A case of pulmonary embolism due to heparin-induced thrombocytopenia after the placement of hepatic arterial infusion catheter

A 68-year-old woman developed acute pulmonary embolism after hepatic arterial infusion therapy for advanced hepatocellular carcinoma. Because the platelet count was significantly reduced, heparin-induced thrombocytopenia (HIT) due to heparin usage in hepatic arterial infusion therapy was clinically suspected. Subsequently, the patient tested positively for HIT antibodies, and a definitive diagnosis was obtained. Antithrombotic therapy with heparin was discontinued and treatment with argatroban was started. After the heparinized hydrophilic catheter was removed, the platelet count improved immediately. HIT should be considered when a decrease in platelet count and thrombosis are involved with the usage of heparin.     

Two cases of heparin-induced thrombocytopenia (HIT) and a review of the literature

We experienced two cases of heparin-induced thrombocytopenia (HIT) which occurred during unfractionated heparin treatment. The first patient was a 72-year-old man, who was admitted to our hospital because of sudden onset dyspnea in January 2000. He was diagnosed as having a pulmonary embolism and heparin was started. Nine days later, progressive embolization of the pulmonary artery and femoral vein was found and thrombocytopenia (platelet count 20 x 10(9)/l) was observed 14 days after that. Cessation of heparin and administration of argatroban resulted in progressive normalization of the platelet count. The second patient was a 62-year-old woman, who was admitted to our hospital in April 2001, with the chief complaint of sudden onset dyspnea. She was diagnosed as having acute left-sided heart failure and heparin was started. Fifteen 15 days later, thrombocytopenia (platelet count 17 x 10(9)/l) was observed. Cessation of heparin resulted in normalization of the platelet count. Both cases were positive for anti-heparin-platelet factor 4 (PF4) antibody. Here we report on the clinical course of two cases of HIT with a review of the literature.     

Venous thromboembolism in heparin-induced thrombocytopenia

Deep-vein thrombosis (DVT) and pulmonary embolism are among the most common complications of heparin-induced thrombocytopenia (HIT), an antibody-mediated adverse effect of heparin that leads paradoxically to in vivo activation of platelets and the coagulation system. Inappropriate treatment of HIT-associated DVT with warfarin can cause the DVT to progress to limb gangrene: this results from impaired ability of the protein C natural anticoagulant pathway to down-regulate thrombin generation, thus leading to microvascular thrombosis and tissue necrosis. Appreciation of the importance of coagulation system activation in HIT provides a rationale for treatments that reduce thrombin generation, either via inhibiting factor Xa (danaparoid) or via inhibiting thrombin directly (lepirudin). Clinicians should know how to distinguish HIT from other thrombocytopenic disorders: for example, thrombocytopenia associated with pulmonary embolism can mimic HIT (pseudo-HIT), and acute dyspnea that can mimic acute pulmonary embolism can result from acute in vivo platelet activation in a patient with HIT antibodies who receives heparin bolus therapy (pseudo-pulmonary embolism).     

Heparin-induced thrombocytopenia complicated with massive thrombosis of the inferior vena cava after filter placement.

A 45-year-old man presented with deep vein thrombosis of the right leg and bilateral pulmonary embolism. Heparin was administered on the initial one and a half days. On the 3rd day, an inferior vena cava (IVC) filter was placed with a heparin flush, after which massive IVC thrombosis developed. The platelet count was 221000/mm3, decreased 42% from the initial level, but remained within the normal range. Heparin was replaced by argatroban on the 13th day. The platelet count increased to 355000/mm3 on the 15th day. The patient was positive for antibody against complexes of heparin and platelet factor 4, and was diagnosed as heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). When thrombosis develops during heparin treatment, it is important to suspect HITTs and to assay for the associated antibodies, regardless of the actual platelet count.     

Heparin-induced thrombocytopenia in hemodialysis. Case report and review of the literature

Thrombocytopenia is a potential complication of heparin therapy. There are two forms of heparin-induced thrombocytopenia (HIT). Type-I HIT is characterized by a mild decrease in platelet count that occurs within the first 2-4 days after heparin initiation. The platelet count often returns to normal without stop heparin treatment. The mechanism of thrombocytopenia appears to be due to a direct effect of heparin on platelet activation. The second form (type-II) is an immune-mediated disorder characterized by severe thrombocytopenia, which may include both arterial and venous thrombosis. We present a case of type-II HIT occurred in a hemodialysis patient resulting in acute pulmonary embolism and peripheral venous thrombosis, and review the literature.     

Heparin-induced thrombocytopenia from venous thromboembolism treatment

OBJECTIVES: We aimed to characterize the clinical experiences of patients in whom heparin-induced thrombocytopenia (HIT) complicated heparin therapy for venous thromboembolism (VTE) and who switched to argatroban. DESIGN: A retrospective analysis of previously reported prospective, multicentre, historical-controlled Argatroban-911 and Argatroban-915 studies of argatroban therapy in HIT. SETTING: Inpatient. SUBJECTS: Patients (n = 145) administered heparin for VTE and who developed HIT were identified. INTERVENTIONS: Patients were treated with argatroban 2 mcg kg(-1) min(-1) for up to 14 days, adjusted to maintain activated partial thromboplastin times 1.5 to three times baseline. Patient characteristics, anticoagulation and outcomes were summarized. The primary end-point was a composite of death, amputation, or new thrombosis within 37 days of argatroban initiation. RESULTS: During heparin therapy, platelet counts decreased (mean +/- SD nadir: 78 +/- 67 x 10(9) L(-1)), and 75 (52%) patients developed thrombosis. After heparin was discontinued, patients received argatroban (mean dose 2.1 +/- 1.2 mcg kg(-1) min(-1)) for 6.8 +/- 4.3 days. By day 6 of argatroban therapy, the mean platelet count rose to >150 x 10(9) L(-1). The primary end-point occurred in 41 (28.3%) patients (values of 26-44% are reported for argatroban therapy of HIT from any heparin indication). Seventeen (11.7%) patients, including 12 who had also experienced thrombosis whilst on heparin, developed new thrombosis after argatroban initiation, typically on the day argatroban was discontinued or later (n = 10). Seven (4.8%) patients experienced major bleeding. CONCLUSIONS: For VTE patients with HIT, argatroban provides effective anticoagulation, with outcomes comparable with those reported for other argatroban-treated HIT patients. New thrombosis in this setting occurred most often in patients with existing HIT-associated thrombosis, before HIT recognition or either at/after argatroban discontinuation.     

Argatroban use during pediatric interventional cardiac catheterization.

Argatroban is a synthetic direct thrombin inhibitor that does not interact with or induce heparin-dependent antibodies. It is approved for use in adults for prevention and treatment of thrombosis associated with heparin-induced thrombocytopenia (HIT). It has been administered safely in adults with HIT during coronary interventions. There are no reports of argatroban use for anticoagulation in pediatric patients. The present case describes the use of argatroban during coil embolization of a Fontan fenestration in a child with a history of HIT. The patient received a single bolus dose of 150 microg/kg of argatroban at the onset of the intervention. The fenestration was successfully occluded with a detachable coil. The activated clotting time (ACT) was > 200 sec throughout the procedure. The ACT returned to baseline 72 min after the bolus. No complications occurred. This case demonstrates the safe and successful use of argatroban during a transcatheter intervention in a pediatric patient with a history of HIT. The use of argatroban is promising for anticoagulation in children who require an alternative to heparin.     

Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review

Recently published reports have established a heparin-induced thrombocytopenia (HIT)-mimicking thromboembolic disorder without proximate heparin exposure, called spontaneous HIT syndrome. Although the pathophysiology remains unclear, anti-platelet factor 4 (PF4)/heparin antibodies possibly triggered by exposure to knee cartilage glycosaminoglycans or other non-heparin polyanions found on bacterial surfaces and nucleic acids have been postulated. We present a 53-year-old female receiving antithrombotic prophylaxis with aspirin following right total knee replacement surgery (without perioperative or any previous lifetime heparin exposure) who acutely presented with high-risk pulmonary embolism (PE) and right great saphenous vein thrombophlebitis on postoperative day (POD) 14; her platelet count at presentation was 13 × 10⁹/L. Prior to diagnostic consideration of spontaneous HIT syndrome, the patient briefly received unfractionated heparin (UFH) and one dose of enoxaparin. The patient’s serum tested strongly positive for anti-PF4/heparin antibodies by two different PF4-dependent enzyme-linked immunosorbent assays (ELISAs) and by serotonin release assay (SRA). Failure of fondaparinux anticoagulation (persisting HIT-associated disseminated intravascular coagulation) prompted switching to argatroban. Severe thrombocytopenia persisted (platelet count nadir, 12 × 10⁹/L, on POD21), and 9 days after starting argatroban symptomatic right leg deep-vein thrombosis (DVT) occurred, prompting switch to rivaroxaban. Thereafter, her course was uneventful, although platelet count recovery was prolonged, reaching 99 × 10⁹/L by POD45 and 199 × 10⁹/L by POD79. The patient’s serum elicited strong serotonin release in the absence of heparin (seen even with 1/32 serum dilution) that was enhanced by pharmacological concentrations of UFH (0.1 and 0.3 IU/mL) and fondaparinux (0.1–1.2 μg/mL, i.e., in vitro fondaparinux “cross-reactivity”). Ultimately, platelet count recovery was associated with seroreversion to a negative SRA (documented at POD151). Our literature review identified joint replacement surgery, specifically knee replacement, to be a relatively common trigger of spontaneous HIT syndrome. Further, including our patient case, 5 of 7 patients with spontaneous HIT syndrome post-orthopedic surgery who received treatment with argatroban developed new and/or progressive lower-limb DVT or recurrent PE despite anticoagulation with this parenteral direct thrombin inhibitor, suggesting that this patient population is at high risk of breakthrough thrombotic events despite treatment with this HIT treatment-approved anticoagulant. Our case also illustrates successful outcome with rivaroxaban for treatment of spontaneous HIT syndrome, consistent with emerging literature supporting safety and efficacy of direct oral anticoagulant therapy for treatment of acute HIT.     

Use of systemic bivalirudin with catheter‐directed thrombolysis in a patient with heparin‐induced thrombocytopenia: A case report

In patients with submassive pulmonary embolism, the use of catheter‐directed thrombolysis (CDT), using low‐dose alteplase is associated with improvement in overall hemodynamics. The data for use of CDT in patients with heparin‐induced thrombocytopenia are limited. We report a case of CDT in a patient with HIT using bivalirudin anticoagulation. Data of the use of bivalirudin and argatroban for systemic anticoagulation with CDT are limited.     

Efficacy and safety of argatroban in patients with heparin induced thrombocytopenia undergoing endovascular intervention for peripheral arterial disease

Objectives: This study aimed to evaluate the efficacy and safety of argatroban during percutaneous interventions for peripheral arterial disease (PAD). Background: Endovascular interventions are commonly used in patients with peripheral arterial disease. Heparin is routinely administered during these procedures, but cannot be used in patients with a history of heparin‐induced thrombocytopenia (HIT). Argatroban is an approved direct thrombin inhibitor for treatment of patients with HIT. There are currently few data on the efficacy and safety of argatroban during endovascular interventions for PAD. Methods: Patients who underwent endovascular interventions for PAD on argatroban between 2002 and 2005 were identified from out database. Efficacy was evaluated using a composite of death, urgent revascularization, and amputation, while safety was assessed by TIMI major bleeding during the index hospitalization. Results: A total of 48 patients undergoing lower extremity revascularization on argatroban were identified. Thirty two of these patients (67%) had antibody‐confirmed HIT and the other 16 (33%) had suspected HIT. A mean dose of argatroban was 173.5 ± 143 μg/kg bolus, followed by a 10.7 ± 9.64 μg/kg/min infusion during the procedure. Twelve patients (25%) met the composite end point (two deaths, one urgent revascularization, nine amputations because of progressive peripheral arterial disease). TIMI major bleeding occurred in three (6%) patients. Conclusion: In patients with confirmed or suspected HIT undergoing endovascular intervention for PAD, argatroban appears to be effective and safe. A larger study is warranted to confirm these findings from a single center. © 2008 Wiley‐Liss, Inc.     

Hirudin in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT), a serious side effect of heparin treatment, requires alternative anticoagulation in most affected patients. The recombinant hirudin (r-hirudin) lepirudin has been approved for this purpose after two prospective trials in laboratory-confirmed HIT patients. Other drugs available for this purpose are danaparoid sodium (a heparinoid) and argatroban, a synthetic direct thrombin inhibitor. In this article, recommendations for optimal use of r-hirudin in HIT are given, covering therapy in uncomplicated patients as well as in special situations such as heparin reexposure of HIT patients. Because lepirudin's half-life depends on renal function, it may vary between 1 and 200 hours, which requires individual dose adjustments. Lepirudin compares favorably with danaparoid, based on retrospective data. No direct comparisons of lepirudin with argatroban are available, but argatroban might offer advantages in patients with renal failure, because it is mainly eliminated hepatically. Major hemorrhage, the main risk of lepirudin treatment, occurring in about 15% of patients, makes close monitoring important. New monitoring tools, such as the ecarin clotting time (ECT), might further reduce bleeding risks. Antihirudin antibodies, which can alter the pharmacokinetics as well as the pharmacodynamics of hirudin, can also be countered by close monitoring and appropriate dose adjustments. Whereas hirudins have not yet managed to gain importance in non-HIT indications such as unstable coronary syndromes, they have a major role to play in the treatment of HIT. The choice between the available drugs for HIT, namely lepirudin, danaparoid, and argatroban, has to be made according to the clinical presentation of the patient.     

The approach to heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating antibodies that recognize multimolecular complexes of platelet factor 4 (PF4) bound to heparin. HIT is an intense hypercoagulability state (increased thrombin generation in vivo) that is complicated more often by venous thromboembolism (deep vein thrombosis, pulmonary embolism) than by arterial thrombosis. HIT is a risk factor for coumarin-induced microthrombosis, particularly affecting acral regions of limbs with deep vein thrombosis (venous limb gangrene). Coumarins (e.g., warfarin) are therefore contraindicated during the acute (thrombocytopenic) phase of HIT. Venous thromboembolism can occur early during an episode of HIT, sometimes even before HIT-associated platelet count declines become clear. Recognition of HIT may be facilitated through the use of a clinical scoring system, the 4Ts ( Thrombocytopenia, Thrombosis, Timing, and o Ther explanations). Anti-PF4/polyanion enzyme-immunoassays (EIAs) and washed platelet activation assays readily detect HIT antibodies, and thus have high diagnostic sensitivity; however, only the platelet activation assays have high diagnostic specificity, suggesting that HIT is likely to be overdiagnosed in settings where EIAs are used exclusively for diagnosis. Treatment of HIT emphasizes substitution of heparin with an alternative nonheparin anticoagulant, such as a direct thrombin inhibitor (lepirudin, argatroban), or an indirect (antithrombin-mediated) inhibitor of factor Xa (danaparoid, fondaparinux?).     

Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome associated with thrombosis. Alternative anticoagulation to heparin is needed for HIT patients during percutaneous coronary intervention (PCI). We evaluated argatroban, a direct thrombin inhibitor, for anticoagulation in this setting. Ninety-one HIT patients underwent 112 PCIs while on intravenous argatroban (25 microg/kg/min [350 microg/kg initial bolus], adjusted to achieve an activated clotting time of 300-450 sec). Primary efficacy endpoints were subjective assessments of the satisfactory outcome of the procedure and adequate anticoagulation during PCI. Among patients undergoing initial PCIs with argatroban (n = 91), 94.5% had a satisfactory outcome of the procedure and 97.8% achieved adequate anticoagulation. Death (zero patients), myocardial infarction (four patients), or revascularization (four patients) at 24 hr after PCI occurred in seven (7.7%) patients overall. One patient (1.1%) experienced periprocedural major bleeding. For patients who had subsequent hospitalizations (mean separation of 150 days) for repeat PCI using argatroban anticoagulation (n = 21), there were no unsatisfactory outcomes. Overall, outcomes were comparable with those historically reported for heparin. Argatroban therefore is a reasonable anticoagulant option in this setting, where current options are limited.     

Venous limb gangrene and fatal hemorrhage: adverse consequences of HIT "overdiagnosis" in a patient with antiphospholipid syndrome

This unfortunate patient case highlights the problems with "overdiagnosis" of HIT. Despite "positive" tests for HIT antibodies, the low pretest probability for HIT and the known propensity of patients with APS to yield false-positive HIT antibody results suggests that the patient did not have a true diagnosis of HIT. Moreover, the early administration of warfarin and the choice of argatroban for parenteral anticoagulation when monitoring was hindered by a prolonged baseline aPTT likely play a key factor in the progression of UE DVT to VLG. Ironically, the problems of anticoagulant monitoring posed by the prolonged baseline aPTT likely contributed to the subsequent overanticoagulation and fatal pulmonary hemorrhage. With benefit of hindsight, avoiding the temptation to test for HIT in a low pretest probability situation, and treatment with either heparin using anti-factor Xa monitoring or with non-aPTT-monitored therapy such as LMWH or fondaparinux would likely have resulted in a more favorable clinical course.     

Heparin-induced thrombocytopenia

Opinion statement Treatment with heparin is associated with two types of thrombocytopenia. The most worrisome of these is the immune-mediated heparin-induced thrombocytopenia (HIT type II). Suspicion of HIT type II mandates immediate cessation of heparin adminis-tration and consideration of an alternative anticoagulation therapy. Hirudin and argatroban are approved alternative anticoagulants with no cross-reactivity with the HIT antibody. HIT type II is a clinicopathologic syndrome, and therefore diagnosis requires clinical and laboratory confirmation. The laboratory evaluation for HIT type II should also determine whether or not there is HIT-antibody cross-reactivity with danaparoid and low molecular weight heparin. Patients with HIT type II who require coronary artery bypass graft surgery present a particularly difficult situation, as there is no ideal alternative to heparin anticoagulation.     

Argatroban: a direct thrombin inhibitor for heparin-induced thrombocytopenia and other clinical applications

Argatroban, a direct thrombin inhibitor derived from arginine, is an effective anticoagulant indicated for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). Argatroban has been used as an alternative anticoagulant in patients with HIT in various clinical conditions including interventional cardiovascular procedures that require anticoagulation. Satisfactory clinical outcomes with acceptable complications have been reported in these patients. Whether argatroban offers additional clinical advantage over conventional heparin therapy in patients without HIT remains unclear. Argatroban has been evaluated as an alternative anticoagulant to replace heparin in various clinical studies, especially in patients with coronary artery disease or cerebral vascular disease. To date, it remains unclear if argatroban is more effective than heparin, although the agent seems to cause less bleeding complications. This article reviews the pharmacology of argatroban and its clinical application beyond the management of HIT, with particular emphasis on interventional cardiology procedure, acute myocardial infarction, unstable angina pectoris, cerebral thrombosis or ischemic stroke, peripheral obstructive arterial disease, and extracorporeal circulation.     

Timing of oral anticoagulation therapy in the treatment of angiographically proven acute pulmonary embolism

The optimal time to begin oral anticoagulation therapy with warfarin sodium in the treatment of acute pulmonary embolism has not been defined. To evaluate the relative cost, efficacy, and safety of early initiation of warfarin therapy, we reviewed the medical records of 38 patients with angiographically proven pulmonary embolism. Patients were divided into two groups: those who received warfarin early (less than or equal to 3 days after initial heparin sodium bolus, n = 17) and those who were treated late (greater than 3 days after initial heparin bolus, n = 21). After three months of follow-up, there was a similar incidence of mortality, recurrent pulmonary embolism, and bleeding complications in both treatment groups. Length of hospitalization was substantially less in the early group (9.6 +/- 2.0 vs 11.8 +/- 2.1 days). Early warfarin therapy in the treatment of acute pulmonary embolism appears to be both cost-effective and safe. A prospective multicenter controlled trial should be performed.     

Successful liver transplantation in a patient with splanchnic vein thrombosis and pulmonary embolism due to polycythemia vera with Jak2v617f mutation and heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatment resulting in a severe acquired thrombophilic condition with an associated mortality of about 10 %. We report the first case of successful urgent liver transplantation (LT) in a patient with end-stage liver disease due to a Budd–Chiari syndrome, portal vein thrombosis and pulmonary embolism due to acquired thrombophilia associated to polycythemia vera carrying JAK2V617F gene mutation and HIT in the acute phase. Lepirudin was used to provide anticoagulation in the LT perioperative period that was performed without haemorrhagic and thrombotic complications despite the donor received heparin during liver explantation.     

Successful Coronary Interventions Performed with Argatroban Anticoagulation in Patients with Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

Patients with heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) frequently have coincident vascular disease. Patients with HITTS who require vascular procedures have often been excluded from vascular intervention because intravascular procedures require heparin. Re-exposure to heparin places these patients at great risk for reactivation of thrombosis related to HIT antibody. We present our initial experience with an alternative anticoagulant to heparin, argatroban in patients with HIT antibody who underwent 14 coronary interventions. All 14 coronary lesions were treated successfully and no patient suffered an HITTS-related or an argatroban-related complication.     

Prolonged half-life of argatroban in patients with renal dysfunction and antiphospholipid antibody syndrome being treated for heparin-induced thrombocytopenia

Argatroban is a direct thrombin inhibitor approved for the treatment of heparin-induced thrombocytopenia (HIT) type II. Argatroban is predominantly metabolized in the liver. It is widely believed that no dosage adjustment is required in patients with renal insufficiency, making it a preferred agent in patients on renal replacement therapy (Reddy and Grossman, Ann Pharm 2005;39:1601-1605). The elimination half-life of argatroban is approximately 50 min. Lupus anticoagulants can cause baseline elevation of the PTT and hence it is difficult to monitor the effects of anticoagulants such as heparin, lepirudin, or argatroban in patients with antiphospholipid antibody syndrome. Heparin levels may be used as an alternative for heparin monitoring but plasma levels of argatroban are not commercially available. A chromogenic antifactor IIa assay could be useful for monitoring argatroban in the presence of a lupus anticoagulant, but it is not widely available at present. We report a patient with end-stage renal disease, maintained on peritoneal dialysis with HIT, who demonstrated a markedly prolonged half-life when treated with argatroban despite the discontinuation of therapy. This case also demonstrates the lack of guidelines for the monitoring of argatroban therapy in the presence of an underlying lupus anticoagulant.