Expert Column
Featured Expert: Jeffrey Lawson, MD, PhD
In this section, Dr. Lawson provides a written overview of postoperative coagulopathy, with particular emphasis on immune-mediated coagulopathy. An associate professor of surgery and assistant professor of pathology at Duke University, Dr. Lawson is also director of clinical research and the director of the vascular research laboratory at Duke University Medical Center.
- Postoperative Coagulopathy
- Immune-Mediated Coagulopathy
Introduction
Surgery is a complex stress to human physiology, which incites an array of hemostatic, inflammatory, and wound-healing responses. This postoperative period of stress is one that can both manifest and illuminate underlying coagulopathies, resulting in the phenotype of either hemostasis or thrombosis.
Coagulopathy
First, the term coagulopathy requires definition. From a functional point of view, coagulopathy is best defined as a clinical event—such as bleeding or thrombosis—that is not the result of direct mechanical/surgical misadventure. It seems logical to propose that this definition should also extend to laboratory test abnormalities in coagulation parameters that require the alteration of a patient’s care, medical therapy, or hospital stay—even in the absence of overt bleeding or thrombosis. Thus, examples of coagulopathy can range from a high-titer, anti-factor V antibody resulting in postoperative bleeding, or the formation of a lupus anticoagulant that renders anticoagulation tests invalid.
Postoperative Coagulopathy
When thinking about the etiology of postoperative coagulopathy, it is important to consider an array of possible explanations as to the biologic cause of bleeding or thrombosis. First and foremost in the surgeon’s mind must be to rule out technical causes of inappropriate bleeding or clotting (ie, a direct breach in the vascular architecture that was caused by the surgical procedure). Beyond the technical aspects of surgical bleeding or thrombosis, to correctly diagnose and appropriately treat postoperative coagulopathy, the surgeon should have a basic understanding of the most common bleeding and clotting disorders. Some of the relevant categories of bleeding disorders—each an educational topic of its own—include inherited and acquired bleeding disorders, as well as inherited and acquired clotting disorders. Here we will focus on acquired bleeding disorders.
Autoantibodies directed against a specific coagulation factor may lead to severe bleeding disorders. The most common coagulation factors involved are factors V and VIII. The mechanism by which these autoantibodies are generated is still an important area of research, but there appears to be significant evidence that immune exposure to non-human coagulation proteins is a key step in the process.
Liver disease predisposes patients to bleeding because coagulation factors are synthesized by the liver. Since vitamin K is essential for post-translational modification of the coagulation factors II, VII, IX and X, deficient states such as those secondary to malabsorption syndromes, also increase patients’ bleeding tendencies.
Extensive surgery can cause a state of disseminated intravascular coagulation (DIC). This acquired coagulopathy is initiated by massive tissue destruction and endothelial injury in trauma or extensive surgery that, among other mechanisms, lead to the release of tissue factor into circulation. Laboratory tests will reveal D-dimers; thrombocytopenia; often a prolonged PT, PTT, and thrombin time; and decreased fibrinogen levels.
Finally, the surgeon has to keep in mind that other elements may play a role during surgery and predispose the patient to bleeding, namely hypothermia and acidosis. Hypothermia has been shown to slow the enzymatic reactions of the coagulation cascade, decrease platelet counts and function, and stimulate fibrinolysis. Acidosis impedes fibrin polymerization and therefore clot strengthening. Anemia (hematocrit <30%) further aggravates bleeding diathesis, as red blood cells (RBCs) are thought to assist in platelet margination against an injured vessel wall. On the other hand, massive RBC transfusions lower the plasma concentration of calcium, thus inhibiting enzymatic reactions of the coagulation cascade.
Anticoagulants and antiplatelet agents are often used in vascular surgery to balance the hemostatic system when pathology is present, or when necessitated by a procedure. They can also introduce complications when trying to evaluate and diagnose a coagulopathic patient. It is therefore essential to have a complete medication history when evaluating a postoperative coagulopathy.
Immune-Mediated Coagulopathy
Of the arrays of coagulation abnormalities that can occur in the postoperative period, immune-mediated coagulopathy is one type of acquired bleeding disorder that can be hard both to diagnose and to manage. This will be our main educational focus here.
The first challenge of managing a patient with immune-mediated coagulopathy is being aware that the problem exists. The second challenge is making the diagnosis and knowing which tests support the diagnosis. The third challenge is determining how to treat this troubling syndrome, once it is identified.
What, then, defines an immune-mediated coagulopathy? Simply put, it is the development of antibodies against one’s own coagulation factors that render the complex machinery of the hemostatic system dysfunctional. In their most extreme forms, immune-mediated coagulopathies can be functionally indistinguishable from severe hemophilia, meaning that the patient is functionally deficient in one or more critical proteins of the coagulation system. The acquired hemophilia appears to be the result of the formation of autoantibodies, suggesting that immune-mediated coagulopathy is both the development of an acquired hemophilia and of autoimmune diseases. This type of immune-mediated coagulopathy occurs for several reasons, but appears to be most commonly associated with direct immune exposure to non-human coagulation proteins.
There are well-documented examples of factor VIII-deficient patients who were treated with porcine factor VIII, and ultimately developed both anti-porcine and anti-human factor VIII antibodies that rendered factor VIII replacement therapy ineffective. Further, there is significant documentation that patients who are exposed to non-human forms of thrombin are at risk for the development of anti-factor V, anti-thrombin, and antiphospholipid antibodies. This observation has been documented in numerous clinical reports, supported in animal trials, and included in the labeling for topical bovine thrombin preparations in the form of a boxed warning (commonly referred to as a “black box warning”). The product label warns that patients with pre-existing antibodies to bovine thrombin preparations should not be re-exposed. Unfortunately, there is no commercially available test to determine which patients have bovine thrombin antibodies.
The label for bovine thrombin preparations notes an occasional association with the development of coagulopathies. The true incidence of immune-mediated coagulopathy in patients exposed to non-human hemostatic products is unknown. From a historical perspective, the rate of antibody formation against bovine factor V and bovine thrombin has ranged from as high as 95% of patients exposed to the product, to as low as 20%, depending on the source of the thrombin and the clinical and laboratory specifics of the report. The more recent publications report results at the low end of this range. Further, some recent clinical studies have not detected an association between antibody response to bovine thrombin and adverse clinical outcomes, although these trials were designed and powered for other endpoints.
Regardless of the specific number, it appears that a significant portion of immunocompetent individuals, who are exposed to non-human thrombin products, are able to mount an immune response to the product, and may develop cross-reactive (auto-reactive) antibodies against their own human coagulation proteins. The effect of these cross-reacting antibodies may range from abnormalities in lab parameters with no discernible clinical effects, to serious bleeding events. It is not known what long-term effect sensitization of the immune system to non-human coagulation proteins has.
If a patient is suspected of having immune-mediated coagulopathy, how can the diagnosis be made? First, a rational history of the patient’s surgical care must be obtained. Was the patient exposed to non-human coagulation proteins (eg, bovine thrombin)? Was this the patient's first exposure to the product, or have they undergone other procedures that may have been related to exposure? Is the patient bleeding or clotting abnormally in the absence of a technical problem with surgery?
Commonly, a patient who demonstrates bleeding will have a prolongation of his or her standard coagulation tests—the PT and the PTT. Further, if the diagnosis is suspected, a detailed assessment of specific clotting factor levels, particularly factor V and thrombin, should be obtained. Finally, a “mixing study” of the patient’s plasma with normal plasma should be conducted. If the mixing study is prolonged in the setting of low factor levels, the diagnosis of circulating inhibitor (antibody) of the coagulation factors should be strongly considered. If a patient develops an acute hypercoagulable state after a surgical procedure in which bovine thrombin has been used, the diagnosis of antiphospholipid antibody syndrome should be considered. Appropriate testing for antiphospholipid and anticardiolipin antibodies should be obtained and, if positive, formal anticoagulation therapy should be started.
What therapeutic options are available once the diagnosis of immune-mediated coagulopathy is made? Supportive care seems most appropriate in the absence of overt bleeding and hemodynamic instability. The patient should be transferred to a medical center, with advanced critical care and hematology programs, if there are significant signs of bleeding in the presence of a high-titer coagulation factor inhibitor. In this setting, two treatment options have been utilized with varying success, and the literature in this area is not very robust. Some centers have advocated immunosuppression, followed by plasmapheresis and factor replacement. Unfortunately, in some severe cases, exsanguination has been reported during the plasmapheresis cycle. An alternative strategy uses a short burst of systemic IVIG treatment, followed by significant platelet transfusion. The rationale for the platelet transfusion is that circulating platelets carry an intracellular supply of factor V, which remains hidden from the immune system until the platelet is activated in the area of vascular bleeding.
No large clinical trial has validated these treatments, but as life-saving maneuvers they have been reported to be successful. In cases where an acquired inhibitor secondary to bovine thrombin exposure has been diagnosed, the patient should be informed of the situation and cautioned to avoid future exposure to bovine thrombin. The FDA has recently approved two new thrombin products from alternative sources: recombinant technology and pooled human plasma.
The keys to understanding, diagnosing, and treating immune-mediated coagulopathy seem to be rooted in three crucial points. First, the syndrome is real, although the incidence is unknown. Second, to make the diagnosis, you have to think about the problem, identify potential causes, and order the appropriate diagnostic tests. Third, if you make or suspect the diagnosis, consulting with a hematologist and/or a transfusion specialist can play a crucial role in an accurate diagnosis and treatment.
In severe cases, advanced hematology and critical care support are essential, and a transfer to a specialty center may be appropriate. Ultimately, these events are iatrogenic, and thus preventable.