Heparin-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 heparin-induced 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 × 103/μL, and they usually recover even if heparin administration is continued (1–3). HIT I is solely a clinical diagnosis; heparin-dependent 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 × 103/μL) 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, heparin-containing flush solutions and ointments, heparin-bonded catheters, or systemic heparin administration (1,8). The condition is most often associated with unfractioned heparins (4,8,9). However, low-molecular-weight 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 14C 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 14C 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 the original method (15), whereas the PF ELISA is performed in case of HIPAA indeterminate and/or HIPAA-negative results (15) (see Table 1). Recent studies (17,21) have demonstrated a disturbing lack of agreement among the various tests for identifying HIT II. This underscores the importance of clinical criteria in diagnosing the condition.
As many as 35%–90% of patients affected with HIT experience venous and/or arterial thrombosis (with a high potential for stroke), myocardial or mesen- teric infarction, or ischemia of the extremities. They are generally associated with devastating outcomes (1,4,8,11,22,23) [e.g., a mortality of more than 35% (22) and major amputation (8)]. The ratio of arterial-to-venous thrombosis is 1:4 (23). In cardiac surgery, HIT II was associated with a mortality of 37% (13). Therefore, a diagnosis of HIT II warrants the immediate cessation of heparin administration and the implementation of an alternate form of anticoagulation.
Recombinant hirudin (r-hirudin) has been used successfully and effectively as an anticoagulant in patients with HIT II during cardiopulmonary bypass (CPB) (24,25), and in patients with HIT II under the following three conditions: 1) small-dose thrombosis prophylaxis (18,26); 2) acute therapeutic intervention (18) and further parenteral anticoagulation (26) under the condition of HIT II-induced thromboembolism; and 3) systemic anticoagulation during the static condition of cardiac surgery with CPB (18). In these latter conditions, r-hirudin prevented death, limb amputations, intracranial bleeding, and recurrence of thromboembolic complications. In two recent clinical reports (19,27), r-hirudin was validated for patients with HIT II undergoing urgent (27) or emergent CPB (19).
In recent years, procedures have been developed and popularized for cardiac and vascular surgery without the need for CPB (e.g., minimally invasive cardiac surgery). These procedures are characterized by near-static and/or static blood flow conditions. Thus, they require effective and safe anticoagulation. However, no studies have evaluated the use of r-hirudin as a substitute for heparin during cardiovascular surgery without CPB in the patient diagnosed with HIT II. We report herein on three relevant cases.
Two patients requiring cardiac surgery without CPB (Patients 1 and 3) and one patient scheduled for vascular surgery without CPB (Patient 2) were diagnosed with HIT II (Table 2).
In all patients, instrumentation included an arterial catheter, a trilumen central venous catheter (8.5 gauge), and a 9.5 gauge nonheparin-bonded continuous cardiac output catheter (Baxter, Heidelberg, Germany). All flushing solutions were heparin-free. Anesthesia was performed according to departmental standards (total IV technique with propofol and sufentanil, and pancuronium bromide supplemented on demand).
According to departmental standards, alternative anticoagulation was accomplished using r-hirudin (Refludan®, Hoechst, Frankfurt a.M., Germany) (approved by European regulatory authorities: March 17, 1997; FDA approval: March 6, 1998). r-Hirudin inhibits plasmatic thrombin and both platelet- and clot-bound thrombin as well (28), thus providing anticoagulation while effectively inhibiting major steps in the HIT II reaction cascade.
Pre- and postoperative oral anticoagulation was performed according to established guidelines. The activated partial thromboplastin time (aPTT) was used to evaluate the effectiveness of the r-hirudin concentrations achieved by continuous infusion. The aPTT values were maintained sufficient to prevent further HIT II-related thromboembolism (60–80 s) (18,19,26) and to provide thrombosis prophylaxis (40–60 s) (19,26). Intraoperative anticoagulation with r-hirudin was achieved by adjustment of the r-hirudin concentration to the dose recommended for use during CPB (18,19,24,27). In keeping with accepted practice (18,19,24,25,27), intraoperative monitoring of r-hirudin effect was obtained by measurement of the ecarin clotting time (ECT) in citrated whole blood. The principle of ECT measurement is based on the conversion of prothrombin to meizothrombin (a prothrombin conversion-intermediate) via the prothrombin activator, ecarin (a snake venom) (29). Meizothrombin inhibits hirudin while converting fibrinogen to fibrin. Thus, a coagulation time can be related to a predetermined r-hirudin concentration. ECT measurements were performed in parallel with the following two methods: 1) a modification of the original mechanical procedure (18,24); and 2) the new “TAS” ECT method (Thrombolytic Assessment System, Cardiovascular Diagnostics, Raleigh, NC), which has been reported recently for reliable point-of-care r-hirudin monitoring during CPB in patients with HIT II (19,27). The latter method is based on the automated detection of coagulation by application of an opticomechanical principle. For both ECT methods, blood samples were supplemented 1:1 with standard human plasma (Behringwerke, Frankfurt a.M., Germany). This is necessary to provide sufficient prothrombin and fibrinogen levels (≥60%) when using r-hirudin concentrations of more than 2 μg/mL (24). In addition, for theoretical reasons, the r-hirudin concentrations were measured in plasma using the standard anti–IIa-based chromogenic laboratory assay (COBAS MIRA Analyzer, Behringwerke, Marburg, Germany) (24). Individual calibration curves were constructed prior to in vivo ECT measurement. All measurements were performed in duplicate. The results obtained with the two ECT methods (n = 40) revealed a close correlation to the chromogenic-measured r-hirudin concentration (i.e., r2 = 0.89 for the point-of-care method [TAS ECT] and r2 = 0.85 for the modified original procedure).
A 35-yr-old man had received a left ventricular assist device (LVAD) (Novacor, Baxter, Oakland, CA) as a treatment for end-stage heart failure (Table 2). Surgery had been performed using CPB and anticoagulation with unfractioned heparin (Liquemin, Hoffman-La Roche, Grenzach-Wyhlen, Germany). During the postoperative period, heparin infusion had been maintained for thrombosis prophylaxis by adjustment to the activated clotting time (160–180 s). On the fourteenth day after surgery and exposure to heparin, the patient suddenly demonstrated a rapid decrease in platelet count (from 150 × 103/μL to 26 × 103/μL) (Table 2). This thrombocytopenia was associated with clinical signs of stroke, including aphasia and left-lateral hemiplegia. Due to the LVAD, magnetic resonance imaging was precluded for further diagnosis. However, the cranial computed tomography scan indicated a middle cerebral artery-related ischemic infarction. On the basis of these clinical signs for HIT II, HIPAA was performed. A positive finding for this test (Tables 1 and 2), indicating a cross-reactivity to the heparinoid orgaran, confirmed the clinical diagnosis for HIT II. IV anticoagulation with unfractioned heparin was immediately switched to r-hirudin. The dose for r-hirudin consisted of a 10-mg bolus, followed by a continuous infusion, which was adjusted to an aPTT value from 60 to 80 s (18,19) to prevent further HIT II-related thromboembolism and provide sufficient anticoagulation for the LVAD. To control the r-hirudin effect and evaluate the decrease of circulating heparin/PF 4 antibodies, platelet counts were determined at 4-h intervals. Resolution of the thrombocytopenia occurred after one day (i.e., platelet count increased from 26 × 103/μL to 67 × 103/μL). Subsequently, additional oral anticoagulation was begun using coumarin. According to departmental standard and published recommendations for anticoagulation in patients who have an implanted Novacor VAD (30), the patient was also placed on oral antiaggregative therapy with aspirin. Within three days, the platelet count returned to 153 × 103/μL, and the r-hirudin infusion was stopped. Within the ensuing 12 days, the patient’s neurological deficits subsided and cardiac function recovered. He was discharged uneventfully on the fourteenth day and readmitted three months later for explantation of the LVAD.
On admittance, there were no clinical signs of new or recurrent thromboembolism nor any aggravation of the previous neurological deficits. Prior to surgery, oral anticoagulation with coumarin was switched to continuous infusion of r-hirudin (aPTT = 60–80 s). During surgery (prior to removal of the LVAD), the rate of the LVAD was reduced to 10 bpm. Because no data exist regarding the use of r-hirudin under this near-static condition, a single IV bolus of r-hirudin (0.2 mg/kg) was injected to inhibit clot formation in the slowed LVAD. This dose for r-hirudin resulted in a blood r-hirudin concentration of 2 μg/mL, which was considered appropriate because it corresponded to the minimal recommended dose for CPB [2.5 μg/mL (18,19,24)]. The r-hirudin concentration remained constant for the ensuing one-hour period, which provided a window of opportunity to reinstall the LVAD if the patient did not tolerate its removal. After the operation (90 min), the patient was extubated in the operating room and delivered to the Intensive Care Unit (ICU) without inotropic support. According to departmental standard, the subsequent postoperative anticoagulation with r-hirudin was adjusted to an aPTT of 40–60 s to provide time for oral anticoagulation with coumarin to take effect, which was necessary because of the remaining intraventricular inflow and aortic outflow cannulae. The cannulae were kept in place, according to departmental standards, to avoid the necessity for rethoracotomy and CPB after explantation of the LVAD. There was no visible clot formation in the LVAD. Clinical signs for thromboembolism were not observed during the entire postoperative period. Total blood loss was 220 mL and did not necessitate any transfusion (Table 2). The neurological status of the patient remained unaltered, and renal function was normal. On the thirteenth postoperative day, the patient was discharged from the hospital uneventfully. Examination after three months indicated a left ventricular ejection fraction of 35% and complete restoration of neurological function (Table 2).
A 67-yr-old woman (Table 2) had a history of insulin-dependent diabetes mellitus, occlusive vascular disease, recurrent exposure to heparin, and stable angina. Because of recurrent chest pain, she underwent left heart catheterization and stenting of the left anterior descending artery (LAD), which was performed in an outside hospital. During heparinization (Liquemin, Hoffmann-La Roche, Grenzach-Wyhlen, Germany) accompanying the procedure, she experienced acral embolism (left and right hands), a significant reduction in platelet count (from 170 to 46 × 103/μL), and symptoms consistent with aorto-iliac occlusive disease. She was treated immediately with r-hirudin, which was controlled via the aPTT (53 s). Because the HIPAA had not been available at that hospital, the clinical picture of HIT II was confirmed 12 h later by direct detection of the antibodies using the PF 4 ELISA (Tables 1 and 2). Thereafter, she was transferred to our hospital for urgent implantation of an abdominal aortic prosthetic graft, while continuous aPTT-controlled administration of r-hirudin was maintained (60–80 s).
On admittance to our hospital, the reduced platelet count had already resolved (120 × 103/μL). Before cross-clamping the abdominal aorta, a bolus of 0.25 mg/kg hirudin was injected intravenously. The dose for r-hirudin was based on the dose recommended to start CPB [i.e., 0.2 mg/kg added to the prime, and 0.25 mg/kg given to the patient (18,19,24,27)], and it resulted in a r-hirudin blood concentration of 3.0 μg/mL, which corresponded to the recommended dose required during CPB (2.5–4.0 μg/mL) (18,19,24,27). This r-hirudin concentration was deemed necessary because of the total occlusion of the aorta and the requirement for aortic clamping (65 min). By the end of surgery (4.5 h), r-hirudin concentration had decreased to 1.0 μg/mL, indicating normal renal elimination (29). In the ICU, an infusion of r-hirudin was initiated to achieve an aPTT value of 40–60 s, sufficient for thrombosis prophylaxis (26,27) and to provide time for oral anticoagulation with coumarin to take effect. There was no clinical evidence of thromboembolism during the entire course of the operation and the postoperative period. The total blood loss was 450 mL (Table 2). Examination after three days via angiography confirmed integrity of the anastomosis and the stent. The patient was discharged from the hospital 10 days after surgery without complications or need for transfusion (Table 2). Examination after one month showed an uneventful course. Another angiography one month later confirmed patency of the prosthesis, the stented LAD, and complete revascularization of the extremities.
A 57-yr-old man had a history of arterial hypertension and chronic obstructive pulmonary disease. He was admitted to another hospital due to acute anterior myocardial infarction. In this hospital, a continuous infusion of heparin was started, which was controlled via aPTT (40–60 s). After a 10,000 IU bolus of heparin, left heart catheterization was performed the same day and revealed an isolated occlusion of the LAD. Angioplasty was attempted, but it was unsuccessful. Because the patient demonstrated cardiac failure that was refractory to catecholamine treatment (continuous infusion of dobutamine, 5–8 μg · kg−1 · min−1; cardiac index 1.2 L · min−1 · m−2; mixed-venous oxygen saturation 51%), an intraaortic balloon pump was implanted. Anticoagulation was accomplished using continuous IV infusion of heparin, which was titrated to an aPTT of 60 s. This aPTT was maintained more than 4 days. On the fifth day, the patient experienced a sudden decrease in platelet count (from 240 to 45 × 103/mL) (Table 2). After other causes of thrombocytopenia, such as infection, other drug-induced or autoimmune thrombocytopenia were excluded, this massive decrease in platelets was attributed to HIT II. Anticoagulation was immediately switched to r-hirudin. The dose for r-hirudin consisted of a 10-mg bolus, followed by continuous infusion (aPTT 60–80 s) (18,19). The onset of HIT II was confirmed using HIPAA, which also proved a cross-reactivity to orgaran (Tables 1 and 2). The platelet count resolved within the first three days after cessation of heparin exposure (from 45 × 103/μL to 185 × 103/μL), and thrombosis prophylaxis with r-hirudin was adjusted according to aPTT values of 40–60 s (19,26). On the seventh day after the operation, the intraaortic balloon pump was explanted, while continuous aPTT-controlled r-hirudin administration was maintained (40–60 s).
Three weeks later, the patient was admitted to our department for surgery. Revascularization was performed by anastomosis of the left thoracic internal artery to the LAD. Because of an impaired left ventricular function (ejection fraction 35%) and the poor general health of the patient, the operation was performed without CPB through an 8-in. anterolateral thoracotomy using one-lung ventilation. Intubation was performed with a left bronchial (39F) Robertshaw double-lumen tube. The left lung was inflated to a continuous pressure of 5 cm H2O. Before clamping the LAD, a bolus IV injection of r-hirudin was made (0.25 mg/kg), resulting in a blood r-hirudin concentration of 3.5 μg/mL. This concentration was considered sufficient to perform pumpless surgery involving static conditions, and it corresponded to the recommended dose for cardiac surgery with CPB [2.5–4.0 μg/mL (18,19,24,27)]. During clamping of the LAD (33 min), heart rate was reduced to 40 bpm with the β-adrenergic receptor antagonist, esmolol. By the end of surgery, r-hirudin concentration had decreased to 1.5 μg/mL, indicating normal renal elimination (29). After arrival in the ICU, an IV infusion of r-hirudin was initiated to achieve aPTT values of 60–80 s (18,19,26). After angiography documented patency of the revascularized vessel, the infusion rate for r-hirudin was titrated to an aPTT of 40–60 s to provide time for oral antiaggregative therapy with aspirin to take effect. There was no visible clot formation during clamping. Also, no clinical signs were observed, thus indicating onset of thromboembolism during the course of surgery (186 min) and the entire postoperative period. Total blood loss was 125 mL (Table 2). Left heart catheterization three days later confirmed patency of the anastomosis on the LAD. The patient was discharged uneventfully on the tenth postoperative day. Examination after three months demonstrated substantially augmented cardiac function (ejection fraction 55%, obtained by dobutamine-induced stress Doppler) and improved general health, with no signs or symptoms indicating thromboembolic events (Table 2).
In three patients with HIT II, cardiac and vascular surgery without CPB were performed successfully and safely using r-hirudin as an anticoagulant. In these patients, anticoagulation was necessary to prevent thrombus formation in either the arterial vessel (Patients 2 and 3) or the LVAD (patient 1) (Table 2). Moreover, after reversal of the arterial clamps or the LVAD a fast restoration of coagulation was necessary to prevent bleeding, whereas HIT II-related, postoperative complications had to be prevented. After HIT II was initially suspected on clinical signs and confirmed by in vitro tests (Tables 1 and 2), heparin administration in any form was halted immediately and replaced with r-hirudin. The remaining course of the patients (Table 2) indicated that the r-hirudin management was effective. It avoided further consumption of platelets and further systemic or regional thromboembolic complications (Table 2) or bleeding.
Large-dose anticoagulation poses a problem in patients with HIT II undergoing surgery. Protection from thromboembolism and bleeding requires an alternative anticoagulant, which ideally should meet the following criteria: 1) rapid onset of action; 2) short duration of action; 3) no cross-reaction with heparin; and 4) suitable intra- and postoperative monitoring. Among the various options discussed in the literature (18,19,23,24,27,29,31–36), the direct thrombin inhibitor, r-hirudin, has gained a pivotal role because it satisfies all these criteria. First, the anticoagulating effect is achieved immediately. This allows effective and safe use of r-hirudin even in patients undergoing emergency CPB (19). Second, r-hirudin has a short, approximately 60-min half-life and is eliminated rapidly via the kidneys in approximately 40 min (8,18,19,27,29). Thus, normal renal function ensures rapid elimination of r-hirudin effect despite lack of an antidote (27,29), as evidenced by the low r-hirudin concentrations at the end of surgery in Patients 2 and 3. Third, in contrast to the glycosaminoglycans (e.g., heparins and heparinoids), r-hirudin does not cross-react with heparin-induced heparin/PF 4 antibodies. This is derived from its amino acid structure, which renders it unreactive with the antibodies to heparin. In contrast, the cross-reactivity in the functional HIPAA in two of the patients (Nos. 1 and 3) (Tables 1 and 2) indicated that orgaran would not have been a safe option. Finally, effectiveness of r-hirudin effect can be monitored reliably (8,18,19,24,27). Although the standard whole blood coagulation assays, such as the aPTT and the activated clotting time, are generally not suitable for monitoring effectiveness of large-dose r-hirudin intraoperatively (8,18,19,24,27), the whole blood ECT has been shown to provide reliable monitoring of the r-hirudin effect (18,24,25), even to the point of patient care (19,27).
In conclusion, r-hirudin—combined with monitoring of ECT—was a safe, effective, and easily managed anticoagulant technique in these reported cases. It prevented further thromboembolic formation during acute HIT II, even in the presence of arterial cross-clamping, aorto-iliac occlusion, or the near-static conditions engendered by the slowed LVAD. Moreover, because r-hirudin is eliminated from the body rapidly, it was not associated with appreciable perioperative bleeding and the need for transfusion of homologous blood products. After 30–90 days after surgery and cessation of r-hirudin, reexamination (Table 2) demonstrated that none of the patients had suffered bleeding events or a new or recurrent thromboembolic complication. The cases presented herein extend the safe and successful use of r-hirudin to patients undergoing cardiac or vascular surgery without CPB.
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