What Every Pharmacist Should Know about Heparin-Induced Thrombocytopenia
Steph’s Note: We return this week with Dr. Josef Nissan, who recently provided us with the long-awaited, much-anticipated article on vasopressors. (If you haven’t perused that one yet, you really should. Who knew Mike Tyson could be so educational?) This time, he’s tackling a topic that every pharmacist should be familiar with - heparin-induced thrombocytopenia (HIT). As a potentially fatal medicated-related adverse event, we all need to be cognizant of this not-as-rare-as-you-may-think complication so we can head off trouble…before it becomes T-R-O-U-BLE!!
If you’re looking for a handy guide to carry around with you when you’re covering the ICU/ED, check out our Pocket Guide to Pharmacotherapy Management of Acute Medical Emergencies. It covers HIT and a bunch of other essential critical care topics.
The number of times heparin is administered in a hospital on a given day, according to Carl Sagan. (Image)
If you’ve worked in a hospital at all, then you’ve undoubtably seen heparin used hundreds of times. Seems like we hand it out like candy. Heparin can be used for the inpatient management of numerous disease states, such as venous thromboembolism (VTE) prophylaxis, VTE treatment, myocardial infarctions, dialysis catheter flushes, new onset atrial fibrillation, and the list goes onnnn.
Why do we use it so much?
Because overall, it’s very effective, fairly safe, has a short half-life, does not require renal or hepatic dose adjustments (YAY for pharmacists), and therapeutic levels can be monitored by trending the aPTT. For all of these reasons, heparin is quite an attractive option for inpatient anticoagulation. But is it all good?
I mean come on, everybody has flaws. And yes, yes, heparin has flaws as well. The biggest one is the increased risk of developing heparin-induced thrombocytopenia (HIT).
Ughh HIT. It’s the worst.
Before we go too deep into how awful HIT is, we need to make sure we’re being extra clear here. So let’s distinguish between the two main classifications of HIT: Type I and Type II.
HIT Type I, also known as HAT or heparin-associated thrombocytopenia, is practically irrelevant. It’s not clinically significant and is typically associated with a mild drop in platelets with NO risk of thrombosis. Treatment includes supportive care and monitoring to ensure that platelet counts recover (which they should).
On the other hand, HIT Type II is an autoimmune medical emergency associated with an increased risk of developing life-threatening thrombosis. See below for a quick summary of the differences between HIT Type I and HIT Type II.
Our focus today is on HIT Type II. So any time I say HIT from now until the end of this post, always assume that I am talking about HIT Type II.
So as the table above shows, HIT is a medical emergency that occurs in up to 5% of patients receiving heparin products (unfractionated heparin and/or low molecular weight heparin). If not diagnosed and treated quickly, it can be life-threatening with a mortality rate of up to 30%.
How can HIT be fatal, you ask?
HIT is associated not only with a drop in platelets but also with hypercoagulability. Wait, did I just say hypercoagulability…meaning increased risk of clotting? But I thought you said there’s a drop in platelets? How does that make any sense? Shouldn’t a drop in platelets increase the risk of bleeding instead since they help the body clot? (Ahh yes, a topic that persistently confused me as an APPE student.)
This may seem confusing, but it really isn’t, I promise. To prove it, let’s dig deeper into the pathophysiology of HIT.
Pathophysiology of Heparin-Induced Thrombocytopenia (HIT)
Let’s make this as simple as possible (the KISS rule, #amIright?).
Our platelets contain a small chemokine called Platelet Factor 4 (PF4). The normal physiological function of PF4 is to promote blood coagulation. So let’s say you’re making a nice chicken curry dinner when you accidentally cut your finger with a knife. Your platelets activate, causing a release of PF4, which promotes clotting to help stop the active bleed.
In the case of HIT and exposure to heparin, this released PF4 (for some reason) decides to bind to heparin forming a PF4-Heparin complex. This triggers the release of antibodies, such as IgG, IgM, and IgA (hence why this is an autoimmune disease state). IgG falls in love with the PF4-Heparin complex and decides it wants to bind to that complex. The binding of IgG to the Heparin-PF4 complex then activates platelets and causes the release of thrombin, leading to hypercoagulability.
So we now know where the hypercoagulability comes from. But where does thrombocytopenia enter the picture?
Well, it occurs for two reasons. First, platelet activation and aggregation decreases serum platelet counts since these platelets are being used to form thrombus. So as you continue to form a clot, more platelets are used in that clot, which means lower serum platelet levels. Aka thrombocytopenia. Second, our macrophages activate to help consume the IgG-tagged platelets, leading to their destruction. Aka thrombocytopenia. Here is a nice picture that explains everything we just discussed:
(Image)
Assessment and Diagnosis of HIT
Usually I don’t really stress too much about the diagnosis portion of disease states. However, as pharmacists, it’s our responsibility to be able to recognize signs and symptoms of HIT given that we are the medication experts - and this is a medication-related disease state.
Luckily, evaluating for HIT is actually relatively straightforward. There are four main factors to consider when evaluating the probability of an acute HIT reaction. What are these 4 factors?
They’re called the 4T’s: Thrombocytopenia, Timing of platelet decrease, Thrombosis, and Other causes of thrombocytopenia. Let’s look at the table below to see how to calculate a 4T score:
In the end, a higher 4T score is associated with a higher probability risk of an acute HIT reaction:
0-3 points: low probability of HIT (<1%)
4-5 points: moderate probability of HIT (~10%)
6-8 points: high probability of HIT (~50%)
Because the 4T score is so easy to assess from a quick chart review, it’s usually the first step towards risk stratifying a patient for HIT. But it’s just that - a risk assessment, not a diagnostic tool. In order to truly diagnose a patient with HIT, additional lab work is necessary.
These diagnostic labs include the anti-PF4 ELISA and the Serotonin Release Assay (SRA). The anti-PF4 ELISA detects the presence of immunoglobulin antibodies directed against PF4. This test has a high sensitivity for HIT but a low specificity. This combination means that a negative value pretty accurately rules out HIT - but a positive value doesn’t necessarily rule in acute HIT. (For a refresher on sensitivity versus specificity, check this out.)
So in the case of a positive anti-PF4 ELISA result, it’s essential to then proceed to a confirmatory platelet function assay, which is commonly the SRA. This test exposes donor platelets to a patient’s serum in the presence of heparin. If the patient’s blood has anti-PF4, it will activate those donor platelets, leading to serotonin release. Voila, pretty slick, right?
(An alternative is the Heparin Platelet Aggregation Test, or HPAT. But it has a lower sensitivity for HIT than the SRA, which is why it’s not preferred.)
Neither the SRA nor the HPAT functional assays are as sensitive as the anti-PF4 ELISA, but they do have a higher specificity, which is why they can be used to confirm and rule in a diagnosis of HIT. Just know that the SRA is generally only performed as a reflex assay in the case of a positive anti-PF4 ELISA test. And taken together, the results of these two sequential tests are highly sensitive for acute HIT diagnosis.
BTW - This is a lot of information. We’ve got a downloadable (and printer-friendly) PDF of this article that you can download here. It’s great for offline viewing and for writing notes.
Treatment of HIT
Alright folks, strap in because we’re going for a ride on the anticoagulation train.
First, ALWAYS start treatment as soon as you calculate a 4T score ≥4 (i.e., moderate probability of HIT). The MOST important step is to discontinue ALL forms of heparin. This means scanning not only the scheduled medications for heparin TID, but also looking for any heparin infusions, PRN boluses, heparin flushes, coated catheters, and heparin in dialysate. When I say all forms of heparin, I mean ALL forms!!
Stopping the heparin is imperative for preventing further formation of the PF4-Heparin-IgG complex, which results in less platelet activation and decreased risk of thrombus formation.
Second, after stopping all heparin products, we MUST start therapeutic anticoagulation to treat/prevent acute thrombosis. So which anticoagulants do we use? Non-heparin ones of course! Let’s review our options:
Direct Thrombin Inhibitors
Argatroban
Bivalirudin
Dabigatran
Factor Xa Inhibitors
Fondaparinux
Direct Oral Anticoagulants (DOACs)
Preferred Agents for Treating HIT
There are so many options. Which should you choose?
Unfortunately, it’s not all that easy because every patient is different, and no single drug fits all cases. That being said, the intravenous agents, such as argatroban and bivalirudin, are usually preferred for initial therapy. This is due to their short half-lives and rapid reversal upon discontinuation in the setting of a bleed or an emergent procedure.
As far as choosing between those two agents…
Argatroban is hepatically eliminated, and dose adjustment is required for patients with hepatic impairment. On the other hand, bivalirudin is renally eliminated, and dose adjustment is required for patients with renal impairment. Long story short:
If your patient has RENAL impairment, use argatroban.
If your patient has HEPATIC impairment, use bivalirudin.
If your patient has NEITHER hepatic NOR renal impairment, use either argatroban or bivalirudin.
If your patient has BOTH hepatic AND renal impairment, use either argatroban or bivalirudin - but at LOWER DOSES.
Alternative Agents for Treating HIT
The non-IV anticoagulants, including fondaparinux, dabigatran, and the DOACs, are usually second-line options for the acute management of HIT. Let’s review quick clinical pearls for each agent:
How to Choose an Anticoagulant for HIT
Like I said before, every patient case is different, and no one agent fits all cases. That being said, there are better agents for certain scenarios. So let’s review some practical applications:
Patients with acute thromboses that require rapid full-dose anticoagulation…
PREFERRED agents: argatroban or bivalirudin
Patients who may require invasive procedures or those who have a high risk of bleeding…
PREFERRED agents: argatroban or bivalirudin
Patients with chronic kidney disease or acute kidney injury…
PREFERRED agent: argatroban
Patients with significant hepatic impairment…
PREFERRED agents: bivalirudin or fondaparinux
Patients with combined renal and hepatic impairment…
PREFERRED agents: argatroban or bivalirudin at reduced doses
Patients with lack of IV access…
PREFERRED agents: fondaparinux, dabigatran, or DOACs
Pregnant patients…
PREFERRED agents: argatroban, bivalirudin, or fondaparinux
Duration of Anticoagulation for HIT
The length of anticoagulation treatment following an episode of HIT has NOT been defined in any prospective study. The American College of Chest Physicians (ACCP) and the American Society of Hematology (ASH) guidelines recommend the following:
Patients WITHOUT thrombosis: continue therapeutic anticoagulation for a MINIMUM of 4 weeks
Patients with ACTIVE thrombosis: continue therapeutic anticoagulation for a MINIMUM of 3 months
The tl;dr of HIT
Heparin-induced thrombocytopenia (HIT) can be classified as HIT Type I or HIT Type II. HIT Type I (aka heparin-associated thrombocytopenia or HAT) is clinically insignificant and is associated with a mild drop in platelets with NO risk of thrombosis. On the other hand, HIT Type II is an autoimmune medical emergency associated with an increased risk of developing life-threatening thrombosis.
Thrombosis occurs due to antibodies (IgG) binding to the PF4-Heparin complex, leading to the activation of platelets and release of thrombin. Thrombocytopenia occurs due to excess platelet aggregation and activation. As more platelets become activated to form clots, the circulating platelet reserve becomes smaller.
Or maybe it means to STOP ALL heparin products! (Image)
Calculating the 4T score is crucial in determining the probability risk for an acute HIT reaction. Cessation of all heparin products and initiation of non-heparin anticoagulation should be implemented whenever a 4T score of 4 or greater is calculated. A confirmatory platelet function test like the serotonin release assay (SRA) is required following a positive anti-PF4 ELISA test.
Non-heparin anticoagulants used for the treatment of HIT include argatroban, bivalirudin, fondaparinux, dabigatran, and DOACs. IV agents such as argatroban and bivalirudin are usually preferred for initial therapy given their short half lives and rapid reversal upon discontinuation in the setting of a bleed or an emergent procedure. Alternative non-heparin anticoagulants may be utilized in specific scenarios based on patient characteristics.
The length of treatment with anticoagulation following an episode of HIT is not well studied. The general consensus is that therapeutic anticoagulation for HIT should continue for at least 4 weeks if there’s no thrombosis or at least 3 months if a clot is present.
Alright, now that you’ve been armed with this knowledge about HIT, happy platelet monitoring!
If you haven’t already, check out our Pocket Guide to Pharmacotherapy Management of Acute Medical Emergencies. It’s the ride-or-die resource you’ll want to carry with you when you’re working in critical care.