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Lessening the Punch of Heparin-Induced Thrombocytopenia
References 1 Mangione CM, Goldman L, Orav J, et al. Health-related quality of life after elective surgery. J Gen Intern Med 1997; 12:686 – 697 2 McDowell I, Newell C. Measuring health: a guide to rating scales and questionnaires. Oxford, UK: Oxford University Press, 1996; 384 –385, 446 – 455 3 Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67:361–370 4 Shields GN. General thoracic surgery. Malvern, PA: Williams and Wilkins, 1994; 279 –287
Lessening the Punch of Heparin-Induced Thrombocytopenia bleeding remains the most common seriW hile ous complication of heparin use, heparin is also
a common cause of drug-related thrombocytopenia.1 Heparin-induced thrombocytopenia (HIT) occurs either as an acute, transient, and innocuous phenomenon due to nonimmunologic heparin effects (type I HIT), or as a morbid syndrome that usually occurs after a week of heparin therapy and is associated with platelet activation and a high rate of thromboembolism (type II, commonly termed “HIT”).2 Heparinassociated thrombocytopenia and heparin-associated thrombocytopenia with thrombosis are older classifications now folded into the rubric HIT. Thrombocytopenia usually denotes ⬍ 100 ⫻ 109 platelets per liter. HIT often is described in the context of antiheparin antibodies in patients with ⬎ 100 ⫻ 109 platelets per liter, if they have a falling platelet count and/or thrombotic events. A decrease in platelets during illness is usually not due to concomitant heparin therapy.3 Sepsis, disseminated intravascular coagulation, bone marrow suppression by drugs or illness, hypersplenism, or platelet consumption from pulmonary embolism, cardiac bypass, and orthopedic surgery can all decrease platelet counts acutely.4 HIT has a relatively low incidence of 1 to 3% in patients treated with unfractionated heparin (UFH). When do we need to suspect HIT? In this issue of CHEST (see page 37), we are provided with a study that increases our diagnostic accuracy of HIT. Lubenow and colleagues undertook a retrospective chart review of HIT onset in relation to the start of heparin therapy. They used a database of 119 surgical and medical patients with HIT who were enrolled in a prospective multicenter clinical trial of lepirudin therapy as an alternative anticoagulant. They defined HIT as thrombocytopenia ⬍ 100 ⫻ 109 platelets per liter in the presence of circulating antiheparin antibodies, whether thrombosis was present or not. www.chestjournal.org
Chiefly, they found that HIT is uncommon in the first 5 days of heparin therapy, unless heparin was administered in the preceding 3 months. HIT occurred similarly whether heparin was administered subcutaneously or IV. Heparin-reexposed patients (n ⫽ 46) had HIT develop at an average of 5 days of therapy (many on day 2), while heparin-naı¨ve patients (n ⫽ 79) had HIT develop at an average of 12 days (only 6% before day 6). Of the heparin-reexposed patients, only those who received heparin in the past 3 months were likely to get HIT before day 5 of heparin. Most HIT cases from heparin reexposure still occurred “late,” after 5 days of heparin. Few HIT cases involved low-molecular-weight heparin (LMWH). Whether this discrepancy was due to limited use of LMWH at the participating centers or due to the lower immunogenicity of LMWH is unclear. However, the preponderance of HIT cases among UFH-treated patients is consistent with two prospective studies of heparin prophylaxis in orthopedic patients,6 which revealed significantly less HIT in the LMWH-treated patients compared to those treated with UFH.4 How can the study of Lubenow and colleagues help us improve our early diagnosis of HIT? HIT antibody test results may take days. Stopping heparin while awaiting assay results may be unnecessary. Using the findings of Lubenow and colleagues, decreasing platelet counts are likely not due to HIT for a heparinnaı¨ve patient in the first 5 days of heparin treatment for an acute thrombosis. However, deciding whether a patient is heparin naı¨ve may not be simple. Heparin from hemodialysis, IV catheter flushes, and even on heparin-coated central venous catheters7 can cause HIT. In heparin-naı¨ve patients, platelet monitoring would be of little value before day 5 of heparin, yet should be instituted daily for patients exposed to any heparin in the prior 3 months. If one cannot rule out recent heparin exposure, monitor platelet counts early. The conclusions of this study are consistent with those of another retrospective study8 of the temporal aspects of HIT with a different definition of thrombocytopenia (⬎ 50% fall in platelet count). HIT must be considered in all heparin-treated patients with a significant fall (⬎ 30%) in platelet count, even in the absence of thromboembolism or actual thrombocytopenia. While most HIT patients in the lepirudin trial database had ⬍ 100 ⫻ 109 platelets per liter, thromboembolic events due to HIT in that and other studies clearly can occur with platelet counts in the normal range,5 yet all such HIT patients had a significant fall in platelet count. The occurrence of thromboembolism in HIT reflects platelet activation, formation of cross-linked platelet aggregates via platelet Fc receptors, platelet microparticle generation, and thrombin activation9 that occur after specific IgG (or IgM) antibodies bind to a complex of platelet factor 4 and heparin on CHEST / 122 / 1 / JULY, 2002
5
platelet and endothelial surfaces.10 After heparin therapy is stopped, these antibodies remain and trigger thromboembolic complications in many HIT cases. Thus, therapy of HIT is not just stopping heparin treatment. Anticoagulation may not only be needed for the original indication, but for the high risk of thromboembolism due to HIT antibodies. Clinical benefits and platelet recovery were demonstrated in prospective trials5,11 of alternative anticoagulants in HIT. Based on these studies, consensus guidelines recommend immediate therapy of HIT to limit thrombin generation, either with one of the direct thrombin inhibitors lepirudin5 and argatroban, or the factor Xa inhibitor danaparoid, a desulfated heparinoid.11 Only danaparoid is approved for thromboembolism prevention in patients with previous HIT. LMWH crossreacts with HIT antibodies and should never be used in HIT. All three alternative agents are not reversible, cause bleeding, and have contraindications and pharmacodynamic quirks that mandate involvement of a clinician familiar with their use. The use of warfarin alone during the acute phase of HIT is discouraged, due to reports of thrombosis from warfarin-mediated protein S depletion in the face of ongoing antibody-mediated thrombin generation. Interestingly, HIT antibodies are transient and HIT antibody generation does not involve an anamnestic response. The platelet factor IV heparin enzyme-linked immunosorbent assay remains positive for an average of 3 months, while the heparin-induced platelet activation assay (serotonin release) remains positive after an average of 50 days.8 Reflecting this, Lubenow and colleagues found that subjects with prior HIT who were inadvertently reexposed to heparin after 3 months rarely had early HIT develop; their circulating antibodies had cleared. Nonetheless, all HIT patients should have heparin listed as an allergy, and any future heparin therapy can be done only for compelling indications, only when HIT antibodies disappear, and for as briefly as possible. Substitution of alternative anticoagulants may be safer, though their use for cardiac bypass and in renal failure is problematic. Recurrent HIT due to inadvertent readministration of heparin within 3 months of the first HIT event is well documented and preventable. How do we lessen the punch of HIT? Early diagnosis and immediate cessation of heparin therapy are necessary. Urgent administration of an alternative anticoagulant is recommended. We should rarely stop heparin therapy before day 5 in heparinnaı¨ve patients, as we have learned that HIT is unlikely in that group. Avoiding heparin use in routine catheter flushes should prevent some HIT. Future prevention may involve more widespread use of LMWH or alternative anticoagulants in place of UFH. The higher cost of these agents and the low 6
incidence of HIT from UFH therapy limits the appeal of such a strategy. For now, HIT is here to stay. James P. Maloney, MD Milwaukee, WI Dr. Maloney is Assistant Professor, Division of Pulmonary and Critical Medicine, Medical College of Wisconsin. Correspondence to: James P. Maloney, MD, Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226; e-mail: jmaloney@ mcw.edu
References 1 Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119:64S–94S 2 Singer RL, Mannion JD, Bauer TL, et al. Complications from heparin-induced thrombocytopenia in patients undergoing cardiopulmonary bypass. Chest 1993; 104:1436 –1440 3 Bonfiglio MF, Traeger SM, Kier KL, et al. Thrombocytopenia in intensive care patients: a comprehensive analysis of risk factors in 314 patients. Ann Pharmacother 1995; 29:835– 842 4 Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecularweight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330 –1335 5 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 6 Leyvraz PF, Bachmann F, Hoek J, et al. Prevention of deep vein thrombosis after hip replacement: randomized comparison between unfractionated heparin and low molecular weight heparin. BMJ 1991; 303:543–548 7 Feinberg BI, LaMantia KR, Addonizio VP, et al. Pulmonary artery catheter-associated thrombocytopenia: effect of heparin coating. Mt Sinai J Med 1987; 54:147–149 8 Warkentin TE, Kelton JG. Temporal aspects of heparininduced thrombocytopenia. N Engl J Med 2001; 344:1286 –1292 9 Aster RH. Heparin-induced thrombocytopenia and thrombosis. N Engl J Med 1995; 332:1374 –1376 10 Newman PM, Chong BH. Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation. Blood 2000; 96:182–187 11 Hirsh J. New anticoagulants. Am Heart J 2001; 142:S3–S8
Does Splinting From Thoracic Bone Ischemia and Infarction Contribute to the Acute Chest Syndrome in Sickle Cell Disease? into and treatment of sickle cell disease R esearch (SSD) have been the province largely of hematologists and pediatricians. With the realization that
Editorials
Lessening the Punch of Heparin-Induced Thrombocytopenia bleeding remains the most common seriW hile ous complication of heparin use, heparin is also
a common cause of drug-related thrombocytopenia.1 Heparin-induced thrombocytopenia (HIT) occurs either as an acute, transient, and innocuous phenomenon due to nonimmunologic heparin effects (type I HIT), or as a morbid syndrome that usually occurs after a week of heparin therapy and is associated with platelet activation and a high rate of thromboembolism (type II, commonly termed “HIT”).2 Heparinassociated thrombocytopenia and heparin-associated thrombocytopenia with thrombosis are older classifications now folded into the rubric HIT. Thrombocytopenia usually denotes ⬍ 100 ⫻ 109 platelets per liter. HIT often is described in the context of antiheparin antibodies in patients with ⬎ 100 ⫻ 109 platelets per liter, if they have a falling platelet count and/or thrombotic events. A decrease in platelets during illness is usually not due to concomitant heparin therapy.3 Sepsis, disseminated intravascular coagulation, bone marrow suppression by drugs or illness, hypersplenism, or platelet consumption from pulmonary embolism, cardiac bypass, and orthopedic surgery can all decrease platelet counts acutely.4 HIT has a relatively low incidence of 1 to 3% in patients treated with unfractionated heparin (UFH). When do we need to suspect HIT? In this issue of CHEST (see page 37), we are provided with a study that increases our diagnostic accuracy of HIT. Lubenow and colleagues undertook a retrospective chart review of HIT onset in relation to the start of heparin therapy. They used a database of 119 surgical and medical patients with HIT who were enrolled in a prospective multicenter clinical trial of lepirudin therapy as an alternative anticoagulant. They defined HIT as thrombocytopenia ⬍ 100 ⫻ 109 platelets per liter in the presence of circulating antiheparin antibodies, whether thrombosis was present or not. www.chestjournal.org
Chiefly, they found that HIT is uncommon in the first 5 days of heparin therapy, unless heparin was administered in the preceding 3 months. HIT occurred similarly whether heparin was administered subcutaneously or IV. Heparin-reexposed patients (n ⫽ 46) had HIT develop at an average of 5 days of therapy (many on day 2), while heparin-naı¨ve patients (n ⫽ 79) had HIT develop at an average of 12 days (only 6% before day 6). Of the heparin-reexposed patients, only those who received heparin in the past 3 months were likely to get HIT before day 5 of heparin. Most HIT cases from heparin reexposure still occurred “late,” after 5 days of heparin. Few HIT cases involved low-molecular-weight heparin (LMWH). Whether this discrepancy was due to limited use of LMWH at the participating centers or due to the lower immunogenicity of LMWH is unclear. However, the preponderance of HIT cases among UFH-treated patients is consistent with two prospective studies of heparin prophylaxis in orthopedic patients,6 which revealed significantly less HIT in the LMWH-treated patients compared to those treated with UFH.4 How can the study of Lubenow and colleagues help us improve our early diagnosis of HIT? HIT antibody test results may take days. Stopping heparin while awaiting assay results may be unnecessary. Using the findings of Lubenow and colleagues, decreasing platelet counts are likely not due to HIT for a heparinnaı¨ve patient in the first 5 days of heparin treatment for an acute thrombosis. However, deciding whether a patient is heparin naı¨ve may not be simple. Heparin from hemodialysis, IV catheter flushes, and even on heparin-coated central venous catheters7 can cause HIT. In heparin-naı¨ve patients, platelet monitoring would be of little value before day 5 of heparin, yet should be instituted daily for patients exposed to any heparin in the prior 3 months. If one cannot rule out recent heparin exposure, monitor platelet counts early. The conclusions of this study are consistent with those of another retrospective study8 of the temporal aspects of HIT with a different definition of thrombocytopenia (⬎ 50% fall in platelet count). HIT must be considered in all heparin-treated patients with a significant fall (⬎ 30%) in platelet count, even in the absence of thromboembolism or actual thrombocytopenia. While most HIT patients in the lepirudin trial database had ⬍ 100 ⫻ 109 platelets per liter, thromboembolic events due to HIT in that and other studies clearly can occur with platelet counts in the normal range,5 yet all such HIT patients had a significant fall in platelet count. The occurrence of thromboembolism in HIT reflects platelet activation, formation of cross-linked platelet aggregates via platelet Fc receptors, platelet microparticle generation, and thrombin activation9 that occur after specific IgG (or IgM) antibodies bind to a complex of platelet factor 4 and heparin on CHEST / 122 / 1 / JULY, 2002
5
platelet and endothelial surfaces.10 After heparin therapy is stopped, these antibodies remain and trigger thromboembolic complications in many HIT cases. Thus, therapy of HIT is not just stopping heparin treatment. Anticoagulation may not only be needed for the original indication, but for the high risk of thromboembolism due to HIT antibodies. Clinical benefits and platelet recovery were demonstrated in prospective trials5,11 of alternative anticoagulants in HIT. Based on these studies, consensus guidelines recommend immediate therapy of HIT to limit thrombin generation, either with one of the direct thrombin inhibitors lepirudin5 and argatroban, or the factor Xa inhibitor danaparoid, a desulfated heparinoid.11 Only danaparoid is approved for thromboembolism prevention in patients with previous HIT. LMWH crossreacts with HIT antibodies and should never be used in HIT. All three alternative agents are not reversible, cause bleeding, and have contraindications and pharmacodynamic quirks that mandate involvement of a clinician familiar with their use. The use of warfarin alone during the acute phase of HIT is discouraged, due to reports of thrombosis from warfarin-mediated protein S depletion in the face of ongoing antibody-mediated thrombin generation. Interestingly, HIT antibodies are transient and HIT antibody generation does not involve an anamnestic response. The platelet factor IV heparin enzyme-linked immunosorbent assay remains positive for an average of 3 months, while the heparin-induced platelet activation assay (serotonin release) remains positive after an average of 50 days.8 Reflecting this, Lubenow and colleagues found that subjects with prior HIT who were inadvertently reexposed to heparin after 3 months rarely had early HIT develop; their circulating antibodies had cleared. Nonetheless, all HIT patients should have heparin listed as an allergy, and any future heparin therapy can be done only for compelling indications, only when HIT antibodies disappear, and for as briefly as possible. Substitution of alternative anticoagulants may be safer, though their use for cardiac bypass and in renal failure is problematic. Recurrent HIT due to inadvertent readministration of heparin within 3 months of the first HIT event is well documented and preventable. How do we lessen the punch of HIT? Early diagnosis and immediate cessation of heparin therapy are necessary. Urgent administration of an alternative anticoagulant is recommended. We should rarely stop heparin therapy before day 5 in heparinnaı¨ve patients, as we have learned that HIT is unlikely in that group. Avoiding heparin use in routine catheter flushes should prevent some HIT. Future prevention may involve more widespread use of LMWH or alternative anticoagulants in place of UFH. The higher cost of these agents and the low 6
incidence of HIT from UFH therapy limits the appeal of such a strategy. For now, HIT is here to stay. James P. Maloney, MD Milwaukee, WI Dr. Maloney is Assistant Professor, Division of Pulmonary and Critical Medicine, Medical College of Wisconsin. Correspondence to: James P. Maloney, MD, Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226; e-mail: jmaloney@ mcw.edu
References 1 Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119:64S–94S 2 Singer RL, Mannion JD, Bauer TL, et al. Complications from heparin-induced thrombocytopenia in patients undergoing cardiopulmonary bypass. Chest 1993; 104:1436 –1440 3 Bonfiglio MF, Traeger SM, Kier KL, et al. Thrombocytopenia in intensive care patients: a comprehensive analysis of risk factors in 314 patients. Ann Pharmacother 1995; 29:835– 842 4 Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecularweight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330 –1335 5 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 6 Leyvraz PF, Bachmann F, Hoek J, et al. Prevention of deep vein thrombosis after hip replacement: randomized comparison between unfractionated heparin and low molecular weight heparin. BMJ 1991; 303:543–548 7 Feinberg BI, LaMantia KR, Addonizio VP, et al. Pulmonary artery catheter-associated thrombocytopenia: effect of heparin coating. Mt Sinai J Med 1987; 54:147–149 8 Warkentin TE, Kelton JG. Temporal aspects of heparininduced thrombocytopenia. N Engl J Med 2001; 344:1286 –1292 9 Aster RH. Heparin-induced thrombocytopenia and thrombosis. N Engl J Med 1995; 332:1374 –1376 10 Newman PM, Chong BH. Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation. Blood 2000; 96:182–187 11 Hirsh J. New anticoagulants. Am Heart J 2001; 142:S3–S8
Does Splinting From Thoracic Bone Ischemia and Infarction Contribute to the Acute Chest Syndrome in Sickle Cell Disease? into and treatment of sickle cell disease R esearch (SSD) have been the province largely of hematologists and pediatricians. With the realization that
Editorials