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International Journal of Clinical Medicine, 2012, 3, 36-39
doi:10.4236/ijcm.2012.31007 Published Online January 2012 (
Catastrophic Complications of Intravenous Line Flushing
with Unfractionated Heparin

Giuseppe Colucci1*, Maximilian Jahns1, Tobias Silzle2, Lorenzo Alberio1
1Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland; 2Department of Haematology and Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland. Email: {*giuseppe.colucci, maximilian.jahns, lorenzo.alberio}, [email protected] Received October 6th, 2011; revised November 19th, 2011; accepted December 16th, 2011 ABSTRACT
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 gland was misdiagnosed as adrenal adenoma. On day 10 thrombocytopenia was noted and the next day a myo-
cardial 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.
Keywords: Heparin-Induced Thrombocytopenia; Adrenal Haemorrhagic Necrosis; 4T Score; PF4/Heparin-Antibodies
1. Introduction
was noted and later on complicated by myocardial in-farction, intracardial ventricular thrombus and limb ar- Heparin-induced thrombocytopenia (HIT) is a severe an- tery thrombosis in the context of persistent high titer anti- tibody-mediated adverse effect of heparin. Affected pa- tients are at risk for both arterial and venous throm-boembolic complications [1]. Antibodies (usually IgG) directed against heparin-bound platelet factor 4 (PF4), 2. Methods
together with heparin chains and PF4-tetramers, consti- 2.1. Determination of the 4T Score
tute macromolecular ternary complexes, which are able to activate platelets, endothelial cells and monocytes, The pre-test probability for HIT was calculated according leading to excessive in vivo thrombin generation [2,3]. to the 4T-score described by Warkentin [5,7]. Thrombo- cytopenia, timing of platelet count fall, presence or ab- clinicopathologic syndrome because diagno- sis is based on both clinical symptoms and laboratory sence of thrombosis and other cause for thrombocyto- data [4]. In the presence of venous and/or arterial throm- penia were evaluated. Depending on the score, HIT pro- bosis and concomitant administration of heparin, HIT bability can be clinically defined as high (6 - 8 points), should be always suspected. Potential thromboembolic intermediate (4 - 5 points) or low (0 - 3 points). complications are in particular deep venous thrombosis, pulmonary embolism, limb artery thrombosis, thrombotic 2.2. Detection of Anti-PF4/Heparin-Antibodies
stroke, myocardial infarction and adrenal hemorrhagic Rapid detection of antibodies directed against the PF4/ necrosis (indicating adrenal vein thrombosis) [4]. When- heparin-complex was achieved by a particle gel immu- ever HIT is suspected, its pretest probability score should noassay (ID-H/PF4-PaGIA, DiaMed SA, Cressier sur be determined by the 4T-score [5,6] and diagnostic pro- Morat, Switzerland). Briefly, 10 µl of plasma were pi- petted into the reaction chamber of the test IDcard fol- We describe an instructive case of HIT initially pre- lowed by 50 µl of polymer particles (red high-density senting with bilateral hemorrhagic infarction of the ad- polystyrene beads coated with heparin/PF4 complexes). renal glands before a relevant drop of the platelet count After incubation at room temperature for 5 min, the *Corresponding author.
ID-card was centrifuged for 10 min in the dedicated Copyright 2012 SciRes. IJCM
Catastrophic Complications of Intravenous Line Flushing with Unfractionated Heparin ID-centrifuge (DiaMed SA). If there was not a significant manufacturer’s instruction using an automated quantita- level of anti-PF4/heparin-antibodies in the test sample, tive immunoassay (VIDAS D-dimer; bioMérieux, Marcy the particles sank to the bottom of the gel chamber. If anti-PF4/heparin-antibodies were present, the red poly-mer particles were cross-linked and remained on the top 2.5. Case Presentation
of the gel chamber. In case of a positive test with the A 70-year-old man was hospitalised because of local left undiluted sample, we repeated the assay with undiluted foot infection after removal of one nail. He had a history and serially diluted plasma or serum until the result was negative [8]. Thus, for a 1:2 dilution, 50 µl of plasma or of arterial hypertension, dyslipidemia and long-standing serum were diluted with 50 µl of Diluent II (DiaMed SA), diabetes mellitus type 2. Current medication consisted of and subsequently dilutions were obtained by mixing 50 insulin, aspirin, ACE-inhibitor and beta-blocker. Labo- µl of the preceding one with 50 µl of Diluent II. The re- ratory data showed inflammation (CRP 75 mg/l, normal ported titre is the last positive detection followed by ei- < 5 mg/l) hyperglycaemia (glucose 15.39 mmol/l, normal ther indeterminate or negative results, as previously de- 4.56 - 6.38 mmol/l) and renal insufficiency (creatinin 114 µmol/l, normal 62 - 106 µmol/l). Coagulation testing Anti-PF4/heparin-antibodies were also detected by com- (Prothrombin time, Quick 100%, aPTT 29.6 sec, normal mercially available enzyme-linked immunosorbent as- 25 - 40 sec) and haematological analysis (haemoglobin says (GTI-PF4 Enhanced, Genetic Testing Institute, 156 g/l, leucocytes 10.5 G/l, platelets 212 G/l) were Waukesha, WI, USA) and measured at 405 nm with a normal. Foot osteomyelitis was ruled out and a diagnosis microtitre plate reader (Anthos ht III; Hemotec, Gel- of a pedal erysipelas was made. Antibiotic therapy with terkinden, Switzerland). Based on our and others’ ex- amoxicillin-clavulanate was installed. Thromboembolic perience, we defined positive ELISA results as “poten- prophylaxis with heparin was omitted, however the in- tially clinically relevant” when OD was ≥ 1.000 [3]. travenous line was flushed daily with small amounts (300 U) of unfractionated heparin (UFH). 2.3. Heparin-Induced Platelet Aggregation Test
Despite antibiotic therapy no amelioration of local in- fection was noted and therapy was switched to cefepime. Heparin-induced platelet aggregation test (HiPAT) was The clinical course was characterised by abdominal pain performed according to Stricker et al. [9]. In a light on day seven. A CT-scan showed bilateral hemorrhagic transmission aggregometer (model PAP-4, Bio Data, infarction of the adrenal glands initially misdiagnosed as Hatboro, PA, USA) four mixtures each containing 100 µl adrenal adenoma. At this day the platelet count was patient’s platelet-poor plasma and 100 µl platelet-rich within normal range (273 G/l, normal 140 - 380 G/l). No plasma from four different healthy donors are stirred for supplemental diagnostic or therapeutic procedures were 4 min at 37˚C in order to detect spontaneous heparin- performed. On day 10 laboratory tests revealed a throm- independent aggregation. Thereafter, 10 µl of a solution bocytopenia (95 G/l) without signs of a disseminated of unfractionated heparin (Liquemin®, Drossapharm, Ba- intravascular coagulation (PT, Quick 95%, aPTT 29.6 sel, Switzerland) and low molecular weight heparin (the sec, fibrinogen 4.4 g/l (normal 1.8 - 3.5 g/l)). The next preparation administered to the specific patient) are ad- day a myocardial infarction complicated by a left ventri- ded to achieve a final concentration of 0.5 U/ml. Light transmission is recorded for up to 15 min. A positive test cular thrombus was diagnosed and treated conservatively. is defined by at least two out of four samples reaching ≥ On day 12 heparin-induced thrombocytopenia (HIT) was 50% aggregation with abrogation of the reaction by a suspected and the patient referred to our hospital. final heparin concentration of 100 U/ml. 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 2.4. Coagulation Assays
eight and ten (2 points). No other evident causes of throm- Coagulation assays were performed on a Behring Co- bocytopenia were present (2 points) and patient had agulation System automated analyser (Siemens Health- care Diagnostics, Eschborn, Germany). aPTT was per- Laboratory results at our institution confirmed throm- formed with Pathromptin SL (Siemens Healthcare Diag- bocytopenia (30 G/l) and showed a worsening renal nostics) in duplicate and the average of measurements function (creatinin 135 µmol/l, normal 59 - 104 µmol/l) was calculated. Thrombin time was measured in dupli- as well as inflammation (CRP 326 mg/l, normal < 5 cate with thrombin reagent (Siemens Healthcare Diag- mg/l). Coagulation tests were compatible with blood co- nostics), with final concentration of 1.5 U/ml (TT1) and agulation activation (PT, Quick 93%, aPTT 32.4 sec, 5 U/ml (TT2). Fibrinogen was measured according to fibrinogen 5.57 g/l, D-dimers 12,174 µg/l (normal < 500 Clauss [10]. D-dimers were measured according to the µg/l)). The titer of anti-PF4/heparin antibodies by ID-H/ Copyright 2012 SciRes. IJCM
Catastrophic Complications of Intravenous Line Flushing with Unfractionated Heparin PF4-PaGIA was very high (1:1024) and the ELISA for with aspirin was switched to clopidogrel. One month anti-PF4/heparin antibodies was strongly positive (O.D. after HIT-diagnosis the patient was discharged. Despite 2.784). The HiPAT was clearly positive as well. VKA and clopidogrel as well as a percutaneous throm- A diagnosis of HIT complicated by bilateral hemor- bectomy, a forefoot amputation was inevitable. The pa- rhagic infarction of the adrenal gland and myocardial tient was hospitalised again two weeks later. After am- infarction with intracavitary thrombus was made. Ster- putation he was treated with lepirudin overlapping the oids and therapeutic anticoagulation with the direct selective factor-Xa inhibitor fondaparinux, leading to a thrombin-inhibitor lepirudin were started immediately. normalization of D-dimers (Figure 1).
Because of the decreased renal function, the lepirudin starting-dose was 0.040 mg/kg/h, according to internal 3. Discussion
guidelines [11]. Laboratory monitoring was performed 4 HIT is a live-threatening, antibody-mediated, adverse hours after initiation of lepirudin infusion. Dose adjust- effect of UFH or low-molecular-weight heparin. Surgery ments to achieves therapeutic ranges were performed according internal guidelines as well [11]. Under this patients, especially undergoing orthopaedic surgery, are regimen the patient was within therapeutic range four at high risk to develop HIT [12]. The risk decrease in hours after initiation of infusion of lepirudin (aPTT 74.2 general medical population and is low in pediatric and in sec, TT1 unclottable, TT2 21.3 sec) and persisted within patients undergoing chronic hemodialysis. HIT occurs therapeutic limits (results not shown). No bleeding com- more commonly in women than in men but is very rare in plications occurred during therapy. Platelets recovered pregnant woman [13]. Our case shows that HIT can be quickly (normalisation after four days) but dropped again induced by iv-line flushes with UFH and that severe without obvious cause although therapy with lepirudin thromboembolic complications (in this case bilateral he- was correctly performed. D-dimers persisted elevated morrhagic infarction of the adrenal glands) can occur and platelets remained long between 68 G/l and 85 G/l before a clear platelet drop [14]. Venous thromboembolic (Figure 1). An overlapping oral anticoagulation with
complication may be severe but patients are at risk for vitamin K antagonists (VKA) was installed (target INR 2 arterial occlusion as well, in particular in peripheral limb, - 3). However, during this time, the ELISA-OD were brain and coronary artery. Combination of inflammation constantly high (OD ≥ 2.000). Despite therapeutic anti- and small amount of heparin promote development of coagulation with VKA further thromboembolic compli- antibodies directed against the PF4/heparin-complex. cations occurred. Recently diagnosed peripheral arterial This case shows a classical but very rare initial manifest- disease of the left foot worsened over the course of the tation of HIT in a non surgical patient which received following weeks dramatically. Antithrombotic therapy only intermittent low quantity of heparin. This unusual Figure 1. Platelet-count (Tc, foursquare) and D-dimers (ring-shaped) under administration of anticoagulans: unfractionated
h parin (UFH, triangular), Lepirudin (square light), VKA (Marcoumar, square black) and Fondaparinux (square).
Copyright 2012 SciRes. IJCM
Catastrophic Complications of Intravenous Line Flushing with Unfractionated Heparin aspects render our case rare and interesting. Moreover, Pathogenesis and Management,” British Journal of Hae- we show that despite initial anticoagulation with the di- matology, Vol. 121, No. 4, 2003, pp. 535-555. rect thrombin inhibitor lepirudin and switch to VKA, af- ter normalisation of platelet count activated coagulation [6] G. K. Lo, et al., “Evaluation of Pretest Clinical Score (4 can persist, particularly in patients with high titre anti- T's) for the Diagnosis of Heparin-Induced Thrombocyto- penia in Two Clinical Settings,” bodies directed against the PF4/heparin-complex. and Haemostasis, Vol. 4, No. 4, 2006, pp. 759-765. At our institute we assess the titre of anti-PF4/heparin antibodies, on the one hand to overcome the low speci- [7] T. E. Warkentin and N. M. Heddle, “Laboratory Diagnosis ficity of the test [8], on the other one to identify the pa- of Immune Heparin-Induced Thrombocytopenia,” Cur- tients that potentially need a prolonged therapeutic anti- rent Hematology Reports, Vol. 2, No. 2, 2003, pp. 148-157. coagulation, as in this case. We propose to verify treat- [8] L. Alberio, et al., “Rapid Determination of Anti-Heparin/ ment efficacy not only by monitoring platelet count but Platelet Factor 4 Antibody Titers in the Diagnosis of He- also by serial D-dimers measurements and to monitor parin-Induced Thrombocytopenia,” The American Journal anti-PF4/heparin antibody titres. In case of persisting high of Medicine, Vol. 114, No. 7, 2003, pp. 528-536. antibody titres and high D-dimers values we suggest to extend anticoagulation over the recommended 3 months [9] H. Stricker, et al., “Heparin-Dependent in Vitro Aggrega- even if the platelet count has recovered. tion of Normal Platelets by Plasma of a Patient with He- parin-Induced Skin Necrosis: Specific Diagnostic Test for a Rare Side Effect,” The American Journal of Medicine, REFERENCES
[1] T. E. Warkentin, et al., “Heparin-Induced Thrombocyto- penia in Patients Treated with Low-Molecular-Weight [10] A. Clauss, “Rapid Physiological Coagulation Method in Heparin or Unfractionated Heparin,” The New England Determination of Fibrinogen,” Acta Haematologica, Vol. Journal of Medicine, Vol. 332, No. 20, 1995, pp. 1330- [11] M. Tschudi, B. Lammle and L. Alberio, “Dosing Lepi- [2] A. Greinacher, et al., “Heparin-Induced Thrombocyto- rudin in Patients with Heparin-Induced Thrombocytope- penia: A Stoichiometry-Based Model to Explain the Dif- nia and Normal or Impaired Renal Function: A Single- fering Immunogenicities of Unfractionated Heparin, Low- Center Experience with 68 Patients,” Blood, Vol. 113, No. Molecular-Weight Heparin, and Fondaparinux in Differ- ent Clinical Settings,” Thrombosis Research, Vol. 122, [12] T. E. Warkentin, et al., “Impact of the Patient Population on the Risk for Heparin-Induced Thrombocytopenia,” [3] L. Chilver-Stainer, B. Lammle and L. Alberio, “Titre of An- Blood, Vol. 96, No. 5, 2000, pp. 1703-1708. ti-Heparin/PF4-Antibodies and Extent of in Vivo Activa- [13] G. M. Arepally and T. L. Ortel, “Clinical Practice. Hepa- tion of the Coagulation and Fibrinolytic Systems,” Throm- rin-Induced Thrombocytopenia,” The New England Jour- bosis and Haemostasis, Vol. 91, No. 2, 2004, pp. 276-282. nal of Medicine, Vol. 355, No. 8, 2006, pp. 809-817. [4] T. E. Warkentin, et al., “Treatment and Prevention of Heparin-Induced Thrombocytopenia: American College [14] A. Greinacher, et al., “Clinical Features of Heparin-In- of Chest Physicians Evidence-Based Clinical Practice duced Thrombocytopenia Including Risk Factors for Guidelines (8th Edition),” Chest, Vol. 133, Supplement 6, Thrombosis. A retrospective Analysis of 408 Patients,” Thrombosis and Haemostasis, Vol. 94, No. 1, 2005, pp. [5] T. E. Warkentin, “Heparin-Induced Thrombocytopenia: Copyright 2012 SciRes. IJCM


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