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Pharmacy Practice Resident, Virginia Commonwealth University Medical Center/Medical College of Virginia Hospitals, Richmond, VA
Director, Drug Information Services, Virginia Commonwealth University Medical Center/Medical College of Virginia Hospitals
Reprints: Dr. Efird, Virginia Commonwealth University Medical Center/Medical College of Virginia Hospitals, 401 N. 12th St., PO Box 980042, Richmond, VA 23298-0042, fax 804/828-5589, lefird{at}mcvhvcu.edu
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DATA SOURCES: A MEDLINE search (1966-February 2006) was conducted using the search terms fondaparinux, heparin, low-molecular-weight heparin, and thrombocytopenia to identify English-language articles. Additional sources were identified from bibliographies of select articles and the manufacturer.
DATA SYNTHESIS: Fondaparinux, a pentasaccharide that selectively inhibits factor Xa, has been reported to have negligible or no cross-reactivity in vitro with HIT antibodies. Thromboembolic treatment and prophylaxis with fondaparinux in patients with HIT has been described. Three cases reported patients who were successfully treated for thromboembolic events with fondaparinux after developing HIT during therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Another report showed positive outcomes using fondaparinux for prophylaxis in a patient who had previously developed HIT after receiving UFH. Moreover, 2 case series, one using fondaparinux for prophylaxis in patients with a previous diagnosis of HIT and the other using fondaparinux for treatment in patients who developed HIT while receiving UFH or LMWH, reported normal platelet counts during fondaparinux treatment. Finally, results of a retrospective review demonstrated that fondaparinux prevented thromboembolic events or recurrent thrombocytopenia in patients with a prior HIT diagnosis.
CONCLUSIONS: Limited data support the use of fondaparinux for thromboembolic treatment or prophylaxis in patients with antibody assay-confirmed HIT who do not have a contraindication for fondaparinux use. Randomized controlled trials have not been published; therefore, questions remain regarding efficacy, safety, optimal doses, treatment duration, and incidence of thromboembolic events when fondaparinux is used in this setting. Prospective trials evaluating the efficacy and safety of fondaparinux in this patient population need to be conducted to answer these questions.
Key Words: fondaparinux, heparin, low-molecular-weight heparin, thrombocytopenia
Published Online, June 20, 2006. www.theannals.com, DOI 10.1345/aph.1G738
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The heparin molecule is made up of linear chains of repeating disaccharide units. Approximately 75-90% of these sequences are trisulphated, creating a negatively charged molecule. PF4 molecules consist of lysine and arginine residues producing a positively charged molecule. The interaction between the charges of these molecules causes the formation of a PF4/heparin complex that binds to the platelet surface at the Fc receptor site, thereby triggering immunoglobulin G production.6-8 These antibodies cause platelet activation and aggregation, which results in increased thrombin generation and possible venous or arterial thrombosis (ie, HIT with thrombosis syndrome).5,6,9
Complications resulting from thrombosis include deep venous thrombosis, pulmonary embolism, cerebral dural sinus thrombosis, adrenal hemorrhagic infarction, limb arterial occlusions, myocardial infarction, aortic occlusion, cardiac intraventricular thrombosis, and acute thrombotic stroke.10-12 With discontinuation of UFH or LMWH alone, up to a 50% risk of subsequent thrombosis has been reported.13,14 Moreover, morbidity and mortality rates for treated HIT range from 6% to 18% and 9% to 22%, respectively.15 Because cross-reactivity exists between UFH and LMWH, these agents should be immediately discontinued when HIT is suspected and treatment started.6
Currently, direct thrombin inhibitors (argatroban, lepirudin, bivalirudin) are the only treatments approved by the Food and Drug Administration for managing HIT.16-18 These agents have chemical structures different from UFH and LMWH and do not cross-react with HIT antibodies.19 While direct thrombin inhibitors have shown some reduction in morbidity and mortality, their use is sometimes complicated by an indication for continuous intravenous infusion administration, dose modification based on coagulation, and acquisition cost.16-18 Therefore, other HIT treatment options are essential.
Evidence suggests that an increased risk for HIT-related antigen production is dependent on molecular weight and length of polysaccharides (>2.4 kDa and >10 saccharide units, respectively). Structural components for UFH and LMWH are above the minimum requirements for increasing the risk of these antigens (Table 1).20-24 Investigators have hypothesized that fondaparinux, a selective factor Xa inhibitor with a structure consisting of a pentasaccharide chain, is too short to induce an antibody response and could be useful for treating HIT.25 Fondaparinux, administered subcutaneously, is currently indicated for deep venous thrombosis (DVT) prophylaxis in patients undergoing hip fracture surgery (including extended prophylaxis), hip or knee replacement surgery, and abdominal surgery and who are at risk for thromboembolic complications, as well as for treatment of DVT and pulmonary embolism (PE). It binds to and potentiates the effect of antithrombin and has negligible or no cross-reactivity in vitro with HIT antibodies.26 A study comparing the effects of UFH and fondaparinux on platelet aggregation in the presence of HIT sera reported a positive result in 79.8% of UFH samples compared with 3.3% of fondaparinux samples (p < 0.001).27
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LITERATURE REVIEW
Four case
reports,28-31
2 case
series,32,33
and a retrospective medical record
review34
describing fondaparinux treatment in patients with HIT have been published.
The American College of Chest Physicians' (ACCP) diagnostic criteria for HIT
were consistently used throughout the reports and
review.5
Results of these reports and review are described here.
Case Reports
One of the first cases of fondaparinux use in a patient with HIT involved a
32-year-old female with systemic lupus erythematosus who presented with
abdominal pain, vomiting, diarrhea, and acute renal
failure.28
Her blood work was notable for a platelet count of 80 x
109/L and a D-dimer concentration of 10 550 ng/L. An
abdominal ultrasound showed signs of ileitis. UFH was started for DVT
prophylaxis. Her platelet count increased to 150 x
109/L after plasmapheresis, cyclophosphamide, and steroids
were initiated.
On day 11 of UFH, the patient's nadir platelet count was 50 x 109/L and HIT antibodies were confirmed. UFH was discontinued and, secondary to renal failure, a reduced dose of fondaparinux 0.5 mg once daily was administered. Platelet levels returned to normal (no value reported) 2 days after fondaparinux was started. Five days after fondaparinux was initiated, the therapy was transitioned to warfarin; the duration of fondaparinux therapy was not specified. No adverse effects were noted at day 34 of follow-up. Because of fondaparinux's selective inhibition of activated factor Xa and lack of binding to PF4, the authors suggested that it may be an alternative to UFH and LMWH in patients with HIT.28
In another case, physicians used fondaparinux in a 36-year-old male with a history of systemic lupus erythematosus, recurrent thromboembolic episodes, and HIT (antibody titer confirmed).29 The patient was admitted to the hospital for a recurrent PE (diagnosed by spiral computed tomography scan), despite excessive anticoagulation with warfarin (international normalized ratio [INR] 10.6, goal 3-4). Other medications on admission included clopidogrel and aspirin. Warfarin, clopidogrel, and aspirin were discontinued, and lepirudin 0.4 mg/kg (bolus) followed by 0.15 mg/kg/h was administered for 5 days. On day 6, the lepirudin dose was reduced to 0.075 mg/kg/h and fondaparinux 2.5 mg once daily was added. On day 14 of combination therapy, the platelet count normalized (no value reported) and lepirudin was discontinued. Upon the patient's discharge, fondaparinux, with alternating doses of 2.5 mg and 5 mg once daily, clopidogrel, and aspirin were continued. Fondaparinux was administered for at least 8 months without complications. The authors concluded that fondaparinux is safe for long-term use in patients with a history of HIT who are refractory to anticoagulation with warfarin.
Rubin30 reported a case of a 29-year-old female who developed HIT during pregnancy and was successfully treated with fondaparinux. The patient had previously experienced 2 miscarriages and, as a result, underwent a hypercoaguable workup. Anticardiolipin and factor V Leiden mutation were negative, but a low protein S level was noted. During her third pregnancy, the woman developed a PE (ventilation-perfusion scan confirmed) and was started on UFH. Five days after starting UFH, a 50% reduction from baseline for platelet count was noted and HIT was confirmed by antibody assay. UFH was discontinued and lepirudin was started. However, due to risks of its use in pregnancy, lepirudin was discontinued and fondaparinux 2.5 mg twice daily was initiated (duration unspecified). No further complications of HIT or bleeding were noted throughout the pregnancy. The authors concluded that fondaparinux may be a therapeutic alternative in pregnancy due to its absence of placental transfer and decreased incidence of HIT.
Another case report supplemented the available data supporting fondaparinux use in patients with HIT.31 A 32-year-old male with a history of paroxysmal nocturnal hemoglobinuria presented with increased abdominal volume and tenderness. An abdominal ultrasound revealed thrombosis of the suprahepatic veins and inferior cava vein consistent with Budd-Chiari syndrome. Recombinant tissue type plasminogen activator (rt-PA) and UFH were initially started, and treatment was later switched to enoxaparin. On day 11 of enoxaparin therapy, a 50% reduction in platelet count from baseline was noted (baseline 93 x 109/L). Enoxaparin was discontinued and fondaparinux 2.5 mg once daily along with 2 infusions of rt-PA were initiated. The patient's platelet count increased to 101 x 109/L and remained within normal limits during use of fondaparinux (duration unspecified). No adverse events were reported. The author postulated that additional data were needed before fondaparinux could be considered safe in patients with HIT.
Case Series
Harenberg et
al.32
conducted a case series to evaluate the efficacy of fondaparinux for
thromboembolic prophylaxis in patients with a history of HIT (n = 6) or an
acute episode of thrombocytopenia (n = 2) while receiving UFH (n = 5) or LMWH
(n = 3). Six patients had a positive heparin-induced platelet aggregation
assay response, one had a negative response, and one had no results available.
All patients received thromboembolic prophylaxis with fondaparinux 2.5 mg once
daily for 1-2 weeks. Platelet counts remained unchanged in patients with a
history of HIT, while the platelet counts increased in patients with an acute
episode of thrombocytopenia (43-445 x 109/L and 40-172
x 109/L). Thromboembolic events or hemorrhagic adverse
effects were not reported. The authors concluded that fondaparinux is a safe
alternative for thromboembolic prophylaxis in patients with a history of HIT
or thrombocytopenia associated with UFH or LMWH at a dose of 2.5 mg daily.
Fondaparinux was administered to 5 surgical patients who developed HIT (antibody assay confirmed) and thrombosis while receiving UFH.33 Thrombocytopenia was noted between days 6 and 10 of UFH therapy. PE (n = 2), DVT (n = 2), and left atrial and mechanical mitral valve thrombosis (n = 1) were noted. UFH was discontinued in all patients and fondaparinux 7.5 mg once daily was initiated. After fondaparinux was started, platelet counts increased to normal in all patients between days 2 and 9. Warfarin was added when platelet counts exceeded 100 x 109/L. After the INR was 2.0 or more for 2 consecutive days, fondaparinux was stopped. At follow-up, recurrent thrombosis was not reported; however, major bleeding did occur in 2 patients. The authors remarked that further studies are needed to evaluate fondaparinux in the treatment of HIT.
Retrospective Medical Record Review
Bradner et
al.34
conducted a retrospective analysis of 20 patients with confirmed HIT who were
treated with fondaparinux. All of the patients lacked evidence for alternative
etiologies of thrombocytopenia and were treated with fondaparinux for at least
5 days (average 17). The primary endpoint was time to platelet recovery.
Patients who were thrombocytopenic while receiving fondaparinux had an average
platelet recovery of 3.7 days. Ninety percent (18/20) of the patients were
treated initially with fondaparinux 2.5 mg once daily. Ten patients received
fondaparinux after direct thrombin inhibitor therapy, while the other 10
patients received fondaparinux directly after HIT diagnosis. Neither
thrombotic complications nor a recurrence of thrombocytopenia were reported
during fondaparinux therapy (duration unspecified). The authors postulated
that fondaparinux may be a well tolerated, effective treatment for HIT.
LIMITATIONS OF DATA
Evaluation of the evidence on the use of fondaparinux for thromboembolic
treatment and prophylaxis in patients with HIT is complicated by several
limitations. The data are from case reports (often published in abstract form)
or retrospective reviews, included small patient numbers, and were conducted
over relatively short time periods. Patient types, time of overlap with
concomitant HIT therapy, and doses of fondaparinux were not consistent across
reports, which limits extrapolation to all patients with HIT.
SUMMARY
The production of HIT-related antigens seems to be dependent on molecular
weight and a polysaccharide length greater than 10. Accordingly, fondaparinux
has been shown to have negligible cross-reactivity in vitro with HIT
antibodies. Fondaparinux is not currently recommended for HIT treatment in
guidelines established by the ACCP Consensus Conference on Antithrombotic
Therapy; however, its use in this population has been described in several
case reports and a retrospective review. Based on data from these reports,
doses of fondaparinux for thromboembolic treatment or prophylaxis in patients
with HIT are similar to the approved doses, which are based on weight and
renal function. Length of fondaparinux therapy was often unspecified; however,
it was reportedly administered for more than 8 months in one case. The time of
overlap (if any) of fondaparinux with concomitant HIT treatment or
anticoagulation was inadequately described in most cases.
Although minimal, current evidence suggests that fondaparinux may be a viable option for thromboembolic treatment or prophylaxis in patients with antibody assay confirmed HIT who do not have a contraindication for fondaparinux use. Nonetheless, conducting placebo-controlled trials in patients with HIT can be challenging, and well controlled trials have not been published. Therefore, questions remain regarding patient types, efficacy, safety, optimal dosing, treatment duration, and incidence of thromboembolic events when fondaparinux is used in this setting. Prospective trials evaluating the efficacy and safety of fondaparinux for this patient population need to be conducted to answer these questions.
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This article has been cited by other articles:
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  T. E. Warkentin, A. Greinacher, A. Koster, and A. M. Lincoff Treatment and Prevention of Heparin-Induced Thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 340S - 380S. [Abstract] [Full Text] [PDF]
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 A. G.G. Turpie Selective factor Xa inhibition with fondaparinux: from concept to clinical benefit Eur. Heart J. Suppl., April 1, 2008; 10(suppl_C): C1 - C7. [Abstract] [Full Text] [PDF]
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 S. Fugate and J. Chiappe Standardizing the management of heparin-induced thrombocytopenia Am. J. Health Syst. Pharm., February 15, 2008; 65(4): 334 - 339. [Abstract] [Full Text] [PDF]
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 J. H. Levy, K. A. Tanaka, and M. J. Hursting Reducing Thrombotic Complications in the Perioperative Setting: An Update on Heparin-Induced Thrombocytopenia Anesth. Analg., September 1, 2007; 105(3): 570 - 582. [Abstract] [Full Text] [PDF]
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