**3. Clinical features**

#### **3.1 Epidemiology**

200 Venous Thrombosis – Principles and Practice

Heparin is a negatively-charged, highly sulfated glycosaminoglycan that occurs naturally in the body. It was discovered nearly one century ago (Howell & Holt, 1918) and shortly thereafter was used in the medical profession for thromboprophylaxis in post-operative patients (Crafoord, 1936). Amongst the qualities that made it an attractive option for physicians were its immediate onset of action and its short half-life. During the first three decades of its use in the medical field, case reports and series of patients developing thrombosis while on heparin began to emerge in the literature, a phenomenon known as HIT (e.g. Weismann & Tobin, 1958; Roberts et al., 1963). Over the last several decades much has been learned about heparin and the mechanisms that are responsible for this disorder. Physiologically, two types of thrombocytopenia due to heparin exposure have been described. Non-immune heparin-associated thrombocytopenia, historically referred to as HIT type I, describes a response that is self-limiting and rarely causes major complications. Non-immune HIT occurs in 10% to 30% of patients who receive heparin and typically emerges within 4 days of exposure (Jang & Hursting, 2005). Platelet counts do not normally fall below 100K/uL. Heparin use does not need to be discontinued and no treatment is

Currently the term HIT is used to denote what has been historically called HIT type 2. HIT occurs when, following heparin administration, platelet factor 4 (PF4) binds to heparin to form heparin/PF4 complexes. The body identifies these complexes as abnormal and, in response, develops antibodies. Specifically immunoglobulin G (IgG), M (IgM) and/or A (IgA) antibodies are formed. IgG is pathogenic, and binding of the IgG antibodies to the heparin/PF4 complexes results in platelet activation and aggregation. This causes thrombin generation, resulting in thrombotic events. Activated platelet aggregates are removed prematurely from circulation, which leads to development of thrombocytopenia, the main criteria for diagnosis of HIT (Warkentin et al., 1994a; Untch et al., 2002). The heparin/PF4 antibodies (also known as chemokine CXCL4) are typically activated within 5-14 days of heparin exposure, though delayed-onset cases have been reported (Warkentin & Kelton, 2001a). In patients who have a recent history of heparin use, however, significant platelet activation can occur more rapidly after reintroducing a heparin-containing product (Warkentin & Kelton, 2001b). This may be because HIT antibodies are transient and can remain in the body for up to four months after withdrawal of heparin (Lubenow et al.,

Though the exact mechanisms of action are unclear, endothelial cells and monocytes also seem to play a role in the procoagulant state associated with HIT (Blank et al., 2002; Pouplard et al., 2001; Rauova et al., 2010; Arepally & Mayer, 2001). Many processes still remain unexplained in HIT, including the inability of some anti-heparin/PF4 IgG molecules to cause platelet activation (Warkentin, 2005) and the role of individual biological differences in predisposing to development of the disease. There is evidence that the length of the heparin molecule chain may positively correlate with the potential for HIT. Since LMWH's are formed from smaller molecules, this could explain why there is less immunogenic potential in these derived forms of heparin (Gruel et al., 2003). Furthermore, there may be a role of other glycosaminoglycans that are found on the surface of platelets, which may cross-react with heparin/PF4 antibodies and more directly cause thrombus

**2. Pathophysiology** 

needed (Chong, 2003).

2002).

formation (Rauova et al., 2006).

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

#### **3.2 Timing**

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

#### **3.3 Degree of thrombocytopenia**

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

Heparin-Induced Thrombocytopenia 203

sepsis and infection, non-heparin drugs, disseminated intravascular coagulation (DIC), chronic liver disease, immune disorders, and pseudo-thrombocytopenia (Sakr, 2011; Rice et al., 2009). A list of drugs to consider when determining the cause of thrombocytopenia can be found in Table 1 Note that the Table does not include chemotherapeutic agents since most drugs in this class are well-known to cause thrombocytopenia. Serologic confirmation is often delayed for several days and physicians are forced to make decisions based on clinical judgment alone. Therefore, especially in very ill patients, close attention must be

Recent data from the CATCH (Complications After Thrombocytopenia Caused by Heparin) registry suggests that less than 10% of patients who develop thrombocytopenia receive a diagnostic evaluation for HIT (Oliveira et al., 2008). Furthermore, many do not receive diagnostic attention for possible HIT until after a thromboembolic event has occurred (Crespo et al., 2009). Given the potential for significant morbidity and mortality, timely diagnosis is of utmost importance. Diagnosis of HIT should be based on both clinical judgment and laboratory assessment. The patient's presentation and history provide the most important information for initial determination of likelihood of HIT, but verification of anti-heparin/PF4 antibodies through serum or plasma analysis is a significant step for

The Four T's (4T) score can be used to calculate the pre-test probability of HIT in patients experiencing signs or symptoms of the disorder (Warkentin & Heddle, 2003). The 4T score takes into account four domains and generates a score of 0–8 points depending on the patients' signs and symptoms; a total score of 0 to 3 indicates that HIT is unlikely; 4 to 5 indicates an intermediate probability; 6 to 8 indicates high likelihood of HIT. In addition to the severity of thrombocytopenia, the score also takes into account the timing of the fall in platelet count, the occurrence of thrombosis or other sequelae, and the presence of other potential causes of the thrombocytopenia. In general, studies have found that the 4T score has high sensitivity for diagnosis (>95%), but specificity is low, especially in ICU patients (Lo et al., 2006; Pouplard et al., 2007). Most authors suggest that those patients with a high likelihood of HIT based on 4T score should be immediately withdrawn from heparin therapy, be treated with an alternative, and be monitored closely while laboratory tests for HIT antibodies are performed. Withdrawal of heparin should not wait until laboratory

Several other sets of criteria and scoring systems have been developed for determining pretest probability of HIT in both general and specific populations (e.g. Messmore et al., 2011). The HIT Expert Probability Score has recently been developed based on a panel of expert opinions (Cuker et al., 2010), but data regarding its psychometric properties are still lacking. Scoring systems for patients on hemodialysis (Yamamoto et al., 1996) have been created owing to the unique factors associated with HIT in this population. It has also been noted that the use of some scoring systems, such as the 4T score, should be modified in the setting of a critically ill patient; in such cases more emphasis should be placed on ruling out other

results are obtained in any patient where HIT is being strongly considered.

causes of thrombocytopenia (Hall et al., 2010).

given to all possible causes of thrombocytopenia.

guiding treatment and follow-up.

**4.1 Clinical diagnosis** 

**4. Diagnosis** 

### **3.4 Complications**

Thrombosis occurs in 30% to 70% of cases of HIT, depending on the population, and can occur without the presence of significant thrombocytopenia (Warkentin, 2007). Thrombotic events may occur days prior to the onset of thrombocytopenia (Greinacher et al., 2005). In patients who develop a thrombotic event who are either on or have recently completed heparin therapy, the possibility of HIT should be considered (Levine et al., 2006). In addition, it is important to realize that small amounts of heparin, such as those used to perform heparin flushes, can also cause significant manifestations of HIT (Refaai et al., 2007).

When HIT is associated with thrombosis approximately 20-30% of cases are fatal and an additional 20-30% result in permanent disability (Greinacher, 1995). DVT (50%) and PE (25%) are the most common thrombotic events related to HIT. Arterial thrombosis, infrarenal aortic thrombosis (Karkos et al., 2011), acute myocardial infarct (Iqbal et al., 2007), cerebral ischemia (Meyer-Lindenberg et al., 1997), limb ischemia (Kreidy & Hatem, 2004), acute adrenal insufficiency (Poulain et al., 2008) and bilateral adrenal hemorrhage (Ernest & Fisher, 1991; Rosenberg et al., 2011) are less common. Skin lesions, which may or may not be necrotic, can be seen at the heparin injection site in 10% to 20% of patients who develop HIT (Jang et al., 2005). Skin lesions appear to be more common in patients with higher levels of platelet-activating IgG (Warkentin, 1996). Despite the presence of thrombocytopenia, bleeding complications related to HIT are uncommon (Selleng et al., 2007).

Systemic or anaphylactoid reactions can rapidly occur after an IV bolus of UFH. In addition to a marked decline in platelet count, patients may develop fever, chills, respiratory symptoms that may simulate a pulmonary embolus (Hartman et al., 2006; Popov et al., 1997), cardiac arrest, gastrointestinal symptoms such as nausea, vomiting and diarrhea, or even neurologic symptoms such as ischemia or transient global amnesia (Warkentin et al., 1994b; Warkentin & Greinacher, 2009). It is important to note that these reactions are due to the immune-mediated response to heparin therapy (Warkentin & Greinacher, 2009); additional cases of anaphylactic reactions due to contaminated or over-sulfated heparins also exist (Liu et al., 2009). This type of systemic reaction is illustrated in the clinical vignette at the beginning of the chapter.

In hemodialysis patients, a unique set of complications may emerge as a result of HIT. For example, there may be clotting of the extracorporeal circuit or failed arteriovenous fistulae. If an IV bolus of UFH or LMWH is given prior to hemodialysis and systemic reactions occur, it is important to consider HIT as a cause (Syed and Reilly, 2009). Increased circuit pressures, formation of a clot in the drip chambers, clotted dialyzer fibers, or an acute thrombocytopenia with at least a 20% decrease in platelet counts may also be suggestive of HIT (Yamamoto et al., 1996).

#### **3.5 Alternative causes**

Thrombocytopenia is frequently encountered in critically ill patients and can have a variety of etiologies. ICU patients often receive UFH or LMWH for either prophylaxis or treatment of venous thromboembolic disease or for treatment of a variety of other conditions, such as cardiac ischemia or atrial fibrillation. The question of HIT is therefore frequently raised (Sakr, 2011). However, HIT is actually an uncommon cause of thrombocytopenia in this patient population with an incidence of less than 1% (Crowther et al., 2010; Verma et al., 2003). Some more common causes of thrombocytopenia in critically ill patients include sepsis and infection, non-heparin drugs, disseminated intravascular coagulation (DIC), chronic liver disease, immune disorders, and pseudo-thrombocytopenia (Sakr, 2011; Rice et al., 2009). A list of drugs to consider when determining the cause of thrombocytopenia can be found in Table 1 Note that the Table does not include chemotherapeutic agents since most drugs in this class are well-known to cause thrombocytopenia. Serologic confirmation is often delayed for several days and physicians are forced to make decisions based on clinical judgment alone. Therefore, especially in very ill patients, close attention must be given to all possible causes of thrombocytopenia.
