Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia
Classification and external resources
A schematic drawing of platelet factor 4, which when bound to heparin leads to an immune response in HIT.
ICD-10	D69.5
ICD-9	289.84
MedlinePlus	000556
eMedicine	article/1357846

Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia (low platelet counts) due to the administration of one of the forms of the anticoagulant (blood clotting inhibitor) heparin. It predisposes to thrombosis, the formation of abnormal blood clots inside a blood vessel, when the condition is called heparin-induced thrombocytopenia and/with thrombosis (HITT). The condition is caused by the formation of abnormal antibodies. If someone receiving heparin develops new or worsening thrombosis, or if the platelet count falls, HIT can be confirmed with specific blood tests.^[1]

The treatment of HIT requires both protection from thrombosis and choice of an agent that will not reduce the platelet count further. Several agents exist for this purpose, mainly lepirudin and argatroban.^[1] While heparin was discovered in the 1930s, HIT was not reported until the 1960s and 1970s.^[2]

Signs and symptoms

Heparin may be used for both prevention and the treatment of thrombosis. It exists in two main forms: an "unfractionated" form that can be injected under the skin or through an intravenous infusion, and a "low molecular weight" form that is always administered under the skin. Commonly used low molecular weight heparins are enoxaparin, dalteparin and tinzaparin.^[3]

In HIT, the platelet count in the blood falls below the normal range. However, it is generally not low enough to lead to an increased risk of bleeding. Most people with HIT will therefore not experience any symptoms. Typically the platelet count will fall 5–14 days after heparin is first commenced; if someone has received heparin in the previous three months, the fall in platelet count may occur much quicker, sometimes within a day.^[1] The most common symptom of HIT is enlargement (extension) of a previously diagnosed blood clot, or the development of a new blood clot elsewhere in the body. This may take the form of clots either in arteries (arterial thrombosis) or veins (venous thrombosis). Examples of arterial thrombosis are stroke, myocardial infarction (heart attack) and acute leg ischemia. Venous thrombosis may occur in the leg or arm in the form of deep vein thrombosis (DVT) and in the lung in the form of a pulmonary embolism (PE–these usually originate in the leg but migrate to the lung).^[1][4]

In those receiving heparin through an intravenous infusion, a complex of symptoms ("systemic reaction") may occur when the infusion is commenced: fever, chills, high blood pressure, a fast heart rate, shortness of breath and chest pain. This happens in about a quarter of people with HIT. Others may develop a skin rash consisting of red spots.^[1][4]

Mechanism

Heparin does not occur naturally in the human body, and the development of HIT antibodies suggests heparin sulfate is sometimes treated as a foreign "non-self" substance by the immune system. In HIT, the immune system forms antibodies against heparin when it is bound to a protein called platelet factor 4 (PF4). These antibodies are usually of the IgG class. This process takes about five days. However, those who have been exposed to heparin in the last few months may still have circulating IgG, as IgG continues to be produced even when the precipitant has been removed. This is similar to immunity against certain viruses, with the difference that the HIT antibody does not persist longer than 3 months.^[1][4] HIT antibodies have been found in individuals with thrombocytopenia and thrombosis who had no prior exposure to heparin sulfate, but the majority are found in people who are receiving heparin.^[5]

The IgG antibodies form a complex with heparin and PF4 in the bloodstream. The tail of the antibody then binds to the FcγIIa receptor, a protein on the surface of the platelet. This results in platelet activation and the formation of platelet microparticles, which initiate the formation of blood clots; the platelet count falls as a result.^[1][4]

Formation of PF4-heparin antibodies is common in people receiving heparin, but only a proportion of these develop thrombocytopenia or thrombosis.^[1] This has been referred to as an "iceberg phenomenon".^[2]

Diagnosis

HIT may be suspected if blood tests show a falling platelet count in someone receiving heparin, even if the heparin has already been discontinued. Professional guidelines recommend that people receiving heparin have a full blood count (which includes a platelet count) on a regular basis while receiving heparin.^[3][6]

However, not all people with a falling platelet count while receiving heparin turn out to have HIT. The timing, severity of the thrombocytopenia, the occurrence of new thrombosis, and the presence of alternative explanations, all determine the a priori likelihood that HIT is present. A commonly used score to predict the likelihood of HIT is the "4T score" introduced in 2003. A score of 0–8 points is generated; if the score is 0-3, HIT is unlikely. A score of 4–5 indicates intermediate probability, while a score of 6–8 makes it highly likely. Those with a high 4T score may need to be treated with an alternative drug while more detailed tests for HIT are performed, while those with a low score can safely continue receiving heparin as the likelihood that they have HIT is extremely low.^[1][4][7]

• Thrombocytopenia: 2 points if the fall in platelet count is >50% of the previous value, or the lowest count (nadir) is 20–100 × 10⁹/liter. 1 point if the fall is 30–50% or the nadir is 10–19. No points if the fall is less than 30% or the nadir is <10.
• Timing: 2 points if the fall is between days 5–10 after commencement of treatment. 1 point if the fall is after day 10. If someone has been exposed to heparin within the last 30 days and then has a drop in platelet count within a day of reexposure, 2 points are given. If the previous exposure was 30–100 days ago, 1 point. If the fall is early but there has been no previous heparin exposure, no points.
• Thrombosis: 2 points in new proven thrombosis, skin necrosis (see below), or systemic reaction. 1 point if progressive or recurrent thrombosis, silent thrombosis or red skin lesions. No points if there are no symptoms.
• Alternative cause possible: 2 points if no other cause, 1 point if there is a possible alternative cause, no points if there is a definite alternative cause.

The first screening test in someone suspected of having HIT is aimed at detecting antibodies against heparin and PF4. This may be with a laboratory test of the ELISA (enzyme-linked immunosorbent assay) type. The ELISA, however, detects all circulating antibodies that bind heparin-PF4 complexes, and may also falsely identify antibodies that do not cause HIT. Therefore, those with a positive ELISA are tested further with a "functional assay". This test uses platelets and serum from the patient; the platelets are washed and mixed with serum and heparin. The sample is then tested for the release of serotonin, a marker of platelet activation. If this serotonin release assay (SRA) test shows high serotonin release, the diagnosis of HIT is confirmed. The SRA test is complex to perform and is usually only done in regional laboratories.^[1][4]

If someone has been diagnosed with HIT, some recommend routine Doppler sonography of the leg veins to identify deep vein thromboses, as this is very common in HIT.^[4][7]

Treatment

Molecular structure of argatroban, a direct thrombin inhibitor used as an alterative to heparin in HIT.

Given the fact that HIT predisposes strongly to new episodes of thrombosis, it is not sufficient to simply discontinue the heparin administration. Generally, an alternative anticoagulant is needed to suppress the thrombosis tendency while the generation of antibodies stops and the platelet count recovers. To make matters more complicated, the most commonly used other anticoagulant, warfarin, is contraindicated in this setting as there is a very high risk of warfarin necrosis; this is the development of skin gangrene in those receiving warfarin or a similar vitamin K inhibitor. If the patient was receiving warfarin at the time when HIT is diagnosed, the activity of warfarin is reversed with vitamin K.^[1][6] Transfusing platelets is discouraged, as there is a theoretical risk that this may worsen the risk of thrombosis; the platelet count is rarely low enough to be the principal cause of significant hemorrhage.^[6]

Three agents are used to provide anticoagulation in patients with strongly suspected or proven heparin-induced thrombocytopenia: danaparoid, lepirudin and argatroban. Not all agents are registered in all countries. For instance, argatroban is not used in the United Kingdom.^[6]

According to systematic review, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18.^[8]

Epidemiology

The exact number of cases of HIT in the general population is unknown. What is known is that women receiving heparin after a recent surgical procedure (particularly cardiothoracic surgery) have a higher risk, while the risk is very low in women just before and after giving birth. Some studies have shown that HIT is less common in those receiving low molecular weight heparin.^[4]

History

While heparin was introduced for clinical use in the late 1930s, new thrombosis in people treated with heparin was not described until 1957, when vascular surgeons reported the association.^[2][9] The fact that this phenomenon occurred together with thrombocytopenia was reported in 1969;^[10] prior to this time, platelet counts were not routinely performed.^[2] A 1973 report established HIT as a diagnosis, as well as suggesting that its features were the result of an immune process.^[2][11]

Initially, various theories existed about the exact cause of the low platelets in HIT. Gradually, evidence accumulated on the exact underlying mechanism, and diagnostic tests for the condition emerged in the 1980s.^[2] Treatment was initially limited to aspirin and warfarin, but the 1990s saw the introduction of a number of agents that could provide anticoagulation without a risk of recurrent HIT.^[2] Older terminology distinguishes between two forms of heparin-induced thrombocytopenia: type 1 (mild, non-immune mediated and self-limiting fall in platelet count) and type 2, the form described above. Currently, the term HIT is used without a modifier to describe the immune-mediated severe form.^[2]

References