**5. Treatment**

When HIT is suspected or proven, all heparin and LMWH should be discontinued. A careful investigation for heparin exposure from sources such as catheter flushes and hemodialysis is necessary. Even the low doses used to flush a catheter can lead to worsening thrombocytopenia and a systemic reaction in patients with HIT, as in the case presented above. Once heparin therapy is discontinued, platelet count should begin to rise within three days, though this is dependent on the amount of antibodies present in the system (Seleng et al., 2007; Kelton, 2002).

Heparin-Induced Thrombocytopenia 207

used to successfully treat HIT (Lobo et al., 2008), though there have been case reports of worsening thrombocytopenia in patients with HIT or a history of HIT treated with fondaparinux (Pistulli et al., 2011; Warkentin et al., 2007; Modi et al., 2009; Rota et al., 2008). Newer Xa inhibitors such as Rivaroxiban that can be taken orally are becoming available,

For patients requiring longer term anticoagulation once the HIT has resolved, a transition to warfarin can be made. It should not be done until the platelet count has improved to at least 150K/uL and there should be an overlap of at least 5 days of warfarin and the non-heparin

For patients who require anticoagulation with heparin and have a remote history of HIT, heparin can be used for a short duration when antibody assays are negative. Antiheparin/PF4 antibodies are usually undetected by 100 days after discontinuation of heparin therapy (Warkentin & Kelton, 2001b). For those who are antibody positive, or those who need prolonged anticoagulation, a non-heparin alternative should be considered (Warkentin

HIT is an important clinical entity to recognize as it creates a prothrombotic state that can lead to a variety of thromboembolic and systemic consequences. These most commonly include DVT and PE, though arterial thrombosis, acute myocardial infarction, stroke, acute adrenal insufficiency, and other serious complications can occur. Patients with HIT given an IV bolus of heparin may experience acute systemic reactions that can simulate pulmonary embolus or sepsis and even lead to cardiac arrest. Treatment includes discontinuation of all UFH and LMWH. A thorough search for surreptitious sources of heparin exposure should be performed. An alternative, non-heparin anticoagulant, such as a DTI should be started. HIT should be considered in patients who develop DVT or PE who are either receiving or have recently discontinued heparin. Intravenous heparin or LMWH should not be utilized to treat thrombosis in these situations. In the future, newer DTI's and possibly factor Xa

Amiral, J. (1999). Antigens involved in heparin-induced thrombocytopenia. Seminars in

Amiral, J., & Vissac, A.M. (1999). Generation and pathogenicity of anti=platelet factor 4

Arepally, G.M., & Mayer, I.M. (2001). Antibodies from patients with heparin-induced

Bailey, R.T., Ursick, J.A., Heim, K.L., Hilleman, D.E., & Reich, J.W. (1986). Heparin-

Blank, M., Schoenfeld, Y., Tavor, S., Praprotnik, S., Bofia, M.C., Weksler, B., et al. (2002).

antibodies: diagnostic implications. *Clinical and Applied Thrombosis/Hemostasis*, vol.5,

thrombocytopenia stimulate monocytic cells to express tissue factor and secrete

associated thrombocytopenia: a prospective comparison of bovine lung heparin, manufactured by a new process, and porcine intestinal heparin. *Drug Intelligence &* 

Anti-platelet factor 4/heparin antibodies from patients with heparin-induced

inhibitors may simplify treatment and reduce cost in managing this condition.

interleukin-8. *Blood*, vol.98, no.4, (August 2001), pp.1252-1254.

*Clinical Pharmacy* vol.20, no.5, (May 1986), pp.374-378.

Hematology, vol.36, no.1s1, (January 1999), pp.7-11.

no.s1, (October 1999), pp.s28-s31.

however their role in the treatment of HIT is not yet known.

anticoagulant (Warkentin et al., 2008).

et al., 2008).

**6. Conclusion** 

**7. References** 

There are several important principles in the management of HIT. The American College of Chest Physicians published evidenced-based clinical practice guidelines for the treatment and prevention of HIT in 2008 (Warkentin et al., 2008). Given the prothrombotic nature of the disorder, alternate, non-heparin anticoagulants should be administered. Just discontinuing UFH or LMWH or substituting warfarin (Coumadin®) is associated with a significant risk of thrombosis (Warkentin et al., 1998). As test results may take days to come back, treatment cannot wait until final confirmation of the diagnosis is made and should be instituted if the diagnosis is highly suspected.

For patients who develop a thrombotic event while on heparin or soon after discontinuing heparin, the platelet count should be checked and alternate non-heparin anticoagulants should be used until HIT is excluded.

Low molecular weight heparins, such as enoxaparin (Lovenox®) and dalteparin (Fragmin®) cannot be used in patients who develop HIT due to UFH as there may be cross-reactivity. The use of vitamin K antagonists such as warfarin is contraindicated during the acute phase of the illness when the patient is thrombocytopenic to avoid complications such as venous limb gangrene (Srinivasin, 2004; Warkentin et al., 1997) and multicentric skin necrosis (Warkentin et al., 1999). If the patient is on warfarin at the time HIT is diagnosed, Vitamin K should be administered. Platelet transfusions should generally be avoided, although there have been reports of their use without complication (Hopkins & Goldfinger, 2008; Refaai et al., 2010). IVC filters are not recommended during acute HIT (Warkentin et al., 2008). Ultrasound of the lower extremity can be considered as presence of DVT will affect the duration of anticoagulation (Tardy et al., 1999).

Choice of alternative, nonheparin anticoagulants include direct thrombin inhibitors (DTIs), such as argatroban and lepirudin (Refludan®), the heparinoid danaparoid (Orgaran®), and possibly the Xa inhibitor, fondaparinux (Arixtra®). Argatroban and lepirudin are approved for treatment of HIT in the United States. Danaproid has not been available in the United States since 2002. Choice of agent depends on a number of factors including availability and the presence of renal or hepatic dysfunction. An important difference between the DTIs is that argatroban is primarily hepatically eliminated, while lepirudin is primarily renally eliminated. The dose of argatroban should be reduced in the setting of liver dysfunction, congestive heart failure, anasarca, and after cardiac surgery. Lepirudin needs be adjusted for patients with renal insufficiency. Adjustments in the doses of these medications should be based on the aPTT. DTIs can elevate the INR and this can complicate the transition to warfarin when the thrombocytopenia has resolved.

Other DTI's have been utilized for the treatment of HIT. Bivalrudin is approved for patients with HIT or at risk for HIT undergoing percutaneous coronary intervention. It has also been used successfully in cardiac surgery. This agent undergoes enzymatic proteolysis and a minority is excreted renally. Desirudin, another DTI, showed promise as a more economical alternative to argatroban in a recent, small pilot study (Boyce et al., 2011). In addition, observational studies examining the role of desirudin in HIT in patients undergoing orthopedic and cardiac surgery have shown some positive results (Duncan et al., 2011; Levy & Koster, 2011). Desirudin is given subcutaneously every 12 hours as opposed to the other DTI's mentioned above, which are given as continuous intravenous infusions.

Factor Xa inhibitors make an attractive option for use in HIT. Fondaparinux can be given once a day subcutaneously. It costs less and requires less monitoring than the DTIs (monitoring of coagulation parameters to adjust dosing is not required). However, large randomized trials are lacking and it is not approved by the FDA for use in HIT. It has been

There are several important principles in the management of HIT. The American College of Chest Physicians published evidenced-based clinical practice guidelines for the treatment and prevention of HIT in 2008 (Warkentin et al., 2008). Given the prothrombotic nature of the disorder, alternate, non-heparin anticoagulants should be administered. Just discontinuing UFH or LMWH or substituting warfarin (Coumadin®) is associated with a significant risk of thrombosis (Warkentin et al., 1998). As test results may take days to come back, treatment cannot wait until final confirmation of the diagnosis is made and should be

For patients who develop a thrombotic event while on heparin or soon after discontinuing heparin, the platelet count should be checked and alternate non-heparin anticoagulants

Low molecular weight heparins, such as enoxaparin (Lovenox®) and dalteparin (Fragmin®) cannot be used in patients who develop HIT due to UFH as there may be cross-reactivity. The use of vitamin K antagonists such as warfarin is contraindicated during the acute phase of the illness when the patient is thrombocytopenic to avoid complications such as venous limb gangrene (Srinivasin, 2004; Warkentin et al., 1997) and multicentric skin necrosis (Warkentin et al., 1999). If the patient is on warfarin at the time HIT is diagnosed, Vitamin K should be administered. Platelet transfusions should generally be avoided, although there have been reports of their use without complication (Hopkins & Goldfinger, 2008; Refaai et al., 2010). IVC filters are not recommended during acute HIT (Warkentin et al., 2008). Ultrasound of the lower extremity can be considered as presence of DVT will affect the

Choice of alternative, nonheparin anticoagulants include direct thrombin inhibitors (DTIs), such as argatroban and lepirudin (Refludan®), the heparinoid danaparoid (Orgaran®), and possibly the Xa inhibitor, fondaparinux (Arixtra®). Argatroban and lepirudin are approved for treatment of HIT in the United States. Danaproid has not been available in the United States since 2002. Choice of agent depends on a number of factors including availability and the presence of renal or hepatic dysfunction. An important difference between the DTIs is that argatroban is primarily hepatically eliminated, while lepirudin is primarily renally eliminated. The dose of argatroban should be reduced in the setting of liver dysfunction, congestive heart failure, anasarca, and after cardiac surgery. Lepirudin needs be adjusted for patients with renal insufficiency. Adjustments in the doses of these medications should be based on the aPTT. DTIs can elevate the INR and this can complicate the transition to

Other DTI's have been utilized for the treatment of HIT. Bivalrudin is approved for patients with HIT or at risk for HIT undergoing percutaneous coronary intervention. It has also been used successfully in cardiac surgery. This agent undergoes enzymatic proteolysis and a minority is excreted renally. Desirudin, another DTI, showed promise as a more economical alternative to argatroban in a recent, small pilot study (Boyce et al., 2011). In addition, observational studies examining the role of desirudin in HIT in patients undergoing orthopedic and cardiac surgery have shown some positive results (Duncan et al., 2011; Levy & Koster, 2011). Desirudin is given subcutaneously every 12 hours as opposed to the other

Factor Xa inhibitors make an attractive option for use in HIT. Fondaparinux can be given once a day subcutaneously. It costs less and requires less monitoring than the DTIs (monitoring of coagulation parameters to adjust dosing is not required). However, large randomized trials are lacking and it is not approved by the FDA for use in HIT. It has been

DTI's mentioned above, which are given as continuous intravenous infusions.

instituted if the diagnosis is highly suspected.

duration of anticoagulation (Tardy et al., 1999).

warfarin when the thrombocytopenia has resolved.

should be used until HIT is excluded.

used to successfully treat HIT (Lobo et al., 2008), though there have been case reports of worsening thrombocytopenia in patients with HIT or a history of HIT treated with fondaparinux (Pistulli et al., 2011; Warkentin et al., 2007; Modi et al., 2009; Rota et al., 2008). Newer Xa inhibitors such as Rivaroxiban that can be taken orally are becoming available, however their role in the treatment of HIT is not yet known.

For patients requiring longer term anticoagulation once the HIT has resolved, a transition to warfarin can be made. It should not be done until the platelet count has improved to at least 150K/uL and there should be an overlap of at least 5 days of warfarin and the non-heparin anticoagulant (Warkentin et al., 2008).

For patients who require anticoagulation with heparin and have a remote history of HIT, heparin can be used for a short duration when antibody assays are negative. Antiheparin/PF4 antibodies are usually undetected by 100 days after discontinuation of heparin therapy (Warkentin & Kelton, 2001b). For those who are antibody positive, or those who need prolonged anticoagulation, a non-heparin alternative should be considered (Warkentin et al., 2008).
