Heparin-induced thrombocytopenia (HIT) is a clinicopathologic syndrome because diagnosis is based on both clinical symptoms and laboratory data. We report a patient with multiple thromboembolic complications after daily flushing of intravenous line with small amounts of unfractionated heparin (UFH). At day 7 bilateral hemorrhagic infarction of the adrenal glands was misdiagnosed as adrenal adenoma. On day 10 thrombocytopenia was noted and the next day a myocardial infarction complicated by a left ventricular thrombus was diagnosed. On day 12, HIT was suspected. The pre-test probability for HIT according to the 4T-score was high (8/8 points) and detection of antibodies directed against the PF4/heparin-complex by particle gel immunoassay (Titer 1:1024) and ELISA (O.D. 2.784) was strongly positive. HIT can be induced by iv-line flushes with UFH. Arterial and venous thrombotic complications can be present before a clear platelet drop can be recognised.
Heparin-induced thrombocytopenia (HIT) is a severe antibody-mediated adverse effect of heparin. Affected patients are at risk for both arterial and venous thromboembolic complications [
HIT is a clinicopathologic syndrome because diagnosis is based on both clinical symptoms and laboratory data [
We describe an instructive case of HIT initially presenting with bilateral hemorrhagic infarction of the adrenal glands before a relevant drop of the platelet count was noted and later on complicated by myocardial infarction, intracardial ventricular thrombus and limb artery thrombosis in the context of persistent high titer antiPF4/heparin antibodies.
The pre-test probability for HIT was calculated according to the 4T-score described by Warkentin [5,7]. Thrombocytopenia, timing of platelet count fall, presence or absence of thrombosis and other cause for thrombocytopenia were evaluated. Depending on the score, HIT probability can be clinically defined as high (6 - 8 points), intermediate (4 - 5 points) or low (0 - 3 points).
Rapid detection of antibodies directed against the PF4/ heparin-complex was achieved by a particle gel immunoassay (ID-H/PF4-PaGIA, DiaMed SA, Cressier sur Morat, Switzerland). Briefly, 10 µl of plasma were pipetted into the reaction chamber of the test IDcard followed by 50 µl of polymer particles (red high-density polystyrene beads coated with heparin/PF4 complexes). After incubation at room temperature for 5 min, the ID-card was centrifuged for 10 min in the dedicated ID-centrifuge (DiaMed SA). If there was not a significant level of anti-PF4/heparin-antibodies in the test sample, the particles sank to the bottom of the gel chamber. If anti-PF4/heparin-antibodies were present, the red polymer particles were cross-linked and remained on the top of the gel chamber. In case of a positive test with the undiluted sample, we repeated the assay with undiluted and serially diluted plasma or serum until the result was negative [
Anti-PF4/heparin-antibodies were also detected by commercially available enzyme-linked immunosorbent assays (GTI-PF4 Enhanced, Genetic Testing Institute, Waukesha, WI, USA) and measured at 405 nm with a microtitre plate reader (Anthos ht III; Hemotec, Gelterkinden, Switzerland). Based on our and others’ experience, we defined positive ELISA results as “potentially clinically relevant” when OD was ≥ 1.000 [
Heparin-induced platelet aggregation test (HiPAT) was performed according to Stricker et al. [
Coagulation assays were performed on a Behring Coagulation System automated analyser (Siemens Healthcare Diagnostics, Eschborn, Germany). aPTT was performed with Pathromptin SL (Siemens Healthcare Diagnostics) in duplicate and the average of measurements was calculated. Thrombin time was measured in duplicate with thrombin reagent (Siemens Healthcare Diagnostics), with final concentration of 1.5 U/ml (TT1) and 5 U/ml (TT2). Fibrinogen was measured according to Clauss [
A 70-year-old man was hospitalised because of local left foot infection after removal of one nail. He had a history of arterial hypertension, dyslipidemia and long-standing diabetes mellitus type 2. Current medication consisted of insulin, aspirin, ACE-inhibitor and beta-blocker. Laboratory data showed inflammation (CRP 75 mg/l, normal < 5 mg/l) hyperglycaemia (glucose 15.39 mmol/l, normal 4.56 - 6.38 mmol/l) and renal insufficiency (creatinin 114 µmol/l, normal 62 - 106 µmol/l). Coagulation testing (Prothrombin time, Quick 100%, aPTT 29.6 sec, normal 25 - 40 sec) and haematological analysis (haemoglobin 156 g/l, leucocytes 10.5 G/l, platelets 212 G/l) were normal. Foot osteomyelitis was ruled out and a diagnosis of a pedal erysipelas was made. Antibiotic therapy with amoxicillin-clavulanate was installed. Thromboembolic prophylaxis with heparin was omitted, however the intravenous line was flushed daily with small amounts (300 U) of unfractionated heparin (UFH).
Despite antibiotic therapy no amelioration of local infection was noted and therapy was switched to cefepime. The clinical course was characterised by abdominal pain on day seven. A CT-scan showed bilateral hemorrhagic infarction of the adrenal glands initially misdiagnosed as adrenal adenoma. At this day the platelet count was within normal range (273 G/l, normal 140 - 380 G/l). No supplemental diagnostic or therapeutic procedures were performed. On day 10 laboratory tests revealed a thrombocytopenia (95 G/l) without signs of a disseminated intravascular coagulation (PT, Quick 95%, aPTT 29.6 sec, fibrinogen 4.4 g/l (normal 1.8 - 3.5 g/l)). The next day a myocardial infarction complicated by a left ventricular thrombus was diagnosed and treated conservatively. On day 12 heparin-induced thrombocytopenia (HIT) was suspected and the patient referred to our hospital.
According to the 4T-score the pre-test probability for HIT in this patient was high (8/8 points): the platelets decrease was > 50% (2 points) and occurred between day eight and ten (2 points). No other evident causes of thrombocytopenia were present (2 points) and patient had thrombosis (2 points) [
Laboratory results at our institution confirmed thrombocytopenia (30 G/l) and showed a worsening renal function (creatinin 135 µmol/l, normal 59 - 104 µmol/l) as well as inflammation (CRP 326 mg/l, normal < 5 mg/l). Coagulation tests were compatible with blood coagulation activation (PT, Quick 93%, aPTT 32.4 sec, fibrinogen 5.57 g/l, D-dimers 12,174 µg/l (normal < 500 µg/l)). The titer of anti-PF4/heparin antibodies by ID-H/ PF4-PaGIA was very high (1:1024) and the ELISA for anti-PF4/heparin antibodies was strongly positive (O.D. 2.784). The HiPAT was clearly positive as well.
A diagnosis of HIT complicated by bilateral hemorrhagic infarction of the adrenal gland and myocardial infarction with intracavitary thrombus was made. Steroids and therapeutic anticoagulation with the direct thrombin-inhibitor lepirudin were started immediately.
Because of the decreased renal function, the lepirudin starting-dose was 0.040 mg/kg/h, according to internal guidelines [
HIT is a live-threatening, antibody-mediated, adverse effect of UFH or low-molecular-weight heparin. Surgery patients, especially undergoing orthopaedic surgery, are at high risk to develop HIT [
aspects render our case rare and interesting. Moreover, we show that despite initial anticoagulation with the direct thrombin inhibitor lepirudin and switch to VKA, after normalisation of platelet count activated coagulation can persist, particularly in patients with high titre antibodies directed against the PF4/heparin-complex.
At our institute we assess the titre of anti-PF4/heparin antibodies, on the one hand to overcome the low specificity of the test [