Intraoperative anticoagulation management during cardiac transplantation for a patient with heparin-induced thrombocytopenia and a left ventricular assist device

Heparin-induced thrombocytopenia is an immunologically mediated syndrome that is associated with potentially life-threatening arterial and venous thrombosis. Re-exposing patients who have heparin-induced thrombocytopenia to heparin during cardiopulmonary bypass may be hazardous. We describe the re-exposure to unfractionated heparin of a patient with a left ventricular assist device and evidence of heparin-induced thrombocytopenia who needed cardiac transplantation, which was accomplished without complications.     

Delayed-onset heparin-induced thrombocytopenia and thrombosis

BACKGROUND: Heparin-induced thrombocytopenia is a prothrombotic drug reaction caused by platelet-activating antibodies that recognize complexes of platelet factor 4 and heparin. OBJECTIVE: To describe a syndrome termed delayed-onset heparin-induced thrombocytopenia, in which thrombocytopenia and thrombotic events begin 5 or more days after withdrawal of heparin. DESIGN: Case series. SETTING: Secondary and tertiary care hospitals. PATIENTS: 12 patients who presented with serologically confirmed, delayed-onset heparin-induced thrombocytopenia, including 6 outpatients presenting after hospital discharge. MEASUREMENTS: The platelet serotonin-release assay was used to measure IgG-induced heparin-dependent and heparin-independent platelet activation; an enzyme immunoassay that detects IgG against platelet factor 4-heparin complexes was also used. RESULTS: Patients with delayed-onset heparin-induced thrombocytopenia presented with thrombocytopenia and associated thrombosis a mean of 9.2 days (range, 5 to 19 days) after stopping heparin therapy. Nine patients received additional heparin, with further decrease in platelet counts. Compared with controls, patients with delayed-onset heparin-induced thrombocytopenia had higher titers of IgG antibodies to platelet factor 4-heparin and greater IgG-induced heparin-dependent and heparin-independent platelet activation. CONCLUSIONS: Delayed-onset heparin-induced thrombocytopenia should be suspected when patients present with thrombocytopenia and thrombosis up to 3 weeks after exposure to heparin. This syndrome could be caused by high titers of platelet-activating IgG induced by heparin.     

Heparin-induced thrombocytopenia

Two patients with underlying thromboembolic disorders developed severe thrombocytopenia while receiving heparin sodium; one of these patients developed recurrence of the thrombocytopenia and possible heparin-induced pulmonary emboli when heparin was restarted. In a prospective study of patients receiving heparin in a coronary care unit (CCU), nine of 37 patients developed transient mild thrombocytopenia (platelet counts ranging from 88,000 to 150,000/cu mm). Heparin added to citrated platelet-rich plasma caused platelet aggregation in the two original patients. In three of six CCU patients tested, and in 17 of 87 other subjects, with maximum aggregation at concentrations of heparin likely to be present in vivo during therapy. We herein discuss evidence that suggests that heparin may cause or aggravate thrombosis by causing platelet aggregation. The occurrence of severe heparin-induced thrombocytopenia is well documented, and mild transient thrombocytopenia may be more common than has been recognized. Studies of heparin efficacy should take these responses into account.     

The use of direct thrombin inhibitors in cardiovascular surgery in patients with heparin-induced thrombocytopenia

One of the most important adverse drug reactions that physicians encounter is the life- and limb-threatening prothrombotic syndrome known as heparin-induced thrombocytopenia (HIT). Unfractionated heparin (UFH), administered during cardiopulmonary bypass (CPB), is highly immunogenic. Heparin-dependent antibodies can develop in 25 to 50% of UFH-treated cardiac surgery patients within 5 to 10 days. These antibodies can activate platelets and are considered the causative agents of HIT. HIT is a relatively common complication, occurring in 1 to 3% of cardiovascular surgery patients when UFH administration is continued postoperatively. It is strongly associated with new thromboembolic events leading to limb amputation and death. In acute or recent (< 100 days) HIT, alternative anticoagulatory regimens are needed during CPB surgery for prevention of HIT-related thrombosis. Treatment options for such patients now generally include the use of alternative anticoagulants such as lepirudin, bivalirudin, or danaparoid, as well as a combined treatment with platelet-function inhibitors and heparin. In patients with a history of HIT and no detectable antibodies, heparin is currently the safest approach for high-dose anticoagulation during CPB. Before and after surgery, however, alternative anticoagulants should be used. The risk of clinical HIT after heart surgery could potentially be reduced by using low-molecular-weight heparins for postsurgery anticoagulation.     

Orgaran during rotational atherectomy in the setting of heparin-induced thrombocytopenia

Heparin is considered necessary during percutaneous coronary interventions; however, heparin is contraindicated in patients with heparin-induced thrombocytopenia and/or heparin antibodies. We describe the successful use of the heparinoid Orgaran (danaparoid sodium) in addition to abciximab (ReoPro®) in a patient with heparin antibodies who required rotational atherectomy. Cathet. Cardiovasc. Diagn. 45:318–322, 1998. © 1998 Wiley-Liss, Inc.     

Rapid anticoagulation using ancrod for heparin-induced thrombocytopenia

In order to determine the efficacy and safety of ancrod, a rapid acting defibrinogenating drug, for patients with heparin-induced thrombocytopenia, 11 consecutive patients who required anticoagulant therapy because of venous thromboembolism and who developed acute heparin-induced thrombocytopenia or had a history of heparin-induced thrombocytopenia were treated with ancrod. Heparin therapy was discontinued (in patients receiving heparin) and ancrod started at a dose of 1 to 2 U/kg every 24 hours with subsequent daily doses adjusted to maintain fibrinogen levels between 0.5 and 1.0 g/L. Ancrod was continued until warfarin had become effective. The platelet count increased to more than 150 x 10(9)/L within 2 to 10 days in all thrombocytopenic patients. Two patients with a history of heparin-induced thrombocytopenia maintained normal platelet counts while receiving ancrod. Two patients had recurrent venous thrombosis while receiving warfarin, 10 days after ancrod was discontinued: one of these patients had metastatic pancreatic carcinoma and developed phlegmasia cerulea dolens and the other patient developed a venographically proven extension of her deep venous thrombosis. One patient suffered a bleeding episode into the thigh with a 16-g/L decrease in her hemoglobin level while receiving ancrod therapy. No other side effects were noted. Our experience indicates that ancrod therapy is a reasonable approach for patients with heparin-induced thrombocytopenia who require anticoagulant therapy.     

Heparin-induced thrombocytopenia. Perspectives in a therapeutic dilemma]

Severe heparin-induced thrombocytopenia (HIT) is a complication of heparin treatment with a frequency of about 0.5% of the treated patients. It is attributed to an immune mechanism leading to the production of heparin-associated antibodies which bind to the platelets and cause their elimination through consumption, sometimes accompanied by thromboembolic episodes. Therapeutically HIT represents a dilemma since heparin administration must be stopped immediately, whereas anticoagulation is acutely indicated in order to avoid thrombotic complications. Two such cases with this dilemma are illustrated. The diagnosis of HIT was made using platelet aggregation studies and flow cytometry techniques for the detection of heparin-associated platelet antibodies. Therapeutically, low molecular weight heparins were administered with success. Besides the diagnostic problems other available therapeutic solutions are discussed.     

Heparin-induced thrombocytopenia in the emergency department

We describe 3 patients who presented to the emergency department (ED) with stroke, deep venous thrombosis, or pulmonary embolism and renal failure after undergoing cardiac surgery 7 to 17 days earlier. Their onset of thrombosis after previous heparin exposure was temporally plausible for complications of heparin-induced thrombocytopenia, an immune-mediated thrombotic disorder triggered by heparin. The patients had normal platelet counts at presentation, yet each had circulating heparin-induced thrombocytopenia antibodies that were ultimately confirmed. Two patients had heparin reexposure in the ED, 1 of whom developed thrombocytopenia with new thrombosis and died. Alternative parenteral anticoagulation prevented further thrombosis in 2 patients. Because heparin use can be catastrophic in patients with heparin-induced thrombocytopenia, physicians should be vigilant in suspecting heparin-induced thrombocytopenia in patients with thrombosis after recent hospitalization or heparin exposure. Alternative anticoagulants are available for these at-risk patients.     

Unfractionated heparin compared with low-molecular-weight heparin as related to heparin-induced thrombocytopenia

PURPOSE OF REVIEW: Heparin-induced thrombocytopenia is a severe side effect of treatment with unfractionated heparin. The relation of low-molecular-weight heparin to heparin-induced thrombocytopenia is less well understood. This review will summarize what is known about the similarities and differences between thrombocytopenia induced by low-molecular-weight heparin and that induced by unfractionated heparin. RECENT FINDINGS: The pathophysiology of unfractionated heparin-induced thrombocytopenia, caused by the development of antibodies to heparin/platelet factor 4 complexes, holds true for low-molecular-weight heparin because the molecules of the latter are of the same saccharidic structure as those of unfractionated heparin. Owing to their smaller size, however, low-molecular-weight heparin does not interact with platelet factor 4 and platelets as efficiently as does unfractionated heparin. This translates to a two- to threefold lower risk of immune sensitization (antibody generation and occurrence of clinical heparin-induced thrombocytopenia). Low-molecular-weight heparin-induced thrombocytopenia antibodies are more often immunoglobulin A and immunoglobulin M, in contrast to the immunoglobulin G antibodies generated with unfractionated heparin-induced thrombocytopenia, which tend to be more often associated with clinical heparin-induced thrombocytopenia. The clinical expression of low-molecular-weight heparin-induced thrombocytopenia is generally similar to that of unfractionated heparin-induced thrombocytopenia but can have a slower onset, more severe thrombocytopenia, and slower platelet count recovery. Given that low-molecular-weight heparin, of itself, is linked with heparin-induced thrombocytopenia pathophysiology and it can interact with most preexisting heparin-induced thrombocytopenia antibodies generated after exposure to unfractionated heparin, treatment of heparin-induced thrombocytopenia patients with low-molecular-weight heparin is contraindicated. SUMMARY: The risk of the development of heparin-induced thrombocytopenia with low-molecular-weight heparin treatment is reduced relative to the frequency of unfractionated heparin-induced thrombocytopenia, but it is not eliminated, and platelet counts should be monitored with treatment.     

Heparin-induced thrombocytopenia: a case report

The authors report a case of heparin-induced thrombocytopenia, in whom massive pulmonary embolism occurred in spite of heparin anticoagulation. Successful pulmonary thrombectomy was carried out under cardiopulmonary bypass, with limitation of platelet clumping during bypass by aggregation inhibitors. This report is a comprehensive contribution to a better understanding of this rare immunoallergic complication of heparin administration, with a high incidence of serious thromboembolic events. The optimal management for cases of unavoidable reexposure to heparin is discussed.     

Have You Been HIT?

This review is specifically designed to aid the vascular surgeon in the management of heparin-induced thrombocytopenia (HIT). Heparin-induced thrombocytopenia is a rare complication of heparin administration, which poses significant morbidity and mortality. Its onset is usually 5 to 10 days after the heparin administration and should be suspected if platelet counts drop by at least 50%. Confirmation is given by the presence of HIT antibodies on an enzyme-linked immunosorbent assay (ELISA) or in functional platelet activation assays. The major complication is thrombosis and surprisingly bleeding is rare. Heparin must be stopped immediately if there is a clinical suspicion of HIT and alternative anticoagulation must be started. Anticoagulation is required for at least 2 to 3 months to prevent recurrence of thrombosis. Oral anticoagulation with warfarin should not be initiated until the platelet count has been recovered and there should be an overlap of at least 5 days between starting warfarin and stopping the alternative anticoagulant.     

Heparin-induced cardiac tamponade and life-threatening hyperkalema in a patient with chronic hemodialysis

Heparin, a commonly used anticoagulant agent, is frequently used in patients undergoing hemodialysis. As with most medications, heparin has a significant side effect profile. Two of its most important side effects, major bleeding and hyperkalemia, may be devastating without immediate diagnosis and treatment. Major bleeding such as gastrointestinal, genitourinary or intracranial bleeding is occasionally encountered and rarely neglected. However, heparin-induced cardiac tamponade is rarely encountered and may be easily overlooked. Another side effect, heparin-induced hyperkalemia, an unusual but well-described side effect, is frequently forgotten until life-threatening arrhythmia has occurred. We report a case involving a 40-year-old male patient with uremia, who had received heparin for 10 days for deep vein thrombosis in the left lower extremity. Hemopericardium with cardiac tamponade and life-threatening hyperkalemia were both noted in this patient.     

Endothelial cell damage in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia type II is a severe complication of heparin treatment that may result in thrombosis. When thrombosis occurs it carries a 50% mortality rate. The exact pathophysiology is not fully understood but in the majority of cases it is associated with the production of heparin/platelet factor 4 antibodies. The endothelium provides a protective anticoagulant surface over which blood flows. Perturbation of the endothelial cells causes a reversal of the anticoagulant properties of the cells to that of a procoagulant surface. This is often due to release or down-regulation of the anticoagulant membrane proteins such as thrombomodulin and up-regulation of procoagulant factors such as tissue factor. We studied 10 patients in our cardiothoracic institute with clinically and laboratory-confirmed heparin-induced thrombocytopenia type II for evidence of endothelial cell damage. There was a statistically significant rise in the concentrations of von Willebrand factor (P < 0.0001) and soluble thrombomodulin (P = 0.004) when patients with heparin-induced thrombocytopenia type II were compared with healthy laboratory controls and patients having had cardiopulmonary bypass surgery (von Willebrand factor 324 versus 103 versus 108 U/dl and soluble thrombomodulin 9.5 versus 2.3 versus 1.2 ng/ml, respectively). Our findings suggest that endothelial cell damage is a major factor in the pathophysiology of heparin-induced thrombocytopenia.     

Serum antibodies to the heparin/platelet factor 4 complex are an independent predictor of thrombotic complications following pediatric fontan surgery

Antibodies to the heparin/platelet factor 4 complex (heparin/PF4) are linked to the pathogenesis of heparin-induced thrombocytopenia (HIT) and to the thrombotic complications. We investigated thrombotic events during early follow-up in a pediatric cardiac surgical population to ascertain whether there is a relation between heparin/PF4 antibody concentration and post-surgical thrombotic complications. One hundred and five consecutive pediatric patients treated by Fontan surgery were studied. The presence of serum heparin/PF4 immunoglobulins IgG, IgA, and IgM (collectively termed HIT antibodies) were measured in preoperative and postoperative blood samples by enzyme-linked immunosorbent assay. On day six after Fontan surgery, HIT-related thromboses was identified in total of 11 patients (10.5%). HIT antibodies were detected in 34 of 105 patients (32.4%). The post-surgical nadir platelet count was significantly lower in patients who developed antibodies (p < 0.001). We found the odds ratio (OR) for this composite endpoint was 4.06 (p < 0.001). Seropositive status for heparin/PF4 antibodies was an independent predictor of thrombotic events (OR 2.28; p < 0.001). Quintile analysis revealed that the median nadir platelet value was significantly lower in patients with higher HIT antibody titers. Patients in the highest quintile of HIT antibody titer all experienced thrombotic events, while only two thrombotic events occurred in patients in the lowest quintile (p < 0.001). Heparin-induced thrombocytopenia is a rare occurrence in pediatric cardiac surgical patients. Patients who develop antibodies to the heparin/PF4 complex have a significantly higher rate of postoperative thrombotic events than patients who lack these antibodies. Within the seropositive group, the risk of developing thrombosis increased with the plasma antibody concentration.     

Heparin-induced thrombocytopenia

Summary Thrombocytopenia is a frequent and sometimes insidious complication of anticoagulant therapy with heparin. Two types of heparin-induced thrombocytopenia with a distinct aetiology have been recognized. Type I is characterized by a mild thrombocytopenia of early onset which requires careful monitoring but usually not the cessation of heparin therapy. The mild thrombocytopenia is probably due to the mild pro-aggregatory properties of heparin and can be more severe in the presence of other predisposing factors, e.g. sepsis. Type II heparin-induced thrombocytopenia is more severe and usually occurs after a period of 7–10 days. Heparin therapy should be ceased immediately and other anticoagulant therapy initiated. The thrombocytopenia is believed to be due to the development of a heparin-dependent antibody that causes platelet aggregation and release. The precise mechanism of heparin-dependent antibody-platelet interaction is still not entirely clear but probably involves the binding of an antibody-heparin immune complex to the platelet Fc receptor.     

Heparin-induced thrombocytopenia in pediatrics.

As in adult patients, heparin is used for prophylaxis and treatment of thromboembolism in newborns, children, and adolescents. Patients receiving heparin are potentially at risk to develop heparin-induced thrombocytopenia (HIT). HIT type II has been extensively described in the adult population; only a few reports address HIT type II in pediatric patients (total of 15 neonates, 4 young children, 12 older children and adolescents). The available data are discussed, and the case of a patient with recurrent thrombosis and HIT type II without thrombocytopenia is presented. The review of the literature reveals that HIT type II occurs especially in neonates and adolescents, corresponding to the two age peaks of thrombosis in pediatric patients. Risk factors for thrombosis include hereditary factors, immobilization, and surgery. HIT complications are severe and partly lead to life-threatening thromboembolism. In three patients, an increasing heparin demand was found. In five cases, thrombocytopenia was absent. Heparin was replaced mostly by danaparoid sodium; in three patients hirudin was used as an alternative anticoagulant. HIT type II represents a potentially dangerous complication of heparin therapy in pediatric patients and should be taken into consideration whenever heparin is given for prophylactic or therapeutic use in newborns, children, or adolescents.     

Anticoagulation with Bivalirudin during Deep Hypothermic Circulatory Arrest in a Patient with Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia is a well-recognized complication of anticoagulation with heparin. We present the case of a patient with recent heparin-induced thrombocytopenia who subsequently needed surgery on an emergency basis for acute type A aortic dissection. This article reports the successful use of bivalirudin, a direct thrombin inhibitor, as an alternative to heparin throughout cardiopulmonary bypass and deep hypothermic circulatory arrest. We contend that bivalirudin is a safe alternative to heparin when performing surgery for aortic dissection and should be considered as an option for use in patients who present with heparin-induced thrombocytopenia.     

Heparin-induced thrombocytopenia: a frequent complication after cardiac surgery

Thrombocytopenia is a common problem in cardiovascular patients, and heparin-induced thrombocytopenia (HIT) is therefore frequently suspected. Unfractionated heparin during cardiopulmonary bypass is particularly immunogenic as 25% to 50% post-cardiac surgery patients develop heparin-dependent antibodies but only 1 to 3% will develop HIT. These antibodies recognize a 'self protein', platelet factor 4 (PF4), bound to heparin. Antibodies associated with a high risk of HIT are mainly IgG1 which strongly activate platelets and coagulation, thereby causing thrombocytopenia and thrombosis. A biphasic evolution of platelet count with a secondary decrease after a previous increase following CPB or non-recovery of thrombocytopenia within 6 days post-operatively always requires screening for HIT antibodies. Both functional (platelet activation tests) and immunologic assays (antigen assays) are necessary in every patient to establish the diagnosis of HIT. When the clinical probability of HIT is high, the first requirement is to discontinue heparin, without waiting for results of laboratory investigations. An alternative anticoagulant such as danaparoid sodium (Orgaran) or lepirudin (Refludan) must then be administered since heparin withdrawal alone is insufficient to control the prothrombotic state associated with HIT. The risk of HIT will probably soon decrease due to the wider use of fondaparinux, which does not interact in vitro with PF4, but it could remain significant in patients undergoing cardiac surgery with CPB.     

Delayed-onset heparin-induced thrombocytopenia

Delayed-onset heparin-induced thrombocytopenia is a syndrome in which thrombocytopenia and thrombosis begin several days after heparin discontinuation. Delayed-onset heparin-induced thrombocytopenia is caused by immunoglobulin G antibodies that are reactive against the heparin-platelet factor 4 complex in the absence of circulating heparin. We describe 2 patients with delayed-onset heparin-induced thrombocytopenia who presented to the emergency department. An 88-year-old man and a 62-year-old man experienced thrombocytopenia and thrombosis 9 or more days after heparin cessation and demonstrated a further decrease in platelet count on reexposure to heparin. Delayed-onset heparin-induced thrombocytopenia should be included in the differential diagnosis of a patient with recent heparin exposure who presents with thrombosis or thrombocytopenia.     

Thrombocytopenia due to acute venous thromboembolism and its role in expanding the differential diagnosis of heparin-induced thrombocytopenia

Thrombocytopenia is an uncommon but serious consequence of heparin administration. Occasionally patients with massive acute venous thromboembolism (VTE) will develop thrombocytopenia. As heparin or some thrombin inhibitor is strongly indicated in acute VTE, it is important to distinguish this event from heparin-induced thrombocytopenia (HIT). Four patients are presented who developed thrombocytopenia so early in their course of VTE and/or therapy with heparin that HIT was considered unlikely. The mean nadir platelet count for these four patients was 60,000/microl occurring at a mean time of 18 hr after the initiation of heparin therapy. Because of strong indications to continue heparin for their acute VTE in the face of a very low likelihood that they did have HIT, heparin was continued with excellent results and resolution of the thrombocytopenia. The literature of this subject is reviewed. Thrombocytopenia following VTE is actually rather common, but it is usually milder than in these four cases. In some cases such as these four, the thrombocytopenia can be sudden and rather severe causing diagnostic confusion with HIT.