Heparin-induced thrombocytopenia overview

# Overview

# Historical Perspective
The association between heparin and thrombosis with thrombocytopenia was noted in the 1950s. In the 1970s, it was noted that heparin exposure resulted in development of antibodies. In 2000, argatroban became available on the market for treatment of HIT. As of 2012, the American College of Chest Physicians (ACCP) updated their guidelines for management of HIT.

# Classification
Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. There are two forms of HIT: type I and type 2. Type II HIT is the main adverse effect of heparin use.

# Pathophysiology
Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. Heparin exposure triggers the release of PF4 from endothelial surfaces. Complexes of heparin and PF4 serve as neoepitopes, or new antigens, and can induce production of antibodies, since this large complex serves as an unfamiliar antigen to the body. Binding of IgG from the large complexes into the Fc gamma RII receptors triggers activation of the target cells containing the receptors and eventual release of platelet microparticles. This results in production of thrombin, which is highly thrombogenic and contributes to clot formation. Ultimately, this leads to thrombotic complications in the venous and arterial systems.

# Causes
Heparin-induced thrombocytopenia is caused by a variety of factors. It is typically caused by unfractionated heparin (moreso than low-molecular weight heparin). Females are more likely to develop HIT. Patients undergoing cardiac surgery are more likely to develop HIT.

# Differentiating Heparin-induced thrombocytopenia from other Diseases
Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. It should be differentiated by other causes of thrombocytopenia like hemolytic uremic syndrome, thrombotic thrombocytopenia, disseminated intravascular coagulation, post-transfusion purpura, and systemic lupus erythematosis.

# Epidemiology and Demographics
Worldwide, the prevalence of HIT (in persons exposed to heparin) ranges from a low of 200 per 100,000 persons to a high of 5,000 per 100,000 persons. In pediatric populations, the prevalence of HIT (in persons exposed to heparin) ranges from a low of 1,500 per 100,000 persons to a high of 3,700 per 100,000 persons with an average prevalence of 2,600 per 100,000 persons. In neonatal populations, the prevalence of HIT (in persons exposed to heparin) is as low as 330 per 100,000 persons. HIT is more prevalent in the African American race than the Caucasian race and occurs more commonly in females compared to males.

# Risk Factors
Increased risk for heparin-induced thrombocytopenia depends on type of heparin (unfractionated heparin more than low molecular weight heparin), duration of therapy, females, and type of patients (commoner in surgical patients that require large amount of heparin), and other factors. Protective risk factors include use of low molecular weight heparin, low PF4 antibody titers, and others.

# Screening
There are no screening methods for HIT. A diagnostic workup includes assessment of the anti-PF4 IgG optical density. However, this is not a screening tool for HIT.

# Natural History, Complications, and Prognosis
The natural history of HIT evolves over a period of a few weeks and terminates within 1 year. The development of antibodies to heparin-PF4 is the initial event, the disappearance of these antibodies is the final event. The complications of HIT include thrombotic events and hemorrhagic events. Thrombotic events are more common. The most severe complication of HIT is disseminated intravascular coagulation The prognosis of HIT depends on the presence and severity of thrombosis. If a patient experiences a high degree of thrombotic manifestations, the mortality can be quite high.

# Diagnosis

## History and symptoms
The history of HIT always involves exposure to heparin. Typical features of a patient's history depend on the type and location of thrombosis and whether the platelet count is sufficiently low to result in bleeding. Venous and arterial thromboses can result in variable symptoms. Symptoms of deep vein thrombosis include leg pain, swelling, and/or erythema. Symptoms of pulmonary embolism include dyspnea, pleuritic chest, and/or hypotension. Symptoms of arterial occlusion of a limb include limb pain and necrosis. Bleeding can occur spontaneously when the platelet count reaches very low levels, such as less than 10000 per microliter, though this is rare in HIT.

## Physical Examination
The physical exam for HIT focuses on the skin, pulmonary, and musculoskeletal exam. These are the common areas of thrombotic manifestations. Bleeding can also occur in these organs. A complete physical exam can help with evaluation of thrombosis or bleeding in other organs.

## Laboratory Findings
A variety of laboratory tests can be used to aid in the diagnosis of HIT. A complete blood count is always necessary and will show low platelet count. A high value of the PF4 IgG optical density can suggest HIT. Confirmatory testing is done with the serotonin release assay (SRA), heparin-induced platelet aggregation (HIPA) assay, or other functional assay. These confirmatory tests have high specificity.

## Chest X Ray
A chest X-ray is not a standard diagnostic workup test done for HIT, but it is useful for patients who develop thrombotic complications involving the chest. Chest X-ray can show Hamptom's hump, Westermark's sign, or Fleischner's sign.

## CT
CT scan is not part of the standard diagnostic workup for HIT, but it can be very useful if there is concern about bleeding or thrombosis from HIT in certain anatomical areas. For example, CT of the head can reveal intracranial bleeding or thrombosis. As another example, CT of the abdomen or pelvis can reveal intraabdominal bleeding or retroperitoneal hemorrhage.

## MRI
There is no specific role for MRI in diagnosis of HIT. However, MRI can be useful to help delineate a bleeding or thrombotic complication of HIT in a specific anatomical area, similar to the role of a CT scan. MRI offers better anatomical detail and is thus more sensitive that CT scan. However, the test is more expensive, so one must weigh the cost-benefit ratio. MRI is particularly useful for suspected dural venous sinus thrombosis.

## Imaging Findings
There are no other relevant imaging findings that are specific to HIT.

## Other Diagnostic Studies
There are no other diagnostic studies for HIT.

# Treatment

## Medical Therapy
Treatment of HIT involves prompt withdrawal of heparin or heparinoid and replacement with a suitable alternative anticoagulant. Lepirudin, fondaparinux, bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used to treat the thrombotic state. Out of these lepirudin and argatroban are available for use in USA. Clinical practice guidelines are available from the American College of Chest Physicians to direct treatment.

## Prevention
Primary prevention for HIT focuses on avoidance of heparin or heparin products. If there is no exposure to heparin, HIT cannot develop. For patients who much receive heparin, the use of low molecular weight heparin is preferred over unfractionated heparin with regards to prevention of HIT.