A 62y/o F presents in need of femoral endarterectomy and thrombectomy because of thrombosis precipitated by heparin induced t
The had received 4 units of pRBCs 7 days ago to treat a Hgb of 8.1 and it was raised to a peak of 11.1 g/dl, but the hgb had drifted back down to 8.9 g/dl. There was no obvious signs of bleeding. The patient was being treated for thrombosis with an infusion of argatroban at 2 mcg/kg/min and was also receiving IV iron therapy. At the time of surgery her platelet count had rebounded from a nadir of just over 56,000 to above 150,000.
The case was posted as semi urgent by the surgeon. I went to transport the patient from the ICU to the OR and was told that she had no blood available because her T and S (repeated by another physician because her previous type and screen had expired), was positive for antibodies.
This topic has been briefly touched upon in a previous post.
The first portion of this post will deal with the significance of a T&S that comes back positive for antibodies. The second part of this post will briefly review HITS and the pharmacologic options available to the anesthesiologist during surgery.
The type and Screen and the type and Cross: When blood is sent to the blood bank for a type and screen, the blood bank is determining the blood type (A, B, O etc) and also determining the presence of the significant Antigen known as D which is an antigen in on blood cells and is an antigen in the Rh system. If the red blood cells have this antigen they are Rh + (common), but if they do not they are Rh - (about 20 % of the population). This is the type. The screen is looking at the plamsa or serum of the recipient's blood. Now, instead of looking for antigens, the blood bank is screening for antibodies (allo-antibodies) that are unexpected (i.e. non-ABO antibodies). In most patients who have not recieved a transfusion this is negative and a cross match can proceed if needed. In patients who have recently given birth or received a transfusion, it may be positive for unexpected antibodies. This screen is done by incubating the recipients serum or plasma with commercial screening cells that contain all of the critical non-ABO antigens using antihuman globulin (AHG) also known as the indirect antiglobulin test or Coombs test). The antibodies screened for come from seven main antigen systems (MNSs, P, Lewis, Kell, Duffy, Kidd, and sex linked). Go here for a nice table to see the names of the antigens in each antigen system. All of the above described tests take about 45 minutes. In many cases three phases are used for the screen. In phase 1, (the immediate spin) 3 tubes are used and centrifuged looking for agglutination. This phase is often skipped but can be important because it detects reactions due to IgM antibodies which are usually considered nuisance antibodies. Therefore, if this phase is skipped and the phase 3 (coombs phase) is positive, there may be some concern that the positive reaction was a nuisance antibody. Phase 2 is the 37 degree incubation and is required. In phase 3 (coombs phase), is also required, because it detects IgG which are clinically significant antibodies. One further important aspect of the antibody screen is done during phase I, where one test tube is incubated with the patient's own red blood cells which is called the autocontrol. This looks for coating of the red blood cells with antibodies at baseline and indicates possible autoantibodies. However, it can also result from antibodies that have developed from medications that the patients is taking, passively transfused alloantibodies, or alloantibodies coating transfused cells in the patient if they were recently transfused. If this occurs the blood bank should immediately perform a direct antiglobulin test. If this is positive it is a very strong indicator that antibodies are attached to the patient's red blood cells. At this point, if the test is negative and the patient does not have a history of unexpected antibodies in the past, some blood banks will release blood for transfusion after an immediate spin crossmatch or an electronic/computer crossmatch. The immediate spin crossmatch takes about 5 to 10 minutes. The electronic/computer crossmatch may be performed if an FDA approved computer system is available which makes a decision based on a series of validated computer algorithms. The difficult decision going forward in a patient who is in surgery or imminently going to surgery who has a T&S that comes back positive for unexpected antibodies is do you delay potentially necessary surgery to find out what the antibody is and get appropriate blood or do you push ahead? If in surgery the patient is bleeding, at what point does the risk of transfusing a patient w/ unexpected antibodies in a type and screen outweigh the risk of a low Hgb. In animal studies, bleeding animals to very low hemoglobins before transfusing them back up was ok to a point. Once a 3 to 4 hours passed at severely low hemoglobins, irreversible MOD set in and the animal was no longer able to be resuscitated. Essentially this is related to an oxygen debt. Once the oxygen debt becomes too large, no amount of appropriate resuscitation will salvage the organism. The degree of the oxygen debt and thus the chances of survival are a summation of time over which oxygen debt occurs and the degree to which DO2 is below VO2. Once this threshold is reached the triad of acidosis, coagulopathy and hypothermia develops and death follows. Research shows that once this debt is 4,900ml/m^2, mortality is 50%. This results because the vasculaure itself no longer has the energy necessary to vasoconstrict. Therefore, the DO2 critical (the DO2 at which VO2 is dependent on DO2) is the level where an oxygen debt begins to be incurred. In studies this has been found to be between 4 to 7 mL/min/kg (280 to 490 mL/min) for a 70 kg adult. This corresponds to a Hgb of around 5 g/dl assuming a cardiac output of 5.0 l/min. Of course, the metabolic state will also affect this level and a critically ill patient will likely reach DO2 critical before reaching a Hgb of 5.0 g/dl. In practice of course, there is no perfect way to know when your patient has reached DO2 critical and thus needs a transfusion. Nor can we know when we are approaching an oxygen debt of 4,900 mL/m2 (where death is highly likely). Surrogates are needed then. For DO2 critical, the SvO2 is adequate. The other risk to consider is the chance of developing a reaction that is clinically significant when a patient has antibodies. In a large series of studies reviewed by Boisen et al [4], nearly 3,000 patients (11 studies) received nearly 11,000 units of PRBCs of uncrossmatched blood. The rate of detectable hemolysis was 0.1%. In the case where a patient is known to have antibodies and blood is transfused that is known to contain the offending (or matching) antigen (Ag), very few patients experiment significant or meaningful hemolysis. In an enlightening study of this very scenario 262 patients with known antibodies were transfused with uncrossmatched blood. Of these, seven patients were later determined to have received blood that contained antigens that were incompatible with their antibody profile (i.e. the antigens in the transfused blood was able to bind to the antibodies located on the surface of the patients own RBCs). Of these seven patients, only one had biochemical evidence of hemolysis. This was comprised of elevated LDH and total bilirubin with a decrease in haptoglobin. However, these biochemical changes could be accounted for by other clinical conditions of the patient. Furthermore, the patient did not demonstrate any clinical appearance of issues [3]. In another series of 218 patients who received transfusions with unmatched RBCs, six patients who were found to have detectable and clinically relevant antibodies. None of these six patients suffered hemolysis. One other patient who did have positive antibodies with a positive coombs test, hemolyzed and later died. It is unclear whether the hemolysis resulted in the death of the patient however. In conclusion, transfusing patients with PRBCs that may have antigens that correspond to unexpected antibodies is very unlikely to result in meaningful and acute hemolysis. Avoiding elective surgery when compatible blood is unavailable is logical; but the clinician should not allow unexpected antibodies delay needed surgery given the unlikely harm that would come should a transfusion be required.
In the end, the decision to proceed to surgery with a patient who has a positive antibody screen means that you consider the benefits of undergoing surgery to outweigh the risk of not having properly matched blood. This risk benefit ratio is not easily arrived at because of the large number of variables.
Part II: Heparin induced thrombocytopenia-This syndrome can be divided into a type I (mild reduction of platelet count with no other sequelae), or type II, a more significant clinical entity with the potential for thrombosis and death. The incidence varies from 1 to 3% of patients receiving heparin and is more common with heparin of bovine origin as opposed to porcine derived heparin. The most significant morbidity from type II HIT is from thrombotic and embolic phenomenon which occurs in 30 to 50% of patients. When this does occur the mortality rate is as high as 30%. The etiology relates to IgG antibodies against the Platelet factor 4-heparin complex which activates platelets via the Fc portion of the antibody. Typically, any patient who has been on heparin and has a significant drop in platelet count on day 4 through 10 of therapy should have a confirmatory ELISA test to detect the presence of serum anti heparin-PF4 Antibodies. Of course, while waiting test results all heparin products should be discontinued. It will take 50 to 100 days before the IgG antibodies against Heparin-PF4 complexes are cleared from the circulation. Therefore, in patients with HIT alternative medications to prevent blood clots are required. In general, those patients who require anticoagulation but have anti-heparin-PF4 antibodies will require inhibition of thrombin directly. The thrombin enzyme has three sites where inhibition can occur, one is a catalytic site (active site) and the other two are known as exosites (1 & 2). Please see figure 1 and 2.
In general the direct thrombin inhibitors (DTI) differ from heparin in the following ways. They are smaller and do not require Antithrombin to function (thus their name direct thrombin inhibitors). They, being smaller, can bind to thrombin that is already fibrin bound, and thus, can help work at the clot site itself as opposed to heparin, which only acts on thrombin which has yet to partake in clot formation. Lastly, there is no agent that can be given to reverse the effects of these medications. Therefore, care must be taken.
Argatroban is a DTI that is univalent and reversible. It is one of two DTIs that are FDA approved for the treatment of HIT in the US. Argatroban has a few advantages over the other FDA approved agent for the treatment of HIT in the US (lepidrudin). First, Lepirudin in case control studies improved outcome for patients with HIT, but with a higher risk of hemorrhage (14% for lepirudin vs 8% for control). This increased risk for bleeding may be related to its slower offset and the fact that it inhibition of thrombin is irreversible. Second, Lepirudin has been associated with fatal anaphylaxis in patients re exposed to lepirudin within 3 months of a previous exposure. Up to 70% of patients treated with lepirudin develop antihirudin antibodies. These antibodies can have paradoxical effects in that in some patients the dose must be reduced because these patients will clear lepirudin more quickly. It is renally cleared so, in my patient, it would not have been a good choice.
Argatroban is metabolized by the liver (and therefore is preferred in patients with renal dysfunction as was my patient). The 1/2 life is 40 to 50 minutes with anticoagulation effects ceasing after 120 minutes. Activity is measure with the aPTT. The medication is started as an infusion at 2 mdg/kg/min and then titrated up to acheive an aPTT of 1.5 to 3 x normal. After starting an infusion the first aPTT can be drawn at about the 2 hour point. It may also be monitored by an ACT. For starting anticoagulation in a patient undergoing PCI who has HIT, an initial starting dose of 25mcg/kg/min and a bolus dose of 350 mcg/kg over 3 to 5 minutes is given. Check ACT after 5 to 10 min to verify if greater than 300 seconds. If less than 300 sec then give another dose of 150 mcg/kg. If an infusion is running, then increase to 30 mcg/kg/min, if the ACT is greater than 450 sec then decrease infusion to 15 mcg/kg/min. In the OR for ACTs that do not need to be greater than 300 sec a case report using Argatroban for CEA states that a loading dose of 150 mcg/kg was used and then followed by an infusion of 5 mcg/kg/min. The goal for the ACT was 200 s in this report [2].
Hirudin is derived from the saliva of the leech (Hirudio medicinalis). It is cleared by the kidneys and therefore is not the first choice in patients with kidney dysfunction. It is immunogenic, with a 44% incidence of antihirudin antibodies. The incidence of anaphylaxis on reexposure is 0.16%, not insignificant.
Bivalirudin (Angiomox) is a small synthetic hirudin molecule. It's clinical use has been relegated for the most part to PCI. However, in the OR it would also be helpful in that it is partially cleaved by thrombin and other plasma enzymes (80%) changing its affinity and thereby resulting in a shorter half-life (about 25 minutes). Although this medication is not approved by the FDA for the treatment of HITS, it has been shown to be effective in OPCAB for anticoagulation [1]. The concluded that for OPCAB, Bivalirudin was an alternative to unfractionated heparin proving to be reliable, rapid onset, and rapid offset. They utilized a bolus dose of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hr. Their goal was an ACT of 300 sec. They monitored the ACT every 30 min and gave a bolus dose of 0.1 mg/kg to 0.5 mg/kg if the ACT was less than 300 sec.
For anesthesiologists, it is most likely that you will encounter argatroban in your clinical practice dealing with non cardiac surgery patients being treated for HIT. Lepirudin, the other FDA approved treatment is somewhat inferior because of safety concerns when compared to argatroban. The other DTIs are more likely to be used in other clinical scenarios such as for PCI.
1) Koster A, Spiess B, Jurmann M, Dyke C, Smedira N, Aronson S, Lincoff MA. Bivalirudin Provides Rapid, Effective, and Reliable Anticoagulation During Off-Pump Coronary Revascularization: Results of the “EVOLUTION OFF” Trial. A&A, 103(3). 2006.
2) Hallman S., Hebbar L., Robison J., and Uber W. The use of Argatroban for Carotid Endarterectomy in Heparin-Induced Thrombocytopenia. A&A. 100(4); 2005.
3) Goodell PP, Uhl L, Mohammaed M, Powers AA. Am J Clin Pathol 2010; 134:202-6.
4) Boisen ML, Collins RA, Yazer MH, Waters JH. Anesthesiology 2015; 122:191-5
3) Goodell PP, Uhl L, Mohammaed M, Powers AA. Am J Clin Pathol 2010; 134:202-6.
4) Boisen ML, Collins RA, Yazer MH, Waters JH. Anesthesiology 2015; 122:191-5
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