A 76-year-old woman underwent bilateral total knee arthroplasty without any complications. Postoperative deep venous thrombosis (DVT) prophylaxis consisted of aspirin 81 mg twice a day. Approximately two weeks after the procedure, the patient was transferred from a rehabilitation center to the ED due to worsening dyspnea, chest pain, and oxygen desaturation to 80% on room air.
Her medical history consisted of breast cancer treated with a lumpectomy. She did not have personal or family history of venous thromboembolism. The patient did not smoke tobacco and rarely drank alcohol. Outpatient medications included letrozole, 2.5 mg/d, and aspirin, 81 mg/d. An extensive review of the patient's perioperative medication history did not reveal any exposure to heparin.
Upon presentation, the patient was afebrile with a blood pressure of 120/55 mm Hg, a heart rate of 93 beats/min, a respiratory rate of 18 breaths/min, and oxygen saturation of 93% on room air. Physical exam revealed a frail-appearing woman in mild distress. Lung exam demonstrated decreased breath sounds bilaterally. Lower extremities had mild pitting edema bilaterally. The remainder of the physical exam was within normal limits.
Notable labs from admission included a leukocyte count of 20,270 cells/mm3 (from 8,860 cells/mm3 on postoperative day 1) and a platelet count of 53,000 cells/mm3 (from 146,000 cells/mm3 on postoperative day 1). Urine culture grew extended-spectrum beta-lactamase Escherichia coli.
An ultrasound of the lower extremities demonstrated an occlusive thrombus within the right posterior tibial veins and occlusive thrombi within the left popliteal, gastrocnemius, and posterior tibial veins. A CT angiogram of the chest revealed bilateral pulmonary emboli without evidence of right ventricular strain. A transthoracic echocardiogram confirmed no evidence of right ventricular strain.
The patient was started on subcutaneous enoxaparin, 80 mg every 12 hours and aspirin, 324 mg in the ED. The platelet level did not decrease with administration of enoxaparin.
Throughout her admission, the patient was persistently thrombocytopenic, which prompted concern for heparin-induced thrombocytopenia (HIT). An immunoglobulin G-specific platelet factor 4 (PF4)-heparin enzyme immunoassay demonstrated a strong positive result (>3.5 units of optical density; reference range, <0.400 units). The serotonin-release assay (SRA) was positive with 96% serotonin release at 0.1 IU/mL, 100% serotonin release at 0.5 IU/mL, and 31% serotonin release at 100 IU/mL.
Enoxaparin was discontinued on post-operative day 17 once HIT test results returned positive. Subsequently, the patient was started on apixaban, 10 mg twice daily, for seven days, followed by apixaban, 5 mg twice daily by mouth, for six months. Her platelet count recovered after enoxaparin was withdrawn.
HIT is a potentially life-threatening immune-mediated response caused by antibodies recognizing specific complexes located on PF4 bound to heparin or heparin-related compounds.
Patients present with unexpected thrombocytopenia that is strongly associated with venous or arterial thrombosis (11. Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J. 2007;83:575-82. [PMID: 17823223]). HIT is typically associated with preceding exposure to unfractionated heparin or low-molecular-weight heparin, rarely fondaparinux. Onset of thrombocytopenia typically begins five to 10 days after the initial immunizing heparin exposure (22. Burch M, Cooper B. Fondaparinux-associated heparin-induced thrombocytopenia. Proc (Bayl Univ Med Cent). 2012;25:13-5. [PMID: 22275775]). More recently, several cases have been described that resemble HIT without any prior heparin exposure, a disorder called spontaneous HIT syndrome (33. Poudel DR, Ghimire S, Dhital R, Forman DA, Warkentin TE. Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review. Platelets. 2017;28:614-620. [PMID: 28856946]). Total knee arthroplasty is one of the most common triggers of spontaneous HIT syndrome, having been reported previously in 10 patients, or approximately half of all reported cases (33. Poudel DR, Ghimire S, Dhital R, Forman DA, Warkentin TE. Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review. Platelets. 2017;28:614-620. [PMID: 28856946]). Spontaneous HIT syndrome has never been observed following hip arthroplasty, suggesting that factors specific to knee arthroplasty might be relevant (33. Poudel DR, Ghimire S, Dhital R, Forman DA, Warkentin TE. Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review. Platelets. 2017;28:614-620. [PMID: 28856946], 44. Baker K, Lim MY. Spontaneous heparin-induced thrombocytopenia and venous thromboembolism following total knee arthroplasty. Case Rep Hematol. 2017;2017:4918623. [PMID: 28261509]).
The underlying pathophysiology behind spontaneous HIT syndrome is unclear, but several mechanisms have been proposed. Activated platelets contain α-granules that are responsible for releasing the chemokine PF4. Positively charged PF4 attracts negatively charged polyanions, such as heparin, that subsequently combine two PF4 tetramers inducing a conformational change in PF4 (55. Kreimann M, Brandt S, Krauel K, Block S, Helm CA, Weitschies W, et al. Binding of anti-platelet factor 4/heparin antibodies depends on the thermodynamics of conformational changes in platelet factor 4. Blood. 2014;124:2442-9. [PMID: 25150299]). This reaction results in the formation of a large immunogenic complex, consisting of PF4 and heparin, that immunoglobulin G antibodies recognize via platelets crosslinking through the FcγIIa receptors (55. Kreimann M, Brandt S, Krauel K, Block S, Helm CA, Weitschies W, et al. Binding of anti-platelet factor 4/heparin antibodies depends on the thermodynamics of conformational changes in platelet factor 4. Blood. 2014;124:2442-9. [PMID: 25150299]).
Non-heparin triggers have been observed to cause anti-PF4/heparin antibody complexes without a patient ever being exposed to a heparin product. Non-heparin triggers that have been identified include glycosaminoglycans such as chondroitin sulfate, which are released from cartilage during orthopedic surgery; bacterial antigens from recent infection (bacterial cell walls are negatively charged); and polyphosphates released from activated platelets (66. Cines DB, Yarovoi SV, Zaitsev SV, Lebedeva T, Rauova L, Poncz M, et al. Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia. Blood Adv. 2016;1:62-74. [PMID: 29296696], 77. Jaax ME, Krauel K, Marschall T, Brandt S, Gansler J, Fürll B, et al. Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4. Blood. 2013;122:272-81. [PMID: 23673861], 88. Nguyen TH, Medvedev N, Delcea M, Greinacher A. Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity. Nat Commun. 2017;8:14945. [PMID: 28530237], 99. Padmanabhan A, Jones CG, Bougie DW, Curtis BR, McFarland JG, Wang D, et al. Heparin-independent, PF4-dependent binding of HIT antibodies to platelets: implications for HIT pathogenesis. Blood. 2015;125:155-61. [PMID: 25342714], 1010. Pongas G, Dasgupta SK, Thiagarajan P. Antiplatelet factor 4/heparin antibodies in patients with gram negative bacteremia. Thromb Res. 2013;132:217-20. [PMID: 23830968]). Some patients have developed spontaneous HIT after orthopedic surgeries, potentially because of tissue injury and ischemia from tourniquet use, and it is suggested that the polyanions are released in the form of nucleic acids or lipopolysaccharides that bind with positively charged PF4 (1111. Jay RM, Warkentin TE. Fatal heparin-induced thrombocytopenia (HIT) during warfarin thromboprophylaxis following orthopedic surgery: another example of ‘spontaneous' HIT? [Letter]. J Thromb Haemost. 2008;6:1598-600. [PMID: 18513213], 1212. Pruthi RK, Daniels PR, Nambudiri GS, Warkentin TE. Heparin-induced thrombocytopenia (HIT) during postoperative warfarin thromboprophylaxis: a second example of postorthopedic surgery ‘spontaneous' HIT [Letter]. J Thromb Haemost. 2009;7:499-501. [PMID: 19087219]). The immunogenic complexes formed in the absence of heparin are capable of mediating platelet activation and the massive immune response that augments the prothrombotic risks of HIT.
Current diagnostic criteria for HIT utilize a pretest clinical score known as the 4T's score to differentiate patients with HIT from those with non-HIT thrombocytopenia (1313. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759-65. [PMID: 16634744]). The 4T's scoring system includes thrombocytopenia, timing of platelet count fall, thrombosis or other sequelae, and other more likely causes for thrombocytopenia. According to the points allocated for each item, patients are assigned to low-risk (0 to 3 points), intermediate-risk (4 or 5 points), or high-risk groups (6 to 8 points). The probability of HIT is estimated to be 0.2% (95% CI, 0.0% to 3.0%) in low-risk 4T's scorings, 14% (95% CI, 9% to 22%) in intermediate-risk scorings and 64% (95% CI, 40% to 82%) in high-risk scorings (1313. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759-65. [PMID: 16634744]). It has been recommended that when assessing patients for possible spontaneous HIT syndrome after knee replacement surgery (i.e., when there is no exposure to heparin), knee surgery itself should be considered “time 0” for evaluating of “timing” of platelet count fall (1414. Warkentin TE. 4Ts score for the diagnosis of HIT. ECAT. 2014;4 (Special Issue, Heparin-Induced Thrombocytopenia):18-22.). Using this approach, our patient would have scored 6 points (high probability for HIT) based on: 2 points (Thrombocytopenia) + 1 point (Timing) + 2 points (Thrombosis) + 1 point (“oTher” explanation for thrombocytopenia, that is, thrombosis-associated consumptive thrombocytopenia).
To corroborate a suspected diagnosis of HIT, it is crucial to perform laboratory testing for HIT antibodies, preferably using both a PF4-dependent immunoassay (e.g., enzyme-immunoassay) as well as a functional (platelet activation) assay, such as the serotonin release assay (1717. Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program. 2011;2011:143-9. [PMID: 22160026]). We performed both types of assay in our patient, and both yielded strong-positive results. Given the strong clinical picture for spontaneous HIT syndrome, these test results corroborate the diagnosis.
Classic HIT typically features a heparin-dependent immune response, where if there is no heparin present in the sample, there is no serum-induced serotonin release. These sera typically cause strong serotonin-release at low (pharmacologic) heparin concentrations (0.1 to 0.5 IU/mL); at suprapharmacologic heparin concentrations (100 IU/mL), the amount of serotonin release is inhibited, usually by at least 50%. Inhibition of serotonin release at 100 IU/mL heparin is a feature of both classic HIT and spontaneous HIT syndrome and was seen with our patient (96% and 100% serotonin release at 0.1 and 0.15 U/mL of heparin, but only 31% serotonin release at 100 IU/mL of heparin). In so-called autoimmune HIT syndromes, such as spontaneous HIT syndrome, heparin-independent platelet activation can be seen, that is, strong serum-induced serotonin release even in the absence of heparin. Unfortunately, U.S. laboratories typically do not perform the serotonin release assay at 0 IU/mL of heparin, potentially contributing to under-recognition of spontaneous HIT syndrome (1515. Poudel DR, Ghimire S, Dhital R, Forman DA, Warkentin TE. Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review. Platelets. 2017;28:614-620. [PMID: 28856946], 1616. Greinacher A, Selleng K, Warkentin TE. Autoimmune heparin-induced thrombocytopenia. J Thromb Haemost. 2017;15:2099-2114. [PMID: 28846826]).
Treatment for spontaneous HIT is very similar to that for an acute HIT episode. It has been suggested that patients be treated with a non-heparin anticoagulant such as argatroban, lepirudin, or bivalirudin (1717. Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program. 2011;2011:143-9. [PMID: 22160026]). Fondaparinux is not as readily recommended because spontaneous HIT cases have been reported with it and because exacerbation of thrombocytopenia and disseminated intravascular coagulation (DIC) can occur with fondaparinux (22. Burch M, Cooper B. Fondaparinux-associated heparin-induced thrombocytopenia. Proc (Bayl Univ Med Cent). 2012;25:13-5. [PMID: 22275775], 1515. Poudel DR, Ghimire S, Dhital R, Forman DA, Warkentin TE. Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review. Platelets. 2017;28:614-620. [PMID: 28856946]). The FDA-approved anticoagulant for treating HIT, argatroban, is not necessarily effective in treating spontaneous HIT syndrome. In a recent review, seven spontaneous HIT cases were treated with argatroban; treatment failed in five of those patients, with one developing fatal hemorrhage and four having new-onset or progressive thrombosis (1818. Warkentin TE. Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls. Expert Opin Drug Saf. 2014;13:25-43. [PMID: 23971903]). The authors suggested that this could be due to partial thromboplastin time (PTT) “confounding.”
Understanding the baseline or pretreatment levels of PTT and international normalized ratio (INR) can be instrumental in managing a patient with spontaneous HIT. PTT confounding and INR confounding have resulted in misleading PTT and INR values. For example, a patient with severe spontaneous HIT-associated DIC had high supratherapeutic levels of PTT while being treated with argatroban (1818. Warkentin TE. Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls. Expert Opin Drug Saf. 2014;13:25-43. [PMID: 23971903]). The PTT levels were elevated due to the effects argatroban and DIC, leading the physician to inappropriately reduce the amount of anticoagulation. The recommended treatment would be rivaroxaban or fondaparinux. Indeed, our patient's “baseline” PTT at time of presentation of spontaneous HIT syndrome was elevated (PTT, 39 s), supporting the use of a DOAC rather than a PTT-adjusted therapy, with its attendant risks of systematic underdosing due to PTT confounding. Therefore, argatroban may not be suitable for treatment of spontaneous HIT.
Oral anticoagulants such as rivaroxaban, apixaban, edoxaban (factor Xa inhibitors), or dabigatran (thrombin inhibitors) are likely to be effective for treating spontaneous HIT syndrome, as was seen in our patient. It is not appropriate to treat such a patient with warfarin or another vitamin K antagonist, given the risk of warfarin-induced venous limb gangrene and other microthrombosis syndromes in patients with severe HIT (1919. Warkentin TE, Elavathil LJ, Hayward CP, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127:804-12. ). In cases of severe, refractory autoimmune HIT, high-dose IV immunoglobulin can be utilized (2020. Ning S, Warkentin TE. IV immunoglobulin for autoimmune heparin-induced thrombocytopenia [Editorial]. Chest. 2017;152:453-455. [PMID: 28889872]).
Approximately 20 cases of spontaneous HIT have been reported previously (2121. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia. Thromb Haemost. 2016;116:813-822. [PMID: 27656712]). This case demonstrates how both infection and total knee arthroplasty may be potential causes of spontaneous HIT. After extensive review of her operative reports, it was verified that this patient did not have any prior heparin exposure. Another key point in diagnosing her with spontaneous HIT is that her platelet counts were very low even before being exposed to heparin for the first time on postoperative day 13. Because this is such a rare occurrence, more data need to be collected on patients presenting with persistent thrombocytopenia and thrombotic events after orthopedic surgeries.
In summary, a patient presenting with a hypercoagulable state in the postoperative setting without heparin exposure may be manifesting an autoimmune response now understood to be spontaneous HIT syndrome. It is crucial to order baseline INR/PTT, serotonin release assay (requesting that the laboratory perform the test also in the absence of heparin as well as at pharmacologic and suprapharmacologic heparin concentrations), and the PF4-heparin enzyme immunoassay to accurately diagnose this rare condition. Recommended treatments are mainly direct oral anticoagulants such as rivaroxaban, apixaban, or edoxaban or the direct thrombin inhibitor dabigatran. If a patient has severe, refractory autoimmune HIT, high-dose intravenous immunoglobulin is an alternative treatment option.