Fritz Mertzlufft

Anticoagulation during Cardiopulmonary Bypass in Patients with Heparin-induced Thrombocytopenia Type II and Renal Impairment Using Heparin and the Platelet Glycoprotein IIb-IIIa Antagonist Tirofiban

BackgroundPatients with heparin-induced thrombocytopenia type II require an alternative to standard heparin anticoagulation. However, in patients with renal impairment, anticoagulation during cardiopulmonary bypass with agents such as danaparoid sodium or r-hirudin are associated with hemorrhage. Anticoagulation with unfractionated heparins combined with prostacyclin, a potent platelet aggregation inhibitor, is associated with severe hypotension. The authors investigated a new concept using unfractionated heparins after platelet inhibition with the short-acting platelet glycoprotein IIb–IIIa antagonist tirofiban. MethodsTen patients with heparin-induced thrombocytopenia type II and renal impairment were enrolled in the investigation. All had heparin-induced thrombocytopenia type II antibodies present as proved by the heparin-induced platelet aggregation assay, the heparin–platelet factor 4 enzyme-linked immunosorbent assay, or both. In all patients, preoperative anticoagulation to an activated partial thromboplastin time of 40–60 s was performed with r-hirudin. Anticoagulation during cardiopulmonary bypass was achieved with a bolus of 400 IU/kg unfractionated heparins after a bolus of tirofiban 10 &mgr;g/kg followed by an infusion of tirofiban at a rate of 0.15 &mgr;g · kg−1 · min−1 until 1 h before conclusion of cardiopulmonary bypass. Additional unfractionated heparins were only administered if activated clotting time decreased below 480 s. Coagulation was monitored by a abciximab-modified TEG® and the adenosine diphosphate–stimulated (20 &mgr;m) platelet aggregometry. D-dimer concentrations, as a marker of venous thromboembolism, were measured before and 12, 24, and 48 h after surgery. Postoperative antithrombotic therapy was started immediately with r-hirudin to anticoagulation to an activated partial thromboplastin time of 40–60 s. ResultsThe postoperative blood loss ranged from 110 to 520 ml. No patient needed reexploration. In no patient was there clinical evidence of thrombosis or embolism in the postoperative period or of a critical increase of the D-dimer concentrations, suggesting venous thromboembolism. Transfusion of platelets was necessary in only two patients. ConclusionsThe protocol is easy to perform and no increased postoperative bleeding and no thromboembolic complications occurred. The combination of unfractionated heparins and tirofiban may be an alternative to other anticoagulation strategies in patients with heparin-induced thrombocytopenia.

Elimination of recombinant hirudin by modified ultrafiltration during simulated cardiopulmonary bypass: Assessment of different filter systems

Recombinant hirudin (r-hirudin) is being used increasingly in patients with heparin-induced thrombocytopenia type II. Renal failure has been demonstrated to prolong the half-life of r-hirudin and to cause bleeding in patients who have undergone cardiopulmonary bypass (CPB). We assessed the ability of different filter systems for modified ultrafiltration to eliminate r-hirudin in vitro using simulated CPB. r-Hirudin concentration was measured (chromogenic laboratory standard plus ecarin clotting time) before and after filtration, and its elimination was calculated using both controlled system flow and arterial inflow (separate pump). Four hemofilters (Renoflow II, Baxter; Arylane H4, Cobe; Ultraflux AV 600, Fresenius; and BCS 110 Plus, Iostra) and two plasmapheresis filter systems (ASAHI Plasmaflow OP, Diamed; and PF 2000 N, Gambro) were assessed (5 filters of each brand = 30 filters) in a closed in vitro CPB system applying conditions usually occurring during CPB. Ten plasmapheresis filters showed a greater ability than 20 hemofilters to eliminate r-hirudin (60%–70% vs 15%–42%) within the shortest time (80 vs 180 s). Among the four hemofilter systems, the Arylane H4 filter provided the most effective (42%) r-hirudin elimination. Elimination of r-hirudin was markedly improved using plasmapheresis systems, compared with hemofilter systems. Our findings may be relevant to patients with impaired renal function, who have been administered r-hirudin during CPB. Implications Modified ultrafiltration may enhance the elimination of recombinant-hirudin, although plasmapheresis systems provide the most rapid and complete elimination of recombinant-hirudin during simulated cardiopulmonary bypass. The decision to use a specific system will ultimately depend on the prevailing clinical situation and overall health of the patient.

Prevalence and persistence of heparin/platelet factor 4 antibodies in patients with heparin coated and noncoated ventricular assist devices.

Thromboembolism is a major complication in patients with ventricular assist devices (VAD). Anticoagulation with heparin, coumarin, and anti-platelet agents, particularly the development of biocompatible surfaces such as inner pseudo-endothelial layers or a coating with heparin, are intended to reduce these complications. However, the administration of heparin can lead to heparin induced thrombocytopenia type II (HIT II). Predominantly heparin/platelet factor 4 (HPF4) antibodies are responsible for the development of HIT II. The goal of the present investigation was to assess the prevalence of these antibodies in patients with heparin coated and noncoated VADs. Fifty-five patients were enrolled in the investigation. A heparin coated system was implanted in 30 patients, and a noncoated system was implanted in 25 patients. Antibodies were evaluated before, on days 7 and 14, and 3 months after implantation. Testing was performed with the Heparin/Platelet factor 4 enzyme-linked immunosorbent assay (ELISA) (Stago, France). In 40 of the 55 patients, the formation of HPF4 antibodies was observed (73%). In 35 of these patients (88%), HPF4 antibodies were present before surgery. There were no differences between the groups. In 11 patients (equal from both groups), the antibodies disappeared after termination of systemic heparinization. We conclude that in a rather high percentage of patients with VADs HPF4 antibodies are found. This finding may be explained by the repetitive and prolonged exposure of these patients to heparin. Immobilized heparin, as presently used in the carmeda coating, seems not to influence the formation and persistence of HPF4 antibodies. Further studies will have to prove whether HPF4 antibodies contribute to thromboembolic complications in these patients.

Cardiovascular surgery without cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II using anticoagulation with recombinant hirudin

H eparin-induced thrombocytopenia (HIT) is a major complication of surgery associated with the use of heparin. Two types of HIT have been distinguished: Type I HIT (HIT I) and Type II HIT (HIT II) (1–3). HIT I is thought to result from heparininduced microaggregation of platelets. Consequently, platelets may decrease within the first days after therapy with heparin. This thrombocytopenia is transient, self-limited, and asymptomatic. Platelet counts seldom decrease below 100 3 10/mL, and they usually recover even if heparin administration is continued (1–3). HIT I is solely a clinical diagnosis; heparindependent activation tests are negative. There is no specific treatment for HIT I and the main clinical importance of HIT I is to distinguish it from the more serious HIT II. HIT II is the result of a cascade of events related to the binding of heparin to platelet factor 4 (PF 4) (1). These complexes induce the formation of antibodies that bind to the complexes, thus stimulating platelet aggregation and a further release of PF 4 (1–6). Consequently, platelets are progressively consumed in the formation of thromboses and emboli (1,4–6). Rapid and pronounced decreases in platelet count (to levels below 30 3 10/mL) are frequently associated with HIT II; however, these decreases usually resolve after cessation of heparin exposure (1). HIT II-related thromboembolism has been observed in the absence of a decrease in platelet count (7). HIT II may be initiated by small, prophylactic doses of heparin, heparincontaining flush solutions and ointments, heparinbonded catheters, or systemic heparin administration (1,8). The condition is most often associated with unfractioned heparins (4,8,9). However, low-molecularweight heparins and heparinoids may also elicit an immunological cross-reaction with heparin-induced antibodies (8–10). The reported incidence of HIT II varies widely from 1% to 30% of surgical patients (11). HIT II was identified in 1% of patients undergoing cardiac surgery (12), although heparin antibodies were found in 19% (13) to 61% of these cases (14). HIT II is a clinical diagnosis, which is supported by laboratory tests (1). It can be identified from clinical criteria (i.e., a massive decrease in platelet count, thromboembolism, and resolution of thrombocytopenia after cessation of heparin), along with detection of heparin-dependent antibodies (1,15,16). Various laboratory tests can be used to verify the onset of HIT II (8,15,17): 1) the platelet C serotonin release assay; 2) the heparin-induced platelet aggregation assay (HIPAA); 3) the heparin-PF4 enzyme-linked immunosorbent assay (PF 4 ELISA); 4) platelet aggregation with simultaneous measurement of ATP release (lumiaggregometry); and 5) flow cytometric assays. However, in a recent study (17), none of these assays has been found to qualify as “gold standard.” The C serotonin release assay has a sensitivity of 94% and a specificity of approximately 100%, but the test is technically difficult and time-consuming, and requires the use of radioactive isotopes. Thus, the functional HIPAA, in which platelet aggregation is measured optically, and the PF 4 ELISA, which is an immunological test depending on the direct detection of heparin-induced antibodies, are increasingly being used. Both assays provide reliable results within 3–6 h (1,15,18,19) and are suitable for daily routine practice. The specificity of the HIPAA is more than 90% (15), and its sensitivity can approach 100% (15,20,21). At our institutions, the HIPAA is modified according to Accepted for publication October 15, 1999. Address correspondence and reprint requests to Fritz Mertzlufft, MD, PhD, Klinik fuer Anaesthesiologie und Intensivmedizin, Universitaetskliniken des Saarlandes, D-66421 Homburg-Saar, Germany. Address e-mail to mertzlufft@t-online.de.

In vitro cross-reactivity of danaparoid sodium in patients with heparin-induced thrombocytopenia type II undergoing cardiovascular surgery

STUDY OBJECTIVES To assess the cross-reactivity of danaparoid sodium in patients undergoing cardiovascular surgery. DESIGN Prospective investigation. SETTING A major European heart center and university hospital. PATIENTS 81 patients who underwent cardiovascular surgery during the period between January 1998 and April 1999 and were diagnosed with heparin-induced thrombocytopenia (HIT) II. INTERVENTIONS Testing was performed in patients who revealed a decrease in the platelet count >30% or a platelet count <100,000/microL during heparin therapy. Testing for HIT was performed by the use of the heparin-induced platelet-aggregation assay. Patients were evaluated as positive if an agglutination occurred in two of four of the 0.2 IU/mL heparin chambers. Patients were judged to be cross-reactive with danaparoid sodium when an agglutination occurred in two of four chambers that contained 0.2 IU/mL Orgaran. MEASUREMENTS AND MAIN RESULTS 281 patients (5.4% of the patients who underwent surgery during the period of the investigation) were tested for HIT II. Of these, 81 (1.5% of the total) gave a positive heparin-induced platelet-aggregation assay and 23 (28%) revealed a cross-reactivity with danaparoid sodium. CONCLUSION Cross-reactivity with heparin-induced platelet antibodies occurred in 28% of the patients who tested positive for heparin-platelet antibodies. In these patients, Orgaran would not have been a safe option. In patients with HIT II undergoing cardiac surgery, cross-reactivity with danaparoid sodium must be excluded before initiation of therapy with Orgaran, otherwise, or in cases of cross-reactivity, other options such as r-hirudin are preferred.

Cardiopulmonary Bypass in a Patient With Heparin-Induced Thrombocytopenia II and Impaired Renal Function Using Heparin and the Platelet GP IIb/IIIa Inhibitor Tirofiban as Anticoagulant

In a patient with heparin-induced thrombocytopenia II and impaired renal function, anticoagulation during cardiopulmonary bypass was successfully performed by the use of unfractionated heparin and the platelet glycoprotein IIb/IIIa inhibitor tirofiban. Postoperative antithrombotic therapy with recombinant hirudin was immediately initiated. This regimen for anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia II appears to be particularly appropriate for patients with impaired renal function or for hospitals without special experience with other alternative anticoagulation strategies.

Assessing Errors in the Determination of Base Excess

We compared estimates for base excess of extracellular fluid (BEecf; mmol/L) obtained in five clinically used blood gas analyzers: AVL Compact 2 (Roche Diagnostics, Mannheim, Germany), Ciba-Corning 860 (Bayer Diagnostics, Fernwald, Germany), IL 1620 (Instrumentation Laboratories, Lexington, MA), Stat Profile Ultra (Nova Biomedical, Waltham, MA), and ABL 510 (Radiometer, Copenhagen, Denmark). A total of 134 measurements per analyzer were obtained in arterial and venous blood samples from 10 patients undergoing cardiac surgery and 65 measurements per analyzer in venous blood samples from 2 healthy volunteers. The blood samples were equilibrated in a tonometer with gases of known composition (37°C). Additional theoretical studies were performed to evaluate the relationship between pH and calculated BEecf value (with varied Pco2) using the formulas of the various analyzers. The standard deviations of repeated measurements were 0.24 mmol/L for ABL 510 and approximately 0.45 mmol/L for the other 4 analyzers. The maximal systematic difference between the average of all measurements of each analyzer was 3.7 mmol/L; this was primarily attributable to differences in measuring pH, and, to a lesser extent, to differences in calculation and determination of Pco2. Comparison of the results from samples with different oxygen saturation showed that the relative alkalinity of deoxygenated hemoglobin (Haldane effect) can also influence the determinations of BEecf.

Reliability of the heparin management test for monitoring high levels of unfractionated heparin: in vitro findings in volunteers versus in vivo findings during cardiopulmonary bypass.

Background The authors assessed the heparin management test in vitro in volunteers and in vivo during cardiopulmonary bypass. Methods In vitro, the heparin management test was analyzed for heparin levels between 0 and 6 IU/ml using variations in hematocrit, platelets, procoagulants, and storage time. The in vivo studies consisted of two groups: In group I (cardiopulmonary bypass ≤ 90 min, n = 40), anticoagulation was performed according to the activated clotting time (with or without aprotinin); in group II (cardiopulmonary bypass ≥ 180 min, with aprotinin) included use (n = 10) and nonuse of coumadin (n = 10) and anticoagulation according to the automated heparin dose–response assay. Tests were performed in duplicate (whole blood, two heparin management test analyzers) and compared with anti-Xa activity (plasma). Results In vitro, the results of the heparin management test (n = 1,070) correlated well with heparin concentration (r2 = 0.98). Dilution and storage time did not affect the heparin management test; a hematocrit of 60% and reduced procoagulants (10%) prolonged clotting time. In vivo, the correlation (heparin management test vs. anti-Xa) was strong in group I (r2 = 0.97 [with aprotinin] and 0.96 [without aprotinin]; n = 960) and group II without coumadin (r2 = 0.89, n = 516). In group II with coumadin, the overall correlation was r2 = 0.87 and 0.79 (n = 484), although the range varied widely (0.57–0.94, between-analyzer differences 0–47%). Conclusions The results of the heparin management test were influenced by hematocrit, plasma coagulation factors, and the heparin level, but not by use of aprotinin. The heparin management test provided reliable values in vitro in group I, and in group II without coumadin but was less reliable in group II with coumadin.

A quick anti-xa-activity-based whole blood coagulation assay for monitoring unfractionated heparin during cardiopulmonary bypass : A pilot investigation

We developed a quick and easy method to perform anti-Xa-activity-based whole blood assay and assessed its reliability for online monitoring of unfractionated heparins (UFHs) during cardiopulmonary bypass. Seventy-five microliters of a mixture of 1:3 large- and small-range Heptest®™ reagent were tran

Fechtner's syndrome: considerations of anesthetic management.

IMPLICATIONS Fechtners syndrome is a rare form of macrothrombocytopenia (potentially associated with other hemostatic deficiencies, e.g., von Willebrands disease and protein Z deficiency), which can exacerbate the risk of uncontrollable bleeding during surgery. We describe the management of a patient with Fechtners syndrome involving desmopressin, prednisone, and platelets, which produced safe and effective results during cochlear implant surgery.