Treatment

What would you recommend to the patient’s surgery team?

Tell them to continue heparin

Not a good idea!

Ask them to stop heparin, but no need for further anticoagulation

Discontinuation of heparin without starting substitute anticoagulant may not immediately reduce the risk of thromboembolism.

Suggest that heparin be stopped and an inferior vena cava filter be placed

2018 ASH clinical practice guideline states: “In patients with acute HITT (HITT = HIT complicated by thrombosis) or acute isolated HIT, the ASH guideline panel recommends against routine insertion of an inferior vena cava (IVC) filter”.¹

Recommend stopping heparin and starting an alternative anticoagulant

As we will see, both steps are CRUCIAL: immediately STOP heparin, and START a different anticoagulant, pending immunoassay results.

Add an alternative anticoagulant on top of heparin

All heparin must be stopped immediately.

Returning to a schematic we saw in the Labs section, the results of the 4T score determine the course of action not only with regard to further investigation (immunoassay) but also with regard to management (continue or stop heparin). If heparin is stopped, an alternative non-heparin anticoagulant must be started.

Our patient had a 4T score of 6. As we discussed in the section on labs, blood should be sent for an immunoassay. In addition, heparin should be discontinued, and a suitable anticoagulant started in its place.

What are acceptable alternative anticoagulants to heparin?

Low molecular weight heparin (LMWH)

Neither LMWH nor any other heparin preparation should be used for the treatment of HIT.

Fondaparinux

Per the 2018 ASH guideline, fondaparinux is a reasonable option in clinically stable patients at average risk of bleeding.¹

Argatroban

In patients with critical illness, increased bleeding risk, or increased potential need for urgent procedures, argatroban or bivalirudin may be preferred because of shorter duration of effect. Avoid argatroban in patients with severe hepatic dysfunction.

Bivalirudin

In patients with critical illness, increased bleeding risk, or increased potential need for urgent procedures, argatroban or bivalirudin may be preferred because of shorter duration of effect.

Coumadin

The administration of vitamin K antagonists (VKA) such as coumadin in patients with HIT may lead to skin necrosis and venous limb gangrene; VKA therapy should not be started until platelets have substantially recovered (usually to at least 150 × 10⁹/L).

In the previous question, DOACs were not offered as an option. Can we use DOACs in a patient with heparin-induced thrombocytopenia (HIT)?

Yes

The 2018 ASH clinical practice guideline states that DOACs are “reasonable options in clinically stable patients at average risk of bleeding. May not be ideal In patients with HIT complicated by life- or limb-threatening thromboembolism. Most published experience in HIT is with rivaroxaban, at a dose of 15 mg twice per day for 3 weeks followed by 20 mg once per day for HITT, and rivaroxaban 15 mg twice per day until platelet count recovery (usually a platelet count of ≥150 × 109/L) followed by 20 mg once per day for acute HIT”.¹

Table of anticoagulants used to treat patients with heparin-induced thrombocytopenia (HIT).

Drug	Mechanism	Route of administration	Elimination
Argatroban	Small molecule direct thrombin inhibitor	IV, continuous infusion	Liver
Bivalirudin	Synthetic analog of hirudin (from leech), a direct thrombin inhibitor	IV, continuous infusion	Enzymatic
Fondaparinux	Synthetic pentasaccharide factor Xa (FXa) inhibitor	SC	Kidney
Rivaroxaban	Direct FXa inhibitor	PO	Kidney

IV, intravenous; SC, subcutaneous; PO, oral

Table of anticoagulants used to treat patients with heparin-induced thrombocytopenia (HIT) (cont’d).

Drug	Dose	Lab monitoring	Comments
Argatroban	Normal organ function → 2 μg/kg/min Liver dysfunction (bilirubin >1.5 mg/dL) Heart failure, multiple organ system failure, severe anasarca, or postcardiac surgery → 0.5-1.2 μg/kg/min	Adjust to aPTT 1.5-3.0 times baseline.	Preferred agent if patient has impaired renal function; contraindicated in patients with severe hepatic failure.
Bivalirudin	Normal organ function → 0.15 mg/kg/h Renal or liver dysfunction → dose reduction may be appropriate	Adjust to aPTT 1.5-2.5 times baseline.	Recommended for those undergoing cardiac surgery or percutaneous coronary interventions.
Fondaparinux	<50 kg (110 lbs) → 5 mg once per day 50-100 kg (110-221 lbs) → 7.5 mg once per day >100 kg (221 lbs) → 10 mg once per day	None	Cannot be used in patients with renal dysfunction.
Rivaroxaban	HITT: 15 mg twice per day × 3 weeks, then 20 mg once per day HIT: 15 mg twice per day until platelet count recovery	None	Included in the 2018 ASH guideline as an acceptable alternative, though not in those with complicated by life- or limb-threatening thromboembolism.

What would you recommend if the patient was taking warfarin/coumadin at the time of onset of heparin-induced thrombocytopenia (HIT)?

I would continue the vitamin K antagonist, though only in the presence of an alternative non-heparin anticoagulant

I would recommend stopping the warfarin/coumadin

I would recommend stopping the warfarin/coumadin and administer vitamin K while starting a non-heparin anticoagulant

ASH clinical practice guideline: “In these patients, the VKA would be discontinued, and intravenous vitamin K would be administered concomitant with initiation of a non-heparin anticoagulant.”¹

Should I add aspirin to the treatment regimen?

Yes

Aspirin is not routinely recommended in patients with HIT, though such a decision may be affected by presence of other indications for antiplatelet therapy (for example, coronary artery disease or recent coronary stent placement).

You recommend that the surgery team start argatroban. What is argatroban?

A von Willebrand factor inhibitor

A factor VIII inhibitor

A thrombin inhibitor

A direct thrombin inhibitor, meaning that it does not require antithrombin for its action.

A fibrinolytic agent

How is argatroban dosed and monitored?

Orally, no monitoring

SC, no monitoring

IV, no monitoring

IV, monitoring of factor Xa levels

IV, monitoring of aPTT

Correct. Adjust to aPTT 1.5-3.0 times baseline.

Meanwhile the immunoassay comes back positive, at high titer. What is the next step?

Recommend 6 months of anticoagulation

Obtain a serotonin release assay

Correct. Some would argue that patients with a high-probability 4Ts score and very strongly positive immunoassay can forgo a serotonin release assay (since it will likely be positive), but as a general rule: positive immunoassay –> obtain a serotonin release assay. Functional assays such as the serotonin release assay are regarded as gold-standard for the diagnosis of HIT. However, these tests are time-consuming and available in few laboratories.

Stop all anticoagulants

This could have catastrophic consequences.

Place an inferior vena cava (IVC) filter

IVC filters should not be placed in patients with HIT.

Diagnosis of heparin-induced thrombocytopenia (HIT) confirmed, continue anticoagulants without further workup

The immunoassay is sensitive, not specific for HIT.

For information on HIT immunoassays, click here.

For information on the serotonin release assay, click here.

What would you do if the immunoassay came back negative?

Discontinue non-heparin anticoagulant and resume heparin

Correct. The VAST majority of patients with a negative immunoassay do NOT have HIT. If a false negative immunoassay result is suspected, it can be repeated or a serotonin release assay can be ordered.

Continue the non-heparin anticoagulant

Diagnostic and initial treatment algorithm. Based on ASH pocket guide.

Because the immunoassay in this case was positive, you order a serotonin release assay. It is a send out test and takes several days to come back. While you wait for the result, what action would you take?

Discontinue non-heparin anticoagulant and resume heparin

No. You should assume the patient has heparin-induced thrombocytopenia (HIT) until proven otherwise by the serotonin release assay.

Continue the non-heparin anticoagulant

The serotonin release assay comes back positive. This patient’s actual result is shown below:

You may run into the terms pretest probability and post-test probability in the heparin-induced thrombocytopenia (HIT) literature.

The pretest probability is the probability of having HIT based on the initial 4T score. For example, patients with a score of 6 or higher (such as our patient) have a high pretest probability (> 60%) of having HIT.
The post-test probability is the probability of having HIT (as diagnosed by the gold standard serotonin release assay) based on the results of the immunoassay.

Back to our patient, should you consider transfusing him with platelets?

Yes

ASH clinical practice guideline states: “In patients with acute HITT or acute isolated HIT who are at average bleeding risk, the ASH guideline panel suggests against routine platelet transfusion (conditional recommendation, low certainty in the evidence about effects). Remark: Platelet transfusion may be an option for patients with active bleeding or at high risk of bleeding”.¹

The surgery team looking after the patient asks whether they should screen for deep vein thrombosis (DVT) in the legs. The patient has no leg swelling, pain or discoloration. What is your recommendation?

Yes, screen for DVT

ASH clinical practice guideline states: “In patients with acute isolated HIT, the ASH guideline panel suggests bilateral lower-extremity compression ultrasonography to screen for asymptomatic proximal deep vein thrombosis (DVT).”¹

No, do not screen for DVT

The patient’s platelet counts improve over the next several days while receiving argatroban. He is ready to go home. What are your recommendations for continued anticoagulation?

Stop all anticoagulants at time of discharge

If the patient did not have evidence of venous thromboembolism, recommendations vary from discontinuation of anticoagulants once platelet count recovers to treatment with an anticoagulant for 6 weeks.

Switch from argatroban to vitamin K antagonist

Switch from argatroban to a DOAC

The 2018 ASH guideline suggests treatment with a DOAC (e.g., dabigatran, rivaroxaban, or apixaban) rather than a vitamin K antagonist (VKA) in patients with isolated HIT (no thrombosis) whose platelet count recovers, yet are treated for a period of time with anticoagulation. A similar approach may be used if there is another indication for anticoagulation, as in this case the patient’s development of pulmonary embolus, which should be treated for at least 3 months.¹

HIT, heparin-induced thrombocytopenia; HITT, heparin-induced thrombocytopenia with thrombosis.

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Treatment

How rapdily should plasma exchange be initiated?