Today's approach to the treatment of heparin-induced thrombocytopenia

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are 2 of the most commonly prescribed medications in the hospital setting. They have a number of indications, including the prevention and treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) and the management of acute coronary syndrome. These agents are also given to patients during dialysis and to patients undergoing percutaneous coronary intervention or other cardiac or vascular surgical procedures.

The thrombotic complications of UFH were first reported almost 50 years ago by 2 surgeons, Weismann and Tobin.¹ This condition, now known as heparin-induced thrombocytopenia (HIT), is a well-reported complication of the use of UFH or LMWH, yet it remains frequently overlooked or misdiagnosed by many physicians.

The incidence of HIT varies depending on the type of heparin preparation, patient population, duration of exposure, dose, and definition of thrombocytopenia used (Table 1).² It is estimated to be as high as 3% to 5% in patients exposed to UFH but is less common (less than 1%) in persons receiving LMWH.³

In this article, we will review both the diagnosis and management of HIT.

Pathogenesis

HIT is an immune-mediated disorder that develops after exposure to UFH or LMWH. The administration of either of these anticoagulants stimulates the release of platelet factor 4 (PF4), which is a heparin-neutralizing protein found in the a granules of platelets. An immune response leads to the formation of HIT antibodies, usually IgG antibodies.

IgG and PF4-heparin form an immune complex that binds to the FcgIIa receptor on platelet surfaces. This complex releases additional PF4, activates the coagulation cascade and, in susceptible persons, leads to thrombosis and thrombocytopenia. HIT antibodies are transient and usually are undetectable by 100 days after exposure.

Three mechanisms have been proposed to explain the development of thrombosis and thrombocytopenia in this setting:

• The IgG/PF4-heparin immune complex triggers platelet activation and aggregation as well as the release of prothrombotic platelet-derived microparticles.

• The IgG/PF4-heparin immune complex binds to endothelial cells, causing injury.

• This complex also binds monocytes, initiating the release of tissue factor and activating the coagulation cascade.⁴

Clinical features

The most common clinical feature of HIT--thrombocytopenia--is generally defined as a platelet count under 150,000/µL (Table 2).³ Thrombocytopenia does not develop in all patients; however, in one large series of 142 serologically confirmed cases of HIT, platelet counts as high as 500,000/µL were reported, although the median platelet count was 59,000/µL.⁵ More recently, a 50% drop in the patient's pre-heparin treatment platelet count has become recognized as a more sensitive marker for this syndrome.^2,6

More than half of all patients with HIT will experience thrombosis, with or without concomitant thrombocytopenia.⁷ This complication was originally thought to occur predominantly on the arterial side of the circulation, but it is now reported that venous thrombosis develops in 4 of 5 patients with HIT.⁷The most common venous events are DVT of the lower extremity and PE; the latter occurs in as many as 25% of patients.² DVT in the upper extremity is more often associated with placement of a central venous catheter or pacemaker.⁸

Arterial thrombosis most commonly presents as acute limb occlusion. It usually develops in areas of arteriosclerosis, at the site of a recent endovascular procedure, at a surgical site, or following vascular trauma. HIT may also result in acute thrombotic stroke, myocardial infarction, intracardiac thrombus, or thrombosis of an extracorporeal circuit or prosthetic graft.

Several unusual complications of HIT have been recognized, including warfarin-induced venous limb gangrene, warfarin-induced skin necrosis, heparin-induced skin necrosis, an acute systemic reaction following an intravenous bolus of UFH, disseminated intravascular coagulation, adrenal hemorrhagic infarction, and cerebral venous thrombosis (Table 3). Both warfarin-induced venous limb gangrene and skin necrosis can develop when an oral anticoagulant is initiated prematurely during an acute HIT episode, before the patient's platelet count has recovered, or when warfarin is administered unopposed without the addition of an alternative anticoagulant.

Warfarin-induced venous limb gangrene is characterized by distal extremity necrosis with an ipsilateral limb DVT and a supratherapeutic international normalized ratio (INR). It differs from warfarin-induced skin necrosis (also known as coumarin-induced skin necrosis), which develops more commonly in areas of fatty tissue, including the breasts, buttocks, and thighs.^9,10 These conditions have also been reported during transition to warfarin (in the setting of persistent thrombocytopenia) even with the addition of a direct thrombin inhibitor (DTI).¹⁰

Heparin-induced skin necrosis is observed in areas where subcutaneous injections of UFH or LMWH are administered. They are ischemic--characterized by a central eschar and surrounded by a ring of erythema--and are very painful.

Acute systemic reactions are rarely reported but occur within 5 to 30 minutes after an intravenous bolus of UFH. An abrupt fall in the platelet count is seen, and the most common signs include fever, chills, tachycardia, dyspnea, and hypertension. Flushing, headache, nausea, vomiting, diarrhea, chest pain, and transient global amnesia have also been recognized, and sudden cardiorespiratory collapse and death may occur.²

Disseminated intravascular coagulation is characterized by hypofibrinogenemia, a transient acquired deficiency of antithrombin and/or protein C deficiency, and prolonged INR and activated partial thromboplastin time (aPTT). Schistocytes are seen on review of the peripheral blood smear, and livedo reticularis, renal failure, and other signs of microvascular thrombosis may be observed (Figure).

Adrenal hemorrhagic infarction and cerebral venous thrombosis have also been described, although they are uncommon. Fever, abdominal pain, and hypotension resulting from thrombosis of the adrenal veins occur in patients with adrenal hemorrhagic infarction. In patients with cerebral venous thrombosis, thrombosis of the dural venous sinuses causes seizures, focal neurologic signs, and headache.

Temporal patterns of HIT

Three temporal patterns of HIT have been identified: typical-onset, rapid-onset, and delayed-onset (Table 4).¹¹ Typical-onset HIT occurs in most patients and usually develops within 5 to 14 days after a first-time exposure to UFH or LMWH.

Rapid-onset HIT can occur within hours to days after treatment with either anticoagulant is initiated. In a series of 243 patients with serologically confirmed HIT, the median time to onset of thrombocytopenia was 10.5 hours.¹¹ These persons had recent exposure to UFH or LMWH, generally within the past 100 days and more commonly within the previous 30 days. Rapid-onset HIT is the result of persistent circulating heparin-PF4 antibodies that developed during a previous exposure.

The least common temporal pattern is delayed-onset HIT, which usually develops within 7 to 40 days after UFH or LMWH has been discontinued. In 2 series involving 26 patients, most of the patients had already been discharged home, only to return with new thrombosis.^12,13 Five of the patients subsequently died of complications of HIT. In most cases, thrombocytopenia was overlooked during the patient's hospital stay. Patients with delayed- onset HIT usually have very high titers of HIT antibodies.

Laboratory testing

Physicians are frequently consulted about acutely ill patients who have thrombocytopenia or thrombosis that developed during hospitalization, and the possibility of HIT must always be considered in patients who are receiving UFH or LMWH. Sepsis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, drug- or alcohol-induced thrombocytopenia, aplastic anemia, myelodysplasia, hypersplenism, other causes of disseminated intravascular coagulation, and hemodilution must be considered in the differential diagnosis of thrombocytopenia.

Although thrombosis may be a complication of hospitalization, age, inactivity, recent surgery, or an underlying hypercoagulable condition, HIT must also be considered in the differential diagnosis. Patients who have HIT may also present with resistance to UFH, defined as an inability to maintain therapeutic aPTT values while receiving UFH, despite increasing the dosage.

The diagnosis of HIT is based on the clinical presentation and the results of laboratory testing. Two types of laboratory tests are available to assist in the diagnosis--functional assays and antigen assays, or immunoassays. These tests should be ordered only when HIT is clinically suspected.

Functional assays have greater specificity but less sensitivity and include the heparin-induced platelet aggregation assay (HIPA) and serotonin release assay (SRA). The HIPA uses platelet-rich plasma mixed with the patient's own plasma, and heparin. It has a high negative predictive value but only a moderate positive predictive value; it is most useful in ruling out clinically significant HIT.¹⁴

The SRA uses donor platelets that are labeled with radioactive ¹⁴C serotonin to detect platelet activation in response to HIT-positive serum in the presence of heparin. It is more sensitive and specific than HIPA and is the standard by which other tests are judged; however, it is more technically demanding to perform (it requires radioisotopes) and is not readily available at all centers.

The antigen assay, or immunoassay, includes the enzyme-linked immunosorbent assay (ELISA) and, more recently, the rapid manual immunoassays. ELISA is technically easier to perform than the functional assays, and it detects antibodies to heparin-PF4 complexes. It is reported as optical density, with values of 0.40 or higher considered positive.¹⁵ One of the rapid immunoassays, the particle gel immunoassay, can be performed in less than 1 hour; this test was developed to provide physicians with a faster means to detect HIT antibodies.

Once HIT is suspected clinically, a functional assay and immunoassay should be performed. If both test results are positive, HIT is likely; if both are negative, HIT is unlikely.

If one test result is positive and one negative, repeating the studies at a later date may be helpful. Remember that HIT remains a clinical diagnosis, and the results of laboratory testing may not always coincide with the clinical picture.

Warkentin and associates^2,14 developed a scoring system, known as the four Ts, to assess the pretest probability of HIT. It is based on 4 criteria: thrombocytopenia, timing of platelet count fall, thrombosis, and exclusion of other causes for thrombocytopenia (Table 5). This method may be most helpful in deciding which patients need serologic testing.

Management of HIT

Once the diagnosis of HIT is suspected, all forms of UFH or LMWH must be discontinued immediately (Table 6). This includes any heparin that may be found in unsuspected locations, such as bound to heparin-coated catheters; used as flushes in arterial lines; added to contrast for radiology procedures; administered during dialysis; or added to total parenteral nutrition solutions.

Simply discontinuing UFH or LMWH is inadequate, even if there is no evidence of acute thrombosis. Numerous studies have clearly demonstrated an increased risk of new thromboembolic events, amputation, and even death if an alternative anticoagulant is not used.^15-20 Treatment should not be delayed while waiting for laboratory confirmation, since studies have demonstrated that this approach increases the risk of thrombosis and death.¹⁶

Two DTIs have been approved by the FDA for the treatment of HIT: argatroban and lepirudin. Lepirudin is a recombinant form of hirudin, the natural anticoagulant of the medicinal leech, Hirudo medicinalis. It irreversibly binds thrombin, is eliminated by the kidney, and has a half-life of about 1.3 hours.

Lepirudin can be given intravenously or subcutaneously, although the latter method is not FDA- approved. A weight-based bolus is usually administered, followed by continuous infusion. It is monitored using the aPTT targeted to 1.5 to 2.5 times the baseline level. Monitoring should be done by checking the aPTT 4 hours after initiating therapy, every time there is a dose adjustment, and daily once therapeutic levels of aPTT have been achieved.

Lepirudin lacks cross-reactivity with UFH or LMWH, but anti-hirudin antibodies develop in as many as 60% of patients.²¹ These antibodies are not associated with an increased risk of thrombosis, but they may extend lepirudin's half-life, requiring more frequent dose adjustments. There have also been reports of anaphylaxis and death occurring in patients who are reexposed to lepirudin.²²

Argatroban is a small synthetic molecule derived from l-arginine that binds in a reversible fashion to the catalytic site of thrombin. It is eliminated via hepatobiliary excretion and has a half-life of about 39 to 51 minutes. Argatroban lacks cross-reactivity with UFHand is approved for the prevention and treatment of HIT as well as for patients with HIT who require percutaneous coronary intervention. It is given by continuous intravenous infusion; no loading dose is required.

Argatroban ismonitored using aPTT with a target of 1.5 to 3.0 times the baseline level. The aPTT should be evaluated initially 2 hours after starting the infusion and daily thereafter once therapeutic levels have been attained. Dosage adjustments are recommended in patients with moderate or severe liver disease.

All DTIs prolong the INR; however, this is particularly apparent with argatroban. The target INR for patients taking argatroban is higher than normal and should be 4.0 or higher during co-therapy with warfarin. These anticoagulants should be overlapped for a minimum of 5 days. No antibody formation has been demonstrated with the use of argatroban.

Alternative therapies

Bivalirudin is a DTI that has been used off-label for the treatment of HIT in a number of small studies.^23,24 It has several advantages, including a shorter half-life (25 minutes), mostly enzymatic (80%) and minimal renal (20%) metabolism, low immunogenicity, and a minimal effect on INR.²⁵

Bivalirudin has been used extensively in patients with the acute coronary syndrome and is under investigation as an alternative anticoagulant to UFH in on-pump and off-pump cardiac surgery. Dose adjustments are usually necessary for patients with moderate to severe renal insufficiency.

Fondaparinux is a synthetic pentasaccharide that is metabolized renally, has a half-life of 17 to 20 hours, and is administered subcutaneously with 100% bioavailability. It is approved for venous thromboembolism prophylaxis in orthopedic patients as well as for treatment of DVT and PE in hospitalized patients. Fondaparinux does not appear to cross-react in vitro with HIT antibodies and may be an alternative to the DTIs in this setting, although experience is limited.¹⁵

It should be noted that none of these anticoagulants has an antidote. If clinically significant bleeding occurs, the agent should be discontinued immediately and supportive therapy initiated. More specific instructions are available in the package inserts of these products.

Long-term anticoagulation in patients with HIT requires the addition of an oral anticoagulant. However, it is becoming well recognized that warfarin should be avoided in patients with acute HIT (whose platelet counts have not recovered) to avoid warfarin-induced venous limb gangrene or warfarin-induced skin necrosis. Recently published guidelines from the American College of Chest Physicians advise that warfarin therapy be initiated in low doses (less than 5 mg), used concurrently with a DTI, and started only when the patient is improving clinically and the platelet count has recovered to 100,000/µL, and preferably 150,000/µL.¹⁵

Warfarin should be overlapped with the DTI for a minimum of 5 days, and the DTI should be discontinued only after the INR is therapeutic for 2 consecutive days.^9,10 If warfarin therapy has already begun at the time HIT is recognized, reversal with oral or intravenous vitamin K administration is advised to prevent venous limb gangrene or warfarin-induced skin necrosis.¹⁵

Reducing the incidence of HIT

Prevention is best achieved by close monitoring of the platelet count while the patient is receiving UFH or LMWH. The use of any of the LMWH preparations for DVT prophylaxis helps reduce the incidence of HIT, because the LMWHs are less likely to trigger HIT. Fonda- parinux is an alternative for DVT prophylaxis that has not been associated with the development of HIT.

For patients receiving UFH or LMWH for acute DVT or PE, early transition to warfarin (before HIT has a chance to develop) is recommended. It is also advised that a porcine heparin preparation be used rather than bovine products. All patients receiving either UFH or LMWH should have their platelet count monitored regularly.

Special topics

The readministration of UFH in patients who have a history of HIT is controversial. It may be necessary in select patients who require cardiopulmonary bypass or a vascular surgical procedure when no acceptable alternative anticoagulant is available. In this setting, it is advisable to wait about 100 days after the last heparin exposure to allow time for the antibody to disappear. If testing confirms the absence of HIT antibodies, readministration of UFH only during the procedure appears to be safe. This application has been confirmed in several small series of patients with a history of HIT who were reexposed to heparin. No complications were reported, and HIT antibodies developed in only 1 patient.^11,26

Isolated HIT (the development of thrombocytopenia without thrombosis) was once treated by just discontinuing UFH. It has now been clearly demonstrated that this places patients at increased risk. Several series have reported new thromboembolic rates of 20% to 50% if this approach is followed.^27,28 Current guidelines recommend treatment with an alternative agent (a DTI or an equivalent), followed by a short course of warfarin therapy initiated after platelet recovery.¹⁵ Venous duplex ultrasonography should be considered because of the high frequency of asymptomatic DVT associated with HIT, and this may influence the duration of warfarin therapy.²⁹

References:

REFERENCES

1. Weismann RE, Tobin RW. Arterial embolization occurring during systemic heparin therapy.

Arch Surg.

1958;76:219-225.
2. Warkentin TE. Heparin induced thrombocytopenia: pathogenesis and management.

Br

J Haematol.

2003;121:535-555.
3. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.

N Engl J Med.

1995;332:1330-1335.
4. Kelton JG. The pathophysiology of heparin- induced thrombocytopenia: biological basis for treatment.

Chest.

2005;127:9S-20S.
5. Warkentin TE. Clinical presentation of heparin-induced thrombocytopenia.

Semin Hematol.

1998; 35(suppl):9-16.
6. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients.

Arch Intern Med.

2003;163:2518-2524.
7. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia.

Am J Med.

1996;101:502-507.
8. Hong AP, Cook DJ, Sigouin CS, Warkentin TE. Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia.

Blood.

2003; 101:3049-3051.
9. Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.

Ann Intern Med.

1997;127:804-812.
10. Srinivasan AF, Rice L, Bartholomew JR, et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia.

Arch Intern Med

. 2004;164:66-70.
11. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia.

N Engl J Med

. 2001;344:1286-1292.
12. Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis.

Ann Intern Med.

2001;135:502-506.
13. Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced thrombocytopenia.

Ann Intern Med

. 2002;136:210-215.
14. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia.

Curr Hematol Rep

. 2003;2:148-157.
15. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy [published correction appears in

Chest

. 2005;127:416].

Chest

. 2004;126(3 suppl):311S-337S.
16. Greinacher A, Eichler P, Lubenow N, et al. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range.

Blood

. 2000;96:846-851.
17. Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.

Circulation

. 2001;103: 1838-1843.
18. Greinacher A, Volpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study.

Circulation

. 1999;99:73-80.
19. Greinacher A, Janssens U, Berg G, et al. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) Investigators.

Circulation

. 1999;100:587-593.
20. Hirsh J, Heddle N, Kelton JG. Treatment of heparin-induced thrombocytopenia: a critical review.

Arch Intern Med

. 2004;164:361-369.
21. Song X, Huhle G, Wang L, et al. Generation of anti-hirudin antibodies in heparin-induced thrombocytopenic patients treated with r-hirudin.

Circulation

. 1999;100:1528-1532.
22. Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia.

Circulation.

2003;108:2062-2065.
23. Chamberlin JR, Lewis B, Leya F, et al. Successful treatment of heparin-associated thrombocytopenia and thrombosis using Hirulog.

Can J Cardiol

. 1995;11:511-514.
24. Ramirez L, Carman T, Begelman SM, et al. Bivalirudin in patients with HIT or clinically suspected HIT [abstract].

Blood

. 2005;106:269a. Abstract 918.
25. Bartholomew JR. Bivalirudin for the treatment of heparin-induced thrombocytopenia

.

In:Warkentin TE, Greinacher A, eds.

Heparin-Induced Thrombocytopenia.

3rd ed. New York: Marcel Dekker; 2004.
26. Potzsch B, Klovekorn WP, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia.

N Engl J Med

. 2000;343:515.
27. Wallis DE, Workman DL, Lewis BE, et al. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia.

Am J Med

. 1999; 106:629-635.
28. Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.

Arch Intern Med.

2003;163: 1849-1856.
29. Tardy B, Tardy-Poncet B, Fournel P, et al. Lower limb veins should be systematically explored in patients with isolated heparin-induced thrombocytopenia.

Thromb Haemost.

1999;82:1199-1200.