Heparin-induced thrombocytopenia resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Karol Gema Hernandez, M.D. [2], Rim Halaby, M.D. [3]

Definition

Heparin induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that predisposes to elevated risks of arterial and venous thromboembolism.

Types of HIT according to onset:

• Typical-onset HIT: within 5 to 10 days following the initiation of heparin
• Early-onset HIT: within 24 hours following the initiation of heparin
• Delayed-onset HIT: up to 3 weeks following the discontinuation of heparin

Types of HIT according to the presentation

• HITT: Heparin induced thrombocytopenia with thrombosis
• Isolated HIT: Heparin induced thrombocytopenia without evidence of thrombosis
• Subacute HIT: Platelet level is back to normal following an acute episode of HIT; however, HIT antibodies are still positive.

Causes

Life Threatening Causes

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. HIT is a life-threatening condition and must be treated as such irrespective of the causes.

Common Causes

• Heparin

Screening for HIT

❑ Asses the risk of HIT

Patient Population (Minimum of 4 day Exposure) Incidence of HIT, % Postoperative patients Heparin prophylactic dose 1-5 Heparin therapeutic dose 1-5 Heparin flushes 0.1-1 LMWH prophylactic or therapeutic dose 0.1-1 Cardiac surgery patients 1-3 Medical patients Patients with malignacy 1 Heparin prophylactic or therapeutic dose 0.1-1 LMWH, prophylactic or therapeutic dose 0.6 Intensive care unit patients 0.4 Heparin flushes < 0.1 Obstetrics patients <0.1

Risk <1%

Risk >1%

❑ Do not monitor platelet count

❑ Monitor platelet count every 2 or 3 days from day 4 to day 14 (or until heparin is stopped)

Algorithm based on the 2012 ACCP evidence based clinical practice guidelines.

Diagnostic Approach to HIT

Thrombocytopenia ❑ Platelet count <150,000/mm3, OR ❑ >30-50% decrease of platelet from baseline ❑ Recent heparin or LMWH use in the previous 5- 14 days

Characterize the symptoms (if present): ❑ Arterial thromboembolism (MI, acute limb ischemia or stroke) ❑ Venous thromboembolism (DVT or PE) ❑ Unusual manifestations: - Skin necrosis at SC heparin injection sites - Transient global amnesia ❑ Absence of petechiae and/or significant bleeding

Consider alternative diagnoses: ❑ Infection ❑ Medications other than heparin ❑ DIC ❑ Hemodilution ❑ Intravascular devices ❑ Extracorporeal circuits

Suspicion of HIT Assess the probability of HIT by the 4 T's score

Low clinical probability

Intermediate/high clinical probability

Unlikely HIT ❑ Consider alternative diagnoses ❑ Continue heparin

❑ Discontinue heparin ❑ Begin alternative anticoagulation

❑ Order anti platelet factor 4 antibodies

Moderately/strongly positive test

Weakly positive test PLUS High clinical probability

Weakly positive test PLUS Intermediate clinical probability

Negative

❑ Order functional assay

Unlikely HIT ❑ Consider alternative diagnoses ❑ Continue heparin

Positive test: Likely HIT

Negative test: Unlikely HIT ❑ Consider alternative diagnoses ❑ Continue heparin

The most studied functional assays are serotonin release assay (SRA) and Heparin induced platelet activation assay (HIPA).

The diagnostic algorithm is based on "How I treat heparin-induced thrombocytopenia" from Blood (2012).

Treatment of HIT

High suspicion or confirmed HIT

HITT

Isolated HIT

❑ Perform a lower extremity US to R/O asymptomatic DVT

Presence of asymptomatic DVT

No DVT

❑ Discontinue heparin ❑ Initiate non heparin anticoagulation for 3-6 months: - Argatroban (can be used in renal insufficiency) - Lepirudin - Danaparoid

❑ Discontinue heparin ❑ Initiate non heparin anticoagulation until platelets are back to normal: - Argatroban (can be used in renal insufficiency) - Lepirudin - Danaparoid

❑ Check if patient is/needs to be on vitamin K antagonist (VKA)

❑ Don't start VKA until the platelet count goes back to normal, after which initiate VKA at low doses ❑ When VKA is to be started, overlap it with non heparin anticoagulant for at least 5 days until INR is within the target range ❑ If VKA is started when patient is diagnosed with HIT, administer vitamin K

Special Considerations

Shown below is a table summarizing the appropriate choice of anticoagulation therapy in special situations.

Special situations	Acute HIT or subacute HIT (normal platelets and positive antibodies)	Past medical history of HIT
Cardiac surgery	Urgent cardiac surgery: Use bivalirudin Non urgent cardiac surgery: Delay the surgery until HIT has resolved and antibodies are negative	Negative antibodies: Use heparin (short term) Positive antibodies: Use bivalirudin
PCI	Use bivalirudin or argatroban	Use bivalirudin or argatroban
Renal replacement therapy	Use argatroban or danaparoid	Use regional citrate
Pregnancy	Use danaparoid	-

Dosages of non Heparin Anticoagulants

Agent	Dosage
Direct FXa inhibitors
Argatroban	Continuous infusion: ♦ Normal organ function: 2 μg/kg per minute ♦ Liver dysfunction (total serum bilirubin 1.5 mg/dL), heart failure, postcardiac surgery, anasarca: 0.5-1.2 μg/kg per minute
Lepirudin	Bolus:0.2 mg/kg (only for life- or limb-threatening thrombosis) Continuous infusion: ♦ Cr < 1.0 mg/dL: 0.10 mg/kg per hour ♦ Cr 1.0-1.6 mg/dL: 0.05 mg/kg per hour ♦ Cr 1.6-4.5 mg/dL: 0.01 mg/kg per hour ♦ Cr > 4.5 mg/dL: 0.005 mg/kg per hour
Bivalirudin	Continuous infusion: ♦ Normal organ function: 0.15 mg/kg per hour ♦ Renal or hepatic dysfunction: dose reduction
Indirect factor Xa inhibitors
Danaparoid	Bolus: ♦ < 60 kg: 1500 U ♦ 60-75 kg: 2250 U ♦ 75-90 kg: 3000 U ♦ > 90 kg: 3750 U Accelerated initial infusion: 400 U/hour every 4 hours, then 300 U/hour every 4 hours Maintenance infusion: ♦ Normal renal function: 200 U/hour ♦ Renal insuficiency: 150 U/hour

4 T's Score

Shown below is the 4T's score used to estimate the probability of HIT. Only one option is selected for each of the 4T's criteria and the scores are added up. The probability of HIT is:

• Low if score is 1-3
• Intermediate if score is 4-5
• High if score is 6-8

	Score = 2	Score = 1	Score = 0
Thrombocytopenia	♦ Fall of > 50% in platelet count PLUS platelet nadir of ≥ 20 x 109/L PLUS absence of surgery in the last 3 days	♦ Fall of > 50% in platelet count PLUS surgery in the last 3 days OR ♦ Fall in platelet count 30-50% OR ♦ Platelet nadir 10-20 x 109/L with any platelet fall	♦ Fall of< 30% platelet count OR ♦ Platelet nadir < 10 x 109/L with any platelet fall
Timing (of platelet count fall or thrombosis)	♦ Platelet fall day 5-10 following the initiation of heparin OR ♦ Platelet fall within 1 day following the initiation of heparin PLUS previous exposure to heparin in the last 5 to 30 days	♦ Unclear platelet fall day 5-10 following the initiation of heparin OR ♦ Platelet fall within 1 day following the initiation of heparin PLUS previous exposure to heparin in the last 31-100 days ♦ Platelet fall after day 10	♦ Platelet fall ≤ day 4 PLUS no exposure to heparin in the past 100 days
Thrombosis (or other clinical sequelae)	♦ Confirmed new venous or arterial thrombosis ♦ Skin necrosis at injection site ♦ Anaphylactoid reaction to IV heparin bolus ♦ Adrenal hemorrhage	♦ Recurrent venous thrombosis in a patient receiving anticoagulation therapy ♦ Suspected thrombosis (pending investigation results) ♦ Erythematous skin at the injection sites of heparin	♦ None
OTher causes of thrombocytopenia	♦ No alternative etiologies for platelet fall	♦ Possible other etiologies: ♦ Sepsis ♦ Initiation of ventilator ♦ Other	♦ Probable other etiologies: ♦ Surgery in the last 72 hours ♦ Bacteremia/fungemia ♦ Chemotherapy or radiation within past 20 days ♦ DIC ♦ Posttransfusion purpura (PTP) ♦ Other medications ♦ Non-necrotizing skin lesions at injection site ♦ Other

Do's

• In case of severe thrombocytopenia among patients with HIT, administer platelet transfusions when the patient is bleeding or when performing procedures associated with an elevated risk of bleeding.