Argatroban

Patients with heparin-induced thrombocytopenia (HIT) can have a dramatic presentation and often an unfortunate outcome. Each episode has the real potential to result in clinical catastrophe. From the > 100 such patients that we see yearly, patients have been selected to illustrate aspects of HIT such as history, epidemiology, clinical features, and improving treatment strategies. Delayed recognition continues to contribute to the morbidity and mortality of these patients. It is not adequate to just stop heparin therapy even with isolated HIT, therapy with low-molecular-weight heparins is contraindicated, and care must be used not to initiate warfarin therapy early or unopposed. A moderate suspicion for HIT should trigger the institution of therapy with an alternative anticoagulant even before laboratory confirmation. The potential beneficial impact of therapy with direct thrombin inhibitors makes it more important to maintain awareness of and vigilance for this syndrome.

Key words: direct thrombin inhibitors; drug-induced thrombocytopenia; heparin; heparin-induced thrombocytopenia; thrombosis

Abbreviations: 2-CDA = 2-chlorodeoxyadenosine; ELISA = enzyme-linked immunoassay; HIT = heparin-induced thrombocytopenia; PF4 = platelet factor 4

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As a Hematology fellow at our Veterans Administration Hospital in 1978, I saw five new patients with heparin-induced thrombocytopenia (HIT) over 3 months, each more dramatic than the last. To this day I can recount details. These patients made it hard not to develop an interest in their problem! In dozens of grand rounds on HIT, I always begin with a case presentation or two. These eases attract attention and effectively teach about the clinical aspects of the syndrome. My two clinical colleagues (Kelty Baker and John McCarthy) and I see > 100 patients with HIT yearly. Case presentations and series have also been an important part of our published contributions on this subject. I am pleased to describe several illustrative eases of patients with HIT.

PATIENT 1: POSTOPERATIVE STROKE IN A YOUNG MAN

An otherwise healthy 43-year-old man underwent lumbar laminectomy and received postoperative prophylactic unfractionated heparin, 5,000 U subcutaneously every 8 h. On the seventh postoperative day, he became hemiparetic and aphasic. On the 10th postoperative day, he was unresponsive. An anglogram showed left common and internal carotid occlusion. Postoperative blood work revealed that the platelet count, which had been normal preoperatively, was 32 x [10.sup.9] cells/L. The vascular surgeon retrieved a "white clot" from the carotid artery as heparin and platelet transfusions were given during the patch angioplasty, and vascular catheters continued to be flushed with heparin postoperatively. The next morning, the platelet level remained at 45 x [10.sup.9] cells/L, and the left leg was cold and pulseless. An emergency thrombectomy saved the leg. The hematology department was consulted, HIT was immediately diagnosed, aim all heparin exposures stopped. A test for heparin-induced platelet antibodies was strongly positive (by an aggregation test). The platelet count normalized in few days. After 2 months in the hospital, the patient was transferred to a long-term care facility in a vegetative state.

Comments

This patient illustrates the catastrophic potential of HIT. The patient was first reported > 20 years ago (1) when the clinical features of the syndrome were being delineated (2,3) (ie, a fall in platelet levels, generally by [greater than or equal to] 50%, occurring 5 to 14 days after beginning heparin exposure, often accompanied by thrombotic complications). In this case, confidence in the clinical diagnosis was heightened by the lack of likely alternative explanations. The early literature emphasized the occurrence of arterial thromboemboli (called white clots), but it has since been found (4) that venous thromboembolic complications are actually more common. Heparin exposure in this case consisted of subcutaneous prophylactic doses, emphasizing that all heparins administered by all routes and with all dosages can precipitate the syndrome. We were first to emphasize that heparin given during procedures and as catheter flushes could promulgate the syndrome, increasing the occurrence of complications, as happened in this case. (1,5,6) Earlier recognition of the problem and more effective therapeutic agents (which were unavailable then) likely could have improved the outcome for this patient.

PATIENT 2: PULMONARY EMBOLI AND SUPERIOR VENA CAVA THROMBOSIS WITH A CENTRAL VENOUS CATHETER

A 30-year-old woman with diabetes insipidus, and gum and skin infiltrates, had biopsy specimens demonstrating Langerhans cell histiocytosis. Outpatient therapy was instituted with a 7-day continuous IV infusion of 2-chlorodeoxyadenosine (2CDA). A syringe with 2-CDA was fitted daily to the patient's infusion pump, and the subcutaneous port was flushed with heparin. On day 9 (2 days after completing the 2-CDA therapy), the patient presented to the emergency department with severe pleuritic chest pains and dyspnea. Chest radiograph results were normal. The platelet count had fallen from 200 x [10.sup.9] to 54 x [10.sup.9] cells/L, which was attributed to the chemotherapy by her physicians (there had been no decrement in leukocyte count). She was admitted to the hospital and given parenteral narcotics. Two clays later, a chest CT scan was performed to explore possible histiocytic lung involvement, and it revealed bilateral pulmonary emboli. Simultaneously, the patient's right arm became very swollen and painful, and ultrasonography demonstrated subelavian-axillary venous thrombosis. The portacath was removed from that arm, and enoxaparin, 1 mg/kg twice daily, was administered. The platelet count dropped further to 19 x [10.sup.9] cells/L within hours. The other arm also became swollen and painful, the chest pain and oxygenation worsened, and facial swelling and headache appeared. She was transferred to our hospital in the middle of the night to assist with the "prothrombotic storm." All heparin exposures were then stopped, and therapy with the direct thrombin inhibitor argatroban was instituted. An enzyme-linked immunoassay (ELISA) the next day was strongly positive for heparin-platelet factor 4 (PF4) antibodies. Imaging showed bilateral subclavian-axillary thromboses, almost complete superior vena cava thrombosis, and multiple bilateral pulmonary emboli, including a large clot in the right main pulmonary artery (Fig 1). Thrombolytic therapy was considered but was thought unwise in the presence of her pituitary-hypothalamic disease. Argatroban treatment was initiated, and there was rapid improvement in all symptoms, all signs, and platelet count. She was cautiously transitioned to warfarin therapy and did well on outpatient follow-up.

[FIGURE 1 OMITTED]

Comments

This case illustrates how catastrophes of the highest magnitude may be averted with modern therapies. The only sensitizing heparin exposures were the catheter flushes, which, again, is a problem that we have emphasized, (1,5,6) and that led our hospital to institute policies 15 years ago against heparin use for catheter maintenance. A prospective study (7) has shown that even miniscule amounts of heparin that leach from coated catheters are associated with a 0.5% incidence of the syndrome. This case illustrates the propensity for venous thromboemboli. The use of low-molecular-weight heparins, while they cause HIT about one tenth as often as unfractionated heparin, is contraindicated once HIT develops, and the precipitous fall in platelet count once enoxaparin was given should have been a clue to the treating physicians (since they had not considered HIT sooner). (8) So, the ease of this patient from 4 years ago shows that the level of awareness about this common and catastrophic syndrome remains inadequate even among hematologists. Key to preventing catastrophes is maintaining a high degree of suspicion.

PATIENT 3: ISOLATED HIT AFTER HEART SURGERY

A 74-year-old man underwent coronary artery bypass surgery, which was complicated by transient postoperative atrial fibrillation and volume overload causing him to remain ventilator-dependent. On the seventh postoperative day, the platelet count fell to 70 x [10.sup.9] cells/L. The platelet count had been 200 x [10.sup.9] cells/L preoperatively and 182 x [10.sup.9] cells/L on postoperative day 2. There were no clinical signs of thrombosis, which was confirmed by arterial and venous Doppler ultrasonography of all four extremities. All heparin exposures were stopped, and a platelet aggregation test result was positive for heparin-induced antibodies. The patient improved clinically and was extubated. After heparin therapy was discontinued, the platelet count rose to 132 x [10.sup.9] cells/L after 4 days. On that day (day 11 postoperatively), the patient had a sudden cardiac arrest and could not be resuscitated.

Comments

It had been standard therapy to just stop heparin therapy in cases of isolated HIT (ie, in those patients who did not have a complicating thrombus, particularly if the initial heparin exposure had not been for an ongoing thrombotic problem). Warkentin and Kelton (4) reported on 62 consecutive patients with isolated HIT and found that a new thrombus had developed over the next month in 53%, with the great majority occurring in the first 10 days. Sometimes, the first manifestation of new thromboemboli was sudden death. I think that clots formed in this patient's bypass grafts, leading to ischemia and arrhythmia. A high incidence of new thromboses after heparin therapy cessation has been corroborated by Wallis et al, (9) Greinacher et al, (10) and Lewis et al. (11) Clearly, even isolated HIT mandates the use of an alternative anticoagulant agent and continued anticoagulation therapy through the period of high risk (about 6 weeks).

PATIENT 4: FEVER AND HYPOTENSION AFTER HEART SURGERY

A 51-year-old man underwent coronary artery bypass surgery complicated by postoperative hemopericardium, requiring pericardial window drainage. By the fifth postoperative day, he was ambulating and tolerating the oral ingestion of fluids, and prophylactic therapy with enoxaparin was started. On the ninth postoperative day, his fever spiked to 104.8[degrees]F, his BP fell to 90/70 mm Hg, and his abdomen was distended and mildly diffusely tender with scant bowel sounds. A CBC count revealed that the platelet level, which had been at 182 x [10.sup.9] cells/L when last checked on postoperative day 3, were then at 40 x [10.sup.9] cells/L. Tests for disseminated intravascular coagulation were negative. Therapy with antibiotics was started, and the patient was moved back to the ICU. The infectious disease and hematology consultants agreed that sepsis was a likely explanation for the thrombocytopenia. The time course also fit well with HIT, so a direct thrombin inhibitor was immediately initiated. An abdominal CT scan, performed emergently for suspected bowel ischemia, revealed bilateral hemorrhagic adrenal necrosis (Fig 2). A corticosteroid bolus was administered, and the serum cortisol level checked at the time was later reported to be < 1 [micro]g/mL. There was no further fever or hypotension, and culture findings were negative. The result of an ELISA for heparin-induced PF4 antibodies was very strongly positive. The patient's symptoms, signs, and platelet count rapidly normalized. The patient was discharged from the hospital while receiving adrenal replacement therapy and warfarin.

[FIGURE 2 OMITTED]

Comments

This patient's case (a report on which also appeared in The Hematologist, a newsletter of the American Society of Hematology) illustrates that if there is at least moderate suspicion for HIT, an alternative anticoagulant agent should be administered immediately. Adrenal necrosis is a microthrombotic lesion with secondary hemorrhage, which has been seen before in cases of HIT. (12) This patient was never septic but instead experienced HIT with acute adrenal crisis. The large amounts of unfractionated heparin administered on the pump were sensitizing, and the therapy with low-molecular-weight heparin may have contributed. The study by Greinacher et al (13) showed that the period after which heparin therapy is first stopped represents the greatest risk for new thromboembolic complications, hence one must administer anticoagulation therapy without delay and before laboratory confirmation. (14) So, even though sepsis seemed to be a plausible explanation for the clinical scenario, maintaining a high degree of suspicion and instituting immediate therapy for HIT may have reversed impending bowel necrosis in this case.

PATIENT 5: STROKE AFTER AORTIC VALVE REPLACEMENT

An 80-year-old woman had a porcine aortic valve placed for treatment of aortic stenosis. Her postoperative recovery was benign with discharge from the hospital after 8 days. Six clays after hospital discharge, she presented to a suburban hospital with acute onset of right hemiparesis and aphasia. ACT scan showed cerebral infarction. The platelet count was 66 x [10.sup.9] cells/L, while it had been 186 x [10.sup.9] cells/L on postoperative day 7. IV heparin was administered, and the platelet count several hours later was 22 x [10.sup.9] cells/L. She was transferred to the medical center. Although the neurology consultant ordered, "Begin heparin stroke protocol," the cardiovascular surgeon wrote underneath that no heparin be given "until cleared by hematology." A direct thrombin inhibitor was administered instead. The next day, the result of an ELISA for heparin-induced PF4 antibodies was strongly positive. The platelet count rose over few days, there was remarkable clearing of her neurologic impairments, and the patient was discharged from the hospital while receiving warfarin therapy.

Comments

Delayed-onset HIT has been described for only a few years, (15,16) yet it is now commonly being recognized. Most affected patients are exposed to heparin during hospitalization then are discharged to home only to return to the hospital in 1 to 2 weeks (rarely, up to 6 weeks) with new thromboses. Platelet counts are usually (not always) mildly low on representation. The relationship of the new thrombus to heparin exposure is not usually considered, so heparin is administered, always precipitating a dramatic fall in platelet levels, often dramatic clinical worsening, and, uncommonly, even acute cardiorespiratory collapse. (17) The mortality rate has been reported to be 27%. These patients have very high titers of the heparin-induced PF4 antibodies, which is thought to be important in the pathogenesis. Given that an estimated one third of hospitalized patients have some heparin exposure and that these exposures may be occult, one should always consider delayed-onset HIT when a recently hospitalized patient returns with a new thrombotic problem. I commonly finish talks on HIT by describing this patient because it does give a reason for optimism that educational efforts can impact the problem. The timely recognition of the syndrome by the surgeon was probably life-saving in this case.

Summary

HIT is a relatively common clinical problem that always has a significant potential to inflict catastrophic complications. It can result from any type of heparin exposure, by any route of administration, and from even tiny doses. The patients reported on in this article were sensitized by catheter flushes, by prophylactic subcutaneous doses, and, in three cases, by massive doses accompanying cardiovascular surgery. Complications were promulgated by the subsequent use of low-molecular-heparin. While the onset of disease is generally 5 to 12 days following the initial heparin exposure, the increasing recognition of delayed-onset HIT cases highlights the point that HIT must be considered whenever a hospitalized or recently hospitalized patient develops new venous or arterial thromboses.

These cases highlight the impact of evolving and improved treatment strategies, which makes it all the more important for clinicians to be highly aware of the syndrome, and to maintain vigilance and suspicion. Late recognition of the problem contributed to the complications experienced by patients 1 and 2 (and the condition of patient 1 was also hindered by the lack of effective alternative anticoagulant agents at that time). A moderate suspicion of HIT should trigger immediate direct thrombin inhibitor therapy. A delay is associated with a high rate of thrombotic complications, which likely would have been fatal in someone like patient 4. Just stopping heparin therapy is not adequate, which has been shown in published studies (4,9-11) and is illustrated by the case of patient 3. Other cases published by our group (18) have demonstrated the dangers of early unopposed warfarin therapy with HIT patients. In the extreme hypercoagulable milieu of HIT, the protein C inhibition that occurs early with warfarin therapy initiation can precipitate central skin necrosis and/or venous limb gangrene. The efficacy of direct thrombin inhibitors in improving patient outcomes is apparent in the cases of patients 2, 4, and 5, and likely proved to be life-saving for them.

* From the Department of Medicine, Section of Hematology-Ontology, Baylor College of Medicine, Houston TX.

REFERENCES

(1) Rice L, Jackson D. Can heparin cause clotting? Heart Lung 1981; 10:331-335

(2) Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia: eight cases with thrombotic-hemorrhagic complications. Ann Surg 1977; 186:752-758

(3) King DJ, Kelton JG. Heparin-associated thrombocytopenia. Ann Intern Med 1984; 100:535-540

(4) Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101:502-507

(5) Rice L, Huffman DM, Levine ML, et al. Heparin-induced thrombocytopenia/thrombosis syndrome: clinical manifestations and insights [abstract]. Blood 1986; 68(suppl):339a

(6) Rice L, Huffman DM, Waddell CC, et al. Therapy of thromboembolic disease: the heparin thrombocytopenia/ thrombosis syndrome. In: Thrombosis, anticoagulants and antiplatelet agents in clinical practice. New York, NY: Park Row, 1988; 31-36

(7) Laster J, Silver D. Heparin-coated catheters and heparin-induced thrombocytopenia. J Vasc Surg 1988; 7:667-672

(8) Greinacher A, Warkentin TE. Treatment of heparin-induced thrombocytopenia: an overview. In: Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia. 3rd ed. New York, NY: Marcel Dekker, 2004; 335-370

(9) 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

(10) Greinacher A, Volpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 199; 99:73-80

(11) Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103:1838-1843

(12) Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia. 3rd ed. New York, NY: Marcel Dekker, 2004; 53-106

(13) Greinacher A, Eichler P, Lubenow N, et al. Heparin-induced thrombocytopenia with thromboembolic complications: recta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood 2000; 96:846-851

(14) Rice L. Heparin-induced thrombocytopenia: myths and misconceptions. Arch Intern Med 2004; 164:1961-1964

(15) Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Meal 2002; 136:210-215

(16) Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001; 135:502-506

(17) Mims MP, Manian P, Rice L. Acute cardiorespiratory collapse from heparin: a consequence of heparin-induced thrombocytopenia. Eur J Haematol 2004; 72:366-369

(18) 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

Dr. Rice has been a consultant and on the speakers bureau for GlaxoSmithKline (the makers of argatroban) and Berlex (the maker of lepirudin), a consultant for The Medicines Company (the maker of bivalirudin), and has received small grant support from GlaxoSmithKline.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Lawrence Rice, MD, 6565 Fannin, MS 902, Room 930, Houston, TX 770,30; e-mail address: lrice@bcm. tmc.edu.

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