In vitro experiments, together with animal and clinical studies, support the compartmentalized effect of rFVIIa at the site of injury without systemic activation of coagulation. Supplementation of plasma with rFVIIa to final concentration of 150 IU/mL (which is 50% higher than the level after bolus injection of 120 μg/kg), did not cause an increase in free thrombin and factor Xa. 40 Administration of a high dose of rFVIIa caused no significant changes in activation markers of coagulation, either in hemophilia patients 41 or in the swine model of grade V liver damage, 29 and an animal study in a rabbit stasis model of thrombosis reached similar results. 42 Extensive histologic examination of lungs, kidneys, and small intestine performed in the swine with grade V liver injury treated with 180 μg/kg of rFVIIa revealed no signs of microthrombi. 29 The typical prothrombin time shortening (to shorter than normal values) after administration of the drug is caused by the presence of TF and phospholipid in the test system, and therefore does not reflect a hypercoagulable state, but rather simulates the process at the site of injury.
Previous clinical experience with rFVIIa supports the hemostatic efficacy and high safety of the drug in patients with hemophilia and other congenital and acquired coagulopathies. 19–24 Serious adverse events occurred in < 1%, with only 0.2% possibly related to thrombotic complications in patients who had other reasons for these complications. 43 A recent survey revealed a low incidence of fatal thromboembolic complications in 4 of 5,522 patients treated with rFVIIa between 1996 and 2000 (unpublished data). Immediate hemostasis was achieved by rFVIIa in patients without preexisting coagulation abnormalities suffering intractable bleeds, as in cardiac 44 and abdominal surgery, 45,46 as well as a significant decrease in bleeding in cases where the drug was given prophylactically before prostatectomy 47 and liver transplantation (unpublished data). No increased thromboembolic complications were observed in these patients (a total of 30), which further supports the high benefit/risk ratio of the drug. In a group of 10 patients treated for subarachnoid hemorrhage, one developed brain infarction, 48 a well-recognized complication that is probably caused by vasospasm. This raises the possibility that subarachnoid hemorrhage may not be an appropriate indication, although wider experience is required. Recombinant factor VIIa could potentially induce thrombotic complications in situations where large amounts of TF are exposed to flowing blood, such as in gram-negative sepsis, in which endotoxin (lipopolysaccharide) activates circulating monocytes to express TF on the cell membrane. 49 Tissue factor is also present at high levels in all cellular elements and extracellular lipid core of atherosclerotic plaques. 50,51 Thus, TF may come into contact with circulating blood when the plaque ruptures which, most probably, is the mechanism for acute myocardial infarctions observed in rare cases after administration of rFVIIa. 52 Since the mean age of civilian trauma victims is about 36 years, 2 and in military trauma the victims are even much younger, this risk seems to be negligible. However, the use of the drug in elderly patients with predisposing cardiovascular disease should be limited to desperate cases.
Until recently, conditions with activation of coagulation were considered as contraindicated for rFVIIa (summary of manufacturer’s product characteristics) and, because trauma with or without DIC fits this criterion, the use of the drug was avoided in such patients. As previously elucidated, coagulation abnormalities resembling DIC in trauma patients reflect consumption coagulopathy—activation and consumption of platelets and coagulation factors at the site of tissue damage, without the diffuse intravascular microthrombi component seen in true DIC. In fact, most patients with severe trauma suffer at the early stage from hemorrhagic diathesis rather than hypercoagulation; therefore, the contraindication mentioned is not applicable to these patients. The absence of clinical evidence of thromboembolic complications in our patients, who had coagulation abnormalities “resembling DIC,” as well as the absence of microthrombi in the aforementioned swine with grade V liver injury who had a similar coagulopathy, 29 supports this assumption.
All patients received FVIIa after transfusion of numerous packed cells and other blood components, when all conventional treatment modalities failed and fatal outcome seemed inevitable. Surgical hemostatic measures such as cauterization, ligation, packing, and even argon beam (patient 3) were used concomitantly with rFVIIa. However, these measures were ineffective before, but achieved hemostasis only after administration of rFVIIa, which suggests a role for rFVIIa in the hemostatic process. Fibrin glue was only used after hemostasis was achieved. Fibrin glue is ineffective during massive bleeds, since it is washed away by the flowing blood and its role in such cases is to prevent bleeding recurrence. The rationale for addition of fibrin glue to rFVIIa is the short half-life of the latter (about 2 hours), which may expose the patient to the risk of rebleeding when the effect is over. This theoretical risk may not be real, since the formation of a strong and resistant clot (“superclot”) by rFVIIa may prevent rebleeding, but more experience is required to evaluate this assumption. Earlier treatment with rFVIIa may prevent deterioration of the patient’s condition and reduce bleeding-related mortality and morbidity, as well as complications related to massive transfusions, but this remains to be proven in larger studies. The present report of a small number of anecdotal cases is by no means conclusive, but raises the possibility that rFVIIa may play a beneficial role as an adjunctive, hemostatic measure in addition to the conventional surgical hemostatic techniques in hemorrhage control in trauma patients, and deserves further controlled animal and clinical studies.
Dr. John Holcomb (Houston, Texas): Dr. Martinowitz and colleagues have presented the first series of five cases documenting the use of factor VIIa in nonhemophiliac trauma patients with significant acquired coagulation disorders. This report complements their activities in nontrauma patients with or without hemophilia. Furthermore, Dr. Martinowitz and I recently collaborated on an animal study evaluating the effectiveness of the drug.
Recombinant factor VIIa is a Food and Drug Administration–approved drug for use in hemophiliacs and has been safely used since described by Dr. Hedner in 1988. Although unfamiliar to most surgeons, in hemophiliac patients it is considered standard care and safe enough even for home use, as Dr. Martinowitz has said. What is new is that in this series the drug was used as an adjunct to control the bleeding in a group of trauma patients with an acquired coagulopathy that have a very high mortality.
Intravenous forms of hemorrhage control in trauma patients have either been ignored or significantly underused. In conjunction with good surgical technique, damage control maneuvers, and the other hemostatic drugs and devices that are being developed, I think that this site-specific intravascular approach to hemostasis is right on target.
These results are exciting in their promise; however, I am not sure that this study really delivers more than just a hint of what may come later. I have several comments followed by several more questions.
The comments are that this was a short series of case reports and, therefore, there was no control group, and thus we really don’t know if the patients would have survived with or without drug treatment. There is no clear uniform indication for treatment and there was a highly variable drug regimen used. There is no clear indication that there was or was not an increased incidence of diffuse intravascular clotting, deep venous thrombosis, pulmonary embolism, myocardial infarction, or stroke.
Now, the questions. Dr. Martinowitz, how do you monitor this drug in this clinical use, and is there a laboratory value that correlates with clinical efficacy? In the two patients that lived, were their complications related to drug use?
Third, what exactly were these patients bleeding from; large main vessels, small vessels, or microvascular bleeding secondary to the coagulopathy? Fourth, in your clinical experience, how fast do you see a clinical effect after injection of the drug?
Significant blunt tissue or brain injury may release tissue factor into the bloodstream. If the drug is used in this type of patient, will intravascular clotting result?
Does the normalization of prothrombin time despite the hypothermia equate to clinical effectiveness? You alluded to this in your discussion, but can you elaborate on how you are currently using the drug in Israel?
A word of caution: this drug may become very useful in patients who undergo massive transfusions; however, the potential risk of diffuse intravascular coagulation should not be ignored and deserves further study.
Saying that, I firmly believe that prospective controlled trials are required to delineate the true risk/benefit ratio of this drug. From these studies, I think we will answer many of the previously asked questions.
In closing, this drug holds great promise. The intravascular approach with site-specific drugs for hemorrhage control complements the methods that our group and others have been studying over the last several years.
One can envision that at some time in the future a combination of these advanced hemorrhage control techniques will be routinely used by surgeons and prehospital personnel. I would like to thank the Association for the privilege of new membership and the opportunity to discuss this interesting and very worthwhile study.
Dr. Kenneth L. Mattox (Houston, Texas): Six surgeons died here in San Antonio 150 years ago at the massacre at the Alamo. Unknown to most people in this audience, there was one survivor. There were several survivors, but one of the survivors of the Alamo was a surgeon by the name of Dr. Sullivan. Had I been Dr. Sullivan and you had a supply of rFVIIa and we were in the United States without a phase I or II study and you could have given me, Dr. Sullivan, all of the rFVIIa I wished, would you have given it to me to save more people at the Alamo with the knowledge base that you have?
Dr. Martin A. Schreiber (Houston, Texas): Dr. Martinowitz, Dr. Holcomb raised concerns about patients with soft tissue injuries and brain injuries where a large amount of tissue factor may be exposed. What about patients with long bone fractures and the potential for fat embolism syndrome where these patients have diffuse thrombosis as well?
Dr. Uri Martinowitz (closing): Thank you, Dr. Holcomb. Yes, I agree that it is not a controlled trial and has a limited validity. However, I believe that we can learn a valuable lessen from these cases: until our first trauma case, nobody was even daring to think to use rFVIIa outside of hemophilia; but the first case that was reported in newspapers around the world, quoted in Lancet News and published as a fast track publication in the Lancet, raised an immediate interest.
Shortly thereafter, the surgeon general sent me to San Antonio to start animal studies on the efficacy and safety of the drug on a swine trauma model. Two weeks later, John Holcomb and his team came to my institution to continue the study (results reported in the meeting by John Holcomb).
The animal study together with the present cases support the compartmentalized action of rFVIIa at the site of injury rather than systemic activation of the coagulation cascade. It raises the possibility that the drug may have a beneficial role in hemorrhage control in trauma and that the subject deserves further controlled animal and clinical trials.
Now, how do we monitor? The best monitoring is to look at the patient and see if the bleeding ceased. Presently, there is no laboratory test that correlates directly to clinical response. We usually measure prothrombin time, and typically it is shortened to below the normal range (to 7–9 seconds). However, this is a laboratory effect that only shows that the patient has received rFVIIa, but does not predict or prove a clinical effect.
Dr. Mattox, the answer is not easy; this is a complicated ethical problem. Our first soldier was very close to exsanguination, but my young on-call physician, who was present in the operating room and who was convinced that this was the patient’s only chance to survive (at that stage, the surgeons had left the operating room to tell the parents that the patient was dead!) refused to inject the drug.
This is not an off-label use but a treatment against a written contraindication, where the patient’s chance to survive seems to be close to zero, and it may be inconvenient if the patient dies immediately after the injection and the autopsy will show diffuse thrombosis—you may be sued and even lose your license. However, can you leave a young soldier to die when you are convinced—from a deep knowledge of the literature and the mechanism of action—that you have something that may save his life? Can you live with the idea that a young man died because you are coward?
In any case, I had to rush to the operating room and inject the drug myself. The anesthesiologist wrote in the chart: “Dr. Martinowitz himself is injecting rFVIIa on his own responsibility.” I had a few moments of cold sweat. The next morning, in the hematology round, all 22 of our hematologists admitted that they would be afraid. But surgeons have more guts, and I am sure many would do the same.
Dr. Schreiber, I don’t know the answer. Theoretically, in all these cases, when you have a release of tissue factor, you have at the same time a release of the tissue factor pathway inhibitor that may inhibit it, but it has to be investigated. At least one of our patients (our doctor that fell from a building) had multiple fractures and multiple organ damage with brain contusion and hemorrhage, and there were no thrombotic complications.
In Thailand, they gave it to three patients with Dengue fever with stormy DIC where tissue factor is known to be expressed on the surface of monocytes, and they saved the life of the patients without evidence of thrombotic complication. We gave it to two patients with gram-negative sepsis with DIC (where tissue factor is known to be present on monocytes) and nothing happened. We didn’t see thromboembolic complications. However, we may see more thrombotic side effects with wider use of the drug. According to a recent survey of the company, among about 5,500 patients (mostly hemophiliacs and a few dozen nonhemophiliacs), the incidence of fatal thromboembolic complications was less than 1%. So if you have a case that is exsanguinating in your hands, the risk seems negligible.
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