transfusion remains an important clinical problem. It is an intricate, multifactorial and multicellular event. Treatment strategies include the maintenance of adequate tissue perfusion, the correction of hypothermia and anemia, and the use of hemostatic blood products to correct microvascular bleeding.

	Introduction

TOP Abstract Introduction I. Pathophysiology of... III. Management of coagulopathy... IV. Conclusions References

 

List of abbreviations

aPTT    activated partial thromboplastin time

BT      bleeding time

DIC     disseminated intravascular coagulation

FFP     fresh frozen plasma

HES     hydroxyethyl starch

MT      massive transfusion

MVB     microvascular bleeding

MWB     modified whole blood

PRBC    packed red blood cells

PT      prothrombin time

RBC     red blood cells

UNCONTROLLED hemorrhage, and by way of consequence, massive transfusion (MT) is a frequent complication of trauma and surgery. MT is commonly defined as the replacement of one blood mass in a period of 24 hr. A dynamic definition of MT, such as the transfusion of four or more red cell concentrates within one hour when ongoing need is foreseeable,¹ or the replacement of 50% of the total blood volume within three hours, is more relevant in the acute clinical setting. Massively transfused patients will show evidence of defective hemostasis in a high percentage of cases. In this review, the term "coagulopathy" is used interchangeably with the more general term "defective hemostasis" and encompasses both defects of primary hemostasis (related to platelet function) and coagulopathy (related to alterations of the plasma phase of coagulation).

The incidence of hemostatic defects associated with MT will vary according to the clinical context (blunt vs penetrating trauma, presence of brain injury, elective surgery),^2,3 according to the definition of coagulopathy (clinical findings vs laboratory test results),³ and according to the blood products administered to the massively bleeding patient (fresh whole blood, stored whole blood, "modified whole blood" (MWB-whole blood from which platelets and/or cryoprecipitate are salvaged before storage),^4,5 packed red blood cells (PRBC), concentrated red cells, etc.).⁶ For example, prior to the era of blood fractionation, the transfusion of large volumes of stored blank blood did not result in a hemorrhagic diathesis in young and previously healthy soldiers wounded during the Vietnam war.⁷ More recently, it has been shown that abnormalities of the prothrombin time (PT) and of the activated partial thromboplastin time (aPTT) occur after the transfusion of 12 units of PRBC and that thrombocytopenia develops after the transfusion of 20 units.⁸ Yet, despite several attempts at defining meaningful laboratory indicators of impending or established coagulopathy, the relationship between laboratory hemostatic abnormalities and abnormal clinical bleeding remains unclear.

Most studies of MT have been conducted in trauma patients and most are retrospective or uncontrolled observational studies,⁹ for obvious reasons. Given the variable and complex clinical context, the results of these studies have seldom led to definitive conclusions. Furthermore, factors other than the transfusion strategy, related to trauma itself, may have led to the observed hemostatic abnormalities.¹⁰ Unfortunately, conventional teaching has sometimes failed to appreciate the evolution of transfusion practices and the context in which these were developed. As a result, anesthesiologists may have been led to apply transfusion strategies, e.g., those developed for trauma patients at a time when MWB was available,^5,11 inappropriately to patient receiving red cell concentrates for massive bleeding during elective surgery. The situation may become even more confusing when disseminated intravascular coagulation (DIC) is associated with trauma and/or MT.

In this article on MT and coagulopathy, we will attempt to review:

- 1. the pathophysiology of coagulopathy in massively transfused, adult and previously hemostatically competent patients in both the elective surgical and trauma settings; and

- 2. the management strategies used in these settings.

We searched Medline for original articles published on "massive transfusion," "transfusion," "trauma," "surgery," "coagulopathy" and "hemostatic defects." In addition, the reference lists of obtained articles were searched to identify other relevant articles. This review does not deal with the obstetrical and pediatric patient populations, nor with specific hemostatic anomalies such as those associated with cardiopulmonary bypass (CPB), liver transplantation and pre-existing coagulation disorders. Nevertheless, when relevant to the discussion, a few articles from those areas have been included in the review.

A preliminary version of the text was circulated to experts of the "Groupe d’intérêt en hémostase périopératoire" [Perioperative Hemostasis Interest Group] for comments and suggestions at a meeting of the GIHP held in La Fouly, Switzerland, in February 2003. A narrative format was adopted since the heterogeneity of published studies is considerable and was not conducive to a more formal review. Because the nature of blood products available to clinicians has changed over time, the retrieved articles were organized and reviewed by date of publication, to understand the evolution of our knowledge on MT and coagulopathy.

	I. Pathophysiology of coagulopathy in MT

TOP Abstract Introduction I. Pathophysiology of... III. Management of coagulopathy... IV. Conclusions References

 
Volume replacement with crystalloids and colloids and temperature control are initial resuscitation measures; these are followed by the transfusion of red cells, coagulation factors and platelets; finally, DIC may become a problem that will require treatment.

A. Hemodilution
1. CRYSTALLOIDS
In elective surgery, rapid hemodilution with crystalloids has been shown to induce changes on thromboelastography suggestive of increased thrombin generation and a hypercoagulable state.^12,13 The clinical significance of this effect, specially in trauma patients who are initially hypercoagulable,⁷ remains unclear. Nonetheless, crystalloid-induced hypercoagulability casts a doubt on studies of the effects of colloids on coagulation that used crystalloids as a control.¹⁴

2. COLLOIDS
The characteristics of the different colloids and their effects on coagulation are presented in Table I.

HES solutions are effective plasma expanders in common use both in Europe and in North America. It has long been known that HES solutions interfere with coagulation¹⁹ and that the effects vary according to the dose and type of solution administered.²⁰ Solutions with a high molecular weight and a high degree of substitution accumulate in the tissues and are responsible for more pronounced hemostatic effects.²¹ Abnormal platelet function occurs more frequently after high molecular weight HES.²² Conversely, HES solutions with a low molecular weight and a lesser degree of substitution are eliminated more rapidly and tend to affect measures of hemostasis less.^23–25

In addition to their effects on hemostasis, the infusion of large volumes of HES solutions will result in significant hemodilution. The resulting drop in hemoglobin and platelet concentrations may compromise primary hemostasis. In addition, Innerhofer et al. have shown that the administration of HES or modified gelatin in patients undergoing knee replacement surgery results in reduced clot strength due to impaired fibrinogen polymerization and that reduced fibrinogen concentrations might be reached earlier than expected.²⁶

Adverse events associated with the use of HES solutions for the resuscitation of patients requiring MT have not been reported, inasmuch as the allowed maximal daily dose is not exceeded.¹⁶ A large retrospective study suggested that the use of 6% HES in primary cardiac surgery with CPB may increase bleeding and transfusion requirements, despite the infusion of volumes smaller than the manufacturer’s recommended dose.²⁷ Conversely, large volumes (up to 5 L) have been infused without major complications,²⁸ but the safety of this practice remains controversial.²⁹

The clinical significance of the effects of HES solutions on hemostasis remains unclear. It may never be possible to determine precisely the effect of volume replacement in massively transfused patients with ongoing bleeding. In these patients, hemostasis is stressed severely by numerous factors other than the type of non-blood-related iv fluid used for resuscitation and the underlying cause of coagulopathy is difficult to ascertain. Nonetheless, it is interesting to note that the use of colloids in trauma patients is not mentioned in the recommendations by the American College of Surgeons.³⁰

B. Hypothermia
An important measure to reduce blood loss through preservation of hemostasis is the maintenance of normothermia both during and after the operation. The definition of hypothermia has varied amongst studies; however, most definitions have used temperatures below 35°C. Hypothermia slows the activity of the coagulation cascade, an enzymatic process, reduces the synthesis of coagulation factors, increases fibrinolysis and affects platelet function.

1. ANIMAL DATA
Several animal studies conducted under hypothermic conditions have shown reversible platelet count decreases and platelet function defects, altered coagulation patterns and an enhanced fibrinolytic response. In dogs cooled to 19°C, Yoshihara et al. found a severe decrease in platelet count and collagen-induced platelet aggregability and an increase in fibrinolysis.³¹ No variations of the PT and aPTT were observed but these tests were performed in vitro at 37°C. These modifications, which could potentially increase bleeding, were not documented in the normothermic control group. Other experimental studies have shown an important prolongation of the PT and aPTT that was inversely and linearly correlated to temperature.^32,33

Pina-Cabral et al. also observed a decrease in platelet count in hypothermic dogs.³⁴ The presence of platelet clumps was detected inside the hepatic sinusoids. The authors concluded that hepatic platelet sequestration could explain the decrease in platelet count in this setting.

In swine, Oung et al. showed a prolongation of the BT (10.9 min vs 5.5 min in the control group), confirming the impairment of hemostasis induced by hypothermia (30°C).³⁵ Prolongation of the BT has also been observed by Valeri et al. in baboons subjected to systemic hypothermia at 32°C and skin hypothermia at 27°C.³⁶

2. HUMAN DATA
In humans, many studies have emphasized the major role of hypothermia on the onset of bleeding during surgical procedures. Valeri et al. observed the effects of skin temperature in 33 patients undergoing CPB.³⁷ Local hypothermia produced an increased BT and a significant reduction in thromboxane B2, an indicator of platelet activation, at the BT site. Local rewarming produced a significant increase in shed blood thromboxane B2. Thus, hypothermia caused a reversible platelet dysfunction and rewarming improved platelet function and reduced the BT. These data have been confirmed by Michelson et al. who demonstrated the involvement of platelet glycoprotein receptor (GP Ib and GMP 140) alterations in this hemostatic defect.³⁸ Again, rewarming completely reversed the activation defect as soon as temperature returned to 37°C.

These abnormalities of routine coagulation tests are clinically significant: mild hypothermia (35 ± 0.5°C) increased bleeding and allogeneic blood requirements in patients undergoing total hip arthroplasty.³⁹ Thus, surgery under normothermic conditions may help prevent bleeding complications and decrease the intraoperative use of transfusions. The additional contribution of hypothermia to the hemorrhagic diathesis may be overlooked since coagulation testing is normally performed at 37°C.⁴⁰

Hypothermia is an important contributor to coagulopathy in trauma patients.⁴¹ Hypothermia (temperature less than 34°C) occurred in 80% of non-survivors and 36% of survivors in the 45 trauma patients reported by Ferrara et al.⁴² Patients who were hypothermic and acidotic developed clinically significant bleeding despite adequate blood, plasma, and platelet replacement. The authors concluded that avoidance or correction of hypothermia may be critical in preventing or correcting coagulopathy in the patient receiving MT.

C. Blood components and alterations of hemostasis
1. RED CELLS
An often-ignored effect of red blood cell (RBC) transfusion is the improvement of hemostatic function. The contributions of RBC to hemostasis are illustrated in Figure 1.

View larger version (44K): [in this window] [in a new window]   FIGURE 1 The contribution of red cells to hemostasis Red cells contribute to the margination of platelets against the vessel wall and their availability to act at the site of a vascular lesion. They have also been shown to modulate the biochemical and functional responsiveness of activated platelets. (Courtesy of Sylvain Bélisle, MD, FRCPC, Montreal Heart Institute).

Another mechanism by which erythrocytes modulate hemostasis is the rheological effect of red cells on the margination of platelets.⁵¹ Under normal circumstances, red cell flow is maximal at the centre of a vessel, tending to push platelets towards the periphery of the vessel lumen, thereby optimizing their interaction with injured endothelium and promoting hemostasis. In rabbit arterioles, platelet numbers are highest near the vessel wall⁵² and platelets align themselves with their equatorial plane parallel to the vessel wall as they move closer toward the periphery of the vessel.⁵³ Experimental data have shown that platelets are expelled toward the RBC depleted marginal layer near the tube wall by mutual interaction with erythrocytes. Under these circumstances, the near wall concentration of platelets is enhanced up to about seven times the average concentration.⁵⁴

The correlation between the BT and hematocrit levels has been studied experimentally. In non-thrombocytopenic rabbits, the microvascular BT varied inversely with the hematocrit, animals with hematocrit levels above 35% having shorter BTs than animals with hematocrits lower than 35%.⁵⁵ In a rabbit model of cyclic arterial thrombosis and clot lysis, Ouaknine-Orlando et al. have shown that decreases in the hematocrit reduced the cyclic arterial thrombosis rate and increased the BT.⁴⁶ Interestingly, normalization of the hematocrit caused thrombosis to reappear.

Transfusion of RBC shortens the BT in anemic thrombocytopenic patients despite persistent thrombocytopenia.⁵⁶ Further, perfusion of blood from transfused, previously anemic thrombocytopenic patients improved the interaction of platelets with the subendothelium in an experimental perfusion model. However, this interaction remained lower than in non-anemic non-thrombocytopenic subjects.⁵⁶ Similarly, RBC shorten the BT and control the hemorrhagic diathesis of uremic patients.⁵⁷ In humans with a normal renal function and platelet counts over 100,000•mm^–3, a modest but statistically significant inverse correlation (r = –0.47; P < 0.001) exists between the hematocrit and the BT.⁵⁸ Patients with a pretransfusion hemoglobin concentration 60 g•L^–1 have a greater chance (relative risk 4.07; 95% confidence interval 1.03 to 16.2; P = 0.04) of a posttransfusion decrease in BT than patients with a hemoglobin of more than 60 g•L^–1.⁵⁹ Valeri et al. have shown that, in healthy volunteers, an acute 15% reduction in hematocrit produced a 60% increase in the BT while the BT remained normal despite a 32% reduction in platelet count.⁶⁰ All this being said, the clinical significance of these findings remains unclear since the relationship between the BT and perioperative blood losses is highly controversial.^60,61

The hemostatic effects of profound normovolemic hemodilution were investigated in eight patients undergoing surgical correction of idiopathic scoliosis by McLoughlin et al.⁶² Abnormal hemostasis developed prior to compromise of global tissue oxygenation suggesting that, in healthy anesthetized subjects, normovolemic hemodilution may be limited more by preservation of normal coagulation. In this report, reinfusion of all collected blood at the end of the procedure did not normalize the PT or the aPTT. Unfortunately, the authors did not describe if the microvascular bleeding (MVB) observed during hemodilution was corrected by increasing the hematocrit. Modified ultrafiltration in pediatric open heart operations has been shown to increase the hematocrit and attenuate the dilutional coagulopathy associated with CPB in infants.⁶³ Use of modified ultrafiltration to increase the hematocrit to 36–42% reduced the rise in total body water and the need for donor blood in children undergoing open heart surgery.⁶⁴

Thus, further investigations into the role of the hemoglobin concentration or hematocrit on hemostasis in massively transfused patients appear warranted. The data presented above tend to support the concept of a minimal hematocrit for optimal hemostasis. At present the optimal hematocrit or hemoglobin concentration to prevent or to initiate treatment of coagulopathy remains unknown. Experimental evidence suggests that relatively high hematocrits, possibly as high as 35%, are required to sustain hemostasis in bleeding patients undergoing MT.

2. COAGULATION FACTORS
It is difficult to isolate precisely the role of coagulation factors in the pathophysiology of coagulopathy associated with MT. Impaired hemostasis is most probably multifactorial in origin and results from the adverse hemostatic effect of multiple concurrent coagulation factor deficits combined with variable degrees of anemia and thrombocytopenia.⁶

While numerous studies have measured changes in the PT and aPTT in relationship with bleeding and MT, few have examined individual hemostatic factors. In 1979, transfusing MWB to patients who sustained major trauma, massive gastrointestinal hemorrhage or aortic aneurysm rupture, Counts et al. reported that the number of units of blood transfused explained less than 20% of the variance in factors V and VIII and was not related to factor VII, X, XI, XII and fibrinogen levels. The authors concluded that it was not necessary to supplement transfusions of stored, MWB with fresh blood or fresh frozen plasma (FFP).⁵ In 1995, using plasma poor red cell concentrates, Hiippala et al. showed that a concentration of fibrinogen of 1.0 g•L^–1 was reached when the blood loss was 1.42 times the calculated blood volume and that blood losses in excess of two blood volumes caused the deficiency of prothrombin, factor V, platelets and factor VII, in this order.⁶⁵ These observations were made in ASA physical status I or II patients undergoing elective major urologic or abdominal surgery and, as a result, may not apply to emergent operations or trauma. Nonetheless, they illustrate well the difference between the times when red cell solutions contained significant amounts of plasma and modern component therapy.

It is important to realize that studies conducted at a time when fresh, stored or modified MWB was in common use seldom reported low levels of coagulation factors as the primary factor responsible for impaired hemostasis.^4,5,7,11,66 Since the widespread use of red cell solutions containing minimal amounts of plasma in the late 1980’s and early 1990’s, dilution or consumption of coagulation factors has become a significant issue requiring specific treatment with, primarily, FFP.^3,6,8,65 Even today, clinicians seldom administer "pure" blood products. PRBC contain a small amount of plasma (30–60 mL), as do platelet concentrates (80 mL approximately). Therefore, it may be difficult to differentiate precisely the therapeutic effect of the different blood components transfused.

3. PLATELETS
Primary hemostasis is characterized by the formation of the "platelet plug." The mechanism is complex and involves the presence of fibrinogen and activation of several glycoprotein receptors on platelets.^67–71 Hemostasis is initiated by injury to the vascular wall, leading to the deposition of platelets adhering to blood vessel subendothelial matrix proteins (collagen and von Willebrand factor) via interactions with platelet membrane glycoprotein receptors. Subsequently, the GP IIb/IIIa receptor is activated. This receptor has a high affinity for fibrinogen (and also for von Willebrand factor at high shear stress). Binding of fibrinogen to adjacent platelets results in irreversible platelet aggregation and the formation of the platelet aggregate.

Since the publication of Miller’s classic study on coagulation defects associated with massive blood transfusions,¹¹ thrombocytopenia resulting from hemodilution has been thought to be the most important hemostatic abnormality associated with MT. This explanation is intuitively appealing: replacement of lost blood with fluids that do not contain platelets (or coagulation factors) results in a dilutional coagulopathy. However, models based on the washout equation (a simple mathematical model of exchange transfusion that calculates the decay of blood components when bleeding and replacement rates are constant and equal) may not apply to bleeding trauma patients where blood volumes fluctuate, bleeding rates vary with blood pressure, and replacement often lags behind blood loss.⁷² Clinically, simple hemodilution has failed to explain several observations.

In young, previously healthy soldiers with wounds excluding burns and head injuries, platelet levels fell rapidly to about 100,000•mm^–3 during rapid transfusion of stored whole blood and remained at that level after the first 6 L of stored whole blood. The PT, aPTT and fibrinogen levels were less severely affected and, most important, significant operative bleeding was not encountered in conjunction with these mild dilutional coagulation changes.⁷ On average, the platelet count fell below 100,000•mm^–3 after transfusion of 18 units of blood in the study by Counts et al.,⁵ but slightly less than half (43%) of the variation in platelet counts could be ascribed to the functional relationship between the amount of blood transfused and the platelet count. In a study conducted to determine the efficacy of prophylactic platelet administration to prevent MVB associated with MT, Reed et al. observed that platelet counts were not different between patients who received prophylactic platelet transfusions and those who did not.⁴ Further, both groups had higher platelet counts than predicted by a standard washout equation. This finding implies that platelets are being released into the circulation and counteract the effects of dilution. Sequestered platelets can be released from the spleen and the lung, in addition to the premature release of platelets from the bone marrow. Elevated stress hormones and the administration of catecholamines, a situation more likely to occur in the trauma patient, will influence release.

As in the study by Counts, Reed et al. found the relationship between platelet counts and units of blood transfused to be significant albeit highly variable (r² = 0.24 for patients receiving platelets and r² = 0.35 for patients receiving FFP),⁴ suggesting that factors other than simple dilution affect platelet count. Finally, in the study by Miller, observed platelet counts did not parallel calculated platelet counts (Figure 2).¹¹

View larger version (19K): [in this window] [in a new window]   FIGURE 2 Calculated vs observed platelet counts in a person receiving platelet-free blood Observed platelet counts are higher than those predicted by hemodilution alone: the observed platelet count after the administration of 25 units of blood is of the order of 60,000•mm–3 while hemodilution predicted a platelet count of approximately 20,000•mm–3. Reproduced with permission from Miller RD, Robbins TO, Tong MJ, Barton SL. Coagulation defects associated with massive blood transfusions. Ann Surg 1971; 174: 794–801.[Medline]

Thus, it appears logical to consider that coagulopathy after MT can be a problem resulting from a combined deficit of platelets and fibrinogen. Focusing only on platelet levels or concentrations of specific coagulation factors may not lead to the most appropriate therapeutic approach.

D. DIC
1. DEFINITION
DIC is an acquired syndrome secondary to the systemic and excessive activation of coagulation. It may be defined by the association of hemostatic defects related to the exaggerated generation of thrombin and fibrin (with or without clinical signs) and the excessive consumption of platelets and coagulation factors. Criteria for the diagnosis of DIC are presented in Table II. The syndrome can be seen in numerous clinical situations and often complicates the management of MT.

In trauma patients, two major mechanisms are responsible for the occurrence of DIC. The first relates to the nature and to the importance of tissue trauma. The second relates to shock and tissue anoxia. Brain injury is associated with a particularly high incidence of coagulopathy. In the study by Faringer et al., more than 40% of patients with penetrating or blunt trauma with associated brain injuries had abnormal coagulation tests on admission, compared with 0% in patients with blunt trauma but without brain injury.² After blunt brain injury, a DIC syndrome secondary to the extravasation of tissue factor can rapidly (within one to four hours after injury) lead to a consumptive coagulopathy that is associated with a high frequency of death.⁷⁶ Regarding the importance of tissue trauma, in the absence of massive head injury and pre-existing disease, life-threatening coagulopathy was associated with a pH of less than 7.10, a temperature of less than 34°C, an injury severity score greater than 25, and a systolic blood pressure of less than 70 mmHg. When all risk factors were present, the incidence of coagulopathy was 98%.⁴¹

At least two studies have attempted to determine which populations of massively transfused patients are most at risk of sustaining DIC. Mannucci et al. studied changes in the hemostatic system in 172 patients undergoing MT for excessive bleeding during or in the early postoperative period after elective, emergent or trauma surgery. Of these, 52 (30%) suffered decompensated DIC and there was no significant relation between the number of whole blood or PRBC units transfused and the values of any variable of hemostasis measured.⁷⁷ In a series of 64 patients receiving more than ten units of red cell concentrates during elective or urgent surgical procedures or resuscitation of multiple trauma, Hewson et al. observed that coagulopathy is related to hemodilution initially, but, within three hours, is related to the duration of antecedent hypotension. Thus, on the basis of the available information, it is difficult to determine which patient population (elective or urgent operations, trauma) is most likely to sustain DIC.

3. THE ELECTIVE SURGICAL SETTING
In the purely elective setting, DIC complicating MT is infrequent. No patient suffered from DIC amongst the 32 young ASA physical status I or II patients undergoing posterior spinal stabilization and MT.³ Clinically increased surgical bleeding was present in 17 patients and in 14 of the 17 patients hemostasis improved after the administration of FFP (approximately 10 mL•kg^–1). Again, these results suggest that when tissue anoxia is avoided and surgical trauma is controlled, the occurrence of DIC may remain low despite MT.

	III. Management of coagulopathy in MT

TOP Abstract Introduction I. Pathophysiology of... III. Management of coagulopathy... IV. Conclusions References

 
A. Diagnosis
Numerous attempts have been made to monitor changes of the coagulation system in relationship to trauma, surgery and MT. Unfortunately, results have been disappointing and, at present, there is no simple, reliable and rapid diagnostic test that allows clinicians to manage massively transfused, critically ill patients. The available tests quantify specific factors in clotting or attempt to measure clotting function.

The platelet count is the only indicator of coagulation that can be obtained rapidly through the use of automated counters, in contrast to conventional tests of hemostasis that take a minimum of 30 min since they require centrifugation of blood samples. Even if platelets play an important role in coagulation, a decreased platelet count is not a specific indicator of coagulopathy. Rather, the significance of a decreased platelet count should be interpreted in the patient’s specific clinical context: is platelet function expected to be normal? Is the fibrinogen concentration sufficient? Is the hemoglobin concentration adequate? Is there any evidence of a consumptive coagulopathy? Answering these questions will assist in making the appropriate diagnosis of coagulopathy.

Usefulness of the BT to diagnose or predict coagulopathy in massively transfused patients has been investigated in a few studies. Overall, the BT increases early in the course of surgery and transfusion,⁷⁸ remains elevated for several days postoperatively⁷⁹ and does not allow the differentiation between bleeding and non-bleeding patients.⁵ In their critical reappraisal of the BT, Rodgers and Levin concluded that there is no evidence that abnormalities in the test occur sufficiently in advance of other indicators of bleeding to allow actions to be taken that could alter outcome favourably.⁸⁰ Consequently, the BT is of no use in the context of MT.

Reliable bedside monitors have become available to monitor the PT and aPTT⁸¹ and may add to the timely management of the bleeding patient. Controversy remains, though, on the proper use of coagulation screening tests to guide replacement therapy. The PT and aPTT are expected to become elevated when levels of factor V, VIII and IX are less than 50% of values found in a control patient population.⁸² It should be noted, however, that the PT and aPTT are prolonged when fibrinogen levels are low in the presence of normal concentrations of coagulation factors (e.g., congenital afibrinogenemia).

As for decreased platelet counts and prolongations of the BT, prolongations of the PT and aPTT are very common in massively transfused patients.^{2,3,5,7,8,11,41,65,73,75,77,83,84} Minor prolongations of the PT or aPTT ratio (ratio = measured value/control value) are poor predictors of bleeding in massively transfused patients.⁵ Ciavarella et al. have shown that, in 36 massively transfused patients, patients with a PT or aPTT ratio greater or equal to 1.8 had an 80 to 85% chance of exhibiting MVB.⁶⁶ When the fibrinogen level is adequate, a PT or aPTT ratio greater or equal to 1.8 reliably predicts that factor V and VIII levels are less than 30%,⁶⁶ a percentage that has been cited as an indication for coagulation factor replacement.^4,66 In the presence of a decreased fibrinogen concentration (less than 0.75 g•L^–1), a PT or aPTT ratio greater than 1.5 is associated with factors V and VIII of less than 20%.⁷³

In summary, only marked prolongations of the PT or aPTT (1.5 and 1.8 times higher than control when the fibrinogen level is low and normal respectively) are likely to be significant from a clinical perspective.

Other instruments have been developed to study coagulation at the bedside, using whole blood. While their use in the context of MT appeared promising, results have, unfortunately, been disappointing. The best known is the thromboelastograph, a device that measures the viscoelastic properties of the clot during its formation and subsequent lysis. In general surgical patients, thromboelastography analysis showed a trend toward increased coagulability with progressive blood loss and contributed to the identification of two patients who required treatment of a coagulopathy.⁸⁵ Thromboelastography has a high negative predictive value (82%) for bleeding after routine cardiac surgery, allowing the differentiation between surgical bleeding and coagulopathy. Unfortunately, the positive predictive value of the test is low (41%).⁸⁶ More studies will be required to establish its usefulness in the management of MT.

Another instrument, the PFA-100® (Platelet Function Analyzer; Dade-Behring, Miami, FL, USA), measures an ex-vivo BT in the presence of different agonists. The device has been used extensively for the diagnosis of hereditary coagulation disorders, particularly von Willebrand’s disease. In patients undergoing routine cardiac operations, the PFA was not correlated with mediastinal chest drainage.^87,88 A Medline search on the use of the PFA during MT failed to retrieve any relevant references.

B. Treatment of coagulopathy
The treatment of coagulopathy associated with MT is not simple. Two approaches are outlined in Table III and in Figure 3. Both approaches should be viewed as complementary.

View larger version (27K): [in this window] [in a new window]   FIGURE 3 The management of massive transfusion in the elective surgical setting Reproduced with permission from Erber WN. Massive blood transfusion in the elective surgical setting. Transfus Apheresis Sci 2002; 27: 83–92.[Medline]

In general, clinicians assume that all blood products are comparable and that the conclusions of studies conducted in similarly developed countries can be applied locally. We compared the characteristics of blood products (PRBC, FFP and platelet concentrates) available in Canada and in three European countries (Belgium, France and Switzerland; characteristics of allogeneic blood products available as Additional Material at www.cja-jca.org). While some differences exist, these are minor and unlikely to result in clinically significant management disparities (Douglas Fish, personal communication).

In light of the above risks, we recommend that blood products be transfused to correct a physiologic deficit likely to be detrimental to the patient. Obviously, this is, most often, not possible in the context of MT, in the presence of ongoing hemorrhage for example. Hemostatic blood components should be transfused mainly to treat a clinical coagulopathy, unless important surgical factors justify transfusion, e.g., prior to invasive procedures in patients with a known hemostatic defect, in neurosurgical procedures where bleeding may have catastrophic consequences, etc., (note that the latter recommendations are based on expert opinion only).

No prophylactic regimen involving the administration of FFP and/or platelet concentrates has been shown to be effective in massively transfused patients.^4,5,77 The prophylactic administration of (potentially) unnecessary transfusions exposes patients to multiple donors, increases the risks to the patient and is unacceptable.^90,91 Nonetheless, given the delay required to prepare and/or obtain blood products, MT associated with evidence of an evolving laboratory coagulopathy may warrant ordering of blood components that will, then, be readily available to treat MVB should it occur.^92,93 Whenever possible, the use of single donor plasma or platelets is preferred to decrease donor exposure.

2. APPROACHES TO THE TREATMENT OF COAGULOPATHY
Figure 3, by Erber et al., summarizes well the use of blood and non-blood products involved in the resuscitation of a bleeding patient.⁹⁴ Initially, crystalloids or colloids are infused to maintain normovolemia. As the percentage of blood volumes lost and replaced increases, PRBC, FFP and platelets will be required, in that order, guided by clinical and laboratory variables. Pharmacological agents are usually administered relatively late in the process [protamine sulfate antagonizes the effect of excess heparin; desmopressin has been used to control hemorrhage, specially after cardiac surgery, with varying success; aprotinin has been suggested in the context of trauma and MT but its use is not supported by any controlled trial; recombinant activated factor VII (rFVIIa) is a promising hemostatic agent under investigation but the optimal timing of administration of rFVIIa remains to be determined]. While this scheme is appealing and applicable in the elective surgical setting where bleeding is usually progressive and coagulopathy can be monitored and anticipated, the situation can be quite different in the traumatized patient.

In the interval between injury and arrival to the hospital, the trauma patient has lost an undefined amount of blood that has been replaced, in part, by crystalloids or colloids.⁷² Tissue trauma, shock, tissue anoxia and hypothermia contribute to the development of DIC and the results of coagulation testing are not immediately available. Clinicians are called upon to intervene rapidly in a very unclear and unstable situation.

Basic recommendations include the maintenance of normothermia and correction of a low hemoglobin concentration. Maintaining a normal body temperature is a relatively simple and probably one of the most effective strategies of blood conservation. Unfortunately, it can easily be overlooked in the trauma setting. When a hypothermic patient bleeds without an apparent surgical cause, restoration of temperature towards normal should be a first-line intervention. Correction of the hypothermia-induced hemostatic defect can be expected as soon as the patient is rewarmed.

A low hemoglobin concentration should be corrected prior to the administration of hemostatic blood products, in view of normalizing hemostasis in bleeding patients. When circumstances allow, allogeneic RBC should be transfused one unit at a time and the effects of transfusion on hemostasis monitored before administering supplemental units. The optimal hemoglobin concentration to sustain hemostasis in the context of MT remains unknown but is probably higher than that required for oxygen transport and delivery.

The use of platelets and/or FFP should depend on the results of coagulation testing and clinical judgment. A markedly prolonged PT and aPTT suggests a coagulation factor deficiency and is best treated with FFP. Decreased levels of fibrinogen will also require treatment with FFP. FFP should be administered in doses large enough to increase coagulation factor levels and maintain them above critical levels. Doses ranging from 5 to 20 mL•kg^–1 have been recommended. In the average adult, four units of FFP (800 to 1,000 mL) should suffice initially but additional bolus doses should be administered according to ongoing blood losses and transfusions.⁶ As shown in Figure 4, it is important to administer sufficient bolus doses of FFP to maintain adequate concentrations of coagulation factors. Further, using a three compartment dynamic computer simulation, Hirshberg et al. suggest that, in trauma patients with exsanguinating hemorrhage, FFP should be given rapidly (with the first units of PRBC replacement) in order to effectively prevent dilutional coagulopathy.⁷²

View larger version (17K): [in this window] [in a new window]   FIGURE 4 Simulation of relative plasma volume according to mode of fresh frozen plasma (FFP) supplementation Reproduced with permission from Hiippala S. Replacement of massive blood loss. Vox Sang 1998; 74: 399–407.

Platelets should be administered to correct a clinical coagulopathy associated with a decreased platelet count and/or platelet function. Clinicians must remember that platelet counts will decrease in a majority of massively transfused patients but that not all patients will bleed excessively as a result of thrombocytopenia. Other hemostatic anomalies may warrant a more urgent (a marked prolongation of the PT and aPTT) or concurrent (a decreased fibrinogen level) correction.

From the time PRBC have replaced whole blood, there is laboratory and clinical evidence in the literature that FFP may be required prior to platelet concentrates to treat a coagulopathy.^3,6,8,73 On the other hand, two studies have shown that survival in massively transfused trauma patients is associated with the increased transfusion of platelet concentrates.^41,96 One may postulate that a more aggressive control of coagulopathy was beneficial in these patients, a situation somewhat analogous to the benefits derived from early goal-directed therapy in patients with severe sepsis and septic shock.⁹⁷ Unfortunately, at present, no monitor allows clinicians to identify which patient is likely to benefit from the increased transfusion of hemostatic blood components (such as platelets or FFP).

Several animal experiments, case reports and case series report the successful use of rFVIIa to treat bleeding that could not be controlled by the administration of hemostatic blood components.^98–106 Originally, rFVIIa was developed to treat hemophiliacs with inhibitors to exogenous factor VIII and its use has been extended to the correction of several hemostatic defects.¹⁰⁷ Since factor VII must interact with tissue factor to initiate the generation of thrombin, coagulation occurs at the site of injury¹⁰⁸ and the risk of thromboembolic effects appears minimal.¹⁰⁹ The initial results with this novel hemostatic agent for "rescue" therapy of MVB are impressive and warrant the conduct of randomized controlled trials to evaluate further the efficacy and safety of this expensive drug.^110,111

	IV. Conclusions

TOP Abstract Introduction I. Pathophysiology of... III. Management of coagulopathy... IV. Conclusions References

 
Our first objective was to review the pathophysiology of coagulopathy in massively transfused, adult and previously hemostatically competent patients in both the elective surgical and trauma settings. The pathophysiology is complex and coagulopathy associated with MT requires a multidisciplinary approach involving anesthesiologists, blood bankers, hematologists, laboratory specialists and surgeons. In the trauma patient, DIC secondary to tissue injury and anoxia often complicates the management of MT. As a result, it is often difficult to ascertain the exact cause of MVB. The "classic" view that thrombocytopenia is responsible for the majority of bleeding complications in massively transfused patients should be abandoned.⁹³ As we have seen, decreased levels of platelets and coagulation factors cannot be predicted by dilution alone. Coagulopathy associated with MT and surgery is an intricate, multicellular and multifactorial event. While the interaction between platelets, fibrinogen and red cells is particularly important, the contribution of fluid replacement therapy, hypothermia and coagulation factor deficiency must not be overlooked.

Our second objective was to review the evidence for strategies used to manage coagulopathy in both the elective surgical and trauma settings. Whether for elective surgery or for the management of trauma patients, reliable bedside monitors of hemostasis are needed urgently. By assisting clinicians in making the correct diagnosis in a timely manner, monitors will contribute to the optimal use of blood products.

Times have changed, blood products have changed, and so has the management of the bleeding patient. Therapy should take into account all the factors known to affect hemostasis in these patients. Transfusion of blood components should be based on appropriate hematological testing and initiated mainly in those patients who bleed actively. Nevertheless, a standardized management of MVB may not always be possible in massively bleeding patients, especially in the context of trauma.

The situation appears to be different in the elective surgical situation. Tissue trauma is more controlled, normovolemia can usually be maintained, tissue anoxia is avoided and there is more time to monitor coagulation variables and anticipate deficits. In this context, coagulopathy is more often related to decreased coagulation factors and best treated initially with FFP. The main differences between elective surgery and trauma are summarized in Table IV.

	Footnotes

 
Reprints will not be available from the authors.

Accepted for publication May 28, 2003. Revision accepted January 5, 2004.

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TOP Abstract Introduction I. Pathophysiology of... III. Management of coagulopathy... IV. Conclusions References

 
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