Heparin-associated Antibodies Research Articles

Cerebrospinal Fluid Drainage With Bivalirudin and rFactor VIIa for Thoracic Aortic Aneurysm Surgery Using Left Atrial–Femoral Artery Bypass

WHEN HEPARIN-INDUCED thrombocytopenia is diagnosed, direct thrombin inhibitors can be used in cases requiring cardiopulmonary bypass. Spinal drains are routinely used in preventing spinal cord ischemia for thoracoabdominal aneurysm repairs. Spinal drains placed before starting heparin anticoagulation are safe and routinely used. 1 Cheung A.T. Guvakov D.V. Weiss S.J. et al. Safety of lumbar drains in thoracic aortic operations performed with extracorporeal circulation. Ann Thorac Surg. 2003; 76: 1190-1196 Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar The use of bivalirudin with a spinal drain for repair of a thoracoabdominal aneurysm in a patient with heparin-associated antibodies is reported. A good outcome was achieved by promoting coagulation with rFactor VIIa when ultrafiltration was not available to remove bivalirudin.

Treatment of Heparin-Induced Thrombocytopenia and Associated Thromboses with Fondaparinux.

Abstract 2096Poster Board II-73 Background:The mainstay of therapy for patients with HIT or HIT-associated thrombosis consists of initial administration of a direct thrombin inhibitor (DTI), including lepirudin, bivalirudin, and argatroban followed by a vitamin K antagonist upon platelet recovery. However the use of DTIs is cumbersome because it mandates inpatient setting for continuous intravenous infusion of the medication. There is strong clinical and laboratory evidence suggesting that fondaparinux, a synthetic pentasaccharide inhibitor of factor Xa, does not cross react with heparin-associated antibodies, and may be a viable alternative to DTIs. Based on this evidence new guidelines have been adopted at MSKCC in the past 3 years, which incorporate the use of fondaparinux as initial therapy for the management of patients with suspected diagnosis of HIT. The objective of this retrospective study is to analyze the outcome of patients that were treated using this approach. Patients and methods:A search of the MSKCC pharmacy database has identified all patients who have received fondaparinux during inpatient hospitalization for suspected HIT based on the development of thrombocytopenia and recent exposure to heparin, between January 2006 and March 2009. We have reviewed the laboratory data of these patients to identify the subset of patients in whom the diagnosis of HIT was supported by the presence of heparin associated antibodies as confirmed by ELISA assay. We have reviewed the medical records of this subset of patients to determine their outcome using fondaparinux. Results:We have identified 21 cancer patients treated with fondaparinux for a suspected diagnosis of HIT that was confirmed by the presence of heparin associated antibodies as determined by ELISA assay. Twelve patients had isolated thrombocytopenia, and 9 had thrombocytopenia associated with thromboses. Nineteen patients received therapeutic doses of fondaparinux upon diagnosis while 2 were initially started on lepirudin and then switched to fondaparinux within 10 days. Successful recovery of platelet count was achieved in 15/21 patients (71.4%) with a mean time to platelet recovery of 9.9 days, (range 2 to 23 days). Among these 15 patients, one developed a new DVT on day 16 of fondaparinux treatment in the setting of a sub-therapeutic anti-Xa level, which led to an increase in the fondaparinux dose. The patient's platelet count subsequently recovered without additional thrombotic complications. Five patients (23.8%), all with end stage metastatic disease, died 2 to 9 days after initiation of fondaparinux and prior to recovery of platelet count. Causes of death were thoroughly investigated and were attributed to progression of underlying widespread malignancy and/or pneumonias in all 5 cases, without suspicion or documentation of new thrombotic event or bleeding. One additional patient with advanced glioblastoma multiforme was diagnosed with intracranial bleeding on day 5 of fondaparinux administration and was subsequently transferred to hospice care without further clinical documentation. One out of the 15 successfully treated patients experienced bleeding prior to platelet recovery, requiring temporary withholding of fondaparinux, which was resumed 4 days later without further bleeding complications. Conclusions:Fondaparinux appears to be an effective alternative treatment in patients with HIT and HIT-associated thromboses. The rates of successful platelet recovery, thrombotic and bleeding complications are comparable to the ones reported with DTI therapy for the treatment of HIT. However, fondaparinux does not require the cumbersome administration and monitoring of DTI therapy and may be the treatment of choice in the management of HIT. Disclosures:Off Label Use: Treatment of Heparin-Induced Thrombocytopenia and Associated Thromboses with Fondaparinux.

The Significance of Anti-Platelet Antibodies Associated with Antibiotic Use, A Descriptive Analysis.

Abstract 4470 IntroductionAntibiotics (Abx) have been implicated in immune thrombocytopenia via drug dependent platelet antibodies (DDPA). Our institution has had a DDPA assay available since 1994 which is used to guide clinical decisions. We performed a retrospective review to determine the significance of DDPA. MethodsWe reviewed the medical records of patients (pts) who tested positive for abx DDPA between 1994 and 2006 and performed a descriptive analysis. Detection of DDPAs was performed using a previously described, modified solid phase red cell adherence assay that detects hapten or immune complex reactions. ResultsA total of 71 pts were included in this analysis. Multiple classes of abx were tested. Platelet nadir was <50 in 70%, between 50 and 100 in 26% and over 100 in 4% of pts. Pts had between 1 and 4 abx tested: 37% had 1, 37% had 2, 15% had 3, and 11% had 4 tested; 65% of pts had one abx positive and 35% had >1 abx positive for DDPA. Of those with >1 abx tested (n=45), 14 (31%) had all tested abx positive. 53% of abx testing took place on or after the abx stop date and 32% of abx tested were administered for <=3 days. Only 29 of 38 pts receiving heparin were tested for heparin-associated antibodies, and 14 had positive results. 49 pts had other non-abx drugs tested, 19 with positive DDPA. Thus, 35% had alternative non-abx testing positive for DDPA. 31% of pts had bleeding complications and 35% of pts died during hospitalization. Excluding pts who died and those with non-abx positive DDPA left 25 pts, median platelet counts were: abx start=142; nadir=22, abx discontinuation=46, hospital discharge=192. ConclusionsAntibiotic DDPA testing is usually performed in ill pts with multiple medical complications and comorbidities. Abx were stopped for concern of DDPA in a number of pts for whom typical immune thrombocytopenia was not present or alternative explanations could be found. Though some pts exhibited improvement in platelet count after abx were stopped, a clear understanding of which pts may benefit from DDPA testing could not be determined based on the retrospective nature of this study and the complexity of pts histories. Further research is necessary to clarify the clinical applicability of DPPA testing. Disclosures:Szczepiorkowski:Cersus Corporation: Research Funding; CaridianBCT: Research Funding; BASF: Research Funding; Terumo Corporation: Research Funding; Fenwel, Inc - Scientific Advisory Board: Research Funding.

Retrospective Cost Analysis of Testing for HIT Antibodies in a Community Hospital

Background: Heparin-Induced Thrombocytopenia is a serious, immune-mediated complication of heparin therapy. At Lenox Hill Hospital when HIT is suspected, a test for heparin associated antibodies is ordered. Like many community hospitals, Lenox Hill Hospital does not perform this test “in house”, so it is sent to a reference lab. We use the Mayo Clinic Laboratory as our reference lab. It takes about 7 days for results to come back to Lenox Hill Hospital from the Mayo Clinic Lab. Meanwhile, patients are started on Argatroban or Lepirudin infusions in order to avoid thrombosis. We performed a retrospective review of all patients suspected of having HIT in a one year period, in order to assess the cost effectiveness of sending out these tests and treating these patients with alternative anticoagulants while waiting for the test results.Methods: We performed a retrospective review of all patients who were tested for HIT Antibodies. We obtained a list of patient specimens sent to Mayo Clinic for heparin associated antibodies from January 2007 to January 2008. A list of patients placed on either Argatroban or Lepirudin infusions was also obtained for the same time frame from our Pharmacy Department. We then recorded the results for the ELISA test for the HIT antibodies from our computer system.Results: There were 150 patient samples sent for heparin associated antibody tests to the Mayo Clinic Laboratory during these 12 months. Only 12 out of 150 patient samples tested positive for HIT by ELISA. Four out of 150 tested equivocal for HIT. All the remaining reports were negative. The hospital was charged $300 for each ELISA test, so our community hospital spent $ 45,000 in one year on heparin associated antibody testing. 15 of these patients were placed on Argatroban infusion while awaiting lab results. All fifteen patients who were placed on Argatroban ultimately tested negative for HIT. Four patients were started on Lepuridin infusions. Only one of the patients on Lepuridin tested positive for HIT. In total, there were 19 patients treated with either Argatroban or Lepuridin during this 12 months period. Only one patient, out of the 19 treated patients tested positive for HIT.The 12 months cost analysis showed that 100 vials of Lepirudin were used at a cost of $158.80/vial, for a total of $15,880. The 12 months cost analysis for Argatroban showed that 15 vials were ordered each month at a cost of $985/vial for a total of $177,300.The total amount spent including testing and expectant came to $238,180.00. Only one patient truly needed to be treated with an alternative anticoagulant.Discussion: Lepirudin and argatroban are two accepted drugs for treatment of HIT. These are direct thrombin inhibitors that are given intravenously. Argatroban binds to the catalytic site of thrombin. It gets metabolized by the liver and should be dose adjusted with careful monitoring in patients with hepatic impairment. No dose adjustment is necessary in patients with renal dysfunction. Lepirudin binds to both catalytic and a fibrinogen-binding site of thrombin. It gets excreted in the urine and should be carefully monitored in patients with renal insufficiency. Both drugs can lead to bleeding complications. These drugs should be used with great caution when there is an increased risk of a hemorrhagic event. The cost of Argatroban and Lepirudin infusions was obtained from the pharmacy purchase orders. The cost of HIT antibody testing was obtained from our main labarotory. The cost of the machine at the Mayo Labarotory that is used in the Special Coagulation laboratory (DSX ELISA processing system) was $52,000. The machine was purchased prior to 2004. We concluded that our community hospital spends a total of $238,000 per year in the evaluation and expected management of heparin-induced thrombocytopenia.Conclusion: In this retrospective review of 150 patients who have had HIT antibodies testing and 19 who were started on anticoagulation therapy and have had their HIT antibodies tests sent out for HIT confirmation, only 1 had a positive result. We concluded that our community hospital spends a total of $238,000 per year in the evaluation and expectant management of heparin-induced thrombocytopenia. The hospital would save money and improve patient care if it purchased the laboratory equipment and ran the tests in-house, providing faster turn around and more accurate assessment of risk.

Unusual Complication of Heparin-Induced Thrombocytopenia After Mitral Valve Surgery: Spontaneous Rupture of Spleen

A 64-year-old man presented with cardiac tamponade 2 weeks after mitral valve surgery. The patient was anticoagulated for persistent atrial fibrillation after cardiac surgery. A pericardial catheter was placed. Five days after presentation the patient was started on intravenous heparin infusion. The patient had abdominal pain and hypotension develop. A splenic hematoma was diagnosed and a splenectomy was performed. Pathology showed multiple fibrin thrombi in the spleen. The heparin-associated antibodies were detected. Heparin-induced thrombocytopenia is a potentially fatal condition in patients requiring heparin after cardiac surgery. Evaluation for heparin-associated antibodies in these patients may be warranted before heparin therapy.

Heparin-induced thrombocytopenia in a pediatric patient receiving extracorporeal membrane oxygenation managed with argatroban???

Heparin-induced thrombocytopenia (HIT) is rare in the pediatric population, with a majority occurring in the pediatric intensive care unit setting. All cases reported to date have been associated with the use of unfractionated heparin. Because unfractionated heparin is the anticoagulant of choice for extracorporeal membrane oxygenation (ECMO) and other extracorporeal therapies, the development of HIT in these patients can be devastating, making management problematic. We report a case of HIT type II with evidence of small-vessel arterial thrombosis in a 17-month-old boy receiving ECMO and continuous renal replacement therapy successfully treated with argatroban. The patient was a 17-month-old boy with severe hypercapnic and hypoxemic respiratory failure secondary to asthma and mucus plugging that failed conventional and unconventional ventilation. Venovenous ECMO was initiated, and within 24 hrs, there was a precipitous decrease in the platelet count, with the development of cutaneous ischemia involving his lower limbs. Argatroban was started and the child maintained on ECMO and continuous renal replacement therapy, with resolution of the cutaneous ischemia and recovery of the platelet count. Heparin-associated antibodies were positive. HIT is rare in the pediatric population. Recognition of HIT is vital because withdrawal of heparin is the first and most important therapy. For patients receiving ECMO or continuous renal replacement therapy who develop HIT, synthetic thrombin inhibitors have been reported as an alternative. However, little information on their use in extracorporeal life support has been published, particularly in the pediatric population. This report documents a pediatric case of HIT type II successfully treated with argatroban, allowing continuation of the ECMO and continuous renal replacement therapy therapy, with resolution of the cutaneous ischemia and thrombocytopenia.

Heparin‐induced thrombocytopenia: recent experience in a large teaching hospital

Heparin-induced thrombocytopenia (HIT) is a potentially serious adverse reaction caused by platelet-activating antibodies. To describe experience with HIT. Twenty-two patients identified by laboratory records of heparin-associated antibodies with a 50% or greater decrease in platelet count were reviewed in our 600-bed metropolitan teaching hospital from 1999 to April 2005. There was an increase in the frequency of HIT diagnosed during the review period, which was associated with a rise in the number of requests for HIT antibodies. Thrombotic complications were identified in 14 of 22 patients with HIT. Mean age was 65 years, and 11 patients were men. Seven patients died and HIT was considered contributory in four. One patient required mid-forearm amputation. Unfractionated heparin was used in all cases and five patients also received enoxaparin. Mean time to HIT screen, reflecting when the diagnosis was first suspected, was 14 days. Platelet nadir ranged from 6 x 10(9)/L to 88 x 10(9)/L, with a percentage drop in platelet count of 67-96%. Alternative anticoagulation (danaparoid) was not used in three patients, two of whom died. HIT is a potentially life-threatening complication of heparin therapy, associated with a fall in platelet count and a high incidence of thromboembolic complications. It is most frequently seen using unfractionated heparin therapy. The increase in frequency of HIT diagnosed in our hospital appears to be associated with a greater awareness of the entity, although detection is often delayed. Platelet count should be monitored in patients on heparin and the presence of antiplatelet antibodies determined if HIT is suspected. Treatment involves both discontinuation of heparin and the use of an alternative anticoagulant such as danaparoid because of the persisting risk of thrombosis.

Heparin-induced thrombocytopenia in a pediatric patient receiving extracorporeal support and treated with argatroban

Heparin-induced thrombocytopenia (HIT) is rare in the pediatric population, with a majority occurring in the pediatric intensive care unit setting. All reported cases have been associated with the use of unfractionated heparin. Because unfractionated heparin is the anticoagulant of choice for extracorporeal life support, the development of HIT in these patients can be devastating. We report a case of HIT with evidence of small-vessel arterial thromboembolism in a 17-month-old child receiving extracorporeal membrane oxygenation and continuous renal replacement therapy successfully treated with argatroban. The patient was a 17-month-old boy with severe respiratory failure secondary to asthma and mucus plugging that failed conventional and unconventional ventilation. Venovenous extracorporeal membrane oxygenation was initiated, and within 24 hrs, there was a precipitous decrease in the platelet count, with the development of cutaneous ischemia involving his lower limbs. Heparin-associated antibodies were positive. Argatroban was started, and the child maintained on extracorporeal membrane oxygenation and continuous renal replacement therapy, with resolution of the cutaneous ischemia and rebound of the thrombocytopenia. HIT is rare in the pediatric population. Recognition of HIT is vital because withdrawal of heparin is the first and most important therapy. For patients on extracorporeal membrane oxygenation or continuous renal replacement therapy who develop HIT, synthetic thrombin inhibitors (hirulogs) have been reported as an alternative. However, little information on their use in extracorporeal life support has been published, particularly in the pediatric population. This report documents a pediatric case of HIT successfully treated with argatroban, allowing continuation of the venovenous extracorporeal membrane oxygenation and continuous renal replacement therapy, with resolution of the thromboembolic ischemia and thrombocytopenia.

Challenges in variation and responsiveness of unfractionated heparin.

Unfractionated heparin (UFH) has been in clinical use for more than half a century. Despite its undoubted contribution to the treatment and prevention of thrombosis, heparin is significantly limited by its variable biochemical composition and unpredictable pharmacokinetics. The situation is compounded by the fact that methods for monitoring heparin do not necessarily reflect its therapeutic effect. The activated partial thromboplastin time (aPTT) is a method for monitoring heparin therapy that is simple, cheap, and readily available. However, it is also poorly standardized and is affected by numerous factors-both analytic and preanalytic-that are unrelated to the heparin effect. Establishing an appropriate therapeutic range for the aPTT is challenging for smaller clinical laboratories, and the antifactor Xa method of measuring heparin levels is not widely available. The College of American Pathologists published consensus guidelines in an effort to improve the laboratory monitoring of UFH therapy. However, it seems unlikely that the laboratory problems associated with monitoring UFH will be resolved. Unfractionated heparin is highly antigenic and carries a significant risk of heparin-induced thrombocytopenia (HIT). Even in the absence of thrombocytopenia or thrombosis, the presence of heparin-associated antibodies may predict adverse clinical outcomes and strengthen the rationale for the ultimate replacement of UFH. Fortunately, alternatives to UFH, such as low-molecular-weight heparins, direct thrombin inhibitors, and more specific factor Xa inhibitors, are becoming available for clinical use. The pharmacokinetics of these agents are more predictable and rely much less on laboratory monitoring. Nonheparin agents also eliminate the risk of HIT. The emergence of these newer anticoagulants makes the continued use of UFH increasingly difficult to justify.

Management of urgent high-risk cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II and coexisting disorders of renal function: Use of heparin and epoprostenol combined with on-line monitoring of platelet function

HEPARIN-INDUCED THROMBOCYTOPENIA TYPE II (HIT II) is an immunologic life-threatening condition that causes stroke, myocardial or mesenteric infarction, or thromboembolism in the lungs or extremities. 1 Shorten GD Comunale ME Heparin-induced thrombocytopenia. J Cardiothorac Vasc Anesth. 1996; 10: 521-530 Abstract Full Text PDF PubMed Scopus (36) Google Scholar , 2 Slaughter TF Greenberg CS Heparin-associated thrombocytopenia and thrombosis: Implications for perioperative management. Anesthesiology. 1997; 87: 667-675 Crossref PubMed Scopus (46) Google Scholar , 3 Bauer TL Arepaly G Konkele BA Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation. 1997; 95: 1242-1246 Crossref PubMed Scopus (284) Google Scholar It is prudent that heparin not be administered in any form whenever possible. This recommendation poses a problem in patients being prepared for cardiopulmonary bypass (CPB). Suitable alternatives for heparin-free anticoagulation include defibrinogenation (ancrod); the synthetic heparinoid, orgaran; or the antithrombin, hirudin. 4 Koster A Kuppe H Hetzer R et al. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology. 1998; 89: 777-780 Crossref PubMed Scopus (68) Google Scholar , 5 Koster A Kuppe H Mertzlufft F Cardiopulmonary bypass with recombinant hirudin in patients with heparin-induced thrombocytopenia type II: A synopsis of 19 cases. Br J Anaesth. 1999; 82: A116 Google Scholar Recombinant hirudin (r-hirudin) has gained a pivotal role because of relevant advantages 4 Koster A Kuppe H Hetzer R et al. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology. 1998; 89: 777-780 Crossref PubMed Scopus (68) Google Scholar , 5 Koster A Kuppe H Mertzlufft F Cardiopulmonary bypass with recombinant hirudin in patients with heparin-induced thrombocytopenia type II: A synopsis of 19 cases. Br J Anaesth. 1999; 82: A116 Google Scholar , 6 Greinacher A Völpel H Janssens U et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: A prospective study. Circulation. 1999; 99: 73-80 Crossref PubMed Scopus (505) Google Scholar (eg, rapid onset, short half-life, and availability of reliable on-line monitoring). If, however, urgent CPB is required in patients with coexisting renal impairment, r-hirudin (as well as the other options) may involve considerable disadvantages, 4 Koster A Kuppe H Hetzer R et al. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology. 1998; 89: 777-780 Crossref PubMed Scopus (68) Google Scholar , 5 Koster A Kuppe H Mertzlufft F Cardiopulmonary bypass with recombinant hirudin in patients with heparin-induced thrombocytopenia type II: A synopsis of 19 cases. Br J Anaesth. 1999; 82: A116 Google Scholar which include the lack of an antidote 4 Koster A Kuppe H Hetzer R et al. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology. 1998; 89: 777-780 Crossref PubMed Scopus (68) Google Scholar , 6 Greinacher A Völpel H Janssens U et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: A prospective study. Circulation. 1999; 99: 73-80 Crossref PubMed Scopus (505) Google Scholar and a prolonged pharmacologic effect resulting from sustained renal elimination. 5 Koster A Kuppe H Mertzlufft F Cardiopulmonary bypass with recombinant hirudin in patients with heparin-induced thrombocytopenia type II: A synopsis of 19 cases. Br J Anaesth. 1999; 82: A116 Google Scholar

HEPARIN-ASSOCIATED ANTIBODIES AND ADVERSE OUTCOMES FOLLOWING CARDIAC SURGERY

Introduction: Heparin-associated thrombocytopenia and thrombosis has long been recognized as a potential complication of heparin administration. Recently, antibodies to the heparin/PF4 complex have been identified as the molecular mediator of thrombocytopenia and thrombosis associated with heparin therapy. Retrospective studies suggest that the preoperative presence of heparin-associated antibodies is associated with adverse outcomes following cardiac surgery. [1] We sought to define the prevalence of the heparin-PF4 antibody in our population and to prospectively examine the association between heparin-associated antibodies and adverse outcomes following cardiac surgery. Methods: Preoperative blood samples were obtained from 85 patients scheduled to undergo cardiac surgery. Heparin-associated antibodies were measured using an ELISA for antibodies to heparin/PF4 complexes. Adverse outcome was defined as either in-hospital death or postoperative length of stay greater than 10 days. Differences in patient comorbidities and expected surgical risk were controlled for using the validated Parsonnet scoring system. [2] Results: Heparin-associated antibodies were detected in 8 of 85 patients (9.4%). Adverse outcomes, as previously defined, occurred in 10 of 85 patients (11.8%). After adjusting for comorbidities, no correlation was observed between the preoperative presence of heparin-associated antibodies and adverse outcome. There were no statistically significant differences in patient demographics, CPB time, cross-clamp time, inotrope use, or blood products transfused. Discussion: The prevalence of heparin-associated antibodies in preoperative cardiac surgical patients is greater than previously recognized. [1] Although we observed no association between heparin/PF4 antibodies and adverse outcome following cardiac surgery, a larger sample size will be required to definitively verify this conclusion.

The glycoprotein IIb/IIIa antagonist c7E3 inhibits platelet aggregation in the presence of heparin-associated antibodies.

Heparin-associated antibodies (HAAb), in the presence of heparin, can cause platelet activation and aggregation. The purpose of this study was to assess whether a platelet glycoprotein (GP) IIb/IIIa receptor antagonist, c7E3, would inhibit platelet aggregation in the presence of HAAb. If aggregation is inhibited by c7E3, enzyme-linked immunosorbent assays (ELISA) would be done to determine whether c7E3 interfered with the binding of heparin and the HAAb. HAAb-positive plasmas from 21 patients (determined by platelet aggregation assays) were studied. Normal donor platelet-rich plasmas (PRP) were incubated (1 minute) with either saline solution or 3 microg/ml of c7E3. Platelet-poor plasma from patients with HAAb and one of three sources of heparin (25 microl, 10 U/ml; porcine heparin, bovine heparin, and low molecular weight heparin [enoxaparin]) were added to the PRP mixture. Aggregation was determined using a platelet aggregometer by measuring time to aggregation, the slope of the aggregation curve, and the percent change in optical density. Platelet aggregation occured in 100%, 100%, and 95% of the saline solution incubations exposed to porcine heparin, bovine heparin, and enoxaparin, respectively. Incubation with c7E3 caused 100% inhibition of platelet aggregation in plasma exposed to porcine heparin, bovine heparin, and enoxaparin. The optical density curves obtained from the ELISA, which were dependent on the binding of HAAb to heparin, were not significantly different when c7E3 was compared to buffer alone. The GP IIb/IIIa receptor antagonist, c7E3, inhibits HAAb-induced platelet aggregation via a mechanism that does not appear to interfere with the binding between heparin and HAAb. Clinical trials are warranted to assess whether GP IIb/IIIa antagonists may allow patients with HAAb to safely receive heparin.

Antithrombin III Deficiency and White Clot Syndrome

Heparin-induced thrombocytopenia with antithrombin III deficiency can be a severe, fulminant systemic disease leading to disastrous complications and often death. An eighteen-month review of the authors' surgical population revealed 7 cases of heparin-induced thrombocytopenia. They present the diagnosis and management of these patients, as well as a literature review. On the basis of their experience, a platelet count that falls below 17% of the baseline should be the impetus to test for heparin-associated antibodies, protein C and S deficiency, and antithrombin III deficiency. Their newer recommendation, along with the use of saline flush and the start of coumadin early in the postoperative period, has prevented the complications associated with heparin-induced thrombocytopenia in their hospital for the past twelve months.

Do patients with the heparin-induced thrombocytopenia syndrome have heparin-specific antibodies?

Patients with the heparin-induced thrombocytopenia syndrome (HIT) have heparin-associated antibodies (HAb+), which, in the presence of heparin, are responsible for platelet activation and aggregation. This study addressed the questions: (1) are the antibodies specific for heparin; and (2) how do the antibodies cause platelet aggregation? Plasmas from 79 patients with HIT were divided into seven plasma samples: HAb+ plasma sample 1 (24 pooled plasmas); HAb+ plasma sample 2 (50 pooled plasmas); and HAb+ plasma samples 3 through 7 (individual plasmas). Normal patient plasmas were used as controls (HAb-). All seven HAb+ plasma samples caused platelet aggregation (PLA) in the presence of heparin and formed a precipitation line with heparin in gel immunodiffusion plates (HAb- plasmas did neither). The HAb+ plasma samples reacted with heparin, as determined by immunoprecipitation in sodium dodecylsulfate-polyacrylamide gel, with the production of a band at 50 kd (no band with HAb- plasmas). The plasma samples 1 and 2 were passed over heparin sepharose beads three times; the unabsorbed plasmas produced 3+ PLA, the first effluent produced 2+ PLA, and the second and third effluents produced no PLA. The heparin sepharose beads stained 3+, 2+, and 1+, after the respective passages, with fluorescein-labeled goat sera containing anti-human immunoglobulin G antibody. HAb+ plasma samples were digested with pepsin to separate the F(ab')2 fragments from the Fc fragments. The F(ab')2 fragments reacted with heparin as determined by immunoprecipitation in sodium dodecylsulfate-polyacrylamide gel with the production of a band at 25 kd, but did not cause PLA in the presence of heparin. Patients with HIT have heparin-specific antibodies that react with heparin in a classic F(ab')2 reaction and require the Fc fragment for platelet aggregation.

Reexposure to heparin of patients with heparin-associated antibodies

Four patients with heparin-associated antiplatelet antibodies who were not receiving platelet function-inhibiting agents received heparin during surgery, angiography, or hemodialysis. Three of the four patients had complications that were attributed to heparin-induced platelet aggregation. The complications included a superficial femoral artery thrombosis, a thrombotic stroke after a carotid endarterectomy, and recurring thrombosis of a graft inserted for dialysis. Nine patients received aspirin (325 mg b.i.d.) or dipyridamole (Persantine) (200 to 300 mg daily) before reexposure to 5000 to 12,000 units of heparin during 11 vascular procedures. The procedures included two carotid endarterectomies, three aortofemoral bypasses, one femoropopliteal bypass, two femorotibial in situ saphenous vein bypasses, one iliofemoral thrombectomy, one bilateral iliac artery angioplasty, and one axillobifemoral bypass. Platelet counts averaged 173,000/mm3 before heparin reexposure, fell to an average of 86,000/mm3 within 24 hours of heparin reexposure, and returned to normal within 48 hours after the reexposure. None of these patients had a thromboembolic or hemorrhagic complication. Patients with heparin-associated antiplatelet antibodies are at risk for developing thrombocytopenia and thromboembolic complications on reexposure to heparin. The platelet function-inhibiting agents, aspirin and Persantine, protect the patients from the thromboembolic complications but not the thrombocytopenia associated with limited heparin reexposure.