MANAGEMENT OF COAGULATION DISORDERS IN THE SURGICAL INTENSIVE CARE UNIT

CHAPTER 89 MANAGEMENT OF COAGULATION DISORDERS IN THE SURGICAL INTENSIVE CARE UNIT



Christopher P. Michetti, Samir M. Fakhry


Surgeons commonly encounter coagulation disorders in the course of caring for patients, especially those with serious injury and those undergoing or recovering from surgery. Whereas bleeding is a condition well known to man since the beginnings of time, understanding the pathophysiology of bleeding and coagulation and developing effective therapies for them have come relatively recently and continue to undergo change as more is learned about the complex mechanism of blood coagulation and fibrinolysis. The ability to treat hemorrhage effectively had to await the discovery of blood types A, B, and O by Karl Landsteiner in 1900 and the AB blood type by Alfred Decastello and Adriano Sturli in 1902.


It would be nearly 40 years before the first blood bank was established in the United States in 1937. The development of reliable techniques of cross-matching, anticoagulation, and storage of blood was followed by the introduction of plastic bags for storage and devices for plasmapheresis making component therapy possible. The discovery of blood coagulation pathways and the development of reliable tests of coagulation made it possible to provide treatment for a variety of coagulation disorders, including those encountered as a result of the newfound ability to keep humans alive by the infusion of blood and the surgical control of bleeding.


The ability to replace blood loss is critically important in modern surgical practice and in trauma care. Equally important is the ability to provide therapy to patients who need individual blood components. Effective use of the precious resource that blood and its products represents is increasingly important as problems of supply continue to exist even while demand increases. The purpose of this chapter is to familiarize the practicing surgeon with the types of coagulation disorders encountered in critically ill or injured patients, reliable ways of diagnosing these disorders, and effective therapeutic strategies for treating them.



INCIDENCE



Congenital Bleeding Disorders



Von Willebrand Disease


Von Willebrand disease (vWD) is the most common inherited bleeding disorder, occurring in 1/100 to 1/1000 live births via autosomal inheritance. The disease consists of deficiency or dysfunction of von Willebrand factor (vWf), which promotes platelet adhesion to damaged endothelium and stabilizes factor VIII. There are three types of vWD. Knowing the specific type is important to direct therapy. In type 1, a deficiency of vWf exists. In type 3, vWf is absent. The main subtypes of type 2, 2a, and 2b, both consist of a qualitative functional defect in vWf.


Diagnosis of vWD is supported by prolonged partial thromboplastin time (PTT), and in types 1 and 3 reduced levels of vWf antigen. Factor VIII activity may be reduced, and bleeding time or other platelet functional assays may be abnormal. The ristocetin cofactor assay is a test that measures the ability of vWf to induce platelet aggregation.


1-deamino-8-D-arginine vasopressin (DDAVP) may be used to stimulate production of vWf and increase factor VIII levels in type 1 and type 2a disease. It is ineffective in type 3, however, and contraindicated in type 2b due to risk of thrombocytopenia and increased bleeding. Concentrates of factor VIII vWf are virus inactivated and are used commonly in types 2 and 3, but also in type 1 that is unresponsive to DDAVP. Cryoprecipitate contains vWf and factor VIII, and may be used in all types of vWD. However, it is pooled and not virus inactivated. It is only recommended as a third-line therapy. Antifibrinolytic amino acids, such as aminocaproic acid and tranexamic acid, are used as adjuvant therapy in all types of vWD along with the previously cited treatments.



Hemophilia A


Hemophilia A is a congenital bleeding disorder that results from factor VIII deficiency. It is phenotypically expressed in males due to its X-linked inheritance pattern, whereas females maintain a carrier state. Bleeding tendency is inversely related to factor VIII levels. As with most factor deficiencies, clinical coagulopathy is usually not evident until factor levels fall below 30% of normal (mild hemophilia). Spontaneous bleeding may occur at levels less than 5% (moderate hemophilia), and those with levels less than 1% (severe hemophilia) are especially at risk. Coagulation studies will show a prolonged PTT, normal prothrombin time (PT), and low factor VIII levels.


Patients with clinically significant bleeding or those undergoing surgery should receive factor VIII concentrates, preferably recombinant products. DDAVP increases endogenous factor VIII levels and may be used in mild cases. Up to 20% of individuals may develop IgG antibodies (“inhibitors”) to factor VIII after factor infusion, rendering future treatments ineffective. In such cases, recombinant factor VIIa (rFVIIa) may be used to induce hemostasis. rFVIIa is discussed in more detail later in this chapter. Cryoprecipitate contains factor VIII in lower concentrations than in factor VIII concentrates, but its use is tempered by risks of viral transmission. Viral transmission from pooled factor concentrates is now extremely rare, and virtually eliminated with use of recombinant factors.



Hemophilia B


Hemophilia B (Christmas disease) is an X-linked disorder of factor IX deficiency. It is clinically similar to hemophilia A, and coagulation tests also show prolonged PTT with normal PT and low factor IX levels. Recombinant factor IX concentrates are available, as well as pooled donated concentrates. Development of inhibitors is less common (1%) than in hemophilia A, and treatment of severe bleeding may also include rFVIIa. Therapy in such cases should be given in conjunction with a hematologist.



Acquired Bleeding Disorders



Coagulopathy of Hemorrhagic Shock


Hemorrhagic shock causes a complex coagulopathy whose etiology is multifactorial, and widely misunderstood. Misinterpretation of clinical and laboratory data may lead clinicians to incorrectly label this coagulopathy as disseminated intravascular coagulation (DIC) or dilutional coagulopathy, which may misdirect treatment. In hemorrhagic shock, blood loss and tissue hypoperfusion result in acidosis from anaerobic metabolism—leading to the generation of lactate. Decreased ATP production from tissue ischemia contributes to hypothermia and inability to maintain core temperature. Coagulopathy is the result, which exacerbates bleeding and perpetuates the “bloody vicious cycle.” Resuscitation with room-temperature fluids worsens hypothermia. In massive resuscitation from hemorrhagic shock, variable degrees of dilution of coagulation factors occur.


Hypothermia and acidosis are the two major contributors to the coagulopathy of hemorrhagic shock, and are discussed in more detail in material following. In the operating room and postoperatively in the intensive care unit (ICU), multiple treatments are obviously conducted simultaneously. However, the priorities in general are to stop the bleeding, resuscitate with crystalloid and blood to reverse ischemia and acidosis, and prevent and treat hypothermia. Because of the overwhelming influence of hypothermia and acidosis, coagulopathy is primarily that of ineffective clotting. This is in contrast to DIC, which implies an overactivated coagulation system with unregulated microvascular thrombosis. Attributing the bleeding to DIC may lead one to focus therapy on providing clotting factors with fresh frozen plasma (FFP), or the rarely needed cryoprecipitate, when time is much better spent on adequate resuscitation and rewarming.


Dilutional coagulopathy (the idea that microvascular bleeding can result from dilution of clotting factors) has limited scientific support. Clotting factor concentrations as low as 30% of normal are sufficient for hemostasis, as are fibrinogen levels greater than 75 mg/dL. Even replacement of an entire blood volume leaves one with about a third of the normal coagulation factor concentration. This is probably the minimum volume of transfusion that can lead to a true dilutional coagulopathy. Although dilution of factors may result in abnormalities in laboratory measures of coagulation such as PT and PTT, these alterations do not necessarily affect hemostasis in vivo. Furthermore, platelet count cannot reliably be predicted based on volume of blood loss. Formula-based replacement (X units of FFP and platelets for every Y units of blood transfused) has little rationale, and should be discouraged. In the perioperative hemorrhagic shock patient, factor replacement with FFP should be based primarily on clinical evidence of microvascular (nonsurgical) bleeding to target clinical hemostasis while efforts to correct hypothermia and acidosis are optimized.



Hypothermia


Hypothermia is often seen in the critical care setting in association with the systemic inflammatory response syndrome (SIRS), sepsis, and shock, in which decreased oxygen consumption prevents maintenance of core body temperature. It routinely accompanies major surgery for hemorrhagic shock, in which it exacerbates the coagulopathy and should prompt a “damage control” strategy. In addition, heat loss from hemorrhage is compounded by the administration of room-temperature fluids and blood products. In trauma patients, temperatures less than 32° C are associated with 100% mortality.


Hypothermia slows the rate of reaction of the proteolytic enzymes of coagulation, resulting in impaired hemostasis. Both coagulation enzyme activity and platelet function are impaired at temperatures below 34° C in trauma patients. Platelet dysfunction is multifactorial, and is caused by defective adhesion and aggregation and decreased thromboxane production.


Prompt and efficient rewarming is essential in the hypothermic coagulopathic surgical patient. Although controlled hypothermia has proven beneficial in other conditions, such as cardiac arrest, no clear benefit has been proven in trauma or general surgery. The priority of therapy is to treat the underlying cause, whether by stopping any ongoing surgical bleeding, evacuating an undrained abscess, treating infection, or debriding necrotic tissue. External rewarming methods, although slow and inefficient, help to prevent further heat loss. Ambient room temperature should be raised, and warm air blankets and fluid pads applied to the patient (including the head). Core rewarming is far more efficacious than external techniques. At the very least, all infused fluids and blood products should be run through a fluid warmer, and warm humidified air given via the mechanical ventilator. When available, the more aggressive rapid technique of continuous arteriovenous rewarming may be used. A randomized prospective study suggests improved early survival and reduced fluid resuscitation requirements with this method when compared with slower methods.



Acidosis


Metabolic acidosis has long been recognized as a consequence of, and contributor to, coagulopathy. However, the specific pathways whereby acidosis impairs coagulation have yet to be clearly defined. Animal data suggest that hypothermia induces a delayed onset of thrombin formation, whereas acidosis decreases the overall thrombin generation rate. The association of severe acidosis (pH < 7.1) with hypotension and hypothermia in severely injured patients virtually guarantees life-threatening coagulopathy. Therapy is again directed at the cause of acidosis and not merely the correction of the pH. While simultaneously addressing the inciting events, lactic acidosis is treated with fluid resuscitation to optimize tissue perfusion. It can be guided by following the trend in base deficit or lactate level. Sodium bicarbonate administration is ineffective and potentially harmful in lactic acidosis, and is not recommended.



Thrombocytopenia


Thrombocytopenia is generally defined as a platelet count lower than 100,000/mm3. Counts of 50,000/mm3 to 100,000/mm3 increase risk of bleeding with surgery or major trauma, and spontaneous bleeding is a risk below 10,000/mm3 to 20,000/mm3. Thrombocytopenia in the ICU setting has a lengthy differential diagnosis, but its etiology can be broadly divided into three categories: decreased production of platelets, consumption or sequestration of platelets, and dilution. Malignancies or chemotherapy may affect platelet production, and massive transfusion and fluid resuscitation can lead to dilution of the total platelet count. In critically ill surgical patients, sepsis can cause a consumptive coagulopathy that in its most severe form manifests as DIC. Platelet consumption also occurs through immune mechanisms (antibodies to platelet glycoproteins), most notably in response to certain drugs. The list of such drugs includes heparin, H2 antagonists, sulfa, rifampin, quinidine, hypoglycemics, and gold salts.


Heparin-induced thrombocytopenia is a rare but highly morbid condition associated with a greatly increased risk of thrombosis. Dilutional thrombocytopenia may occur with massive transfusion because stored blood contains negligible levels of platelets. However, the decrease in platelet count is not proportional to the volume of blood transfusion. Thus, simple dilution is unlikely to be the sole determinant of the low platelet count. Release of platelets from the spleen and bone marrow may partly account for this variability. As with coagulation factors, dilutional thrombocytopenia alone does not account for microvascular bleeding. Treatment and transfusion guidelines are discussed later in this chapter.



Disseminated Intravascular Coagulation


DIC is a syndrome involving diffuse systemic hypercoagulation and fibrinolysis that occurs in response to specific clinical conditions. Disorders associated with DIC in the surgical ICU include sepsis, trauma, severe pancreatitis, malignancies, fulminant liver failure, and transfusion reactions—among others. The syndrome involves excessive fibrin deposition in the microvasculature, with platelet aggregation and microvascular thrombosis. The pathophysiology of DIC is linked to the inflammatory cascade and TF pathway, and is reviewed in more detail elsewhere. The condition ranges in severity from a subclinical low-grade acceleration of thrombosis and fibrinolysis to overt pathologic bleeding. Fulminant DIC is associated with multiple-organ dysfunction and death.


Diagnosis of DIC is made with a few laboratory tests in the proper clinical setting, after other causes of coagulopathy have been excluded. Scoring systems and algorithms have been proposed to aid the diagnosis. However, treatment is mainly supportive and targets the underlying cause, clinical endpoints, and associated laboratory abnormalities. Given the nonspecific nature of DIC, setting a defined threshold for making the diagnosis in the clinical setting is unnecessary—whereas set criteria are still needed for therapeutic trials and research. In addition, the label of DIC is often applied to patients receiving massive transfusion and resuscitation when their coagulopathy stems from other more common and reversible causes. It has also been observed that trauma patients with DIC have a thrombotic and fibrinolytic profile distinct from the usual hemostatic response to trauma.


DIC may be suspected in the setting of a generalized coagulopathy and clinical microvascular bleeding associated with an underlying process such as those described previously. The laboratory profile includes a low platelet count, prolonged PT and PTT, and elevated fibrin split products. D-dimer levels are increased in up to 94% of patients diagnosed with DIC, and the D-dimer assay is the most sensitive test for this condition. Fibrinogen levels may be maintained except in severe forms of DIC.


Therapy for DIC centers on treatment of the underlying disease process to remove the proinflammatory stimulus of the syndrome. Clinical hemostasis is the goal. Platelet counts and the PT/PTT are used to guide response to therapy, but are not endpoints themselves. FFP and platelet transfusion are indicated in patients with active bleeding and those with significant laboratory derangements undergoing surgery or procedures. Cryoprecipitate may be considered to replace fibrinogen if fibrinogen levels fall below 100 mg/dl and are not corrected with FFP infusion.


Many other therapeutic agents have been investigated, but to date no specific treatment has proven successful in improving outcome in patients with DIC. Anticoagulation has been used to attempt to control the hypercoagulation in DIC, and although improvement in certain lab parameters has been reported no survival benefit has been demonstrated with low-molecular-weight heparin, thrombin inhibitors, or antifibrinolytics.



Severe Sepsis


Research in recent years continues to elucidate the complex interrelationship of the inflammatory process and the coagulation mechanism. The initial manifestation of this relationship leads to a hypercoagulable state. Inflammation in sepsis induces tissue factor (TF) expression on circulating monocytes, tissue macrophages, and the endothelial surface—and fibrinolysis is inhibited. As fibrinolysis is impaired, fibrin deposition in the microvasculature proceeds unchecked. In addition, most patients with severe sepsis have low levels of the natural anticoagulants protein C and antithrombin III. Diffuse thrombosis leads to tissue ischemia and the multiple-organ dysfunction syndrome (MODS).


Coagulopathy in sepsis is multifactorial. Sepsis-induced thrombocytopenia occurs through immune mechanisms, platelet sequestration on activated endothelium, and consumption in DIC. Extensive thrombin generation consumes clotting factors, and fibrinogen is often reduced (although levels may be normal due to its generation as an acute-phase reactant). Pathologic bleeding may occur due to lack of circulating clotting factors and platelets that have been consumed, but this is relatively uncommon. Although DIC is estimated to occur in 15%–30% of patients with severe sepsis, the incidence of serious bleeding episodes in a recent study of septic patients was only 5%.


Transfusion of FFP or platelets in septic patients is indicated for active bleeding, or those at high risk for bleeding. As mentioned previously, transfused factors and platelets usually have only a transient impact because they are depleted by the ongoing consumption in the microvasculature. However, in the face of active bleeding aggressive therapy is warranted while every effort is made to treat or remove the source of the sepsis.



Traumatic Brain Injury


Traumatic brain injury (TBI) is associated with changes in the coagulation system, thought to result from release of the brain’s abundant concentration of TF (thromboplastin). Exposed TF incites hypercoagulation, followed by fibrinolysis—similar to the changes seen in trauma patients without TBI. Although laboratory tests may confirm coagulation and fibrinolysis in many patients, the manifestations of this process have a spectrum of severity ranging from clinically undetectable to occasional pathologic bleeding from consumptive coagulopathy. Coagulopathy is associated with increased mortality in blunt and penetrating TBI, but the mechanism for this is not clear.


The importance of the hemostatic changes may lie in promotion of secondary brain injury through cerebral microvascular thrombosis, which may exacerbate cerebral ischemia. Currently, it is not known whether therapy should target hemostasis to prevent further bleeding in the injured brain or block part of the coagulation pathway to prevent microthrombosis and ischemia. Until the pathophysiology is better understood, treatment should be directed only toward clinical endpoints and maintenance of platelets and clotting factors as necessary for hemostasis (as outlined elsewhere in this chapter).

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Jul 7, 2016 | Posted by in CRITICAL CARE | Comments Off on MANAGEMENT OF COAGULATION DISORDERS IN THE SURGICAL INTENSIVE CARE UNIT

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