Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review

Abstract

Recently published reports have established a heparin-induced thrombocytopenia (HIT)-mimicking thromboembolic disorder without proximate heparin exposure, called spontaneous HIT syndrome. Although the pathophysiology remains unclear, anti-platelet factor 4 (PF4)/heparin antibodies possibly triggered by exposure to knee cartilage glycosaminoglycans or other non-heparin polyanions found on bacterial surfaces and nucleic acids have been postulated. We present a 53-year-old female receiving antithrombotic prophylaxis with aspirin following right total knee replacement surgery (without perioperative or any previous lifetime heparin exposure) who acutely presented with high-risk pulmonary embolism (PE) and right great saphenous vein thrombophlebitis on postoperative day (POD) 14; her platelet count at presentation was 13 × 10/L. Prior to diagnostic consideration of spontaneous HIT syndrome, the patient briefly received unfractionated heparin (UFH) and one dose of enoxaparin. The patient's serum tested strongly positive for anti-PF4/heparin antibodies by two different PF4-dependent enzyme-linked immunosorbent assays (ELISAs) and by serotonin release assay (SRA). Failure of fondaparinux anticoagulation (persisting HIT-associated disseminated intravascular coagulation) prompted switching to argatroban. Severe thrombocytopenia persisted (platelet count nadir, 12 × 10/L, on POD21), and 9 days after starting argatroban symptomatic right leg deep-vein thrombosis (DVT) occurred, prompting switch to rivaroxaban. Thereafter, her course was uneventful, although platelet count recovery was prolonged, reaching 99 × 10/L by POD45 and 199 × 10/L by POD79. The patient's serum elicited strong serotonin release in the absence of heparin (seen even with 1/32 serum dilution) that was enhanced by pharmacological concentrations of UFH (0.1 and 0.3 IU/mL) and fondaparinux (0.1-1.2 μg/mL, i.e., in vitro fondaparinux "cross-reactivity"). Ultimately, platelet count recovery was associated with seroreversion to a negative SRA (documented at POD151). Our literature review identified joint replacement surgery, specifically knee replacement, to be a relatively common trigger of spontaneous HIT syndrome. Further, including our patient case, 5 of 7 patients with spontaneous HIT syndrome post-orthopedic surgery who received treatment with argatroban developed new and/or progressive lower-limb DVT or recurrent PE despite anticoagulation with this parenteral direct thrombin inhibitor, suggesting that this patient population is at high risk of breakthrough thrombotic events despite treatment with this HIT treatment-approved anticoagulant. Our case also illustrates successful outcome with rivaroxaban for treatment of spontaneous HIT syndrome, consistent with emerging literature supporting safety and efficacy of direct oral anticoagulant therapy for treatment of acute HIT.

Laboratory diagnosis of heparin‐induced thrombocytopenia

“…These highly pathogenic antibodies are able to bind and cross‐link PF4 molecules with (nonheparin) platelet‐associated polyanions (chondroitin sulfate, polyphosphates) or even in the absence of polyanion altogether. Table lists various presentations of HIT in which most (or all) patients have aHIT antibodies …”

“…Platelet activation assays performed both in the presence and absence of heparin are important in supporting a diagnosis of aHIT: Strong platelet activation at 0 U/mL heparin, which is enhanced in the presence of pharmacological concentrations of heparin (0.1‐0.5 U/mL UFH)—either using neat or diluted serum/plasma—with inhibition at 100 U/mL heparin, is the serological picture . The major U.S. reference laboratories that perform the SRA do not perform the test in the absence of heparin, contributing to aHIT underrecognition.…”

“…Precipitating events have included bacterial infection and knee replacement surgery (the latter despite postoperative nonheparin thromboprophylaxis). A large proportion (~70%) of patients with post‐knee replacement spontaneous HIT syndrome evince adrenal hemorrhagic necrosis …”

“…In these cases, aHIT antibodies have been observed where platelet activation was further enhanced in vitro in the presence of fondaparinux. Rarely, persisting thrombocytopenia and laboratory features of overt DIC have occurred in aHIT patients treated with fondaparinux, in whom in vitro “cross‐reactivity” with fondaparinux was demonstrated …”

Induction of anti-PF4/heparin antibodies after arthroplasty for rheumatic diseases

“…Presumably, PF4 is bound to immunogenic complexes through binding to polyanionic bacterial surfaces or to chondroitin -sulfate released during infections or orthopedic surgery 3) . It has been reported that some patients receiving arthroplasty had positive tests for anti -PF4/heparin antibodies 4) . This review will summarize current clinical and laboratory features of PF4/heparin immunogenicity induced by arthroplasty during rheumatic diseases.…”