**3. Diagnosis**

Usually the first clinical suspicion of HIT occurs when the platelet count drops in a patient being treated with heparin. Thrombocytopenia is usually not severe (40-60,000) or more than 50% of baseline value and it very rarely reaches a level that would cause spontaneous bleeding. The incidence of thrombocytopenia usually has a predictable time pattern. There are 3 possible clinical scenarios.


discharged from hospital. There are some cases of super-acute HIT, which occurs almost immediately after a second dose of heparin and presents in the form systemic syndrome with dramatic picture of disseminated intravascular coagulation (DIC).

Among patients who develop thrombocytopenia caused by HIT, 30-50 % have thrombotic complications (Table 1). For many clinicians this is a paradoxical phenomenon since heparin is supposed to prevent thrombosis. Venous thrombosis commonly occurs in the lower extremities frequently leading to pulmonary embolism (PE) or venous gangrene with distal necrosis of the limb.


Table 1. Thrombosis occurring in HIT.

212 Perioperative Considerations in Cardiac Surgery

HIT develops primarily in patients treated with unfractionated heparin (UFH) but it can also develop in patients treated with low molecular weight heparins (LMWH) however the probability is significantly lower. The classical presentation of HIT might be confusing since the thrombocytopenia is usually not severe (a drop of 50-60% when compared to pre-op values) and the dominating clinical symptoms are usually related to thrombo-embolic complications. The final diagnosis can be confirmed only by additional, relatively complicated laboratory tests, which usually take several days to complete. In the meantime, if HIT is suspected, treatment should be initiated based on strong clinical indications. HIT is an immune reaction associated with the formation of antibodies directed against heparin-Platelet Factor 4 (PF-4) complexes. Once heparin is administered to a patient, platelets release PF-4, which binds heparin. The heparin-PF-4 complex is highly immunogenic and initiates formation of antibodies, which belong to many subgroups (IgG, IgM and IgA). Among these classes of immunoglobulins, only IgG is capable of triggering the reaction responsible for HIT. The immune system of the patient develops sensitivity (memory) to complexes of heparin-PF-4. When a second dose of heparin is given (even a small amount) it causes platelet degranulation and release of PF-4. Antibodies then bind to the complexes (Fab fragment) and to the surface of platelets (Fc fragment) initiating a cascade of events that result in further platelet activation and release of large amounts of PF-4 along with further platelet aggregation and thrombin generation. Strong activation of thrombin leads to clot formation and subsequent thrombo-embolic events. PF-4 can also bind to other substances, which are chemicaly similar to heparin. They belong to a group of molecules called glycosaminoglycans (GAGs). Many GAGs are present on the surface of the endothelial cells. This interaction amplifies the reaction leading to further platelet activation and aggregation, inflammation and propagates clot formation. The above described sequence of events presents clinically as thrombocytopenia accompanied by thrombotic complications. 80% of embolic events take place in the venous system while the remaining 20% occur in the arterial system. Rarely, HIT presents as a systemic reaction, for example disseminated intravascular coagulation (DIC). Therefore, HIT should be considered as a pro-thrombotic disorder leading to venous or major

arterial thrombosis with potentially life-threatening consequences.

heparin again.

**3. Diagnosis** 

are 3 possible clinical scenarios.

most common clinical scenario.

Antibodies against heparin-PF-4 are usually detectable for up to 3 months after the last heparin exposure. After the antibodies disappear the patient can be safely treated with

Usually the first clinical suspicion of HIT occurs when the platelet count drops in a patient being treated with heparin. Thrombocytopenia is usually not severe (40-60,000) or more than 50% of baseline value and it very rarely reaches a level that would cause spontaneous bleeding. The incidence of thrombocytopenia usually has a predictable time pattern. There

1. Thrombocytopenia occurring 5-10 days after initiating therapy with heparin. This is the

2. Thrombocytopenia occurring within 24 h after initiating heparin therapy (so-called acute or rapid-onset HIT). This scenario usually occurs in patients who received

3. Thrombocytopenia with delayed onset. In this scenario the platelet drop occurs many days after discontinuing the heparin therapy, usually after the patient is being

heparin before surgery, for example as a treatment of unstable angina

HIT may also present as a systemic reaction. With the injection of the second dose of heparin (i.e. subcutaneous heparin used for DVT prophylaxis), the patient can develop several systemic symptoms, for example skin necrosis, seizures, shivering, hypo- or hypertension and tachycardia, or an anaphylactic reaction. As mentioned before the most severe form of HIT with systemic presentation is DIC. These symptoms are most likely related to a massive release of platelet contents including PF-4 but also histamine, serotonin and other vasoactive substances. Additionally, it has been suggested that systemic presentation of HIT includes extensive endothelial involvement (PF4 binds to GAGs). Various skin lesions at injection sites (erythema induratum, localized or diffuse urticaria, diffuse exanthema) can be also suggestive of HIT in 20% of cases. Livedo reticularis is observed in some patients and is associated with microangiopathy and microvascular thrombosis of the dermis. Lesions are painful, spread centrifugally, and may appear like necrotic purpura with a hemorrhagic bullous course, and central necrosis. 75% of patients showing cutaneous symptoms do not have any notable thrombocytopenia.

Basic laboratory tests reveal thrombocytopenia, and sometimes the blood film can show fragmentation of destroyed erythrocytes. Severe thrombocytopenia (< 20,000) usually indicates that diagnosis of HIT is unlikely. At the same time we need to rule out the most common causes of thrombocytopenia in patients being treated in the ICU (massive blood loss, sepsis, other drug-induced thrombocytopenia, i.e. vancomycin,). Among other less common syndromes causing thrombocytopenia, which should be included in differential diagnosis are: antiphospholipid syndrome, disseminated intravascular coagulation caused by other precipitating factor, thrombotic thrombocytopenic purpura and post-transfusion purpura.

One of the most popular schemes of assessment and clinical diagnosis of HIT was developed by Warkentin and called 'four T' (Table 2). T stands for **t**hrombocytopenia, **t**iming, **t**hrombosis and o**t**her causes. For each category the patient receives 0, 1 or 2 points. For a score of 0-3 points, the diagnosis of HIT is unlikely, 4-5 points requires laboratory testing to confirm the diagnosis but in most cases does not require treatment, however, if patients receive a score of ≥ 6 points treatment should be initiated immediately.


≥ 6 points mandates initiation of HIT therapy prior to receiving laboratory results confirming the diagnosis.

Table 2. Table describes scoring system used for clinical diagnosis of HIT.

As mentioned before HIT can be only confirmed by a specific laboratory tests. First, a screening test is performed to detect HIT antibodies. This screening test detects all classes of immunoglobulins but as mentioned earlier, only IgG can trigger HIT. For example, in the case of cardiac surgical patients 20-40% of them develop antibodies, but only 1-2% are truly HIT-positive. On the other hand, if the screening test does not detect any immunoglobulins the presence of HIT can be ruled out. In the case of a positive HIT screen we need further confirmation to be able to show that these (detected) antibodies can trigger platelet activation. The most popular assay used is the Serotonin Release Assay (SRA), which uses plasma obtained from the patient, heparin and specially prepared, radio-labeled platelets. If the patient's plasma activates platelets (ie: causes release of serotonin) the patient can be diagnosed as having HIT (positive). Unfortunately, SRA is performed in only a few centers and thus the results of the test are usually not available for several days. An alternative to the SRA performed by some laboratories is the heparin-induced platelet aggregation assay (HIPA), which also demonstrates the presence of a clinically relevant antibody. In the meantime, the medical team needs to initiate treatment based on the clinical symptoms and probability of a positive diagnosis of HIT (>6 points in scale proposed by Warkentin).

Fig. 1.

214 Perioperative Considerations in Cardiac Surgery

One of the most popular schemes of assessment and clinical diagnosis of HIT was developed by Warkentin and called 'four T' (Table 2). T stands for **t**hrombocytopenia, **t**iming, **t**hrombosis and o**t**her causes. For each category the patient receives 0, 1 or 2 points. For a score of 0-3 points, the diagnosis of HIT is unlikely, 4-5 points requires laboratory testing to confirm the diagnosis but in most cases does not require treatment, however, if

**Criteria 2 points 1 point 0 points** 

> 10 days after heparin or during 1st days of therapy if heparin used before (31-100 days)

30-50% of baseline value or 10-20,000

Progressing or recurrent thrombosis or suspicion of thrombosis without proven diagnosis

No other causes Potential causes Confirmed other

No previous use of

< 30% of baseline value or < 10,000

No thrombo-embolic complications

heparin

causes

patients receive a score of ≥ 6 points treatment should be initiated immediately.

5-10 days after heparin or during 1st day of therapy if heparin within previous 30 days

< 50% of baseline value or > 20,000

thrombosis or skin necrosis in injection site or systemic reaction during dosing of heparin

≥ 6 points mandates initiation of HIT therapy prior to receiving laboratory results

As mentioned before HIT can be only confirmed by a specific laboratory tests. First, a screening test is performed to detect HIT antibodies. This screening test detects all classes of immunoglobulins but as mentioned earlier, only IgG can trigger HIT. For example, in the case of cardiac surgical patients 20-40% of them develop antibodies, but only 1-2% are truly HIT-positive. On the other hand, if the screening test does not detect any immunoglobulins the presence of HIT can be ruled out. In the case of a positive HIT screen we need further confirmation to be able to show that these (detected) antibodies can trigger platelet activation. The most popular assay used is the Serotonin Release Assay (SRA), which uses plasma obtained from the patient, heparin and specially prepared, radio-labeled platelets. If the patient's plasma activates platelets (ie: causes release of serotonin) the patient can be diagnosed as having HIT (positive). Unfortunately, SRA is performed in only a few centers and thus the results of the test are usually not available for several days. An alternative to the SRA performed by some laboratories is the heparin-induced platelet aggregation assay (HIPA), which also demonstrates the presence of a clinically relevant antibody. In the meantime, the medical team needs to initiate treatment based on the clinical symptoms and probability of a positive diagnosis of HIT (>6 points in scale proposed by Warkentin).

Table 2. Table describes scoring system used for clinical diagnosis of HIT.

Thrombosis New incident of

Timing (of thrombocytopenia)

Thrombocytopenia (Platelet count)

Other explanations of thrombocytopenia

confirming the diagnosis.
