The Management of Heparin-Induced Thrombocytopenia and Thrombosis

• Background
• Diagnosis
• Investigation
• Treatment / Management
       1.0 Danaparoid
       2.0 Argatroban
       3.0 Haemodialysis patients
       4.0 Other options
       5.0 Anticoagulation in patients with a history of HIT
       6.0 Record keeping

Background

Immune mediated heparin-induced thrombocytopenia (HIT)

Immune mediated heparin-induced thrombocytopenia (HIT) with or without venous or arterial thrombosis (HITT) is a common and serious complication of treatment with heparin affecting up to 5% of individuals exposed to unfractionated and 0.5% of individuals exposed to low molecular weight heparin¹. Thrombocytopenia is an immune response occurring secondary to heparin dependent antibodies. HIT is caused by the development of IgG antibodies directed against a complex of platelet factor 4 (PF4) and heparin¹. The IgG/PF4/heparin complexes can result in activation of platelets and the formation of thrombin^2,3. HIT is distinguished from non-immune heparin induced thrombocytopenia by the clinical features of thrombosis and the presence of heparin dependent antibodies.

If HIT develops, the platelet count typically begins to fall 5 to 10 days after starting heparin therapy, although in patients who have received heparin in the previous 3 months it can have a rapid onset due to pre-existing antibodies^4,5. All patients started on any type of heparin should have a baseline platelet count monitored⁵. For those who have undergone surgery or cardio-pulmonary bypass and received any heparin in the previous 100 days, a count at 24 hours is advised⁵. No further monitoring is recommended for patients on LMWH unless they have undergone cardiac bypass⁵.  Patients on unfractionated heparin should have platelet counts monitored every 2-4 days from days 4-14 or until heparin is stopped⁵.   If the platelet count falls by 30% or more and/or the patient develops new thrombosis or skin allergy or any of the other rarer manifestations of heparin-induced thrombocytopenia (HIT) (see Table 1) between days 4 and 14 of heparin administration, HIT should be considered and a clinical assessment made.   This requires immediate cessation of heparin therapy. It may be complicated by life-threatening thromboembolic events. Approximately 50% of patients with HIT have a new HIT-associated thrombosis at the time HIT is clinically suspected due to the presence of thrombocytopenia.

Reproduced from Watson et al (2012)⁵.

Non-Immune Heparin-Associated Thrombocytopenia 

Unless heparin has been administered in the last 100 days a rapid fall in platelets soon after starting heparin is unlikely to be HIT. Thrombocytopenia is most commonly seen after initiation of therapy with high dose unfractionated heparin especially following thrombolytic therapy or during the early post-operative period. It is a non-immune response and the patient will not have clinical features of thrombosis or the presence of heparin dependent antibodies. It is usually mild and occurs within the first few days of treatment. Patients do not generally show symptoms as a result of this platelet count drop and recover over the following 3 to 4 days in spite of continued heparin use. Heparin should not be stopped in patients who are clinically suspected of having non-immune heparin-associated thrombocytopenia as inappropriate discontinuation of heparin could increase the risk of thrombosis due to the underlying medical condition requiring treatment with heparin¹.

Back to top

Diagnosis

If a patient is suspected of having HIT on the basis of a fall in platelet count in a patient receiving heparin, the probability of HIT should be judged initially on clinical grounds. Patients can have HIT with a “normal platelet” count (but fallen by 50%).

Four features can help to estimate the likelihood of HIT (see Table 2). If the pre-test probability is high, heparin should be stopped and an alternative anticoagulant started in full dosage given whilst laboratory tests are performed⁵ 

Pretest probability score: 6-8 = high; 4-5 = intermediate; 0-3 = low.
Reproduced from Watson et al (2012) ⁵.
Patients with an intermediate or high score require laboratory testing, further investigation and alternative anticoagulation.

Back to top

Investigation

• HIT screening can be requested from the Specialist Coag lab. A 4T score must be supplied AND a clinical opinion from a clinical Haematologist should be sought before testing. The test is hard to find on ICE so wards should use a manual request card marked for the attention of the specialist coag lab at SJUH.
• The screening test has a high negative predictive value but a positive result requires confirmation (this requires a sample to be sent to Sheffield and will be organized through the Specialist Coag lab). Samples required are 1 citrate Blue coag tube and one serum tube
• Out of hours HIT screening testing is available but only if discussed with a Consultant Clinical Haematologist who can authorise a biomedical scientists to attend to run the test.

Back to top

Treatment / Management

Immediate management

• Clinical suspicion alone is sufficient for immediate action. Any score > 3 requires management for HIT before test results are available.
• In patients with a score >3, discontinue unfractionated heparin (UFH) or low molecular weight heparin (LMWH). No “hepflush”
• As HIT is a strong, independent factor for venous and arterial thrombosis start alternative non-cross reacting anticoagulant measures immediately (in the absence of a significant contraindication).
• Remove any heparin coated catheters
• A low platelet count indicates ongoing platelet activation by HIT immune complexes, anticoagulation should be continued at least until the platelet counts recover to a stable plateau¹.
• Avoid platelet infusions unless life threatening bleeding occurs
• If warfarin has already been started when HIT is suspected STOP warfarin and reverse with vitamin K as there is an increased risk of venous limb gangrene with HIT and warfarin.
• In all cases contact the clinical haematology team on-call for advice

Alternative anticoagulation - please discuss with a Haematologist

1.0 Danaparoid

Danaparoid is a mixture of low molecular weight sulphated glycosaminoglycuronans derived from animal mucosa, comprising heparan sulphate, dermatan sulphate and a minor amount of chondroitin sulphate.  It indirectly inhibits Xa and to a lesser degree, thrombin.  If monitoring is required, a specific anti-Xa assay calibrated for danaparoid should be used. Danaparoid shows low cross-reactivity (<10%) with the heparin induced antibody. This can be explained by the absence of heparin in danaparoid and its low degree of sulphation.  The absolute bioavailability of danaparoid sodium after subcutaneous administration approaches 100%. In humans the time to reach peak plasma anti-Xa activity levels is approximately 4-5 hours⁸

1.1 Contraindications to danaparoid

Refer to Medicines Compendium for contraindications.

1.2 Dosage and administration of danaparoid

Before commencing danaparoid

• Assess renal and liver function. Danaparoid should be used with caution in patients with moderately impaired renal and/or liver function with impaired haemostasis.   In patients with severely impaired renal function the half-life of elimination of plasma anti-factor Xa activity may be prolonged.
• Danaparoid should be administered intravenously as
  • a bolus of 2500 anti-Xa units over 15-30 seconds (for patients less than 55kg 1250 units, if over 90kg, 3750 units) followed by an
  • intravenous infusion of 400units/h for 2 hours,
  • then 300 units/h for 2 hours,
  • then, a maintenance infusion of 200 units/h for at least 5 days in 0.9% sodium chloride or glucose 5%.
• In the event of serious bleeding, Orgaran^® should be stopped and a blood transfusion should be considered. Seek haematology advice urgently. Measurement of anti Xa levels may be helpful. Protamine may be considered although its efficacy is unproven.

1.3 Monitoring

• In general monitoring of plasma anti-Xa activity is not necessary. However, in patients suffering from renal insufficiency and/or patients weighing over 90kg, monitoring (using an amidolytic assay) is recommended
• The expected plasma anti-Xa levels are 0.5-0.7 units/mL 5-10 minutes after the bolus, not higher than 1.0 units/mL during the adjustment phase of maintenance infusion and 0.5-0.8 units/mL during the maintenance infusion.

1.4 Switching from parenteral to oral anticoagulation

Warfarin is the anticoagulant of choice for the long-term management of thrombosis in patients with HIT. Do not start warfarin unless the platelet count has recovered to >150 x 10⁹/L. Treatment with warfarin before thrombin generation is reduced can lead to gangrene or fatal thrombosis. It usually takes five days of warfarin therapy before therapeutic hypothrombinaemia is achieved.

When initiating oral anticoagulant therapy, danaparoid infusion should continue until the measured INR is ≥2.0 for 2 days.  A minimum overlap of 5 days between danaparoid and vitamin K antagonist therapy is recommended.

Patients should be therapeutically anticoagulated for 3 months after HIT with a thrombotic complication, and for 4 weeks following HIT without a thrombotic complication.

2.0 Argatroban

Argatroban, a synthetic L-arginine derivative, is a direct thrombin inhibitor that binds reversibly to thrombin. Argatroban exerts its anticoagulant effect independently of antithrombin III and inhibits fibrin formation; activation of coagulation factors V, VIII and XIII; activation of protein C; and platelet aggregation.  Argatroban is capable of inhibiting the action of both free and clot-associated thrombin. It does not interact with heparin-induced antibodies.

2.1 Contraindications to argatroban

Refer to Medicines Compendium for full contraindications.

Argatroban is contraindicated in;

• Patients with uncontrolled bleeding.
• Patients who have hypersensitivity to argatroban or to any of the excipients.
• Patients with severe hepatic impairment.

2.2 Dosage and administration of argatroban 

• Therapy with argatroban is monitored using the activated partial thromboplastin time (APTT).
• Before commencing argatroban, discontinue heparin therapy and check baseline APTT (activated partial thromboplastin time).
• Check patients’ weight.
• Assess liver function; patients with moderate hepatic impairment (Child-Pugh Class B) should receive lower starting doses of argatroban.
• Critically ill patients (i.e. those on ICU) should also receive a lower starting dose

2.2.1 Initial Dosage of argatroban

• Argatroban should be prescribed on a dedicated argatroban prescription chart; these are available from any inpatient pharmacy at LGI or SJUH on request.
• The initial dosage in adult patients (without hepatic impairment) in HIT type II is 2 microgram/kg/min, administered as a continuous IV infusion. No dosage adjustments are required in elderly patients or patients with renal impairment.
• In patients with moderate hepatic impairment or on ICU an initial dose of 0.5 microgram/kg/min is recommended. The APTT should be monitored closely and the dosage should be adjusted as indicated clinically. Argatroban is contra-indicated in patients with severely impaired liver function
• Dilute argatroban 250mg in either 250mL sodium chloride 0.9% or 250mL glucose 5% to give a final concentration of 1mg/mL.
• Check APTT ratio 2 hours after starting infusion, then adjust rate to achieve therapeutic range of 1.5 - 3.0 using the dose adjustment table on the argatroban prescription chart.
• Argatroban infusion must not be stopped to check the APTT.

2.2.2 Dose Adjustments of argatroban infusion

• Dose adjustment may be required to attain the target APTT ratio 1.5-3.0
• In the case of an elevated APTT (greater than 3 times baseline or greater than 100 seconds), the infusion should be discontinued until the APTT is within the desired range of 1.5 to 3 times baseline (typically within 2 hours of discontinuation of infusion), and the infusion restarted at one half of the previous infusion rate. The APTT should then be rechecked after 2 hours.
• The maximum recommended dose is 10 microgram/kg/min. The maximum recommended duration of treatment is 14 days, although there is limited clinical experience of administration for longer periods.

2.2.3 Critically ill patients

• Limited data is available from the use of argatroban in patients with HIT Type II after cardiac surgery and critically ill patients / intensive care unit (ICU) patients with (multiple) organ system failure. Based on the data therapy could be initiated with a starting infusion rate of 0.5 microgram/kg/min (maximum 10 microgram/kg/min) and adjusted to the target APTT range of 1.5-3.0 times baseline value (not exceeding 100 seconds).
• The clinical status of the patient, especially acute changes in hepatic function, should be taken into account and the infusion rate should be carefully adjusted to maintain the APTT in the desired range.
• An increase in the frequency of monitoring is recommended to ensure the target APTT values are achieved and maintained.

2.3 Monitoring

• Monitor APTT 2 hours after initiation and every 2 hours after dosage adjustments (4 hours in critically ill or hepatically impaired patients).
• Once two consecutive APTT levels within the target range (1.5-3.0) are obtained, APTT levels should be checked on a daily basis.
• Full Blood Count (FBC) should be checked daily

2.4 Switching from parenteral to oral anticoagulation

Warfarin is the anticoagulant of choice for the long-term management of thrombosis in patients with HIT. Do not start warfarin unless the platelet count has recovered to >150 x 10⁹/L. Treatment with warfarin before thrombin generation is reduced can lead to gangrene or fatal thrombosis. It usually takes five days of warfarin therapy before therapeutic hypothrombinaemia is achieved.

When initiating oral anticoagulant therapy, argatroban infusion should continue until the measured INR is ≥4.0 for 2 days.  The reason for the higher INR target is that argatroban interferes with the INR assay.  Earlier cessation of parenteral therapy could result in a lapse in therapeutic anticoagulation cover. A minimum overlap of 5 days between argatroban and vitamin K antagonist therapy is recommended.

Patients should be therapeutically anticoagulated for 3 months after HIT with a thrombotic complication, and for 4 weeks following HIT without a thrombotic complication.

3.0 Haemodialysis patients

Danaparoid and argatroban are suitable for use in renal dialysis patients.  Please consult Renal Team and Consultant Haematologists for advice on dosing in this patient group.

4.0 Other options

Therapeutic dose fondaparinux is an acceptable alternative anticoagulant for managing HIT, but it is NOT licensed for this indication.  Please discuss with Consultant Haematologist in all cases.
The efficacy and safety of the novel oral anticoagulants (apixaban, dabigatran, edoxaban and rivaroxaban) has not been established in HIT¹³

5.0  Anticoagulation in patients with a history of HIT

Where a patient with previous HIT requires a period of anticoagulation or anticoagulation prophylaxis, fondaparinux or danaparoid may be used, as may new anticoagulants such as dabigatran, rivaroxaban and apixaban, depending on the clinical indication.  Please discuss with Consultant Haematologist in all cases.

6.0 Record keeping

The diagnosis of HIT must be clearly recorded in the patient’s medical notes and marked as a serious allergy⁵ .

The patient should be advised never to be exposed to any form of heparin in the future including hepflush, hepsal, heparin coated catheters or low molecular weight heparin.

Back to top