Chills and limb pain following administration of low‐molecular‐weight heparin for treatment of acute venous thromboembolism
Authors: Chris Hillis, Theodore E. Warkentin, Karim Taha, John W. Eikelboom
Journal: American Journal of Hematology (2011)

A 68-year-old Caucasian male underwent elective replacement of bicuspid aortic valve with bioprosthesis on Apr 21, 2010 for symptomatic aortic stenosis (valve area, 0.9 cm2). The past medical history was remarkable for seizure disorder treated with phenytoin. Postoperative anticoagulation included unfractionated heparin (5,000 twice daily by subcutaneous injection, given from postoperative days 1 to 5), with warfarin started on postoperative day 2, with plan to continue for 3 months. The in-hospital postoperative course was unremarkable, and the patient was discharged to home on postoperative day 5 (international normalized ratio [INR] = 2.0). Each year, an estimated 100,000 valve operations are done in the United States [1]. At many centers postoperative prophylaxis with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is given (although we are unaware of any randomized placebo-controlled trials supporting efficacy [2]). Moreover, patients who have undergone a bioprosthetic aortic valve replacement commonly receive warfarin anticoagulation for 3 months for reducing risk of valve thrombosis [3]. During the next 6 weeks the INR values were consistently subtherapeutic (mean, 1.4; range, 1.2–1.8; n = 6 values measured from May 6 to June 8 [target range, 2.0–3.0; 2.5 target]). Eventually, it was discovered that there was miscommunication between the medical providers and the patient; the former thought that “21/2” referred to the numbers of 2.5 mg pills being taken each day, whereas the latter believed that 2.5 mg was the intended dose. Subtherapeutic INR results can reflect a variety of explanations [4], including genetic variations in warfarin metabolism and its target enzymes, medication interactions (e.g., long-term phenytoin therapy inhibits warfarin's effect) [5], vitamin K consumption, poor compliance with warfarin administration, decreasing sensitivity to warfarin during the first 3 months after cardiac surgery [6] and—in this situation—confusion between health care provider and patient regarding intended dosing. On June 2, the INR measured 1.5, and the warfarin dose (given as either 2.0 or 2.5 mg/day) was increased from 16 to 17 mg per week; on June 8, the INR measured 1.8, and the warfarin dose (given as either 2.5 or 3.0 mg per day) was increased further to 19 mg per week. On June 10, the patient developed right lower limb discomfort and swelling, but he did not immediately seek medical attention. On June 16, the INR had risen to 2.3. The patient attended the emergency room (ER); however, a physician declined to arrange imaging studies of the right lower extremity or to alter therapy, because the INR of 2.3 measured earlier that same day was therapeutic and “even if clot identified patient is already anticoagulated with Coumadin.” The development of new symptoms suggesting lower-limb deep-vein thrombosis (DVT) warrants concern even if the INR is therapeutic on warfarin therapy. In our patient, the symptoms began only after an increase in warfarin dosing resulted in the INR rising from subtherapeutic to therapeutic, and without overlapping UFH or LMWH. This calls to mind a study performed in the Netherlands almost two decades ago [7]: among patients with DVT, giving a vitamin K antagonist (acenocoumarol) alone was more likely to be associated with symptomatic progression of thrombosis compared with patients who received the vitamin K antagonist in combination with initial heparin. In addition, development or progression of thrombosis while receiving warfarin can indicate “resistance” to warfarin, as has been described in hypercoagulability states such as cancer [8], heparin-induced thrombocytopenia (HIT) [9], and antiphospholipid syndrome. On Friday, June 25, the patient saw his family physician because of worsening of right lower limb pain and swelling. The family doctor arranged for lower-limb compression ultrasound, which was performed later that day, and which demonstrated extensive venous thrombosis involving the mid-to-distal superficial femoral vein, the popliteal vein, the trifurcation, and the calf veins. Given these results, the outpatient radiology clinic told the patient to go directly to the ER. There, his blood pressure was 111/76 and the heart rate was 84/min. There were no signs or symptoms of pulmonary embolism (PE). The INR was 1.7 (subtherapeutic). The hemoglobin was 11.9 g/L (normal, 13.0–18.0 g/L), the white blood count was 5.4 (normal, 4.0–11.0 × 109/L), with normal differential, and the platelet count was 179 × 109/L (normal, 150–400 × 109/L). The physician ordered dalteparin 12,000 U by subcutaneous injection, with a prescription for the patient to self-administer dalteparin on Saturday and Sunday, with follow-up on Monday with the thrombosis service. LMWH is an increasingly common therapy for treatment of proven or suspected DVT or PE, especially for when outpatient treatment is desired [10]. Here, the subtherapeutic INR and the objectively confirmed DVT on compression ultrasound clearly warranted the administration of LMWH or another parenteral anticoagulant. The dalteparin was administered at 23:45 hr, and the patient was discharged to home. He was awakened 90 min later (01:15 hr) when he developed severe “cramping” pain in the right lower limb, beginning in the posterior calf but then extending up into the posterior thigh. Fifteen minutes later (01:30 hr) he developed “shaking chills” and “flushing.” He immediately returned to the ER for further assessment. The development of right lower limb pain suggests possible progression of lower limb DVT. “Chills” suggests infection or some other acute inflammatory process. The close association of these two clinical features suggests some common pathophysiological link. The preceding administration of dalteparin suggests the possibility of an anaphylactoid reaction secondary to heparin administration [11-13]. At 02:45 hr the patient was reassessed at the ER. Vital signs showed marked tachycardia (HR = 122), normal blood pressure that was similar to that measured during his earlier ER visit (106/77), normal respiratory rate, and normal temperature. The patient denied palpitations, dyspnea, or chest pain. The right lower limb remained swollen. One hour later (03:45 hr), the HR returned to usual baseline (84/min). The complete blood count showed: hemoglobin 12.1 g/L, white blood count 8.4, and platelet count, 76 × 109/L. The serum creatinine was normal. Figure 1 shows the platelet counts, including during the preceding hospitalization for aortic valve replacement, as well as during the recent assessment for right lower limb swelling. Platelet count profile of patient with anaphylactoid reaction post-subcutaneous injection of dalteparin. The abrupt 57.5% decrease in platelet count from 179 to 76 × 109/L within 6 hr of administering 12,000 U of dalteparin, and without any other obvious explanation, is consistent with rapid-onset HIT. Patients with rapid-onset HIT almost invariably have received heparin within the previous 3 months [14]; in this case, the preceding heart surgery represents the recent heparin exposure that explains the presence of HIT antibodies at time of occurrence of rapid-onset HIT. Moreover, the clinical features of shaking chills and tachycardia are consistent with an acute anaphylactoid reaction secondary to heparin. This clinical syndrome has been linked to rapid-onset HIT. In addition, acute pain at the site of a DVT has been observed in some patients (Warkentin TE, unpublished observations). There was no evidence to suggest HIT during the initial hospitalization in which the patient underwent aortic valve replacement. The platelet count profile is the classic picture of postoperative hemodilution/platelet consumption, with an early platelet count decline on postoperative days 1–2, followed by platelet count recovery (rising platelet counts) at the time of discharge on postoperative day 5 (see Fig. 1). However, it remains possible that the patient developed “delayed-onset” HIT between postoperative days 7 to 14, a transient thrombocytopenic syndrome associated with increased risk of thrombosis, including venous thromboembolism [15, 16]. CT angiography revealed “a central filling defect in the right lower lobe artery extending to the medial basal segmental artery” with “no other filling defects identified” and “no evidence of right ventricular strain.” Blood was taken for serological investigations for HIT antibodies (discussed subsequently). Fondaparinux 7.5 mg was administered once-daily by subcutaneous injection. Warfarin was continued. The CT angiographic findings of PE raise the issue whether the tachycardia and shaking chills could be features of PE. However, the patient did not have acute dyspnea, and whereas PE can readily explain tachycardia, it does not adequately explain the patient's complaint of a shaking chill. In addition, whereas thrombocytopenia and disseminated intravascular coagulation can be associated with acute PE [17], this is rare and usually improves with heparin administration, whereas in our patient, the platelet count fall occurred abruptly soon after receiving LMWH. The ongoing management of venous thromboembolism—with initiation of therapeutic-dose fondaparinux and continuation of warfarin—requires comment. Fondaparinux is approved for treatment of DVT and PE and—although not specifically approved for treatment of HIT—appears to be effective for management of HIT-associated thrombosis (for review [18]). Moreover, the patient's normal renal function, low bleeding risk, and plan to maintain warfarin made fondaparinux a reasonable choice (fondaparinux is renally excreted, has a half-life of 17–21 hr but no specific antidote, and does not affect INR values). Although reversal of warfarin with vitamin K is recommended for patients with acute HIT (due to risk of precipitating venous limb gangrene) [9, 19, 20], its continuation here reflected the particular patient-specific circumstances of subacute and near-therapeutic warfarin anticoagulation, anticipated rapid achievement of fondaparinux anticoagulation, and expected rapid diminution of HIT-associated hypercoagulability. If instead of fondaparinux a direct thrombin inhibitor (such as lepirudin, desirudin, bivalirudin, or argatroban) had been chosen, warfarin reversal would have become critically important, as partial thromboplastin time prolongation by warfarin can result in systematic underdosing of direct thrombin inhibitor therapy [19]. The platelet count subsequently recovered to normal on fondaparinux, and the patient was discharged to home on warfarin alone. The patient was to learn the results of the tests for HIT antibodies at follow-up in the thrombosis clinic. Table I lists the results of the tests for HIT antibodies: the peak serotonin-release was 97% (normal, <20% release), and an IgG-specific PF4/heparin ELISA was 2.68 optical density units (normal, <0.45 units). The tests are strongly positive for heparin-dependent platelet-activating antibodies, especially when one considers that the blood samples were obtained 68 days following cardiac surgery: even among patients who develop proven HIT, the serotonin-release assay usually reverts to negative after 2 months [14]. Moreover, the ELISA is also strongly positive. These tests—together with the abrupt large-magnitude drop in platelet count soon after administration of subcutaneous dalteparin—support the diagnosis of an acute anaphylactoid reaction following dalteparin administration caused mediated through rapid-onset HIT. Anaphylactoid reactions are a known feature of rapid-onset HIT [11-13]. Table II lists the various signs and symptoms that have been reported [11-13]. Most often, these reactions occur 5–30 min (median, 10 min) after intravenous bolus heparin administration. However, as is illustrated by our patient, these reactions can also occur after subcutaneous administration of LMWH [20, 21]. In this patient, the reaction awoke him from sleep, and occurred ∼90 min after the subcutaneous injection of dalteparin received in the ER. This time course suggests that the onset of reactions following subcutaneous administration of LMWH might occur somewhat later than that observed after intravenous injection of UFH. The pathogenesis of these acute anaphylactoid reactions is obscure. A consistent feature is a large-magnitude drop in the platelet count, suggesting that HIT antibody-induced platelet activation per se, with release of platelet-derived metabolites, could account for some of the symptoms and signs. Consistent with this explanation, normal volunteers infused with adenosine diphosphate—a platelet agonist—have developed various acute signs and symptoms [22]. Alternatively, concomitant activation of leukocytes—as has been reported in HIT [23]—could explain these features. Although the patient had radiologic evidence of PE, the relatively small size of the embolus, the lack of hemodynamic compromise and absence of dyspnea suggest that the PE was an “incidental” finding associated with the patient's DVT, and unrelated to the post-dalteparin anaphylactoid reaction. It is interesting to note that anaphylactoid reactions can mimic acute PE, and have been termed “pseudo-PE” [24]. Administration of therapeutic-dose UFH or LMWH, either by intravenous or subcutaneous route, can trigger life-threatening anaphylactic reactions. In one study of patients without clinical suspicion of HIT, ∼0.4% had a positive serotonin-release assay—indicating presence of platelet-activating heparin-dependent antibodies—at study entry [25]. Most likely these patients had received heparin within the previous 3 months, as was seen in our patient (however, preceding heparin exposures was not recorded in this clinical trial). HIT antibodies are remarkably transient: there is <10% probability of a positive serotonin-release assay at 100-day follow-up, which explains why the syndrome of rapid-onset HIT has been associated with recent, rather than remote, heparin exposure. Among patients who could harbor unrecognized HIT antibodies—most likely because of recent heparin exposure—one way to avoid precipitating acute HIT is to administer fondaparinux rather than UFH or LMWH. Unlike UFH and LMWH, fondaparinux does not promote binding of HIT antibodies to PF4. Moreover, a secondary analysis of two randomized controlled trials comparing fondaparinux with heparin (either UFH or LMWH) showed that fondaparinux was associated with a significantly reduced risk of precipitating rapid-onset HIT among patients who had unrecognized heparin-dependent, platelet-activating antibodies: 0/10 versus 4/4 (P = 0.001). Thus, this patient case supports a change in clinical practice that could reduce the risk of heparin-induced anaphylactoid reactions: when a patient with acute venous thromboembolism has been exposed to heparin within the previous 100 days, treatment with fondaparinux, instead of UFH or LMWH, reduces the risk of precipitating rapid-onset HIT, along with its attendant adverse effects such as acute anaphylactoid reactions. Supported by the Heart and Stroke Foundation of Ontario (operating grant #T6950).