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Aug 18, 2011 - Fondaparinux in acute heparin-induced thrombocytopenia: a case series. .... fondaparinux (paralleling the American College of Chest.
Journal of Thrombosis and Haemostasis, 9: 2389–2396

DOI: 10.1111/j.1538-7836.2011.04487.x

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Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series T. E. WARKENTIN,*  M. PAI,  J. I. SHEPPARD,* S. SCHULMAN,  A. C. SPYROPOULOS  and J . W . E I K E L B O O M   *Departments of Pathology and Molecular Medicine; and  Medicine, McMaster University, Hamilton, ON, Canada

To cite this article: Warkentin TE, Pai M, Sheppard JI, Schulman S, Spyropoulos AC, Eikelboom JW. Fondaparinux treatment of acute heparininduced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost 2011; 9: 2389–96. See also Greinacher A. Immunogenic but effective: the HIT-fondaparinux brain puzzler. This issue, pp 2386–8; Goldfarb MJ, Blostein MD. Fondaparinux in acute heparin-induced thrombocytopenia: a case series. This issue, pp 2501–3.

Summary. Background: Fondaparinux is theoretically an attractive agent for the treatment of immune heparin-induced thrombocytopenia (HIT), a prothrombotic disorder caused by platelet-activating anti-platelet factor 4/heparin antibodies. Although reports of the use of fondaparinux for this indication have thus far been favorable, the diagnosis of HIT in most cases was not based on definitive laboratory confirmation of heparindependent, platelet-activating antibodies. Objectives: To report thrombotic and major bleeding outcomes with fondaparinux in patients with a high likelihood of having acute HIT based on clinical features and a positive result in the confirmatory platelet serotonin-release assay (SRA), a sensitive and specific test for platelet-activating HIT antibodies. Methods/Patients: We reviewed consecutive eligible patients with SRA-positive HIT (mean peak serotonin release, 91% [normal, < 20%]; mean IgG-specific PF4/heparin enzyme immunoassay result, 2.53 optical density units [normal, < 0.45 units]) in one medical center over a 30-month period who received fondaparinux for anticoagulation during acute HIT (platelet count, < 150 · 109 L)1). Where available, plasma samples were used to measure thrombin–antithrombin (TAT) complex levels. Results: Sixteen patients with SRA-positive HIT received fondaparinux: 14 surgical (11 after cardiac surgery; three after vascular surgery) and two medical (acute stroke). Fifty-six per cent of patients had HIT-associated thrombosis at the time of diagnosis. No patient developed new, recurrent or progresCorrespondence: Theodore E. Warkentin, Room 1-270B, Hamilton Health Sciences, General Site, 237 Barton St East, Hamilton, ON L8L 2X2, Canada. Tel.: +1 905 527 0271 (ext. 46139); fax: +1 905 577 1421. E-mail: [email protected] T.E.W. and M.P. are co-first authors, and contributed equally to this report. Received 9 June 2011, accepted 18 August 2011  2011 International Society on Thrombosis and Haemostasis

sive thrombosis; one patient developed a major bleed (calf hematoma). One patient judged to have irreversible tissue necrosis before receiving fondaparinux therapy ultimately required limb amputation. TAT complex levels were reduced within 24 h of starting fondaparinux, and 13 of 13 patients were successfully switched to warfarin. Conclusion: Fondaparinux shows promise for the treatment of patients with SRA-positive acute HIT. Keywords: fondaparinux, heparin-induced thrombocytopenia, serotonin-release assay, thrombosis. Introduction Immune heparin-induced thrombocytopenia (HIT) is a highly prothrombotic adverse effect of heparin, with both the unfractionated and (less commonly) low molecular weight forms [1,2]. HIT is caused by platelet-activating antibodies that recognize multimolecular complexes of platelet factor 4 (PF4) bound to heparin [3,4]. Management of HIT generally includes anticoagulation with a rapidly acting non-heparin anticoagulant, both to treat HIT-associated thrombosis (identified in approximately 50% of patients at the time of diagnosis [5]) and to prevent new, progressive or recurrent thrombosis [6]. Three anticoagulants are approved for the treatment of HIT in numerous jurisdictions: danaparoid, lepirudin, and argatroban [6]. Danaparoid, which is not approved for the treatment of HIT in the USA, is a long-acting mixture of anticoagulant glycosaminoglycans with predominant anti-factor Xa activity [7]. In contrast, lepirudin and argatroban are direct (i.e. antithrombin-independent) thrombin inhibitors (DTIs) with a short half-life. In our center (Hamilton General Hospital), danaparoid has been used to treat HIT for over 15 years, with good results [8]. However, in February 2009, a worldwide shortage of danaparoid led to 2 years of unavailability in Canada.

2390 T. E. Warkentin et al

Fondaparinux (Arixtra), a synthetic antithrombin-binding pentasaccharide approved for the prophylaxis and treatment of venous thromboembolism, resembles danaparoid in several important respects: both agents are relatively long-acting (antiFXa activity half-lives: danaparoid, 25 h; fondaparinux, 17 h); both target FXa, either predominantly (danaparoid) or exclusively (fondaparinux); and both have low (danaparoid) or negligible (fondaparinux) cross-reactivity with HIT antibodies [9–11]. Moreover, the results of preliminary experience with fondaparinux for putative HIT appear to be favorable (for review, see [12]), although most cases of HIT in the published case series (‡ 5 patients per report) were not confirmed by demonstration of the presence of pathogenic platelet-activating antibodies [13–16]. On the basis of these considerations, we began to use fondaparinux to treat patients with HIT when danaparoid became unavailable. We now report our experience with fondaparinux in 16 patients with HIT confirmed by a positive result for platelet-activating antibodies with the platelet serotonin-release assay (SRA). Methods We reviewed laboratory records to identify all patients diagnosed with HIT at the Hamilton General Hospital who had a positive SRA result from February 2009 to July 2011. (This hospital provides regional cardiac and vascular surgery, and has trauma, general medicine and general surgery services.) To ensure that we only included patients with a high likelihood of having HIT, eligible patients had to have both: (i) a 4Ts score of ‡ 4 points (i.e. intermediate or high pretest probability for HIT) [17]; and (ii) a positive SRA result (‡ 20% serotonin release at 0.1–0.3 U mL)1 heparin), and with all control maneuvers – e.g. inhibition at 100 U mL)1 and in the presence of Fc receptorblocking mAb – giving the expected reactions [18]). All patients also had a positive Ôin-houseÕ IgG-specific PF4/heparin enzymeimmunoassay (EIA-IgG) result (normal, < 0.45 units) [19], an expected finding because  99% of patients with SRA-positive HIT have a positive EIA-IgG result [20]. We excluded one patient with a remote history of HIT who developed recurrent HIT following heparin exposure during cardiopulmonary bypass while receiving postoperative lowdose fondaparinux thromboprophylaxis. (This atypical patient will be fully described in a separate report dealing with repeat heparin exposure in patients with previous HIT.) During the study period, only two other patients with SRA-positive HIT diagnosed at our hospital were not treated with fondaparinux (one received argatroban, and the other danaparoid after this anticoagulant became available again in 2011). Thus, our report describes a near-consecutive experience of management of serologically confirmed HIT over 30 months. Nine of the 16 patients underwent serial anticoagulant monitoring for anti-FXa levels, performed with the STA Rotochrom Heparin kit (Diagnostica Stago, Asnie`res-surSeine, France) on the STA-R (Diagnostica Stago), using Arixtra calibrator and control plasmas (HYPHEN BioMed, Neuville-sur-Oise, France); the assay is linear up to

1.3 U mL)1 anti-FXa for fondaparinux. Five patients underwent at least three measurements of in vivo thrombin generation with the Enzygnost thrombin–antithrombin (TAT) ELISA assay (Siemens Healthcare, Marburg, Germany). A paired-samples t-test was conducted to compare TAT complex levels at baseline and 24 h. In general, patients received standard therapeutic dosing for fondaparinux (paralleling the American College of Chest Physicians [ACCP] recommendations for using therapeuticdose danaparoid in HIT [6]), i.e. 7.5 mg once daily by subcutaneous injection (5.0 mg for patients weighing < 50 kg, and 10.0 mg for patients weighing > 100 kg). Some patients were treated with modified fondaparinux dosing based on the results of anti-FXa monitoring (e.g. in the setting of renal insufficiency). HIT is usually diagnosed at our center on the basis of platelet count results received during mid-morning, so the initial fondaparinux dose was usually given in the afternoon. However, the second and subsequent doses of fondaparinux were usually given at 08:00 hours each morning. Thus, the first two doses were often given only 14–20 h apart. The following data were abstracted from medical records: age and sex; body weight; initial indication for heparin; concomitant illnesses; and estimated creatinine clearance (Cockcroft–Gault formula). We recorded the clinical presentation of HIT (Ôtypical onsetÕ, i.e. platelet decrease 5–10 days after the beginning of the immunizing heparin exposure vs. Ôrapid-onsetÕ, i.e. abrupt platelet count drop upon beginning heparin in a patient exposed to heparin within the previous 5– 100 days); the day of onset; the HIT-associated platelet count nadir; the percentage platelet count decline from the peak immediately preceding the onset of HIT; the SRA results (maximum percentage serotonin release at 0.1–0.3 U mL)1 heparin); the optical density (OD) in the EIA-IgG; the 4Ts score; overt disseminated intravascular coagulation (DIC); and all HIT-associated thromboses that occurred prior to the recognition of HIT and initiation of therapy. We defined overt DIC as a strongly positive (‡ 2+) protamine sulfate paracoagulation test result plus at least one otherwise unexplained abnormal coagulation assay result (e.g. elevated international normalized ratio [INR] and reduced fibrinogen). We defined HIT-associated thrombosis as any thrombosis that occurred ‡ 5 days following initiation of the heparin that triggered the episode of HIT. A thrombotic event that led to heparin therapy was not classified as HIT-associated thrombosis (e.g. patients presenting with thrombotic stroke, for which they received heparin). All thrombotic events required objective confirmation by duplex ultrasound for deep vein thrombosis or computed tomography angiography for pulmonary embolism. As per the ACCP guidelines [6], most patients had a duplex ultrasound scan performed at or soon after the diagnosis of HIT. We defined major bleeding as per the Scientific and Standardization Committee of the ISTH [21]. All patients were followed for the duration of their index hospitalization at the Hamilton General Hospital, and for at least 30 days following the diagnosis of HIT. We also evaluated the days of  2011 International Society on Thrombosis and Haemostasis

Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay 2391

fondaparinux–warfarin overlap required to achieve a therapeutic INR (target: 2.0–3.0) and the proportion of patients with a therapeutic INR on the day following fondaparinux cessation. To reduce bias, we reviewed the medical records for all SRApositive patients at the Hamilton General Hospital, obtained from the central laboratory records. To ensure accuracy, all records were reviewed independently by two investigators (T.E.W. and M.P.), with disagreements being resolved by consensus. Data were subsequently reviewed by three other physicians (S.S., A.C.S., and J.W.E.) who had managed the patients clinically. Approval to perform this study and to report the results was obtained from the McMaster University Research Ethics Board. Blood samples for measurement of TAT complexes were obtained from subsamples collected for anti-FXa monitoring. Results Sixteen patients met the studyÕs inclusion criteria. Table 1 shows age, sex, clinical setting, indication for heparin, estimated creatinine clearance, and comorbidities. All but two of the patients had undergone either cardiac surgery (n = 11) or vascular surgery (n = 3). Both medical patients received unfractionated heparin because of acute stroke (one patient had atrial fibrillation). Most of the patients had several comorbidities. Two patients (nos. 4 and 12) had severe renal dysfunction at the time of initiation of fondaparinux (estimated creatinine clearance, < 30 mL min)1). There was no loss to

follow-up of patients in this study, and there were no missing data. One patient (no. 9) was recently reported as a case of acute systemic (anaphylactoid) reaction following administration of low molecular weight heparin [22]. Table 2 summarizes the clinical presentation and timing of onset of HIT, the severity and pattern of HIT-associated thrombocytopenia, HIT-associated thrombotic events, and the 4Ts score. The clinical and serologic profiles of all included patients strongly supported a diagnosis of HIT: the median 4Ts score was 7 (range, 5–8), and nine (56%) of the 16 patients had one or more thrombotic events at the time of diagnosis of HIT. The mean peak percentage serotonin release was 91% (median, 96%; range, 68–100%), and the mean strength in the EIA-IgG was 2.53 OD units (range, 1.62–3.03). Table 3 shows information on: fondaparinux use; concomitant acetylsalicylic acid, clopidogrel and warfarin use; and outcomes (thrombosis and major bleeding). None of the 16 patients developed new, progressive or recurrent thrombosis. Platelet count recovery (to > 150 · 109 L)1) after starting fondaparinux occurred at a median of 4 days (range, 1– 15 days). Patient 6 developed a major bleed. This patient presented with acute limb ischemia almost 4 weeks after vascular surgery to place a left-sided saphenous vein graft, which extended below the knee; he developed rapid-onset HIT when heparin was given to help manage the graft thrombosis. Eight days after the initiation of fondaparinux, he was taken to the operating room for exploration of the graft site, which was thought to be infected. When the vascular surgeons explored the distal portion of the incision, they found a large limb-

Table 1 Patients with acute heparin-induced thrombocytopenia who received fondaparinux: demographic and other parameters Patient no.

Age (years)

Sex

Clinical setting

Indication for heparin

Estimated CrCl (mL min)1)

1 2 3

60 53 62

M F F

Cardiac surgery* Cardiac surgery* Cardiac surgery

CPB; prophylaxis CPB; prophylaxis CPB; prophylaxis

114 152 148

4

80

F

Cardiac surgery

CPB; prophylaxis

24

5

81

F

Vascular surgery

EVS; prophylaxis

57

6 7 8 9 10 11

75 80 57 68 81 62

M M M M F M

Vascular surgery Cardiac surgery Cardiac surgery Cardiac surgery Cardiac surgery Cardiac surgery

EVS; prophylaxis CPB; prophylaxis CPB; prophylaxis CPB; prophylaxis CPB; prophylaxis CPB; prophylaxis

54 56 95 82 46 125

12 13 14 15

85 58 64 62

F F F M

Thrombotic stroke Cardiac surgery* Thrombotic stroke Vascular surgery

28 124 87 69

16

73

M

Cardiac surgery

Acute CVA with AF CPB; prophylaxis VTE prophylaxis Open repair of ruptured AAA; prophylaxis CPB; prophylaxis

VHD, CAD, HTN, CHF VHD, dyslipidemia, treated hypothyroidism CAD, HTN, dyslipidemia, DM2, prior VTE, prior MI, acute postoperative AF CAD, HTN, dyslipidemia, prior MI, CHF, treated hypothyroidism PVD, AAA, HTN, DM2, prior CVA, metastatic colon CA PVD, AAA, HTN VHD, AF CAD, prior MI, prostate CA VHD VHD, HTN, postoperative AF CAD, HTN, dyslipidemia, myasthenia gravis HTN, DM2, dyslipidemia, AF VHD, DM2, HTN, dyslipidemia HTN AAA (acutely ruptured)

60

CAD, HTN, DM2, dyslipidemia

Comorbidities

AAA, abdominal aortic aneurysm; AF, atrial fibrillation; CA, carcinoma; CAD, coronary artery disease; CHF, congestive heart failure; CPB, cardiopulmonary bypass; CrCl, creatinine clearance; CVA, cerebrovascular accident; DM2, diabetes mellitus type 2; EVS, endovascular surgery; F, female; HTN, hypertension; M, male; MI, myocardial infarction; PVD, peripheral vascular disease; VHD, valvular heart disease; VTE, venous thromboembolism. *Surgery included placement of a mechanical aortic valve.  2011 International Society on Thrombosis and Haemostasis

2392 T. E. Warkentin et al Table 2 Clinical and serologic data supportive of a diagnosis of acute HIT Patient HIT no. profile

Day of onset

Platelet count Peak % EIA-IgG OD HIT-associated Platelet count serotonin release units thrombosis nadir (·109 L)1) decline (%)

4Ts score

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

8 7 9 5 10 26  14  6 66  5 26  5–10à 6 5–9à 9 5–9à Typical, day 7§ Rapid, day 33§

69 121 169 79 91 112 78 117 76 28 82 42 22 76 98 10 79§

8 6 8 5 5 8 7 5 7 6 8 8 6 8 7 5 7–

Typical Typical Typical Typical Typical Rapid Rapid Typical Rapid Typical Rapid Typical Typical Typical Typical Typical Typical = 12 Rapid = 4

74 65 66 44 47 75 60 31 58 79 74 82 89 58 55 95 66§

82 93 68 92 97 96 100 97 97 99 77 100 96 98 82 86 91§

2.40 2.82 1.62 3.03 2.60 2.86 2.51 2.70 2.82 2.46 2.23 2.76 2.09 2.47 2.52 2.60 2.53§

Bilateral DVT; DIC Nil* CVA (left MCA) Nil* Nil Arterial graft occlusion Radial artery thrombosis Nil* PE; DVT; ASR Nil* PE; DVT Bilateral DVT; DIC Nil* DVT DVT; PE Nil*; DIC Venous: 6/16 (38%) Arterial: 3/16 (19%)

ASR, acute systemic (anaphylactoid) reaction; CVA, cerebrovascular accident; DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis; EIA-IgG, IgG-specific PF4/heparin enzyme immunoassay; MCA, middle cerebral artery; OD, optical density; PE, pulmonary embolism.*Patients 2, 4, 8, 10, 13 and 16 had negative duplex ultrasound results for lower-limb DVT at the time of diagnosis of HIT.  Rapid-onset thrombocytopenia: the fall in platelets began within 24 h of resumption of heparin; the day shown is the day of repeat heparin exposure (in relation to the day of immunizing heparin exposure, day 0). àDay of onset of thrombocytopenia is expressed as a range of days, because the lack of platelet count monitoring precluded assignment of a precise day of onset. §Mean value. –Median value.

Table 3 Fondaparinux and concomitant treatments and outcomes Patient no.

Daily dose of fondaparinux (mg)

Days given

Anti-factor Xa monitoring

Antiplatelet therapy

Warfarin overlap

Thrombotic Event

Major bleeding event

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

15*  10  10  5à 7.5 7.5 7.5 2.5 7.5 7.5 10  See Fig. 2 15   10 7.5àà 7.5§§ 7.5 (median)

10 8 8 9 > 35§ 5 13 5 2 12 4 12 13 9 22 35 10 (median)

No No No Yes Yes Yes No No No Yes Yes Yes Yes No Yes Yes 9/16 (56%)

ASA ASA ASA ASA ASA, clopidrogel ASA – ASA – – ASA ASA ASA ASA – – 11/16 (69%)

Yes Yes Yes No No§ Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No 13/16 (81%)

No No No No No No No** No No No No No No No No No 0/16 (0%)

No No No No No Yes– No No No No No No No No No No 1/16 (6%)

ASA, acetylsalicylic acid. *This 103-kg patient was given 7.5 mg twice daily, because the patient had a mechanical aortic valve, and because the clinician was concerned that heparin-induced thrombocytopenia (HIT)-associated bilateral deep vein thrombosis might require higher than usual dosing. This patient also had features of HIT-associated disseminated intravascular coagulation: the International Normalized Ratio (INR) was 1.6 (normal, 0.8–1.2), the fibrinogen level was 2.3 g L)1 (normal, 1.6–4.2 g L)1), and protamine sulfate paracoagulation test result was 4+ (normal, negative); after 3 days of fondaparinux, these values normalized or improved (INR, 1.2; fibrinogen, 4.6 g L)1; protamine sulfate test, negative).  Patient weight > 100 kg. à5 mg once-daily as initial dose, with subsequent adjustments made by using anti-FXa monitoring. §After 7.5 mg for 4 days, low-dose fondaparinux (2.5 mg daily) rather than warfarin was given for long-term thromboprophylaxis (metastatic cancer). –Bleeding manifesting as calf hematoma. **Amputation because of ischemic limb necrosis established prior to initiation of fondaparinux.   This 95-kg patient was given fondaparinux 7.5 mg twice daily for 2 days, followed by 10 mg daily because of a mechanical aortic valve. àà12.5 mg once as initial dose, followed by 7.5 mg daily with anti-FXa monitoring. §§Initial dose 7.5 mg, followed by 5 mg for 4 days; because of subtherapeutic antiFXa levels (0.63 U mL)1), the dose was then increased to 7.5 mg daily. After a 21-day course of therapeutic-dose fondaparinux, the patient received an additional 14 days of low-dose fondaparinux (2.5 mg daily).  2011 International Society on Thrombosis and Haemostasis

Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay 2393

threatening calf hematoma that had caused local muscle necrosis. Patient 7 required amputation for a gangrenous right upper limb that preceded initiation of fondaparinux. All of the patients were alive at 30-day follow-up. Thirteen patients underwent fondaparinux–warfarin overlap. The median platelet count at initiation of warfarin therapy was 188 · 109 L)1 (range, 88–784 L)1). A median of 5 days was required to achieve a target INR of 2.0–3.0; for all patients who achieved a therapeutic INR during overlap, the INR remained in the target range on the day following cessation of fondaparinux. Figure 1 shows TAT complex levels measured before and after initiation of fondaparinux. There was a strong, but nonstatistically significant, trend for decreased TAT complex levels (mean ± standard deviation) from baseline to 24 h (from 32.5 ± 31.2 to 10.4 ± 9.9 lg L)1; P = 0.063). For comparison, published historical data [23] for TAT complex levels in SRA-positive HIT patients treated with danaparoid or with ancrod are shown. Figure 2 shows serial anti-FXa levels in patient 12, whose estimated creatinine clearance was low at initiation of fondaparinux therapy (28 mL min)1). The initial dose of fondaparinux was 7.5 mg, and this was followed by 5 mg daily (initially as 2.5 mg twice daily, and later as 5 mg once daily). However, on the basis of declining anti-FXa levels and improving serum creatinine, subsequent dosing was increased to 7.5 mg daily. Discussion We successfully used fondaparinux to treat 16 patients who had strong clinical and laboratory evidence of HIT. First, the patients had a clinical profile consistent with HIT, as judged by the 4Ts scoring system (median score, 7; range 5–8). Second, the patients tested positive in both the SRA and EIAIgG, with strongly positive results being seen in both assays. Third, 56% of the patients had thrombosis at the time of diagnosis of HIT; this is consistent with previous studies of

Thrombin–antithrombin complex (µg L–1)

150

100

50

0

Day –1.87

Ancord

Upper normal Danaparoid limit 0

1 2 3 Time (days) after starting fondaparinux

4

Fig. 1. Thrombin–antithrombin complex levels before and after initiation of fondaparinux. The data points are shown in five different colors, corresponding to patients as follows: red, no. 12; orange, no. 4; brown, no. 5; green, no. 10; and blue, no. 3). Also shown are previously published [23] composite data for 16 patients treated with danaparoid (open circles) and 11 patients treated with ancrod (closed circles).  2011 International Society on Thrombosis and Haemostasis

SRA-positive HIT, in which approximately half of the patients have HIT-associated thrombosis [5], and the remaining half have Ôisolated HITÕ. All 16 patients showed platelet count recovery during fondaparinux treatment without developing new, recurrent or progressive thrombosis. Only one patient developed a major bleed; despite having acceptable creatinine clearance when fondaparinux was started (54 mL min)1), this patient had a decreased estimated creatinine clearance of 26 mL min)1 on the day before his hematoma (based on an increase in serum creatinine from 106 to 225 lM). Unfortunately, no determinations of anti-FXa levels were performed at this time. It is possible that there was fondaparinux bioaccumulation in this patient, leading to supratherapeutic levels and increased bleeding risk. Thirteen of the 16 patients were switched uneventfully to warfarin therapy. Patients 4 and 16, who did not have thrombosis, had fondaparinux discontinued (without transition to warfarin) after receiving 9 days and 35 days of fondaparinux, respectively. Patient 5, who had metastatic cancer, was continued on fondaparinux at discharge rather than being switched to warfarin. Fondaparinux does not increase INR values; thus, it is easier to replace with warfarin than, for example, argatroban, which markedly increases INR values and often requires temporary cessation to ascertain whether the patient is therapeutically anticoagulated on warfarin [24]. We are aware of four previously reported case series [13–16] involving a total of 47 patients with putative HIT who received fondaparinux. Almost all tested positive for HIT in a PF4dependent EIA, but only one patient (not tested with an EIA) was reported as being SRA-positive. Given that  50% of patients with suspected HIT who are EIA-positive have a negative SRA result [20], it is possible that some (and perhaps many) of these 47 patients did not have ÔtrueÕ HIT. None of these 47 patients reported in the previous studies developed a new thrombotic event after initiation of fondaparinux therapy. Our study provides further evidence, based on well-characterized patients, that fondaparinux can be successfully used to treat patients with SRA-positive HIT, including those with thrombotic complications. The rate of limb necrosis requiring amputation in studies involving the use of fondaparinux compares favorably with historical data from HIT patients treated with a DTI. Two of the 47 patients reported in the previous fondaparinux studies experienced limb loss [13–16], yielding a pooled rate (including our series) of limb loss of 3/63 (4.8%), which is similar to or lower than those reported in prospective cohort studies on lepirudin and argatroban in patients with HIT (6% and 14%, respectively) [6]. The occurrence of limb loss despite the use of an antithrombotic therapy that is otherwise effective in the management of HIT indicates that anticoagulant treatment may not alter the natural history of severe HIT-associated limb ischemia, in the same way that an effective anticoagulant commenced after a patient develops a thrombotic stroke may not prevent persisting neurologic deficits.

2394 T. E. Warkentin et al Fondaparinux doses (mg) 7.5 175 125

300

5.0

2.5

7.5

161 1.75

Creatinine (µmol L–1)

75

1.25

Anti-FXa (U mL–1)

25

Platelet count (× 109 L–1)

2.5

0.75 0.49 0.25

232 (pre-HIT peak platelet count) 200

100

85F Admitted 2 Nov. 2010, with: acute thrombotic stroke atrial fibrillation

Bilateral DVT

Platelet count nadir 42 Dalteparin 5000 U × 2 doses 0

UFH 5000 U twice daily s.c.

0

2

Warfarin Fondaparinux (see top of figure and also figure legend for details)

4 10 12 14 16 18 Days after starting immunizing heparin

20

22

24

Fig. 2. Dosing adjustments based on factor Xa measurements. An 85-year-old woman admitted with acute thrombotic stroke and atrial fibrillation received unfractionated heparin (UFH) for 10 days followed by dalteparin for 2 days. On day 12, heparin-induced thrombocytopenia (HIT) was suspected because of a platelet count decline to 42 · 109 L)1; dalteparin was replaced with fondaparinux. Duplex ultrasound showed bilateral lower-limb deep vein thrombosis (DVT). At this time, the serum creatinine had risen to 161 lM; on the basis of a body weight of 77 kg, the estimated creatinine clearance was only 28 mL min)1. Therefore, after an initial dose of 7.5 mg of fondaparinux, subsequent dosing was only 5 mg daily (initially as 2.5 mg twice daily, and then as 5 mg once daily). On day 17, however, the trough anti-FXa level declined to 0.49 U mL)1 (target, 0.7–1.0 U mL)1 anti-FXa), and the serum creatinine declined to 100 lM. Therefore, later on day 17, an additional dose of 2.5 mg was given to bring that dayÕs total dose to 7.5 mg; subsequently, 7.5 mg was given daily. On day 20, warfarin was commenced; when a therapeutic International Normalized Ratio of 2.3 was achieved (day 23), no subsequent fondaparinux was given. s.c., subcutaneous.

In previous reports on fondaparinux for the treatment of putative HIT, three of 47 patients developed major bleeding. All three had undergone cardiac surgery, were critically ill with severe renal dysfunction, and bled during or after an invasive procedure. The patient in our study who developed major bleeding also had renal dysfunction, so drug accumulation probably contributed to the occurrence of the bleed. The rate of major bleeding observed in our study (6.3%) is similar to that reported in previous fondaparinux studies (6.4%), and is consistent with bleeding rates reported for the use of lepirudin, argatroban and danaparoid in the management of HIT (15.4%, 8.0%, and 3.8%, respectively [6]). Although our TAT complex data are limited, they suggest decreased hemostatic activation within 24 h of starting fondaparinux for the management of HIT (Fig. 1). This mirrors data reported for danaparoid [23] and lepirudin [25], and contrasts with the lack of a decrease in TAT complex levels when HIT patients are treated with warfarin [26] and ancrod [23], therapies that are generally regarded as being ineffective for HIT. The promising results obtained with fondaparinux for the treatment of patients with SRA-positive acute HIT parallel those observed in another Canadian center (Jewish General

Hospital, Montreal), where danaparoid unavailability also prompted fondaparinux use for HIT, beginning in 2009 [27]. These investigators used fondaparinux to treat eight patients judged to have a high likelihood of acute HIT, on the basis of clinical and serologic features. Just as we observed, treatment with fondaparinux was judged to be successful: none of the Montreal patients developed thrombosis, major bleeding, or limb amputation. When the Montreal data are pooled with ours and with those of the previous case series [13–16], it is remarkable that 0/71 (0%; 95% confidence interval [CI] 0– 5.1%) patients with putative HIT developed a new thrombotic event after initiation of fondaparinux to treat acute HIT, 4/71 (5.6%; 95% CI 1.6–13.8%) developed a major bleed, and 3/71 (4.2%; 95% CI 0.9–11.9%) underwent limb amputation. Our study has limitations. First, patients were retrospectively identified, which means that there is a potential for ascertainment bias. However, HIT testing at our center is performed at a central laboratory, so we are confident that we identified all patients with serologically confirmed HIT during the study period. Only one patient who developed SRA-positive HIT at our institution during the study period received a DTI (argatroban), and only one other patient received danaparoid.  2011 International Society on Thrombosis and Haemostasis

Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay 2395

Second, the number of patients included in our study is modest, and thus our results cannot provide definitive evidence of the efficacy and safety of fondaparinux in the management of SRA-positive HIT. Finally, all but two of our patients developed HIT following cardiac or vascular surgery, raising the possibility that our results might not apply to other patient populations. However, we found that fondaparinux was effective in treating a wide spectrum of HIT-associated venous and arterial thrombotic complications, including overt (decompensated) DIC in three patients, which suggests that our results are probably generalizable. Our results support emerging data suggesting that fondaparinux is effective for the management of HIT (with and without associated thrombosis) with an acceptable bleeding rate. Additional advantages of fondaparinux are that it is easy to administer, does not require routine laboratory monitoring (although it can be monitored by determining anti-FXa levels, which may be helpful in patients with renal dysfunction, or when planning invasive procedures), and is relatively inexpensive. Unlike DTIs, fondaparinux does not interfere with the transition to warfarin. However, the long half-life of fondaparinux could be problematic in some clinical settings, e.g. critically ill patients. Perhaps most importantly, fondaparinux is an approved and effective anticoagulant for the prevention and treatment of deep vein thrombosis and pulmonary embolism in patients without HIT. Conversely, lepirudin and argatroban are ÔnicheÕ anticoagulants for HIT management, and are not approved for other indications. A large percentage of patients ( 90%) who undergo serologic investigations for HIT are ultimately shown not to have this diagnosis [20,28]. If clinicians do not have access to a sensitive and specific test for HIT, or need to make treatment decisions before the results of such testing are available, they can be reassured that fondaparinux has proven efficacy and safety in preventing and treating thrombosis in diverse clinical settings. In summary, we report our experience with SRA-positive HIT. The data support the thesis that fondaparinux is likely to be an effective anticoagulant for HIT.

Disclosure of conflict of interests This work was supported by the Heart & Stroke Foundation of Ontario (T. E. Warkentin and J. I. Sheppard: T6950) and a McMaster University Department of Medicine Internal Career Research Award (M. Pai). T. E. Warkentin has received lecture honoraria from GlaxoSmithKline, Pfizer Canada, and SanofiAventis, has provided consulting services to, and/or has received research funding from, Canyon Pharmaceuticals, Gen-Probe GTI Diagnostics, GlaxoSmithKline, and Paringenix, and has provided expert witness testimony relating to heparin-induced thrombocytopenia. S. Schulman reports receiving consulting fees from AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, GlaxoSmithKline, and Sanofi-Aventis, lecture fees from Leo Pharma, Sanofi-Aventis, and Boehringer  2011 International Society on Thrombosis and Haemostasis

Ingelheim, and grant support from Bayer Healthcare. A. C. Spyropoulos has provided consulting services to Astellas, Bristol-Meyers-Squibb, Sanofi-Aventis, Bayer Healthcare, Boehringer-Ingelheim, and Eisai. J. W. Eikelboom has received honoraria and/or research support from Astra-Zeneca, Bayer, Bristol-Myers-Squibb, Boehringer-Ingelheim, Canyon Pharmaceuticals, Eli-Lilly, GlaxoSmithKline, Johnson and Johnson, Merck, Novartis, Pfizer, and Sanofi-Aventis. References 1 Warkentin TE. Drug-induced immune-mediated thrombocytopenia – from purpura to thrombosis. N Engl J Med 2007; 356: 891–3. 2 Gruel Y, Pouplard C, Nguyen P, Borg JY, Derlon A, Juhan-Vague I, Regnault V, Samama M; French Heparin-Induced Thrombocytopenia Study Group. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Br J Haematol 2003; 121: 786–92. 3 Amiral J, Wolf M, Fischer A, Boyer-Neumann C, Vissac A, Meyer D. Pathogenicity of IgA and/or IgM antibodies to heparin–PF4 complexes in patients with heparin-induced thrombocytopenia. Br J Haematol 1996; 92: 954–9. 4 Greinacher A, Po¨tzsch B, Amiral J, Dummel V, Eichner A, MuellerEckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4–heparin complex as the major antigen. Thromb Haemost 1994; 71: 247–51. 5 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101: 502–7. 6 Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133 (Suppl. 2): 340S–80S. 7 Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN; Australian HIT Study Group. Prospective, randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis. A clinical outcome study. Thromb Haemost 2001; 86: 1170–5. 8 Lubenow N, Warkentin TE, Greinacher A, Wessel A, Sloane DA, Krahn EL, Magnani HN. Results of a systematic evaluation of treatment outcomes for heparin-induced thrombocytopenia in patients receiving danaparoid, ancrod, and/or coumarin explain the rapid shift in clinical practice during the 1990s. Thromb Res 2006; 117: 507–15. 9 Chong BH, Magnani HN. Danaparoid for the treatment of heparininduced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-induced Thrombocytopenia, 4th edn. New York: Informa Healthcare USA, Inc., 2007: 319–43. 10 Bradner JE, Eikelboom JW. Emerging anticoagulants and heparininduced thrombocytopenia: indirect and direct factor Xa inhibitors and oral thrombin inhibitors. In: Warkentin TE, Greinacher A, eds. Heparin-induced Thrombocytopenia, 4th edn. New York: Informa Healthcare USA, Inc., 2007: 441–61. 11 Warkentin TE, Davidson BL, Buller HR, Gallus A, Gent M, Lensing AWA, Piovella F, Prins MH, Segers AEM, Kelton JG. Prevalence and risk of pre-existing heparin-induced thrombocytopenia antibodies in patients with acute venous thromboembolism. Chest 2011; 140: 366– 73. 12 Warkentin TE. Fondaparinux: does it cause HIT? can it treat HIT? Exp Rev Hematol 2010; 3: 567–81. 13 Kuo KHM, Kovacs MJ. Successful treatment of heparin induced thrombocytopenia (HIT) with fondaparinux. Thromb Haemost 2005; 93: 999–1000. 14 Lobo B, Finch C, Howard A, Minhas S. Fondaparinux for the treatment of patients with acute heparin-induced thrombocytopenia. Thromb Haemost 2008; 99: 208–14.

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 2011 International Society on Thrombosis and Haemostasis