Heparin-induced thrombocytopenia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Assistant Editor-In-Chief: Aric C. Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA [3]

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Overview

Heparin-induced thrombocytopenia (HIT) with or without thrombosis (HITT) is thrombocytopenia (low platelet counts) due to the administration of heparin. While it is mainly associated with unfractionated heparin (UFH), it can also occur with exposure to low-molecular weight heparin (LMWH), but at significantly lower rates. The development of mild to moderate thrombocytopenia (platelet counts of 50-70,000) in the context of heparin exposure is suggestive of a possible diagnosis of HIT while severe thrombocytopenia and platelet counts less than 20,000 are quite unusual for the syndrome. Given the nadirs in the platelet count, clinically significant bleeding associated with the thrombocoytopenia is quite rare. On the contrary, heparin induced thrombocytopenia is primarily a thrombotic disorder, with very high rates of thrombosis, in the arteries with or without venous complications. Of note, the rate of DVT (Deep Vein Thrombosis) is roughly 4 times that of arterial thrombosis, and while thrombocytopenia is the most common "event" in HIT, DVT is in fact the most common complication.

HIT typically develops 4-14 days after the administration of heparin. The onset of thrombocytopenia in less than 4-5 days after the initiation of heparin treatment is extremely rare due to the time required for antibody production, and alternative explanations should be sought for the development of thrombocytopenia this early in therapy. The primary exception to this is in the case of recent heparin exposures (<100 days) where the patient may have pre-existing antibodies against the heparin-PF4 complex.

Heparin (UFH) is used in cardiovascular surgery, as prevention or treatment for deep-vein thrombosis and pulmonary embolism and in various other clinical scenarios. LMWH is increasingly used in outpatient prophylaxis regimes.

There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.

Type I

In this form patients characteristically have a transient decrease in platelet count (rarely <100,000) without any further symptoms. This thrombocytopenia recovers even if heparin is continued to be administered. It occurs in 10-20% of all patients on heparin. It is not due to an immune reaction and antibodies are not found upon investigation. HIT-1 is due to heparin-induced platelet clumping; it is innocuous.

Type II

This form is due to an autoimmune reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and interleukin 8 (IL8) which form complexes with heparin. The most common form is to the heparin-PF4 complex. It appears that heparin binding to platelet factor 4 causes a conformational change in the protein, rendering it antigenic. Antibodies bind to these complexes, activate the surrounding platelets and generate thrombin. The antibodies found are most commonly are of the IgG class with or without IgM and IgA class antibodies. IgM and IgA are rarely found without IgG antibodies. Type II HIT develops in about 3% of all patients on UFH and in 0.1% of patients on LMWH, and causes thrombosis in 30% to 40% of these patients. The other patients are able to compensate for the activation of hemostasis that leads to thrombosis. Clot formation is mainly arterial and rich in platelets ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped red blood cells). Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion. Rapid-onset HIT can result in life-threatening acute systemic reactions (eg rigors, fever, hypertension, tachycardia) and cardiopulmonary collapse.

Delayed-onset HIT occurs in ~3-5% of HIT cases; patients who develop delayed onset HIT have heparin/PF4 reactive antibodies that are able to activate platelets even in the absence of heparin. Single or trivial doses of heparin, such as catheter flushes, can cause HIT. In HIT2 the onset of thrombocytopenia is independent of the type of heparin, dose and route of administration. HIT antibodies can persist for 4-6 weeks but disappear after 3 months.

The presence of HIT antibodies, even at higher titer, doesn't predict an increase in complications. An increase in the titers of the antibodies do, however, give an increase in the in-vitro activaton of the coagulation system. The ELISA test, though not ideal, is the best predictive diagnostic test of HIT2. It has been suggested that HIT2 only occurs with high antibody titers and after persistent exposure to heparin; also it suggests that antigens different from the H-PF4 complex can be involved. There may be a HIT antibody active in a non-heparin dependent manner. Data exists suggesting that there are "superactive" HIT antibodies capable of activating platelets without heparin.

Genetic risk factors for thrombosis such as factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase (MTHFR) polymorphism and platelet-receptor polymorphisms do not increase the risk of developing HIT associated thrombosis.

4 factors that affect the risk of developing HIT are noted as follows. 1) Duration of heparin treatment; long duration, up to 2 weeks is associated with the greatest risk. 2) The type of heparin involved; UFH has a greater risk than LMWH. 3) The type of patient; surgical patients are at higher risk than medical; cardiac surgical patients have the highest risk of all. 4) Females have a higher risk.

CPB bypass: The management of cardiopulmonary bypass (CPB) patients with active HIT is controversial. Direct Thrombin Inhibitors such as agatroban and hirudin are used (and increase the aPTT in a dose dependent manner). However, in the large doses required for CPB hirudin's effects cannot be monitored well. Following CPB surgery the platelet count drops to about 40-60% of normal within the first 2-3 days postop due to hemodilution and platelet consumption. But there is also a risk of HIT. 20-50% of patients develop heparin antibodies during the first 5-10 days following CPB and some develop HIT (1-3% if UFH is continued through the postop period).

Diagnosis

The most specific tests are: the serotonin release assay (SRA), the heparin induce platelet aggregation (HIPA) assays and the solid-phase immunoassay (SPI). The sensitivity of these tests is 94% at best. The gold standard is the SRA where antibodies from the patient’s serum result in release of radiolabeled serotonin attached to platelets from a normal patient. The HIPA looks for platelet aggregation that is present with heparin, platelets and patient serum but does not occur in the absence of heparin. It has a >90% specificity but is limited by low sensitivity. The SPI is an enzyme-linked immunosorbent assay (ELISA) that tests for the presence or absence of heparin-PF4 complexes. Because it does not determine whether the antibodies are functionally significant, it is best used in conjunction with one of the two prior tests.

If HIT is suspected it may take hours to days to obtain the laboratory back. In the meantime it may simply be a safer approach to substitute another agent (eg agatroban) for heparin. If there is a major diagnostic doubt then there is a "4T" system for identifying patients at risk for HIT. It is defined as follows; 0-3 points; low probability 4-5 points; intermediate probability 6-8 points; high probability If the probability is high then discontinue the heparin and begin an alternative anticoagulant; some references recommend the same for those of intermediate risk too.

1) Thrombocytopenia;

    0 points for <30% fall or a nadir <10,000
    1 point for a 30-50% fall or a nadir of 10-19,000
    2 points for a >50% fall or a nadir greater than or equal to 20,000

2) Timing of the decrease in platelet count;

    0 points for less than a day
    1 point for greater than day 10 or timing unclear or less than day 1 if heparin exposure was within the past 30-100 days.
    2 points for day 5-10 or less than or equal to day 1 with recent heparin use (past 30 days)

3) Thrombosis or other sequelae;

    0 points for no thrombosis
    1 point for progressive, recurrent or silent thrombosis; erythematous skin lesions.
    2 points for a proven thrombosis, skin necrosis or acute systemic reaction after heparin bolus.  

4) Other causes of thrombocytopenia;

    0 points if a definitive concurrent cause.
    1 point if there is a possible other  reason for thrombocytopenia.  
    2 points if there are no other possible reasons for thrombocytopenia.  

Isolated HIT: This entity occurs when there is a decreased platelet count but without evidence of thrombosis. It is recommended to stop the heparin and use alternative anticoagulation. It is also recommended to screen for subclinical deep venous thrombosis with a compression ultrasound (~50% of patients show a DVT with this check).

Treatment

Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, lepirudin, fondaparinux, bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used. Low molecular weight heparin is deemed contraindicated in HIT.

According to past reviews, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18.

Pharmacotherapy

Acute Pharmacotherapies

• Check platelet counts twice weekly while on heparin. Withdrawal heparin immediately of HIT is suspected. Platelet transfusion worsens thrombosis and should be reserved for patients with active bleeding. Warfarin therapy should be avoided for 3-5 days after heparin cessation and/or until thrombocytopenia resolves (>100,000).
• Use of direct thrombin inhibitors is the safest and most effective therapeutic approach to HIT for both those who need ongoing anticoagulation and for thrombosis prevention.

Danaproid (Orgaran) is a heparinoid composed of 85% heparan sulphate, 10% dermatan sulphate and 5% chondroitin sulphate that has approximately 10% cross reactivity with heparin. It has been shown to reduce mortality from thrombotic complications to 5% from 28%.

• The in vitro cross reactivity of LMWH with heparin dependent antibodies is approximately 60-100%. Some argue that LMWH is contraindicated for patients who develop HIT because of this cross-reactivity. Nonetheless, a theoretical argument for the use of LMWH in therapy for HIT has been made. The theory is that the LMWH overall interaction of heparin with PF4 will diminish. Though there are reports of LMWH being effective in controlling HIT in the presence of cross-reacting antibodies, the consensus is not to administer LMWH unless the absence of cross reactivity has been determined.

As stated before when HIT is suspected it is recommended to discontinue the heparin and initiate other agents such as direct thrombin inhibitors (DTIs; agatroban, hirudin & bivalirudin). Agatroban (AKA Novastan) doesn't resemble heparin and therefore won't cross-react with heparin antibodies. It is a medication specifically designed as a synthetic intravenous thrombin inhibitor, derived from arginine, to be an anticoagulant in patients with HIT. It is hepatically eliminated (t1/2 = 1 hour). It is contraindicated in patients with problems of hemorrhage and one should avoid intramuscular injections during its use. The infusion is initiated at 2 ug/kg/min; in patients with hepatic impairment it is recommended to reduce the dose to 0.5 ug/kg/min. Adjustment is made to a steady state aPTT of 1.5-3X the baseline. With this regimen greater than half of patients had platelet counts recover by day 3 (in HIT). Abrupt discontinuation of agatroban can lead to a hypercoagulable state. With administration its effects are immediate and a steady state can be achieved in 1-3 hours. When agatroban is given it is advised to begin coumadin. When the INR is >4 discontinue the agatroban and recheck the INR 4-6 hours later. If the INR is below the therapeutic range then resume agatroban. Avoid prothrombotic problems by overlapping the coumadin and agatroban. It has no cross-reactivity with HIT antibodies (to PF4). There is no antibody formation after repeated administration. It does not require dose adjustment in renal impairment. Lepirudin is a DTI but, unlike agatroban, it is eliminated by the kidneys. Hirudin binds to the active site of thrombin by exosite 1, the site at which thrombin binds to its substrates. Bivalrirudin, like hirudin, binds to the active site of thrombin/exostie 1.

Coumadin (and vitamin K antagonists generally) are recommended for long-term anticoagulation however they should not be administered too early, unopposed or in excessive doses. It is important not to initiate coumadin treatment until the platelet count has recovered due to the threat of skin necrosis or gangrene. Discontinuing the heparin and giving Coumadin doesn't prevent the onset of thrombosis in ~50% of patients. Once thrombocytopenia has resolved the coumadin can then be given at a low maintenance dose and alternative anticoagulation should be continued along with coumadin for at least 5 days. The alternative anticoagulant should not be discontinued until the platelet count has achieved a stable plateau and the INR has been the therapeutic range for at least 2 days. The optimal duration of the anticoagulation has not been established.

Patients Undergoing Surgery or PCI

Patients with HIT should be treated with Bivalirudin, a direct thrombin inhibitor to support these procedures.

Secondary Prevention

Patients with HIT should be treated with Bivalirudin, a direct thrombin inhibitor to support future procedures.

External links

• Cleveland clinic page on HIT
• HIT page

Additional Reading

• Kumar, Vinay, Abul Abbas, and Nelson Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. (2005). ISBN 0-7216-0187-1
• Aouifi A, Blanc P, Piriou V, Bastien OH, French P, Hanss M, Lehot JJ. Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia. Ann Thoracic Surg 2001;71:678-683.
• Follis F, Filippone G, Montalbano G, Floriano M, LoBianco E, D'Ancona G, Follis M. Argatroban as a substitute of heparin during cardiopulmonary bypass: a safe alternative? Interact CardioVas Thorac Surg 2010;10:592-596.
• Gates R, Yost P, Parker B. The use of bivalirudin for cardiopulmonary bypass anticoagulation in pediatric heparin-induced thrombocytpenia patients. Artificial Organs. 2010;34(8):667-669.