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Keywords:

  • fondaparinux;
  • heparin-induced thrombocytopenia;
  • serotonin-release assay;
  • thrombosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of conflict of interests
  8. References

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 heparin-dependent, 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 progressive 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.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of conflict of interests
  8. References

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.

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 (anti-FXa 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of conflict of interests
  8. References

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 receptor-blocking mAb – giving the expected reactions [18]). All patients also had a positive ‘in-house’ IgG-specific PF4/heparin enzyme-immunoassay (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 low-dose 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, Asnières-sur-Seine, 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 therapeutic-dose 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 (‘typical onset’, i.e. platelet decrease 5–10 days after the beginning of the immunizing heparin exposure vs. ‘rapid-onset’, 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 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 SRA-positive 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of conflict of interests
  8. References

Sixteen patients met the study’s 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 1.   Patients with acute heparin-induced thrombocytopenia who received fondaparinux: demographic and other parameters
Patient no.Age (years)SexClinical settingIndication for heparinEstimated CrCl (mL min−1)Comorbidities
  1. 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.

160MCardiac surgery*CPB; prophylaxis114VHD, CAD, HTN, CHF
253FCardiac surgery*CPB; prophylaxis152VHD, dyslipidemia, treated hypothyroidism
362FCardiac surgeryCPB; prophylaxis148CAD, HTN, dyslipidemia, DM2, prior VTE, prior MI, acute postoperative AF
480FCardiac surgeryCPB; prophylaxis24CAD, HTN, dyslipidemia, prior MI, CHF, treated hypothyroidism
581FVascular surgeryEVS; prophylaxis57PVD, AAA, HTN, DM2, prior CVA, metastatic colon CA
675MVascular surgeryEVS; prophylaxis54PVD, AAA, HTN
780MCardiac surgeryCPB; prophylaxis56VHD, AF
857MCardiac surgeryCPB; prophylaxis95CAD, prior MI, prostate CA
968MCardiac surgeryCPB; prophylaxis82VHD
1081FCardiac surgeryCPB; prophylaxis46VHD, HTN, postoperative AF
1162MCardiac surgeryCPB; prophylaxis125CAD, HTN, dyslipidemia, myasthenia gravis
1285FThrombotic strokeAcute CVA with AF28HTN, DM2, dyslipidemia, AF
1358FCardiac surgery*CPB; prophylaxis124VHD, DM2, HTN, dyslipidemia
1464FThrombotic strokeVTE prophylaxis87HTN
1562MVascular surgeryOpen repair of ruptured AAA; prophylaxis69AAA (acutely ruptured)
1673MCardiac surgeryCPB; prophylaxis60CAD, HTN, DM2, dyslipidemia

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 2.   Clinical and serologic data supportive of a diagnosis of acute HIT
Patient no.HIT profileDay of onsetPlatelet count nadir (×109 L−1)Platelet count decline (%)Peak % serotonin releaseEIA-IgG OD unitsHIT-associated thrombosis4Ts score
  1. 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). ‡Day 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.

1Typical86974822.40Bilateral DVT; DIC8
2Typical712165932.82Nil*6
3Typical916966681.62CVA (left MCA)8
4Typical57944923.03Nil*5
5Typical109147972.60Nil5
6Rapid26†11275962.86Arterial graft occlusion8
7Rapid14†78601002.51Radial artery thrombosis7
8Typical611731972.70Nil*5
9Rapid66†7658972.82PE; DVT; ASR7
10Typical52879992.46Nil*6
11Rapid26†8274772.23PE; DVT8
12Typical5–10‡42821002.76Bilateral DVT; DIC8
13Typical62289962.09Nil*6
14Typical5–9‡7658982.47DVT8
15Typical99855822.52DVT; PE7
16Typical5–9‡1095862.60Nil*; DIC5
 Typical = 12Typical, day 7§79§66§91§2.53§Venous: 6/16 (38%)
Rapid = 4Rapid, day 33§Arterial: 3/16 (19%)

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-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.

Table 3.   Fondaparinux and concomitant treatments and outcomes
Patient no.Daily dose of fondaparinux (mg)Days givenAnti-factor Xa monitoringAntiplatelet therapyWarfarin overlapThrombotic EventMajor bleeding event
  1. 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. ‡5 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. ‡‡12.5 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 anti-FXa 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).

115*†10NoASAYesNoNo
210†8NoASAYesNoNo
310†8NoASAYesNoNo
45‡9YesASANoNoNo
57.5> 35§YesASA, clopidrogelNo§NoNo
67.55YesASAYesNoYes¶
77.513NoYesNo**No
82.55NoASAYesNoNo
97.52NoYesNoNo
107.512YesYesNoNo
1110†4YesASAYesNoNo
12See Fig. 212YesASAYesNoNo
1315††13YesASAYesNoNo
14109NoASAYesNoNo
157.5‡‡22YesYesNoNo
167.5§§35YesNoNoNo
 7.5 (median)10 (median)9/16 (56%)11/16 (69%)13/16 (81%)0/16 (0%)1/16 (6%)

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 non-statistically 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 μg 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.

image

Figure 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).

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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.

image

Figure 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 μm; 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 μm. Therefore, later on day 17, an additional dose of 2.5 mg was given to bring that day’s 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.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of conflict of interests
  8. References

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 EIA-IgG, 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 SRA-positive HIT, in which approximately half of the patients have HIT-associated thrombosis [5], and the remaining half have ‘isolated HIT’.

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 μm). 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 PF4-dependent 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 ‘true’ 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.

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. 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 ‘niche’ 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of conflict of interests
  8. References

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 Sanofi-Aventis, 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 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. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of conflict of interests
  8. References
  • 1
    Warkentin TE. Drug-induced immune-mediated thrombocytopenia – from purpura to thrombosis. N Engl J Med 2007; 356: 8913.
  • 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: 78692.
  • 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: 9549.
  • 4
    Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4–heparin complex as the major antigen. Thromb Haemost 1994; 71: 24751.
  • 5
    Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101: 5027.
  • 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): 340S80S.
  • 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: 11705.
  • 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: 50715.
  • 9
    Chong BH, Magnani HN. Danaparoid for the treatment of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-induced Thrombocytopenia, 4th edn. New York: Informa Healthcare USA, Inc., 2007: 31943.
  • 10
    Bradner JE, Eikelboom JW. Emerging anticoagulants and heparin-induced 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: 44161.
  • 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: 36673.
  • 12
    Warkentin TE. Fondaparinux: does it cause HIT? can it treat HIT? Exp Rev Hematol 2010; 3: 56781.
  • 13
    Kuo KHM, Kovacs MJ. Successful treatment of heparin induced thrombocytopenia (HIT) with fondaparinux. Thromb Haemost 2005; 93: 9991000.
  • 14
    Lobo B, Finch C, Howard A, Minhas S. Fondaparinux for the treatment of patients with acute heparin-induced thrombocytopenia. Thromb Haemost 2008; 99: 20814.
  • 15
    Grouzi E, Kyriakou E, Panagou I, Spiliotopoulou I. Fondaparinux for the treatment of acute heparin-induced thrombocytopenia: a single-center experience. Clin Appl Thromb Hemost 2010; 16: 6637.
  • 16
    Pappalardo F, Scandroglio A, Maj G, Zangrillo A, D’Angelo A. Treatment of heparin-induced thrombocytopenia after cardiac surgery: preliminary experience with fondaparinux. J Thorac Cardiovasc Surg 2010; 139: 7902.
  • 17
    Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep 2003; 2: 14857.
  • 18
    Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 2730.
  • 19
    Horsewood P, Warkentin TE, Hayward CPM, Kelton JG. The epitope specificity of heparin-induced thrombocytopenia. Br J Haematol 1996; 95: 1617.
  • 20
    Greinacher A, Juhl D, Strobel U, Wessel A, Lubenow N, Selleng K, Eichler P, Warkentin TE. Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost 2007; 5: 166673.
  • 21
    Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 6924.
  • 22
    Hillis C, Warkentin TE, Taha K, Eikelboom JW. Chills and limb pain following administration of low-molecular-weight heparin for treatment of acute venous thromboembolism. Am J Hematol 2011; 86: 6036.
  • 23
    Warkentin TE. Limitations of conventional treatment options for heparin-induced thrombocytopenia. Semin Hematol 1998; 35 (Suppl. 5): 1725.
  • 24
    Sheth SB, DiCicco RA, Hursting MJ, Montague T, Jorkasky DK. Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001; 85: 43540.
  • 25
    Greinacher A. Lepirudin for the treatment of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-induced Thrombocytopenia, 4th edn. New York: Informa Healthcare USA, Inc., 2007: 34578.
  • 26
    Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127: 80412.
  • 27
    Goldfarb MJ, Blostein MD. Fondaparinux in acute heparin-induced thrombocytopenia: a case series. J Thromb Haemost 2011; 9: 25013.
  • 28
    Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost 2008; 6: 130412.