Bilateral renal artery thrombosis due to heparin-induced thrombocytopenia-thrombosis syndrome. Successful treatment with longterm application of lepirudin.

INTRODUCTION

Heparin-induced thrombocytopenia with thrombosis (HITT) is a rare but potentially fatal autoimmune syndrome, which is caused by antibody formation against complexes of heparin and platelet factor 4 (PF4). It typically develops five to fourteen days after the initiation of unfractionated or much less frequently low molecular weight heparin. The mortality rate can reach 20-30% and is associated mainly with thrombosis. Thrombotic events are most frequently venous but arterial thrombosis leading to myocardial infarction and ischemic limb damage requiring amputation also occur.1 No consensus currently exists on the best alternative anticoagulant treatment, especially in cases with renal compromise or other major organ involvement.

We report a case of a patient with HITT syndrome, renal failure and diffuse thrombosis who was successfully treated with intermittent intravenous bolus administration of recombinant hirudin (lepirudin) for a long time (forty days).

CASE REPORT

In May 2003, a 55-year-old woman was admitted to our hospital for evaluation of hypertension. Her past history was unremarkable. The physical examination and laboratory findings were both normal. CT-scan of the abdomen revealed a mass (diameters 3.2×4.2×2.1cm) on the upper pole of the left kidney. Renal angiography showed normal patency of both renal arteries. Surgical resection of the renal mass was performed. Histopathological examination was consistent with an angiomyolipoma. The immediate post-surgical course was uneventful and the patient was discharged on the seventh post-operative day. Ten days after the surgical procedure and twelve days after the angiography, the patient was readmitted to our hospital because of an acute substernal pain with electrocardiogram findings suggestive of acute myocardial infarction. On clinical examination an intense oedema with pain and redness on her right forearm was noticed. A duplex ultrasound study revealed thrombosis in the right subclavian vein. The laboratory tests were as follows: haemoglobin 7.1g/dl, white cell count 22.5×109/l (neutrophils 88%, lymphocytes 8%, monocytes 4%), platelets 45×109/l, coagulation tests were normal except for the presence of elevated D-Dimers, urea 38.5mmol/l (normal range 3.5-14), creatinine 371.3μmol/l (normal range 44.3-105), lactate dehydrogenase (LDH) 750 iu/l (normal range < 190), creatine phosphokinase (CPK) 810 iu/l (normal range < 100). The rest of the biochemical work-up was normal. Doppler examination of renal arteries revealed total absence of blood flow bilaterally. Because of the recent exposure to unfractionated heparin during angiography, there was a strong suspicion of HITT syndrome, which was confirmed, with the identification of antibodies against complexes of heparin and PF4 by gel microtube system 2 (Diamed,R Cressier sur Morat, Switzerland). The patient was admitted to the intensive care unit and because she was completely anuric, renal dialysis was started on the same day. Lepirudin, the only available thrombin inhibitor in Greece, is excreted exclusively by the kidneys and is contraindicated in severe renal failure. The therapeutic target was an APTT value at 1.5 to 2.5 times the baseline value. She received a loading dose of lepirudin (Refludan) 0.08mg/kg bolus iv, thereafter a dose of 0.04 mg/kg iv was repeated every 24 hours. A lepirudin dose was omitted if the APTT was >2.5 times the baseline value. Haemodialysis was performed using a polysulfone low-flux hemodialyser membrane. A locking dose of 0.02 mg of lepirudin was inserted into each lumen of the hemodialysis catheter at the end of dialysis and aspirated before initiation of the next dialysis. Each hemodialysis session was completed successfully, clot formation in the extracorporeal circuit was prevented and no bleeding complications occurred. Her clinical condition gradually improved and the platelet count restored to normal after thirteen days. Sixteen days after the thrombosis, renal function started to recover. There was a gradual increase in daily urine volume while urea and creatinine concentrations gradually decreased to 15mmol/l and 270μmol/l respectively. Magnetic resonance angiography (MRA) revealed a minimal flux on the right renal artery, while the left renal artery was totally occluded. Forty days after the initial thrombotic episode, renal dialysis was stopped. At that time we stopped lepirudin and the patient was commenced on oral anticoagulation with Warfarin (target INR 2.5 to 3.5). Two years later, the patient is in excellent clinical condition with stable renal function.

DISCUSSION

Heparin-induced thrombocytopenia (HIT) is an immune-mediated clinicopathological syndrome where the diagnosis should be based on the concurrence of an appropriate clinical picture together with detection of platelet activating and/or platelet factor 4 (PF4) dependent antibodies. These antibodies (most frequently IgG) activate platelets causing release of prothrombotic platelet-derived microparticles which in turn promote thrombin generation. Thrombosis appears to be due to heparin-like molecules (glycosaminoglycans) on the endothelial cell surface that, like heparin, can bind PF4. Immediate cessation of heparin is mandatory when HIT develops, but this will not stop continuing thrombin generation, nor will it help to avoid subsequent thrombotic events, which occur in as many as 40-50% of patients in subsequent days or weeks. Thus, an alternative anticoagulant should be substituted for heparin when HIT is strongly suspected.1

Direct thrombin inhibition may be beneficial in managing HIT. Several acting anticoagulants able to inhibit thrombin are available. Among them, only lepirudin is currently available in Greece. Lepirudin is the recombinant form of hirudin which is a thrombin inhibitor originally isolated from the salivary gland of the medicinal leech. It is a polypeptide of 65 amino acids which is renally metabolized and excreted with a half-life of 80 min. It does not show any reactivity in vitro for heparin and heparin induced antibodies. Lepirudin inactivates not only free thrombin but also fibrin clot bound thrombin.3 Its anticoagulation effect can be monitored by APTT and/or ecarin clotting time (ECT). Potzsch et al. have further shown that the ECT test is the most appropriate for laboratory monitoring, especially when lepirudin is used in high concentrations or in particular patients.4 Unfortunately, ECT is not commercially available. Bleeding complications are the most important adverse effects of the drug. No antidote currently exists for lepirudin. According to previous studies, the therapeutic target is an APTT value at 1.5 to 2.5 times the baseline value. Despite all limitations, we used lepirudin because it was the only available agent in Greece at that time. No significant experience exists concerning the use of lepirudin in renal failure.5–8 To our knowledge, the longest application of lepirudin in a haemodialysis patient covered more than 50 haemodialysis sessions in one single patient.9 There is currently no ideal haemodialysis anticoagulation agent for a patient with HIT, although Argatroban could have some theoretical advantages. Other procedures and agents which are probably efficient in HIT (plasmapheresis, high dose intravenous gammaglobulin, antiaggregants, prostacyclin analogues, thrombolytic therapy as well as thromboembolectomy) could not be used in our patient because of her unstable clinical condition. In a dose-escalation study, a bolus dose of 0.08 mg/kg lepirudin before haemodialysis was found to be effective. In patients with HIT and acute renal failure, a reduced dosage according to the degree of renal dysfunction is proposed but the optimal dosage schedule to induce therapeutic effect without bleeding is still unknown. Bolus doses as low as 0.005mg/kg have been advocated in anuric patients. Recovering renal function however, can lead to the need for drastically increased doses.10 In our patient, intermittent intravenous administration of lepirudin once daily according to APTT values for forty days was effective. After commencing lepirudin the patient didn't experience any other thrombotic episode, haemodialysis sessions were uneventful and bleeding did not occur. It was surprising that partial recanalization of the right renal artery was gradually restored with the right kidney regaining partial function allowing the patient to become dialysis independent.