**Heparin-Induced Thrombocytopenia**

Kelly L. Cervellione and Craig A. Thurm *Jamaica Hospital Medical Center, Jamaica, New York,* 

*USA* 

### **1. Introduction**

Heparin-induced thrombocytopenia (HIT) is an immune-mediated response to heparin administration that causes thrombocytopenia and a prothrombotic state. Heparin is the most commonly used anticoagulant drug for the prevention and treatment of thromboembolic diseases in hospitalized patients. Heparin exists in two main forms, pure unfractionated heparin (UFH) and low molecular weight heparin (LMWH), which is derived from UFH. Though HIT is relatively rare, occurring in less than 5% of patients receiving UFH and less than 1% of patients receiving LMWH, it has the potential to cause significant morbidity and mortality. The main complication of HIT is thrombosis, most commonly deep vein thrombosis (DVT) or pulmonary embolism (PE). More rarely HIT can manifest as occlusion of a limb artery, acute myocardial infarct, stroke, a systemic reaction or skin necrosis. In the current chapter the topic of HIT will be reviewed in terms of its pathophysiology, diagnosis, and treatment.

#### **1.1** *Clinical Vignette: Patient S-B*

*S-B is a 48-year-old male who was admitted to the orthopedics service for surgical repair of a right acetabular fracture resulting from a fall. He had no significant past medical history. His course was complicated by an ileus. He was given enoxaparin for thromboprophylaxis starting on day 2 of admission. During his hospital stay, he developed a pulmonary embolus and atrial fibrillation and the dose of enoxaparin was increased. An IVC filter was also placed. His platelet count dropped from 278K/uL on admission to a low of 88K/uL on hospital day 10. HIT antibody was positive. Enoxaparin was discontinued and lepirudin was started. Platelet count began improving by the next day and was 190K/uL two days after starting lepirudin. He was transitioned to warfarin. A PICC line was placed for parenteral nutrition as his ileus had not resolved.* 

*Several days later, the patient suddenly developed shortness of breath, chest pain, nausea and fever of 102°F. His heart rate increased to 130; he was normotensive. An arterial blood gas revealed metabolic acidosis and hypoxemia; his lactate level was elevated. Chest x-ray showed no infiltrates and a CT pulmonary angiogram (CTPA) was negative for infiltrates, pulmonary emboli and other pathology. EKG showed sinus tachycardia. Antibiotics were begun for possible sepsis. Platelet count was found to be 114K/uL compared to 231K/uL the previous day. Review of his chart revealed that the patient had received heparin flushes of his PICC line as part of a standing protocol. Heparin flushes were discontinued and lepirudin was restarted. Over the next several hours his fever, tachycardia, and hypoxemia improved. His lactate level normalized and platelets rose to 160K/uL by the following morning. All cultures were negative and antibiotics were discontinued.* 

Heparin-Induced Thrombocytopenia 201

Several factors have been identified as being associated with an increased risk of HIT. At the patient level, HIT has been more frequently reported in females (Warkentin et al., 2006) and in patients over 40 years of age (Stein et al., 2009). Patients on UFH have a higher likelihood of developing HIT than those on LMWH (Martel et al., 2005). Dosage is also an important factor; patients receiving therapeutic doses may be more likely to develop clinical manifestations of HIT than those receiving prophylactic doses (Dager & White, 2003). Patients receiving thromboprophylaxis with UFH for six or more days have a higher incidence of HIT than those receiving it for shorter periods (Martel et al., 2005; Smythe et al., 2007). Furthermore, the preparation type seems to influence risk; bovine UFH is more likely to cause HIT than porcine UFH (Green et al., 1984; Bailey et al., 1986; Francis et al., 2003). In general, surgical patients are at a higher risk of developing HIT than medical patients (Warkentin et al., 2006), but there is variation in incidence between surgical types. Since HIT develops secondary to the formation of heparin/PF4 complexes, it would be logical to assume that patients with higher concentrations of circulating PF4 would be at greater risk, including patients undergoing cardiac surgery on cardiopulmonary bypass (Yoon & Jang, 2011). However, the incidence of HIT in these cardiac surgery patients is less than 3% (Warkentin et al,. 2000), whereas those who undergo orthopedic surgery, which is associated with less PF4 production, has incidence rates of HIT around 5% (Warkentin et al., 2003). The mechanism underlying this difference is not clearly understood, but evidence from data collected in trauma patients suggests a role of inflammatory processes in the

Thrombocytopenia secondary to HIT commonly occurs between 5 and 14 days after the onset of heparin therapy. Patients with recent heparin exposure (e.g. within 30 to 100 days) may develop a significant fall in platelets related to HIT more quickly, even within minutes of re-exposure (i.e. rapid-onset HIT) (Warkentin, 2004; Warkentin and Kelton, 2001b). This is likely due to the continued presence of antibodies from previous exposure (Warkentin and Kelton, 2001b; Lubenow et al., 2002). Conversely, there have been cases of HIT where symptoms do not manifest until 10-14 days or more after heparin withdrawal, a phenomenon known as delayed-onset HIT (Warkentin and Kelton, 2001a). This phenomenon is not completely understood. It is known that the anti-heparin/PF4 antibodies can remain in the system for 100 days or more following discontinuation of heparin therapy and that the antibody titers in patients who develop delayed-onset HIT are very high (Rice et al., 2002; Warkentin & Kelton, 2001a). There may be a role of crossreactivity with other glycosaminoglycans residing on the surface of platelets, thus inducing

In the majority of patients with HIT the platelet count drops below 150K/uL, or falls to less than 50% of baseline. HIT may be overlooked when the platelet count remains above 100K/uL if prior values are not reviewed. The nadir platelet count in HIT typically does not fall below 20K/uL; if such an extensive drop is seen, alternate or additional diagnoses must be seriously considered (Warkentin, 1998). Generally the nadir platelet count in HIT is

development of heparin/PF4 complexes (Lubenow et al., 2010).

platelet activation in the absence of heparin (Rauova et al., 2006).

**3.3 Degree of thrombocytopenia** 

between 40 and 80K/uL (Greinacher et al., 2005).

**3. Clinical features 3.1 Epidemiology** 

**3.2 Timing** 
