How far does the platelet count have to fall to suspect HIT?
First, it is important to appreciate that the patient need not be thrombocytopenic to suspect HIT. It is more important to look at the change in platelet number relative to the pre-heparin count. Most patients will experience a fall of >50% from their baseline. However, smaller falls may occur, and occasionally the platelet count may not fall, even if the patient develops thrombosis.

Can a patient that has developed HIT in response to unfractionated heparin be treated with low molecular weight heparin?
Absolutely not. Although LMWH may be less likely to cause HIT in the first place, once an antibody has formed to unfractionated heparin, it almost invariably crossreacts with the low molecular weight forms. It's use as a treatment for HIT is strictly contraindicated.

How often should the platelet count be monitored?
There is no real consensus on this issue. If the patient has never had heparin before (which is often difficult to determine with certainty), it may be safe to perform a pre-heparin count and then perform counts every other day starting 4 days after treatment began. In all other patients, counts should be performed pre-heparin and at least on alternate days thereafter. Daily counts may be preferable, although no studies have been performed to determine the optimum frequency.

How soon after heparin is started can HIT develop?
In about 70% of cases, HIT develops 5-14 days after starting heparin treatment. However, there is an important variant - termed Immediate Onset HIT - in which the patient may develop symptoms very soon after heparin exposure. Such patients have a pre-existing heparin-PF4 antibody and have usually had a previous exposure to heparin in the last 3 months. We recently described a Delayed Onset form in which a patient may present with thrombotic symptoms days or weeks after heparin exposure.

Medical textbooks refer to HIT as "White Clot Syndrome". Does this mean that thrombosis in HIT is always arterial?
No. Although arterial thrombosis does occur, and can be very serious, venous thrombosis is at least as common. Isolated deep vein thrombosis (DVT) can - and does - occur, as does pulmonary embolism.

What tests are available for confirmation of a diagnosis of HIT?
Tests for HIT are divided into two main types. Functional assays measure the ability of the circulating heparin-platelet factor 4 antibody to activate normal platelets. These mainly include the Serotonin Release Assay (SRA) and platelet aggregation test, although flow cytometry is another effective way to detect functional HIT antibodies. Immunological assays (typified by the enzyme-linked immunoassay - ELISA) detect the presence of the antibody, but do not rely on its ability to activate platelets. In general, the functional assays have greater specificity for HIT, but the immunoassays are more sensitive.

What test should I use - functional or immunological?
This depends on the capabilities of your laboratory. The immunoassays are easier to perform reliably and the reagents are commercially available. However, they also need to be interpreted in the light of the pre-test probability that the patient has HIT. For example, about 50% of patients undergoing open heart surgery will develop a positive ELISA test, yet do not have symptoms of HIT.

Does a negative lab test for HIT exclude the diagnosis?
Not necessarily. No currently available lab test is 100% sensitive for this condition and it therefore remains a clinical diagnosis. In our experience, the ELISA assays for the heparin-PF4 antibody are rarely repeatedly negative in the patient with clinical HIT. However, it should also be noted that these assays may be positive in patients without clinical symptoms, especially after cardiac surgery. Our experience is that initially negative lab tests will become positive in many cases if the test is repeated a day or so later.

What drugs are currently available to treat patients with HIT?
Currently, the treatment of choice for the HIT patient is a Direct Thrombin Inhibitor. As the name suggests, these agents inhibit thrombin directly, preventing thrombosis and further platelet activation. They are not chemically related to heparin, so there is no problem with crossreactivity with the heparin-PF4 antibody.

In the U.S., lepirudin (Refludan®) is approved for the treatment of HIT, while Argatroban is approved for both treatment and prophylaxis. It is likely that other thrombin inhibitors such as bivalirudin (Angiomax®) will also be useful in HIT patients, although the drug is not yet approved by the FDA for this indication. Nevertheless, we have treated a number of patients with bivalirudin very successfully.

Can the anticoagulant effects of direct thrombin inhibitors be reversed?
No, there are no antidotes, or reversal agents, for any of the direct thrombin inhibitors (DTI) currently on the market. Reversing their anticoagulant effect rests primarily on stopping treatment and relying on the relatively short plasma half lives to clear the drug. The effect of lepirudin may be reduced by dialysis, and there is some evidence that the APTT may be shortened by DDAVP in patients receiving DTIs. However, it is not clear whether DDAVP also reduces bleeding risk.

Do the Direct Thrombin Inhibitors affect the INR?
Any agent that blocks thrombin activity has the potential to interfere with a clot-based laboratory test, including the Prothrombin Time, from which the INR is calculated. However, the effect of lepirudin on the INR seems to be much less than that of Argatroban. Our experience is that the effect of bivalirudin monotherapy on the INR is small and predictable.

The results from hypercoagulability work-ups should be interpreted cautiously if the blood was drawn while the patient was receiving DTI therapy.Because these drugs interfere with all clot-based assay, Protein C and S levels are spuriously affected and tests for Lupus Anticoagulants can be falsely positive.

How long should treatment with Direct Thrombin Inhibitors be continued?
The thrombin inhibitor should be used until the platelet count has at least normalized and preferably stabilized. This indicates that the acute platelet activation has subsided.

Can the Direct Thrombin Inhibitors be given subcutaneously?
Currently, the direct thrombin inhibitors approved by the FDA for the treatment and/or prophylaxis of HIT must be given intravenously. There are published data on the use of subcutaneous lepirudin and a commonly used regimen for this agent is 15 mg s.c. b.i.d. There are no data on the subcutaneous use of argatroban, and the very short plasma half life of bivalirudin would most likely preclude its administration in this way.

Are the Direct Thrombin Inhibitors themselves associated with antibody formation?
There is no evidence that Argatroban or bivalirudin elicit antibody formation and these agents can safely be re-administered to patients with a previous exposure history. Lepirudin, in contrast, causes the production of anti-lepirudin antibodies in some 40-50% of patients. These antibodies are non-neutralizing, but are thought to prolong the plasma clearance of the drug. Recently (October, 2002) the FDA stated that they were aware of five patients that had died following acute anaphylactic reactions to lepirudin. Repeat exposure to this drug should therefore only be undertaken with caution, and the use of an alternative Direct Thrombin Inhibitor is recommended in this situation.

Is it safe to re-expose someone to heparin who has a history of HIT?
Possibly. The heparin-PF4 antibody is relatively transient; 90% of antibodies are no longer detectable about 90 days after initial heparin exposure. There are some published data to suggest that LIMITED re-exposure to heparin may be safe as long as the patient is demonstrably antibody negative. It would be important to test with the same assay that the patient originally tested positive by to be sure that the antibody has disappeared. However, the availability of effective, FDA-approved, alternative anticoagulants, means that repeat exposure can, and probably should, be avoided where possible.

Is coumadin an appropriate treatment for HIT?
Not while there is ongoing platelet activation and thrombin generation. In fact, coumadin is absolutely contraindicated as monotherapy for HIT. Coumadin will reduce the patient's Protein C level, making it even more difficult to control thrombin production. Since this occurs in advance of therapeutic depletion of Factors II and X (the basis of coumadin's antithrombotic action) the patient is actually pushed further into a hypercoagulable state. The use of loading (>5 mg) doses of coumadin will exacerbate this problem. Once the platelet activation and thrombin genration is under control, for example with thrombin inhibitors, the patient may safely be converted to coumadin therapy. Patients with HIT are often sensitive to the effect of oral anticoagulants and starting cautiously, with a lower than usual dose (e.g. 1 mg) is recommended.

Where can I get a test for HIT done?
The Florida Hospital Center for Hemostasis and Thrombosis performs the ELISA test for the HIT antibody seven days a week. Samples received in our laboratory by 10 am (e.g. via overnight FedEx) will be tested and resulted by 5 pm the same day.

We also offer the Serotonin Release Assay (SRA) with a turnaround time (from sample receipt) 7 days.

You can call the laboratory directly at (407) 303-2449 or contact Dr. John Francis for more information.