Heparin-induced thrombocytopenia (HIT) in pediatric cardiac surgery: an emerging cause of morbidity and mortality

Heparin-Induced Thrombocytopenia (HIT) in Pediatric Cardiac Surgery: An Emerging Cause of Morbidity and Mortality Bahaaldin Alsoufi, Lynn K. Boshkov, Aileen Kirby, Laura Ibsen, Nancy Dower, Irving Shen, and Ross Ungerleider Unfractionated heparin (UFH) is immunogenic, and heparin-dependent antibodies can be demonstrated 5 to 10 days postoperatively in 25% to 50% of adult postcardiac surgery patients. In a minority of these cases (1% to 3% if UFH is continued longer than 1 week) these antibodies strongly activate platelets, causing thrombocytopenia and massive thrombin generation (HIT syndrome). HIT is an intensely procoagulant disorder, and in adult cardiac surgery patients carries both significant thrombotic morbidity (38% to 81%) and mortality (28%). Despite the ubiquitous use of UFH in pediatric intensive care units, and the repeated and sustained exposures to UFH in neonates and young children with congenital heart disease, HIT has been infrequently recognized and reported in this patient population. However, emerging experience at our institution and elsewhere suggests that HIT is significantly under-recognized in pediatric congenital heart disease patients, and may in fact have an incidence and associated thrombotic morbidity and mortality in this patient group comparable to that seen in adult cardiac surgery patients. This article will review HIT in pediatric patients with congenital heart disease and emphasize the special challenges posed in clinical recognition, laboratory diagnosis, and treatment of HIT in this patient group. We will also outline our experience with the off-label use of the direct thrombin inhibitor, argatroban, in pediatric patients with HIT. © 2004 Elsevier Inc. All rights reserved. Key words: Heparin-induced thrombocytopenia; congenital heart disease; pediatric cardiology.

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nfractionated heparin (UFH) is the anticoagulant of choice in cardiac surgery requiring cardiopulmonary bypass (CPB) because of its efficacy in preventing thrombosis, its ease of monitoring using the activated clotting time, its easy reversibility with protamine, and extensive accumulated clinical experience. However, UFH is quite immunogenic, and 5 to 10 days postoperatively heparin-dependent antibodies can be demonstrated in 25% to 50% of adult postcardiac surgery patients.1-3 In most of these cases the antibodies appear to be nonpathogenic; however, in a minority of cases (1% to 3% overall) these antibodies strongly activate platelets, causing thrombocytopenia, formation of procoagulant platelet microparticles, and massive From the Departments of Surgery, Pathology, and Pediatrics, Oregon Health & Science University, Portland, OR; and the Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. Address reprint requests to Lynn K. Boshkov, MD, L471 Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97231. © 2004 Elsevier Inc. All rights reserved. 1092-9126/04/0701-0022$30.00/0 doi:10.1053/j.pcsu.2004.02.024

thrombin generation. This is the “HIT syndrome” (heparin-induced thrombocytopenia) and carries a strong prothrombotic risk. Odds ratios for thrombosis in HIT appear to be between 17 and 41.1 The thrombosis can be either arterial or venous or both, and tends to localize to sites of preexisting pathology. Risk of HIT in adult cardiac surgery patients is 1% to 3% if UFH is continued longer than 1 week. Once present, HIT in this population carries both significant thrombotic morbidity (38% to 81%) and mortality (28%).4-6 Although in other patient groups with HIT (orthopedic surgery, etc) venous thrombosis appears to predominate, in adult cardiac surgery patients arterial thrombi predominate, likely reflecting comorbid risk factors for thrombosis (atherosclerotic disease, catheterization, etc). HIT in adults undergoing cardiac surgery has been recently reviewed.4

Pathogenesis of Heparin-Induced Thrombocytopenia The complexing of heparin with PF4 (an endogenous platelet protein exteriorized to the platelet

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surface during platelet stimulation) exposes a family of neoantigens on PF4.7,8 Although antibodies form to many of these neoantigens (and appear to be detected by assays such as the PF4 enzyme-linked immunosorbent assays [ELISAs]) only in a minority of cases do the high titer IgG platelet-activating antibodies that cause thrombocytopenia and thrombosis (HIT syndrome) form. These pathogenic antibodies form immune complexes with heparin/PF4 and activate platelets through their Fc receptors causing formation of procoagulant platelet microparticles which lead to thrombin generation and thrombosis. Some role in HIT pathogenesis may also be played by activation of endothelial cells and monocytes by these antibodies.1 Some heparin types appear to be more antigenic with regard to formation of IgG HIT antibodies than others: UFH of bovine lung origin ⬎ UFH of porcine gut origin ⬎ low-molecular-weight heparin.9 In addition, there may be batch-to-batch variability.

Diagnosis of Heparin-Induced Thrombocytopenia in Adults: Clinical Features Heparin-induced thrombocytopenia in adults has been called a “clinicopathological syndrome” by Warkentin, with diagnosis of HIT requiring the presence of both an appropriate clinical setting (quantified in the “4 Ts”1 and below) and of confirmatory laboratory testing. HIT in adults has recently been extensively reviewed.1,10-12 The thrombocytopenia in HIT tends to be moderate (average platelet nadir 55 ⫻ 109/L) and to begin around day 5 of heparin exposure, with risk increasing with each day of heparin exposure between day 5 and 14. If heparin has been given recently (within 100 days) more rapid onset of thrombocytopenia may occur. Small numbers of patients have also been reported with delayedonset HIT; typically returning to hospital with thrombocytopenia and thrombosis 2 to 3 weeks post discharge. Other rare manifestations of HIT are acute anaphylactoid reactions, heparin-induced skin necrosis, and adrenal infarction and hemorrhage. HIT generally appears to be more common in surgical than in medical patients and is slightly more common in females than males. Full-dose therapeutic heparin is more likely to result in HIT than prophylactic-dose heparin, although HIT can occur to heparin given by any

route. Change from prophylactic-dose heparin to full-dose heparin may cause abrupt thrombocytopenia and onset of HIT. Once established, HIT can be perpetuated by extremely small doses of heparin (subcutaneous, line flushes, heparincoated catheters). In adult cardiac surgery patients, basically three patterns of HIT have been described postoperatively.4 “Typical-onset HIT” occurs in patients receiving UFH with surgery, followed by short-term line flushes postoperatively, followed by subcutaneous UFH in prophylactic doses postoperatively. Here the platelet count falls with surgery, rises subsequently (characteristically into the 200s), and on postoperative day (POD) 5 or later again begins to decline on subcutaneous heparin. “Rapid-onset HIT” can occur if intraoperative exposure and short-term line flushes are followed several days later by a bolus of UFH. Here there is typically a normal reactive thrombocytosis postoperatively (platelets rise into the 400s) followed by abrupt decline in the platelet count by 50% or more following the heparin bolus. The third pattern is “delayed-onset HIT” in which UFH is administered as in the second pattern, but without development of the normal reactive postoperative thrombocytosis, and with subsequent development of thrombocytopenia after POD 5 in the absence of further heparin administration. Apart from the rare hemorrhage into infracted adrenals, significant bleeding is virtually never a problem in HIT; rather, the clinical problem is life-threatening thrombosis. As discussed later in this review, in all clinical contexts in which HIT occurs it has become increasingly apparent that simple cessation of heparin alone, even if there is no obvious thrombosis at the time of diagnosis, is insufficient to prevent thrombosis in HIT, and if heparin is simply stopped, about 50% of patients will go on to develop arterial or venous thrombosis or both. Thus, the standard of care once HIT is diagnosed is to anticoagulate with an alternative anticoagulant (most often a direct thrombin inhibitor [DTI]). The “4 Ts” clinical eight-point scoring system for HIT probability1 incorporates the degree of Thrombocytopenia (maximum two points for a platelet nadir of 20 to 100 ⫻ 109/L or a platelet fall ⬎50%), the Timing of the platelet fall or other sequelae (maximum two points for day 5 to

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10 or less than day 1 with recent heparin), the presence of Thrombosis (maximum two points for proven thrombosis), and the fact that no oTher cause for thrombocytopenia is evident (maximum two points for no evident other cause). In addition, laboratory testing for HIT should be positive.

Diagnosis of Heparin-Induced Thrombocytopenia in Adults: Laboratory Tests (PF4 ELISAs Versus Functional Assays) The issue of the sensitivity and specificity of HIT antibody testing as related to assay type and patient population has been recently reviewed.1,13-18 Laboratory tests for HIT come in two basic types, each with assets and problems. Antigenic tests (such as the PF4 ELISAs) measure antibodies to PF4 complexed with heparin or other polyanions. These tests are easy to perform in the routine clinical laboratory and require less blood than functional assays. However, while quite sensitive for clinical HIT (false-negative rate generally ⬍5%). these tests will detect both pathogenic and nonpathogenic heparin-dependent antibodies, accounting for the 25% to 50% of adults identified to have antiheparin antibodies postcardiac surgery without evidence of thrombocytopenia or thrombosis. Thus, while sensitive, PF4 ELISAs are not very specific for clinical HIT in the adult cardiac surgery population. Also there may be significant variability between kits from different manufacturers, despite the quoted false-negative rate above of ⬍5%, a recent report determined the false-negative rate of one of the kits (Asserachrom) to be as high as 20%. Both positive and negative predictive values of PF4 ELISAs also depend heavily on the specific population being tested. For example, the frequency of PF4 HIT positives to UFH is significantly higher in cardiac surgery patients than in orthopedic surgery patients (50% v 10%). However, a positive PF4 is less likely to be associated with either thrombocytopenia (2% v 5%) or thrombosis (1% v 3%) in cardiac surgery patients versus orthopedic surgery patients.1 Generally, strongly positive PF4 ELISAs appear more predictive of clinical HIT than weakly positive ones; however, use of degree of assay positivity in diagnosis of clinical HIT still requires validation.

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In contrast to the PF4 ELISAs, functional assays (such as the serotonin release assay and others) detect HIT antibodies based on their characteristic platelet-activating properties. Although functional assays tend to be a bit less sensitive than antigenic assays, particularly in the earliest stages of HIT, they are considerably more specific for the diagnosis of clinical HIT, particularly in patient groups where the incidence of nonpathogenic antibodies appears high. Functional assays, particularly the best of these which use washed platelets, are technically quite demanding and tend not to be performed by routine clinical laboratories. Thus, if functional assays are not available on site and need to be sent out to a reference laboratory, there can be a delay of several days for receipt of a result. Functional assays also require more blood than PF4 ELISAs. Heparin-dependent platelet aggregation in platelet-rich plasma is a type of functional HIT assay performed at some centers that is less technically demanding than the washed platelet functional assays and which is more specific for clinical HIT than the PF4 ELISAs. Unfortunately, this assay is not as sensitive as washed platelet assays and our experience, and that of others, suggests this assay may be falsely negative particularly in the early stages of HIT. Heparin-induced thrombocytopenia antibodies detected by both PF4 ELISAs and by functional assays tend to be transient (2 to 3 weeks–3 to 6 months) with the PF4 ELISAs tending to be more persistent. Thus, neither type of HIT testing is particularly useful for confirming previous HIT unless the episode in question has been fairly recent.

Heparin-Induced Thrombocytopenia in Pediatrics and Pediatric Intensive Care Units Reports in the Literature Despite the ubiquitous use of UFH in pediatric intensive care units (ICUs) generally, and in the congenital cardiac population specifically, HIT has been infrequently recognized and reported in neonates and pediatric patients.19-23 While most of these case series have emphasized the severity of thrombotic complications observed in these patients, others19 have reported the clinical course of HIT in pediatric patients to be milder

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that in adults. Caution must be used in interpreting many of these case reports because the most specific washed platelet functional assays have not normally been used to confirm the diagnosis of HIT. Rather the diagnosis of HIT was either clinically based or confirmed serologically using PF4 ELISA or heparin-dependent platelet aggregation. In a review of the literature, Ranze et al22 reported on eight children aged 3 months to 15 years and 14 newborns with HIT. Severin and Sutor’s review21 found 31 cases of HIT in the reported literature (total of 15 neonates, four young children, 12 older children and adolescents). Age distribution in HIT patients appeared bimodal with no HIT reported in patients aged 3 to 7 likely reflecting incidence of heparin exposure in different age groups. Most patients with HIT had received UFH during cardiac surgery, dialysis, or as treatment for deep venous thrombosis and in most of the reported cases thrombotic sequelae had occurred including shunt or conduit thrombosis, intracardiac thrombosis, deep venous thrombosis, and stroke. Spadone et al23 reported the incidence of clinical HIT in 1,329 newborns admitted to the neonatal ICU over a 21⁄2 year period. Approximately 70% received UFH, of which 34 patients (3.7%) were suspected to have HIT because of thrombocytopenia (platelets ⬍70 ⫻ 109/l) (n ⫽ 23), precipitous (30% to 50%) fall in platelet count (n ⫽ 5), or thromboses (n ⫽ 6) that developed while they were receiving heparin. Median time to development of HIT was 22 days, a considerably longer time interval than the 5 to 14 days typically seen in adults. Heparin-associated antiplatelet antibodies were demonstrated in 14 infants (1.5%) by platelet aggregation testing. Of these 14 infants, 13 had umbilical catheters, and aortic thrombosis was documented by abdominal ultrasonography in 11 of these 13 cases (85%). In contrast only five of 20 infants (25%) with an umbilical catheter without heparin-associated antiplatelet antibodies developed aortic thrombosis. Recently, Schmugge et al19 in a retrospective cohort study reported the incidence of HIT in pediatric intensive care unit patients. Over a 21⁄2 year period, all patients who received UFH for ⱖ5 days were studied. Where possible, the diagnosis of HIT was confirmed serologically by PF4

ELISA. Of 1,950 children admitted during the study period, 612 were exposed to heparin for ⱖ5 days. Thrombosis occurred in 57 patients (9.3%). Plasma samples were available for 38 cases, of which 14 satisfied clinical HIT criteria. The calculated incidence rate for HIT-associated thrombosis was 2.3% for patients exposed to heparin ⱖ5 days). Nine patients suffered from venous, two patients from arterial, and three had combined arterial and venous thrombosis. None of the 14 patients died or underwent amputation. Six of the 14 patients had PF4 ELISA antibody cutoffs above those for adults, the remaining eight patients had levels below the adult cut-off but significantly higher antibody levels than a matched control group. In the cases cited by Severin and Sutor,21 HIT was reported in four neonates on extracorporeal membrane oxygenation (ECMO) support. Sequelae in three patients included intracardiac thrombi, thrombosis of the inferior vena cava, and peripheral arterial thrombosis. There have been other reports of patients with HIT following Fontan operation (n⫽ 2),24 and following ECMO (n ⫽ 1, fatal).25 Two additional cases of HIT and thrombosis in children with congenital heart disease (CHD), one of whom required ECMO, were recently described by Deitcher et al.20

Experience Our experience in 10 cases of HIT in neonates and young children suggests patients with CHD have a perioperative incidence of HIT (and associated morbidity and mortality) similar to adult cardiac surgery. Emerging experience at our center and others26 has suggested that HIT in neonates and young children with CHD is under-recognized and underappreciated as a cause of morbidity and mortality, and that HIT in these patients may, in fact, have an incidence, morbidity, and mortality comparable to that seen in adult cardiac surgery patients. We have now recognized eight cases of clinical HIT in our pediatric ICU in the past 2 years, seven of them in congenital cardiac patients (an incidence of 1.3% of CHD surgery patients). This is comparable to the 1% to 3% rate reported in the literature in adult cardiac surgery patients. In addition, we have been extensively involved in the care of two additional HIT cases in CHD patients at another institution (see Table 1). In all cases HIT was identified by

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Table 1. Baseline Characteristics and Major Outcomes of our Pediatric Patients With Heparin-Induced Case

Age/Sex

C1

2 wk/F

C2

2 wk/F

C3

5 mo/M

C4

1 wk/F

C5

8 mo/M

C6

7 wk/F

C7

9 mo/M

C8

5 yr/M

C9

3 yr/M

C10

31⁄2 mo/F

Diagnosis CHD: 1st op: BlalockTaussig shunt for hypoplastic L heart variant CHD: 1st op: Repair of Tetralogy of Fallot/ pulmonary atresia CHD: 2nd op: Bidirectional Glenn and repair anomalous pulmonary return (had stage I Norwood as neonate) CHD: 1st op: Stage I Norwood for hypoplastic L ventricle CHD: 1st op: Repair of tetralogy of Fallot/AV canal defect CHD: 1st op: Repair of tetralogy of Fallot CHD: 2nd op: Rastelli procedure CHD: 2nd op: Fontan (had thrombosed IVC below renals, femoral artery and vein, innominate vein, and dural sinus in HITrelated thrombosis as neonate undergoing stage I Norwood) Abdominal surgery (pull through for Hirshsprung’s) complicated by intraabdominal sepsis (only exposure to UFH was lines) CHD: 1st op: Complete AV canal repair

HIT Thrombosis

HIT Death

Argatroban Use

Shunt and leg

Yes

None

None

No

Thrombosed pulmonary vein on ASA

No

None acute; treated with ASA. Argatroban used for cath at 22 mos. Infusion, cath

Pulmonary embolism and dialysis line Superior vena cava

Yes

Infusion, cath, ECMO

No

Infusion, cath

None

No

Infusion

Shunt

No

Infusion, cath, CPB

No (thrombosed fenestration and shunt following 2nd op on UFH; lab testing negative for HIT)

No, septic death

Infusion, cath

R lobe of liver, dialysis lines

No

Hemodialysis

PICC line thigh

No

Infusion

Abbreviations: ASA, aspirin; cath, cardiac catheterization; CHD, congenital heart disease; CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation; UFH, unfractionated heparin.

failure of platelets to rise appropriately postoperatively ⫾ the presence of concomitant thrombosis. All cases were confirmed by functional HIT assays. Maternal HIT was negative in three of three mothers of HIT-positive neonates tested. Only one of these three mothers had a history of heparin exposure and it was remote (years prior). The mother of a fourth HIT-positive neonate was not tested but had no history of heparin expo-

sure. Thus, the HIT antibodies detected in our HIT-positive neonates do not appear to have originated transplacentally. The nine CHD patients with established HIT ranged in age from 2 weeks to 5 years old. Two, both neonates (cases C1 and C4), died of HITrelated thrombosis (mortality 22%). Again this mortality rate is comparable to the 28% reported in the largest adult cardiac series. One case (C1)

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was untreated and one case (C4) died despite argatroban treatment. An additional three patients suffered significant thrombotic morbidity (C3, C5 and C10; overall thrombotic rate, 66%). Again this thrombotic rate is comparable to the 38% to 81% thrombotic rate reported in adult cardiac surgery patients with HIT. Two patients were initially treated with aspirin alone (C2 and C3), and one (C3) developed pulmonary vein thrombosis. The clinical courses of two illustrative cases (C1 and C3) are shown in Figs 1 and 2 and an additional two cases (C4 and C5) in Fig 3. Of note with regard to C4 and C5 in Fig 3 is the fact that the functional assay we had been using at our institution (heparin-dependent platelet aggregation in platelet-rich plasma) was not a washed platelet assay. As shown in Fig 3, this assay was negative early in the course of HIT in C4 and C5. We believe earlier diagnosis and initiation of alternative anticoagulant therapy might have prevented the subsequent thrombosis that occurred in both these patients and because of this we have begun using a washed platelet assay at our institution.27 In summary, our experience suggests neonates and young children can and do make pathogenic HIT antibodies and that HIT in congenital cardiac surgery patients may have an incidence, morbidity, and mortality comparable to that in adult cardiac surgery. It also suggests that HIT in this population has an unfavorable natural history if heparin is simply stopped, even if an antiplatelet agent is added, and that the risk/benefit is probably in favor of prophylactic anticoagulation even if no thrombosis is yet clinically evident. Specific problems related to choice and dosing of alternative anticoagulants in this patient group are discussed in further detail later in this review.

Reasons Heparin-Induced Thrombocytopenia Might occur Disproportionately in Patients with Congestive Heart Disease: Potential Scope of the Problem Each year in the United States over 2,000 infants with CHD are born. About one third of these neonates will have life-threatening defects requiring urgent or semi-urgent cardiac surgery with CPB to correct or palliate. These children often require subsequent surgery to palliate their defects. Others will have less severe defects re-

quiring surgery with CPB within the first months or years of life.28, 29 If HIT is in fact occurring in these children at rates comparable to adults (1% to 3%), this would potentially represent 200 to 600 cases per year. If adult morbidity and mortality rates apply, over half these patients will experience significant thrombotic morbidity and 20% to 30% may die. Why do neonates and young children with CHD appear to be disproportionately prone to develop HIT versus other sick children in pediatric ICUs. We believe some of the following reasons may apply: 1. They have repetitive exposures to UFH (line patency, catheterization, CPB, ECMO, and ventricular assist devices [VAD], multiple surgeries) including exposure to high-dose heparin during CPB and while on other extracorporeal circuits such as ECMO and VAD. 2. They have prolonged CPB runs (several hours are not unusual in complex cases) with concomitant exposure to high levels of UFH and PF4-coated platelets. PF4 is displaced from endothelial cells by high doses of heparin as well as being exteriorized because of platelet stimulation by the extracorporeal circuit and by thrombin generation during CPB. Also, transfused platelets have abundant PF4 on their surface. 3. They frequently need VADs or ECMO postoperatively. 4. They frequently have comorbid illness (such as sepsis) resulting in platelet activation and endothelial damage. 5. They have abnormal flow through cardiac defects and artificial conduits that may predispose to thrombosis.

Therapeutic Considerations: Do’s and Don’ts from the Adult Experience and Adult Cardiac Experience Detailed discussions of treatment of HIT in adults can be found in recent reviews.1,10,11,30 Detailed discussion of treatment of HIT in adult cardiac patients can be found in the article by Warkentin and Greinacher.4 We summarize the major treatment issues below.

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Figure 1. (A) Clinical course of patient C1 from Table 1. A 2-week-old (surgery was delayed to permit treatment of neonatal meningitis) term female infant with a complex congenital heart defect (hypoplastic left ventricle variant) underwent a modified Norwood procedure with insertion of a 3.5-mm Blalock-Taussig shunt. Platelets fell from 228 to 48 ⫻ 109/L on POD 3. Following sternal closure on POD 5, she had ongoing thrombocytopenia, hypoxemia, and hemodynamic instability despite sternal reopening. Angiogram revealed a large filling defect at the shunt base. Reoperation on POD 6 retrieved a 3 mm thrombus. She received heparin in lines/flushes, during angiograms, during CPB, and by infusion following the initial operation and reoperations. She arrested 1 hour after completion of her surgery on POD 6 and died. Her left leg (the leg where the angio access had occurred) was noted to have turned blue and cold at the end of the POD 6 surgery, at which point a possible diagnosis of HIT was entertained and a HIT assay sent for laboratory evaluation. The functional washed platelet assay was strongly positive, confirming the diagnosis of HIT. (B) Angiogram of patient C1 from Table 1 showing a large thrombus in the Blalock-Taussig shunt on POD 5 which was removed surgically on POD 6.

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Figure 2. Clinical course of patient C3 from Table 1. A 5-month-old boy with hypoplastic left heart syndrome status post-stage I Norwood procedure as a neonate underwent a bidirectional Glenn shunt and repair of partial anomalous pulmonary venous return. Postoperatively, he required ECMO. He was weaned from ECMO and decannulated on POD 3, but platelets remained low. Postoperative day 5 functional HIT assay was moderately positive. All heparin in lines and flushes was stopped. There was no evidence of thrombosis and he was treated with aspirin. Platelets rose and he developed a persistent chylothorax. On POD 20 a cardiac catheterization performed using argatroban showed thrombosis of the left pulmonary vein, almost certainly a previously unrecognized thrombotic sequelae of HIT. He received a trial infusion of argatroban in preparation for possible surgical correction of the lesion. Unfortunately, on surgical re-exploration, repair could not be performed.

Treatment of Acute Heparin-Induced Thrombocytopenia ⴞ Thrombosis Once HIT is diagnosed or strongly suspected clinically, all heparin in any form (including lowmolecular-weight heparin) and by any route (including heparin-coated catheters) should be discontinued. Heparin-induced thrombocytopenia accompanied by thrombosis mandates alternative antithrombotic therapy. Even apparently asymptomatic HIT, given the unfavorable natural history of this disorder, should prompt clinical evaluation for thrombosis, and even if thrombosis is not found prophylactic anticoagulation with an alternative anticoagulant is strongly recommended to prevent formation of thrombi.31,32 In particular, two things should be avoided. The first is acute administration of warfarin, because this can precipitate venous gangrene by driving pro-

tein C levels down acutely.33-35 The second is platelet transfusion as bleeding is almost never a clinical problem in HIT and there is fairly strong anecdotal evidence that platelet transfusion can precipitate thrombosis.

Alternative Anticoagulants to Standard Heparin Low-molecular-weight heparin should be avoided because of high clinical and serologic cross-reactivity rates. The alternative anticoagulants36 for which the most data are available (eg, efficacy in treating HIT are the heparinoid danaparoid sodium)37 (recently withdrawn from the US market) and the DTIs lepirudin (recombinant hirudin)38-40 and argatroban.41-46 Direct thrombin inhibitors have become the anticoagulants of choice in HIT because of their central role of

HIT in Pediatric Cardiac Surgery

Figure 3. Platelet counts and timing of negative and positive HIT assays in cases C5 (top) and C4 (bottom) from Table 1. In both cases, delay in diagnosis of HIT resulted in delayed initiation of prophylactic argatroban therapy, which might have prevented some of the subsequent thrombotic sequelae. Case C5 (top): An 8-month-old boy with tetralogy of Fallot/ atrioventricular canal defect underwent complete repair. His postoperative coarse was complicated by a junctional rhythm. His ventricular compliance remained poor and he did not diurese well, but he was extubated on POD 3. Thrombocytopenia was noted but POD 4. HIT assay was negative. On POD 5 his respiratory status worsened and he required re-intubation. His chest film was asymmetric with haziness on the right, and oxygenation was poor. High-frequency oscillatory ventilation was initiated with rapid improvement in oxygenation and subsequent weaning. On POD 5, repeat HIT assay was positive. All heparin was stopped and full argatroban anticoagulation was initiated. A cardiac catheterization on POD 7 demonstrated no pulmonary emboli but suggested the presence of a nonocclusive clot in the superior vena cava. This was confirmed by echocardiogram. He weaned quickly and was back on conventional ventilation within 48 hours. He continued to improve over the next several days and was extubated on POD 12. Case C4 (bottom): A term one-week-old girl with critical aortic stenosis and a hypoplastic left ventricle underwent

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thrombin in the pathogenesis of HIT-related thrombosis.1,47,48 Other newer agents for which anecdotal success in treating HIT has been reported are the synthetic hirudin analog bivalirudin,49,50 and the anti-Xa pentasaccharide fondaparinux. The oral thrombin inhibitor ximelagatran has not been reported to be used in HIT yet, but is potentially attractive as a treatment option. Information regarding major treatment alternatives in HIT is summarized in Table 2. As indicated above, even HIT patients with isolated thrombocytopenia without thrombosis should be prophylactically anticoagulated because of the high subsequent thrombotic rate (approximately 50%) if HIT is left untreated. It is unclear how long this increased thrombotic risk persists in HIT following cessation of heparin therapy. At a very minimum, alternative anticoagulation should be continued until there has been full recovery of platelets and the patient is clinically

4

a Norwood stage I procedure. Postoperatively she was on a ventricular assist device (NoMoVad). On POD 2 she developed tamponade, her chest was explored and clot removed. She was decannulated with chest closure on POD 3. She had poor hemodynamics, pulmonary function, and renal insufficiency. Dialysis by CVVH was attempted on POD 4 but was complicated by thrombocytopenia and a clotted circuit. Initial HIT assay was negative on POD 4. Because of a possible IVC clot, a heparin infusion was briefly used. Platelets remained low and a repeat HIT assay was positive on POD 7. Full argatroban anticoagulation was initiated. She developed a chylothorax and her hemodynamics deteriorated significantly. She was placed back on NoMoVad with CVVH on POD 13, with argatroban anticoagulation. On POD 18 an oxygenator was added to her extracorporeal circuit. On POD 20 she was taken back to the operating room for shunt revision and lung biopsy, which revealed organizing thrombi consistent with pulmonary emboli. TPA was started but was complicated by significant bleeding. She was decannulated on POD 26. As expected, she did poorly and support was withdrawn. Autopsy showed multiple bilateral areas of hemorrhage and thrombosis in the lungs and kidneys. Maternal HIT assay was negative.

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Table 2. Alternative Anticoagulants Used in Acute Heparin-Induced Thrombocytopenia

Agent

Where Licensed/ Available for Treatment of HIT

Usual Adult Dose (Therapeutic Infusion)

t1⁄2

How Monitored

Lepirudin

US, Canada, Europe, others

⫾ bolus 0.4 mg/ 90 min kg IV then 0.15 mg/kg/hr adjusted to PTT 1.5-2.5⫻ patient’s baseline or midrange normal

Argatroban

US, Canada

2 ␮g/kg/min 40-50 min PTT, ACT adjusted to PTT (intra-op) of 2.0-3.0 ⫻ normal

Danaparoid

Canada (withdrawn IV bolus of 2,250 from US market U (body wt 602002) 75 kg) followed by infusion (400 U/hr ⫻ 4 h, then 300 U/hr ⫻ 4 h, then 200 U/h adjusted per anti-factor Xa levels) Bivalirudin Approved in US for No bolus. IV use in cardiac infusion of 0.15 catheteriza-tion mg/kg/hr in patients with previous HIT; other limited offlabel use Fondaparinux Limited off-label Not established in use HIT. Full therapeutic dose in other disorders (DVT) is 5.0 mg SQ qd (wt ⬍ 50 kg), 7.5 mg SQ qd (wt 50-75 kg) and 10.0 mg Ximelagatran No current clinical experience in HIT

23 h

PTT, Ecarin clotting time (ECT— intra-op)

Anti-factor Xa levels

Antidote

Comment

None

● t ⁄ markedly prolonged in even minor renal insufficiency (Cr ⬎ 1.6) ● Can be given SQ and IV ● Higher bleeding than with heparin ● Antibody formation a problem especially with re-exposures ● Crosses placenta in animal studies ● t1⁄2 markedly prolonged in hepatic insufficiency (use 25% dose in clinical jaundice) ● IV administration only ● Prolongs PT INR as well as PTT complicating transition to oral anticoagulants ● Both SQ and IV administration

None

None

12

● Substantial clinical experience in pregnant patients

⬃25 min

Ecarin clotting time preferred

None

● Bivalent DTI based on hirudin ● IV administration ● Predominant enzymatic degradation

14-18 h

4-6 h

Anti-factor Xa activity using fondaparinux curve to standardize (cannot use LMWH curves)

None

● Antifactor Xa activity, dependes on antithrombin for activity ● Does not appear to crossreact with HIT antibodies

None

● Oral DTI in clinical development for prophylaxis and therapy ● Potential for therapy or transition to this oral agent in HIT patients

Abbreviations: HIT, Heparin-induced thrombocytopenia; DTI, direct thrombin inhibitor; LMWH, low molecular weight heparin.

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stable. However, increased risk may persist for up to 3 to 4 weeks and possibly longer, and consideration should be given to a longer period of anticoagulation particularly in high-risk patients. Warfarin therapy should not be instituted until there has been full recovery of the platelet count.

Transitioning to Long-Term Anticoagulation For HIT patients with established thrombosis it is necessary to transition from a DTI to longerterm anticoagulation, usually with warfarin. Warfarin anticoagulation should be instituted only after full platelet recovery and then performed, without a loading dose, under coverage of the DTI with full therapeutic overlap of the two agents for 2 days before discontinuing the DTI. In the case of argatroban, baseline prothrombin time international normalized ratio will be prolonged as well as the partial thromboplastin time, complicating transition to warfarin. There are various approaches to this problem. At our institution we wait until the prothrombin time international normalized ratio is ⬎4.0, then hold the argatroban infusion and measure the prothrombin time international normalized ratio 4 to 6 hours later, restarting argatroban and adjusting the dose of warfarin as necessary. Alternatively, it is rational to measure a chromogenic factor X level without interrupting argatroban therapy, and to consider warfarin fully therapeutic when the factor X level is ⬍0.3.

Repeat Exposure to Unfractionated Heparin in Patients With Previous Heparin-Induced Thrombocytopenia Although HIT does not invariably recur with subsequent exposure to heparin, particularly if the HIT has been remote (more than 100 days prior with serologic tests for HIT antibody-negative), given the major thrombotic risk HIT poses, it would appear most prudent to avoid future exposures to heparin in patients with previous HIT if at all possible. In recent HIT (less than 100 days or in the presence of residual serologic positivity) heparin exposure should be absolutely avoided. Recommendations for adult cardiac surgery patients with HIT have been recently reviewed.4,51-53 Protocols exist for the use of argatroban, lepirudin, and bivalirudin not only for treatment of HIT, but also for invasive procedures (catheterization, angiography). However , as far as moni-

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toring and ready reversibility of bleeding are concerned there really is no satisfactory alternative to UFH for CPB or extracorporeal circuits, although danaparoid sodium,4 and more recently bivalirudin, lepirudin, and argatroban26,54 have been used. However, monitoring and bleeding have both been issues with these agents. Heparin has also been used in combination with antiplatelet agents such as epoprostenol and tirofiban with anecdotal success. Warkentin and Greinacher4 essentially recommend deferring surgery if possible for several weeks following HIT until serological tests are negative and then using UFH only during CPB itself. If alternative anticoagulants must be used for cardiac surgery, they recommend an off-pump technique (which uses lower doses of anticoagulants) if possible. If CPB must be performed using alternative anticoagulants, they recommend either bivalirudin or lepirudin (if the ECT is available), danaparoid (if drug and antifactor Xa monitoring are both available) or heparin in combination with either epoprostenol or tirofiban.

Special Considerations and Unanswered Questions in Diagnosing and Treating HeparinInduced Thrombocytopenia in Neonates and Young Children Reasons to suspect HIT may differ in the pediatric cardiac setting from the adult setting. In adult cardiac surgery patients, as covered earlier in this review, HIT has been reasonably well characterized as to its incidence, type of thrombotic morbidity, and mortality. Additionally, in the adult cardiac surgery population the clinical patterns suggestive of HIT, predictive values of common laboratory tests for HIT (PF4 ELISAs and functional assays), and treatment for HIT including risks and benefits of therapeutic and prophylactic anticoagulation with antithrombins have been defined.1,4 Unfortunately, no such solid information exists for neonatal and pediatric patients undergoing surgery for CHD, and there are multiple reasons to suspect there may be a difference from the adult setting. These include: 1. The sustained and repetitive exposures of neonates and young children with CHD to standard heparin–to maintain catheter patency in

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3.

4.

5.

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ICUs preoperatively and postoperatively, during catheterization and angiography, during CPB, during support with ECMO and VAD, and because of the necessity, in the most severe cases, for multiple surgeries over months or years to repair or palliate defects. The prolonged pump runs and frequent platelet transfusions in neonates and young children (which assure concomitant longer exposure to high heparin doses and activated platelets with PF4 on their surface). The differing immune responsiveness in neonates and young children that may result in different timing and magnitude of the antibody response. The likely different patterns of platelet fall perioperatively and platelet recovery postoperatively in neonates and young children because of greater dilutional effects and differing perturbations in procoagulant and anticoagulant balances due to bypass.55-57 The different and often abnormal blood flow patterns though complex repairs and congenital malformations that may result in different thrombotic localization. Possible different risks and benefits of anticoagulation (especially prophylactic) with DTIs such as argatroban and lepirudin.

In adults with HIT and isolated thrombocytopenia alone, prophylactic anticoagulation with a DTI is recommended to prevent thrombosis. Both argatroban and lepirudin appear effective for this purpose. Efficacy is less once thrombosis is established. Dosage of neither agent has yet to be established in pediatrics. However, baseline bleeding risk in adults appears to be somewhat greater with DTIs than with UFH (probably because DTIs, unlike UFH, inactivate clot-bound thrombin). Also, bleeding risk in young children on heparin appears greater than it is in adults. This suggests caution in anticoagulating young children with DTIs in the face of thrombocytopenia may be warranted in cases where the diagnosis of HIT is not established.

Experience With Laboratory Testing for Heparin-Induced Thrombocytopenia in Congenital Heart Disease Populations PF4 ELISAs. Given their ease of performance, sensitivity, and need for less blood than functional assays, it would be useful if positive

PF4 ELISAs were helpful in predicting or diagnosing HIT in pediatric patients with CHD. As stated previously, the incidence of positive PF4 ELISAs in adults undergoing reoperative cardiac surgery appears to be approximately 50% between POD 5 and 10. Regrettably, an abstract by Mullen et al58 suggests this pattern may also apply in neonates and young children. These investigators looked at 40 neonates (median age, 5 days) and 64 pediatric patients undergoing repeat CPB (reoperations) (median age, 29 months). Patients were tested for HIT antibodies by PF4 ELISA preoperatively and on PODs 5 and 10. All tests were negative preoperatively. On POD 5, one of 40 neonates and 10 of 64 reoperations had detectable antibodies; this was one of 40 neonates and 31 of 64 reoperations at POD 10. Only one case of clinical HIT was seen (in a reoperation patient). Thus, if the results in this abstract are confirmed, the PF4 ELISA would seem to be less than ideal as a prospective screening test for HIT. Functional Assays. Information about functional HIT testing in neonates and young children with CHD is scant and published data is available only in abstract form. We have been using a functional HIT assay at our institution (heparin-dependent platelet aggregation in platelet-rich plasma) that does not use washed platelets. This assay has the virtue of being less technically demanding than washed platelet assays and more specific for HIT than the PF4 ELISAs, although it is less sensitive than either of these. Disturbingly, we have noted that our assay has been negative early in the course of HIT in two cases (Fig 3). Both of these patients subsequently developed thrombotic sequelae, which might have been prevented had prophylactic anticoagulation with argatroban been begun. We are currently implementing a washed platelet assay and a PF4 ELISA to attempt to improve assay sensitivity and specificity. Etches et al59 used a washed platelet assay to prospectively investigate the incidence of HIT in a pediatric ICU population. Three of 233 patients had a positive HIT assay on samples obtained between day 10 and 21 of ICU admission; day-0 assays were negative in all three patients. All three patients were post-cardiovascular surgery and had received prior heparin exposure. None had a platelet fall of more than 50% or evidence

HIT in Pediatric Cardiac Surgery

of clinical thrombosis. Five additional cardiovascular surgery patients had equivocal results on HIT assay. Of these, one out of five had a platelet fall of more than 50% and a thrombotic event. This study suggests the incidence of HIT in pediatric ICU patients is low, that the thrombocytopenia associated with cardiovascular surgery appears to be multifactorial, and that interpretation of a positive-function HIT assay in this patient group may be difficult.

Reported Treatments of HeparinInduced Thrombocytopenia in Neonates and Young Children No alternative anticoagulant used in adult HIT is currently approved for pediatric use anywhere. Anecdotal reports of alternative anticoagulants used in the treatment of HIT in pediatric patients include use of danaparoid sodium,21,22,60 hirudin and lepirudin, and argatroban. Most patients in the reports by Ranze et al22 and Severin and Sutor21 were treated with danaparoid or hirudin. There have also been anecdotal reports in the literature using danaparoid for CPB in a Fontan patient61 and for hemodialysis.62 More detailed experience regarding our recent use of argatroban to treat HIT in neonates and young children is given below.26

Treatment Considerations At our institution, the DTI argatroban is the agent normally used to treat adult HIT. Neither argatroban nor any other alternative anticoagulant reported as having been used successfully in adult HIT (lepirudin, danaparoid sodium, bivalirudin, fondaparinux) is currently approved for pediatric use anywhere in the world. Furthermore, experience with heparin and other drugs indicates that dosing may be different in neonates and young children because of the different kinetics of drug clearance and altered volume of distribution of drugs in neonates and young children. Because of our recognition of HIT in neonates and young children with CHD at our institution, and of the serious thrombotic sequelae that appear to accompany it, we have begun using argatroban in these patients both in acute HIT and for subsequent therapeutic procedures in patients with previous HIT. Our experience with argatroban in this patient group is summarized in Table 3. Our experience with argatroban suggests:

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1. Argatroban anticoagulation can be used successfully in neonatal/pediatric patients with HIT or previous HIT: ● For prophylaxis or treatment of thrombosis ● During procedures: catheterization, VAD, ECMO, CPB, and hemodialysis ● Following and concurrent with tissue-type plasminogen activator administration (as with heparin, argatroban dose is halved if given concurrently with tissue-type plasminogen activator administration and plasma transfused to supply plasminogen). 2. We believe, as in the adult situation, argatroban given early in HIT will prevent new thrombosis or progression of thrombosis; it appears to be less effective at reversing established catastrophic thrombosis. 3. The risk/benefit of prophylactically anticoagulating neonates and young children with argatroban in the face of isolated thrombocytopenia and proven HIT appears to favor anticoagulation to prevent thrombosis. 4. Activated clotting times, APTTs and plasma argatroban levels usually moved in concert in neonates and young children on argatroban (data not shown) consistent with a largely predictable pharmacokinetic profile. Significant bleeding occurred only with concomitant tissue-type plasminogen activator use or with major overanticoagulation and was successfully treated in the latter instance with transfusion and administration of recombinant Factor VIIa (case C7, Table 3). 5. Impressive variation in argatroban requirements (10- to 30-fold) were noted in the same patient at different times in their hospital course (cases C4 and C7, Table 3). These appeared to parallel clinical status (lower doses when “sicker”) and did not appear to correlate in any simple fashion with liver enzymes. Overall, however, our experience suggests neonates and young children may require greater infusion doses than adults. 6. Transitioning of young children with HIT (who require longer-term anticoagulation) to warfarin can be challenging because warfarin dosing is difficult to control in this age group. We have had anecdotal success transitioning one patient (C10) to subcutaneous fondaparinux at 0.15 mg/kg. To confirm therapeutic levels we measured these but this involved

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Table 3. Argatroban Dosing in our Neonates and Young Children With Heparin-Induced Thrombocytopenia: Prophylactic and Therapeutic Infusions, Cardiac Catheterization, Extracorporeal Membrane Oxygenation, Cardiopulmonary Bypass, and Hemodialysis Patient (From/ Table 1) (age) C2 (22 mo) C3 (5 mo)

C4 (1-3 wk)

C5 (8 mo)

C6 (7 wk) C7 (9-10 mo)

Use of Argatroban

Target PTT/ACT

Cath*

NA/300

Cath

NA/300

Duration of Therapy and Dose of Argatroban Bolus 250 ␮g/kg then 15 ␮g/kg/min Bolus 250 ␮g/kg then 15 ␮g/kg/min 26 h: 7.5-10 ␮g/kg/min

Infusion— dose finding† Infusion— therapeutic ECMO ⫹/⫺ oxygenator

65-100/160-200

Above ⫹ tPA (0.2 mg/ kg/hr) Cath

NA/200

12 h (during tPA infusion): 0.3-0.4 ␮g/kg/min

NA/300

Bolus 150 ␮g/kg then 10 ␮g/kg/min 7d: Bolus 150 ␮g/kg then 5 ␮g/kg/min 5d: Bolus 75 ␮g/kg then 3 ␮g/kg/min 2d: Bolus 200 ␮g/kg then 7.5 ␮g/kg/min

60-80/NA NA/200

Infusion— 60-90/200 therapeutic Infusion— 60-80/NA prophylactic Infusion— 70-100/NA therapeutic pre-op CPB NA/400-500

Infusion— post-op

C8 (5 yr)

Cath

C9 (3 yr)

Infusion— therapeutic post-tPA clot lysis Hemodialysis

C10 (3-4 mo)

Infusion— therapeutic

70-100/NA

NA/300

4d: Bolus 200 ␮g/kg/min then 7.5 ␮g/kg/min 13d: 50 ␮g in circuit prime then 0.15-1.8 ␮g/kg/min

NA NA

Requirements stable

⬃400-600 ⬃400-600 ⬃400-600 NA ⬃250-2,900 ⬃350-800 NA

NA

20d: 1.1-10 ␮g/kg/min then 41d (rethrombosis): 6.7-12 ␮g/kg/min

NA

Bolus 150 ␮g/kg then 5 ␮g/ kg/min

NA

15d: 0.3-2.0 ␮g/kg/min

65-75/180-200

Bolus 65 ␮g/kg then infusion 0.5 ␮g/kg/min during dialysis 14d: 4.0-7.0 ␮g/kg/min

Dose Adjustment/Comments 3 h cath: required 2 to 7.5 ␮g/kg/min None

NA

Bolus 100 ␮g/kg then 10 ␮g/kg/min 3 stepwise 1 buoluses/infusion rates to 65 ␮g/kg/min

65-85/180-210

70-100/NA

Argatroban Level (ng/ mL)

⬃200-1,800

⬃280-600 Pending

Infusion 2 3.0-4.0 ␮g/ kg/min Lower doses when “sicker” and cardiac function 2 Argatroban dose halved during tPA infusion None Infusion 2 2.0-3.5 ␮g/ kg/min Infusion 2 1.2-1.6 ␮g/ kg/min Infusion 2 5.4 ␮g/kg/min ACT intra-op ⬎ 999 3 major bleeding 3 red cells, plasma, platelets and 2 doses rFVIIa (90 ⫹ 120 ␮g/kg) Lower doses when “sicker” and cardiac function 2; Converted to warfarin In shock so starting dose 2; infusion 1 7.5-10 ␮g/kg/min Lower doses when “sicker” and cardiac function 2 R hepatic infarct: initial dose 2 (25%); infusion 1 1.0 ␮g/kg/min Converted to fondaparinux

Abbreviations: Cath, cardiac catheterizatio, CPB, cardiopulmonary bypass, ECMO, extracorporeal membrane oxygenation, NA, not applicable/not available, tPA, tissue plasminogen activator. *Comparable to adult cath dose. †Usual adult infusion rate (PTT 1.5-3 ⫻ normal) ⫽ 2 ␮g/kg/min

generation of a fondaparinux curve (standard low-molecular-weight heparin curves cannot be used). This is not readily performed in the routine clinical laboratory.

A clinical trial is currently being planned to determine pharmacokinetics and response to argatroban in pediatric patients (including neonates and young children) with HIT and with

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other disorders that make heparin use problematic (antithrombin deficiency). This trial is being conducted under the auspices of GlaxoSmith Kline (protocol 105043/013). Thirteen centers have been selected for participation. Argatroban anticoagulation will be used as seen fit by participating investigators in a variety of clinical contexts including prophylactic and therapeutic infusions, extracorporeal circuits (CPB, ECMO, VAD, and hemodialysis), and for procedures (catheterization). Suggested dosing is indicated in the study protocols. The first Investigator’s Meeting was held in early 2004, with the study anticipated to be recruiting patients by late spring or early summer of 2004.

Summary and Directions for Future Studies There is much that needs to be delineated regarding HIT in the CHD population. 1. What is the incidence of HIT in the CHD population? Thrombosis in pediatric cardiac patients is frequent,63 and heparin-attributable thromboses will need to be identified. 2. What is the incidence of thrombotic morbidity and mortality and what form does this morbidity take? 3. Are there any identifiable predispositions to HIT in CHD patients (specific abnormalities, surgical types, duration and intensity of heparin exposure, duration of deep hypothermic circulatory arrest, use of VAD or ECMO, platelet transfusion, initial operation v reoperation) more likely to be associated with development of HIT? 4. Can the “4 Ts” clinical scoring system used in adult HIT patients be applied to diagnosis of HIT in the CHD population or are modifications warranted? 5. What are the sensitivity and specificity of the PF4 ELISA and a washed functional platelet assay alone and in combination in diagnosing HIT in suspected cases and in predicting the development of HIT prospectively? 6. What is the risk/benefit of anticoagulation in HIT in neonates and young children and what doses of available alternative anticoagulants (argatroban, lepirudin, or others) are optimal for prophylaxis, therapy, and procedures (catheterization, ECMO/VAD, CPB, hemodialysis).

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A multi-institution HIT registry is desirable and is currently planned. In addition, a pediatric argatroban trial is in the early inception stages as indicated.

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