Heparin-induced Thrombocytopenia in a Patient Treated With Fondaparinux

Heparin-induced Thrombocytopenia in a Patient Treated With Fondaparinux

Shiva K. Ratuapli, MD, Brijesh Bobba, MD, Haider Zafar, MD

Department of Medicine, Banner Estrella Medical Center, Phoenix, Arizona

Case Report

A 45-year-old female presented with complaints of left leg cramps lasting 2 weeks and 1 day of leg swelling. Doppler ultrasound revealed left lower extremity deep vein thrombosis (DVT), which was thought to be secondary to trauma. The patient had a history of ampullary cancer that had metastasized to the liver, for which she underwent a Whipple procedure, radiotherapy, and chemotherapy. Additional history included hypothyroidism and a hysterectomy. The patient had a 20-year smoking history, but quit upon diagnosis of malignancy. She denied the use of alcohol or illicit drugs. Family history was negative for thrombophilia. Medications prior to admission included levothyroxine and pancrelipase. Hematology was consulted, DVT treatment with enoxaparin and warfarin was started, and the patient was discharged without any other events. During her first outpatient evaluation, her international normalized ratio (INR) was found to be 8, and therefore warfarin and enoxaparin were discontinued. Two days later, her INR was greater than 5; 4 days later, her INR was 3.7, but she began developing pain and swelling in the right leg that day. Upon hospital admission 2 days later, she was diagnosed with a second DVT (idiopathic) in the right lower extremity. Because of the development of the new

DVT with an INR greater than 3, the patient was anticoagulated with enoxaparin as an outpatient, but warfarin was not restarted. Cephalexin was prescribed for phlebitis, and the patient was discharged. The patient was subsequently scheduled for an outpatient computed tomography (CT) scan, which showed evidence of pulmonary embolism, and she was re-admitted to the hospital. Anticoagulation was continued with enoxaparin therapy, and then switched to an unfractionated heparin (UFH) weight-based treatment protocol. A Greenfield filter was placed, and treatment doses of enoxaparin were resumed. A liver biopsy was performed secondary to lesions being identified on CT scan; it revealed metastatic pancreatobiliary adenocarcinoma. Additionally, the patient was noted to have swelling and cyanosis in the first toe of the right foot. Vascular surgery was consulted, and mild phlegmasia was suspected, for which medical management was recommended. The patient was discharged on erlotinib (Tarceva, Genentech), gemcitabine, enoxaparin, oxycodone/acetaminophen, levothyroxine, lidocaine patch, and levofloxacin for pulmonary infiltrate and leukocytosis. Upon discharge, the platelet count was 148,000/μL.

Two days after discharge, the patient returned to the hospital via emergency medical services with complaints of increasing shortness of breath in the previous few days and chest pain that began the night before. Upon this admission, the platelet count was 22,000 μ/L, hemoglobin was 8.7 g/dL, and hematocrit was 26.0 g/dL. The previously cyanotic toe had progressed to become necrotic with involvement of multiple toes on the same foot. The patient was given 1 dose of enoxaparin prior to hematology consult, which was subsequently discontinued, and lepirudin (Refludan, Bayer Healthcare) intravenous infusion was started for suspected heparin-induced thrombocytopenia (HIT). Platelet factor 4 (PF4) antibodies were checked and were found to be positive. The next day, platelet count increased to 79,000/μL and to 138,000/μL the following day. At this time, fondaparinux (Arixtra, GlaxoSmithKline) 7.5 mg once daily was given in anticipation of discharge and continuation for outpatient anticoagulation. The next day, the patient was given the same dose, and platelets declined to 86,000/μL.

Fondaparinux was discontinued and intravenous infusion of lepirudin was resumed. The next day, the platelet count increased to 158,000/μL. The following day, the count was 215,000/μL. Four days after lepirudin was resumed, the intravenous infusion was converted to subcutaneous administration at 50 mg, and the patient was discharged to hospice on lepirudin 60 mg subcutaneously every 12 hours with a platelet count of 168,000/μL.

Discussion

Thrombocytopenia associated with heparin use is a commonly encountered complication seen in clinical practice. In most cases, the reduction of platelet count is usually mild, not associated with thrombotic complications or hemorrhage, and is known as heparin-associated thrombocytopenia (formerly HIT I).1 The more significant complication is the marked reduction of platelet count associated with immune heparin-related procoagulant activity (formerly HIT II) leading to life-threatening thrombo-occlusive complications rather than bleeding.2 The basic pathophysiology of HIT involves formation of immunoglobulin G antibodies directed against heparin-bound PF4 activating platelets, monocytes, and endothelial cells, leading to excessive thrombin generation and clot formation.3 HIT with platelet antibodies is seen more commonly in patients treated with UFH 20% compared to 8% in patients treated with low molecular weight heparin (LMWH).4

Treatment of HIT first involves discontinuing the use of heparin and direct thrombin inhibitors (DTIs). The U.S. Food and Drug Administration has approved 3 DTIs: lepirudin, argatroban (Pfizer), and bivalirudin (Angiomax, The Medicines Co.) for use in management of HIT. Fondaparinux, another DTI, has also been used successfully, off-label in many cases, with good results.5-9 Fondaparinux is a new anticoagulant that works by inhibiting factor Xa, thereby preventing thrombin formation.10 Fondaparinux is a synthetic pentasaccharide with molecular structure similar to UFH and LMWH. However, it does not contain the same portion of molecule that binds to PF4, thereby reducing the chances of HIT when compared to other heparins. There have been many reports of the successful use of fondaparinux to anticoagulate patients with established HIT.5-9,11,12

In our case, fondaparinux was used after the platelet count recovered with lepirudin infusion, after HIT was triggered by UFH and LMWH. After starting fondaparinux, the patient again had thrombocytopenia, with a platelet count of less than 100,000/μL in the setting of arterial thrombosis with toe gangrene. Platelet count finally recovered after fondaparinux was discontinued and lepirudin was restarted, indicating the role of fondaparinux in causing recurrent HIT in this patient. A literature review shows many reports of successful outcome with fondaparinux usage in the setting of HIT.5-9,11,12 There have been only a few case reports suggesting the occurrence of HIT with fondaparinux.11,13,14 Most recently, a prospective study by Baroletti and colleagues15 reported a 94% incidence of HIT in patients treated with fondaparinux.

In summary, despite many reports of successful treatment of HIT with fondaparinux, there is a possibility of fondaparinux itself causing HIT, as suggested by our case and several recent reports. Hence, further research and large-scale prospective studies are necessary to guide the use of fondaparinux both in the treatment of DVT as well as in the management of HIT.

References

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2. Tardy-Poncet B, Piot M, Chapelle C, et al. Thrombin generation and heparin induced thrombocytopenia (HIT). J Thromb Haemost. 2009;7:1474-1481.

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12. Wester JP, Leyte A, Oudemans-van Straaten HM, et al. Low-dose fondaparinux in suspected heparin-induced thrombocytopenia in the critically ill. Neth J Med. 2007;65:101-108.

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14. Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med. 2007;356:2653-2655.

15. Baroletti S, Labreche M, Niles M, Fanikos J, Goldhaber SZ. Prescription of fondaparinux in hospitalised patients. Thromb Haemost. 2009;101:1091-1094.