“Spontaneous” Heparin-Induced Thrombocytopenia and Thrombosis After Total Knee Arthroplasty: A Report of 2 Cases

Abstract

“Spontaneous” heparin-induced thrombocytopenia is a rare and virulent form of heparin-induced thrombocytopenia that occurs in the absence of exposure to any drug of the heparin class of anticoagulants. Most reported cases have occurred after knee replacement surgery. Herein we report 2 additional cases following total knee replacement. Clinical suspicion and immediate initiation of appropriate nonheparin anticoagulation are essential to avoid potentially devastating thrombotic complications.

Introduction

Heparin-induced thrombocytopenia (HIT) is a unique, highly thrombogenic disorder caused by the development of immunoglobulin G (IgG) antibodies directed against the complex of heparin and the secretable platelet protein platelet factor 4 [1]. Platelets are activated and aggregated in the circulation leading, in a significant portion of cases, to both thrombocytopenia and thrombosis. Thrombosis may be arterial or venous. The condition occurs in about 1% of patients treated with unfractionated heparin (UFH) and about one-tenth that often with low-molecular-weight heparin (LMWH). HIT occurs between approximately days 4 and 14 of treatment, with a peak occurrence at about days 6 to 7.

The heparin-platelet factor 4 ELISA immunologic assay and the functional platelet serotonin release assay (SRA) are commonly used to substantiate diagnosis. The former test detects antibodies against heparin-platelet factor 4 complexes. Microtiter plates are coated with heparin-platelet factor 4 complexes, patient serum is added, and HIT antibodies if present cause agglutination. The result is read out in optical density units (logarithm, base 10). The test is very sensitive but not highly specific. Absorbance in true positives is almost always 1.0 units or greater. Lower levels are commonly false positives. The functional SRA is more specific. ¹⁴C-serotonin–labeled platelets are incubated with patient serum with 2 concentrations of heparin (0.1 units/mL and 100 units/mL). If antibody is present, platelets are activated, and serotonin is released at the lower heparin concentration (0.1 units/ml). However, release is blocked at the higher heparin concentration (100 units/ml).

Occasionally HIT can occur without administration of drugs in the heparin class (the glycosaminoglycans). This is referred to as “spontaneous HIT”. Among reported cases [[2], [3], [4], [5], [6], [7], [8], 9, [10], [11], [12], [13], [14], [15], [16], [17], [18]], there is a preponderance of knee replacement surgery patients.

Recognition of spontaneous HIT, a very rare complication, is of utmost importance to orthopedic surgeons, as they are likely to be among the first physicians witnessing development of thrombocytopenia and thrombosis postoperatively. Without prompt recognition and appropriate management, morbidity from thrombotic complications can become extreme, and the condition may be fatal [2]. We herein describe 2 additional cases.

Case history #1

A 57-year-old woman underwent an uneventful left total knee replacement (Attune Knee System; DePuy Synthes, part of Johnson & Johnson Medical Devices Companies, New Brunswick, NJ) and was discharged home on postoperative day 4. Aspirin alone was used as venous thromboembolism prophylaxis; no glycosaminoglycan, direct oral anticoagulant, or vitamin K antagonist was given. The platelet count before surgery was 440,000/μL. On postoperative day 6, she had fever and chills with no identified infection. Her platelet count had fallen to 248,000/μL. She was rehospitalized and treated with cefazolin empirically. On postoperative day 10, she developed shortness of breath and left leg swelling. The platelet count was 70,000/μL, and the D-dimer was 10 μg/mL (normal less than 0.5 μg/mL). Computed tomography pulmonary angiography demonstrated acute segmental pulmonary embolism in the right lower lobe, and venous duplex Doppler ultrasound of the lower extremities showed acute left popliteal deep vein thrombosis. Heparin-platelet factor 4 ELISA IgG (1.85 absorption units, normal <0.40) and an SRA (87% at 0.1 U/mL and 0% at 100 U/mL) were both strongly positive. Anticoagulation was initiated with argatroban, her platelet count promptly increased to 300,000/μL, and 1 week later, the D-dimer was 0.90 μg/mL. She was discharged on full-dose rivaroxaban that she continued for the next 6 months.

Case history #2

A 70-year-old woman underwent uneventful right total knee replacement (C-Leg; Ottobock SE & Co. KGaA, Berlin, Germany). Her platelet count preoperatively was 170,000/μL. Aspirin alone was used as venous thromboembolism prophylaxis; no glycosaminoglycan, direct oral anticoagulant, or vitamin K antagonist was given. Over the next 3 weeks, she had occasional sharp pain in the opposite left thigh and sought attention when the distal left leg was bluish. At presentation, platelet counts were 27,000 to 47,000/μL. Arteriography showed extensive thrombosis in the left femoral system. The possibility of spontaneous HIT was not considered. She was anticoagulated with UFH, underwent embolectomy 2 days later, and was then switched to full-dose LMWH.

Five days after embolectomy, she developed severe, unremitting pain in the distal left leg. Arteriography showed extensive rethrombosis; the platelet count was 40,000/μL. The following day, thrombolysis, angioplasty, stenting, and fasciotomy were performed during a 6-hour procedure. With no improvement and severe distal leg ischemia, an above-the-knee amputation was required and performed.

One week later, while on UFH, she developed right lower extremity deep vein thrombosis and submassive pulmonary embolism. The platelet count was 52,000/μL. Heparin-platelet factor 4 ELISA IgG (2.476 absorption units, normal <0.40) and an SRA (90% at 0.1 U/mL, and 0% at 100 U/mL) were both strong positive. Anticoagulation was switched to argatroban, she stabilized clinically, had gradual platelet count improvement over the next 2 weeks, and was discharged on full-dose rivaroxaban.

Discussion

Sixteen spontaneous HIT cases after orthopedic surgery have been reported in the medical literature [[2], [3], [4], [5], [6], [7], [8], 9, [10], [11], [12], [13], [14]]. Several additional spontaneous cases have been reported in the context of serious infection [[15], [16], [17], [18], [19]]. Of the 16 orthopedic cases, 14 occurred after knee replacement surgery [[2], [3], [4], [5], [6], [7], [8], 9, [10], [11], [12]], one after shoulder replacement [13], and another after curettage and bone graft of the femur [14]. Eleven of the 16 cases were female and 4 were male, suggesting a female predominance; the gender of one patient was not reported. Reported cases occurred between 7 and 14 days after surgery in all except for one that presented at about 6 weeks. Thrombosis associated with spontaneous HIT in knee replacement patients may be arterial [2,13] or venous [[2], [3], [4],[6], [7], [8], 9, [10],[12], [13], [14]]. Adrenal crisis due to adrenal hemorrhage resulting from adrenal vein thrombosis has frequently been reported [2,3,[5], [6], [7],11].

Our 2 patients were female, both cases occurred after knee replacement. Neither patient had prior heparin exposure, a central or peripherally inserted central catheter (PICC) line; neither received heparin flushes. A tourniquet was used in both cases. Laboratory testing for HIT was performed in case #2 only after she had been exposed to heparin. Although she does not meet the definition of spontaneous HIT proposed by Warkentin et al. [13]. we are satisfied with the diagnosis of spontaneous HIT. Her presentation was typical, no other explanation for thrombocytopenia and thrombosis was evident, and improvement was immediate after the nonglycosaminoglycan anticoagulant was introduced.

Why spontaneous HIT seems to occur preferentially in knee replacement cases is not established, but a plausible hypothesis is that during the surgery, polyanionic glycosaminoglycans from the knee joint are released into the systemic circulation; tourniquet release may conceivably deliver a bolus [10,11,13]. Polyanionic glycosaminoglycans from the knee joint are presumed to mimic UFH in structure, may bind platelet factor 4, and stimulate the antibody response triggering the cascade of intravascular platelet activation, aggregation, and thrombosis [13,15]. The kind of prosthesis used in our 2 cases and one other [6] were all different, suggesting prosthesis type is unlikely to be a risk factor. The exact frequency with which spontaneous HIT occurs after knee replacement surgery is not established. Of interest is that spontaneous HIT has not been reported to date after total hip arthroplasty.

Table 1 summarizes the key features of spontaneous HIT. Once spontaneous HIT is suspected, anticoagulation is an urgent matter and must be initiated irrespective of platelet count. Argatroban and bivalirudin, given by continuous intravenous infusion, are FDA-approved antithrombin anticoagulants used in HIT. The use of one of these anticoagulants must not be delayed for the sake of confirmatory blood tests. The recurrence of thrombosis in our case #2 during UFH and LMWH use strongly suggests that these drugs should not be given to patients with spontaneous HIT. We suggest that platelet transfusion may potentially be prothrombotic and is thus best avoided except for serious bleeding. Hematology and vascular consultations to assist in management are advisable. Once the patient has stabilized and is ready for discharge, either a direct oral anticoagulant (an antifactor Xa or thrombin inhibitor) or warfarin can be considered. Clinical features determine duration of anticoagulation.

Table 1.

Features of spontaneous HIT.

1	The setting is usually (but not always) total knee replacement.
2	No drug of heparin class has been given postoperatively.
3	The platelet count drops significantly by 30%-50% or more, usually a few days up to 2 weeks, with no alternative explanation for the fall.
4	Thrombosis occurs (arterial, venous, or both) coincidentally with or very shortly after the platelet count falls.
5	Positive results from the heparin-platelet factor 4 ELISA IgG and serotonin release assays confirm.

Summary

Spontaneous HIT is a rare, extremely serious prothrombotic disorder that can result in significant morbidity and mortality. Among reported cases, including the 2 additional cases reported herein, most have occurred after total knee replacement surgery. Prompt recognition is essential, and anticoagulation with argatroban or bivalirudin mandatory, with vascular intervention as may be necessary.

Conflicts of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.