Foot Gangrene From Complication of Heparin-Induced Thrombocytopenia

Introduction

Heparin-induced thrombocytopenia (HIT) is a serious, immune system–mediated complication of heparin therapy. If the condition of HIT is not detected in a timely manner, it often results in devastating thromboembolic outcomes. Since thrombocytopenia is common in hospitalized older patients, occurring in up to 58% of critically ill patients, and can be caused by a variety of factors,¹ HIT, unfortunately, often remains unrecognized. Heparin, especially low-molecular-weight heparin (LMWH), is a widely used drug in hospitals. It is important to be aware of HIT by recognizing signs and symptoms, and then providing immediate intervention with alternative drugs to manage these circumstances.

Case Presentation

A hospitalized 65-year-old man with congestive heart failure was consulted for further evaluation of gangrene on both of his feet. His medical history included hypertension, diabetes mellitus, coronary atherosclerotic disease, stage 5 chronic kidney disease, and congestive heart failure.

The previous month on June 17, he developed chest pain and was diagnosed with acute myocardial infarction. Heparin was used, and left heart catheterization was performed with a stent placed in the right coronary artery. He was discharged home.

The patient was readmitted on July 18 for exacerbation of his congestive heart failure. At this admission, he was also found to have deep vein thrombosis of the left lower extremity, and heparin was started. Three days after heparin was administered, the patient’s platelet count gradually dropped by more than half, with discoloration of both of his feet. The patient was alert and well oriented. His vital signs included heart rate 88 beats per minute, blood pressure 122/67 mm Hg, and respiration rate 18 breaths per minute. Chest had scatted crackles at bases and cardiac findings of 2/6 systolic murmur at the apex. His abdominal examination was unremarkable. Both of his feet had symmetric gangrenous changes (Figure). The patient had black toes with blue/black discoloration involving the forefoot, and had scatted blisters on the dorsum of both feet. Minimal erythema in the feet was noted. Both feet were cold to the touch with no crepitation or fluctuance.

Laboratory data showed that his white blood cell count was 12.3x103/µL, with 83% segmented neutrophiles; blood urea nitrogen was 42 mg/dL; creatinine was 6 mg/dL and hemoglobin was 10.1 g/dL. Platelets on the admission date were 237x103/µL. Platelet count gradually decreased to 110x103/µL on July 21 and to 72x103/µL on July 22. Chest film revealed pulmonary edema with bilateral pleural effusions. Ultrasonogram showed left greater saphenous venous thrombosis. Arterial Doppler illustrated no flow in both feet. Echocardiogram demonstrated severely depressed left ventricular systolic function with ejection fraction of less than 25%. Hepatitis titers for A, B, and C were all negative. An enzyme-linked immunosorbent assay (ELISA) detected heparin-associated antibody.

Discussion

HIT is one of the most serious complications from heparin therapy in hospitalized elderly patients. Because heparin is among the most frequently prescribed medications in the United States for cardiovascular patients,² and these patients have a high likelihood of being exposed to heparin on multiple occasions, HIT has been seen more frequently in cardiovascular practice and is associated with a disproportionately higher incidence of thromboembolic complication.³ In hospitalized patients, thrombocytopenia occurred in up to 58% of critically ill patients and can be caused by a variety of factors.¹ There are two types of thrombocytopenia associated with heparin use.

Type I, or drug-induced non-immune HIT, has a rapid onset with mild, transit, and reversible course of the reduction of platelet. A drop in the platelet count usually occurs within 48-72 hours of administration. In type I HIT, the platelet count rarely falls below 100x103/µL and usually returns to normal within 4 days despite continued heparin therapy. Type I is not associated with increased risk for thrombosis, and no diagnostic test is available.⁴

Type II, also called white clot syndrome, has a delayed onset course with presence of marked thrombocytopenia and longer duration. Type II is also drug-induced, but is an immune-mediated reaction. A platelet count of less than 150x103/µL is almost always present in patients with HIT type II. In some cases, patients will have experienced a 50% decline in platelet count after the initiation of heparin. Type II is usually associated with thrombotic events and can result in life-threatening complications and death. Therefore, immediate action of discontinuation of heparin is always required. Typical HIT symptoms occur 5-10 days after heparin exposure; however, re-exposure can lead to rapid onset of HIT, with symptoms developing almost immediately.⁵

HIT, unfortunately, often remains unrecognized. Therefore, a declining platelet count to less than 50% of baseline within 5 days of heparin therapy or immediate decline of platelet with re-exposure to heparin should alert clinicians to the possibility of HIT. In addition, any new thrombotic event in this situation generally confirms HIT diagnosis unless another cause can be identified. The case patient was exposed to heparin the previous month for a cardiac procedure, and he developed thrombocytopenia; within 3 days of heparin therapy, his platelet count was halved.

A thromboembolic event also was found in both of his feet. ELISAs that detected the presence of the heparin-PF4 antigen confirmed the diagnosis of HIT.3 Treatment of HIT requires immediate discontinuation of all heparin products, including LMWHs, heparin flushes, and heparin-coated catheters. The use of an effective alternative anticoagulation needs to be determined, as most patients still need anticoagulation. In the United States, one of the approved anticoagulants for use in adult patients with HIT is the direct thrombin inhibitor argatroban,⁶ which was used in the case patient.

Another direct thrombin inhibitor, bivalirudin, is also approved by the FDA for use in patients with or at risk of HIT who are undergoing percutaneous coronary intervention.⁷ The most significant component of HIT is thromboembolic complication, which is recognized in more than 40% of HIT cases, and is especially more frequently observed in cardiovascular patients.⁸ Although, overall, there are more venous thromboses in HIT, arterial thromboses are seen more frequently in cardiovascular patients. A significant proportion of patients (33%) require limb amputation following thrombosis of extremity arteries,^4,9,10 as did this patient.

Conclusions

HIT should be recognized early, and immediate intervention should be provided to avoid devastating thromboembolic events. Typical HIT symptoms occur 5-10 days after heparin exposure; however, re-exposure can lead to rapid onset of HIT, with symptoms developing almost immediately.

Outcome of the Case Patient

A diagnosis of HIT was made, and heparin was discontinued. Argatroban was started. Unfortunately, the condition of the patient’s feet did not improve. No viable tissue could be rescued from vascular surgeries. The patient had a bilateral below-knee amputation. He then was moved to a rehabilitation center, where he recovered.

The authors report no relevant financial relationships. Dr. Bi is from Qilu Hospital, Shandong, China; and Dr. Liu is from the Freedman Clinic of Internal Medicine, Alexandria, LA.