Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease, which is characterized by severe systemic inflammation with cytokine storm as well as histologic evidence of hemophagocytosis. Besides, coagulopathy and hemorrhages are two common severe complications in HLH patients. Recent literatures indicate that Epstein–Barr virus (EBV) infection is one of the important triggers for the disease. In the study, we present three cases of EBV related HLH (EBV-HLH) with coagulopathy in patients with distinct backgrounds. Case 1 is a 45-year-old female diagnosed with EBV associated NK/T cell lymphoproliferative disorder (EBV-T/NK-LPD) and EBV-HLH. Case 2 is a 17-year-old male with a diagnosis of EBV-T-LPD and EBV-HLH. Case 3 is a 51-year-old male and also diagnosed with EBV-T-LPD and EBV-HLH. All cases were given with treatment with HLH-94 protocol, and the symptoms of the three patients improved. Furthermore, during the treatment, protamine, which has not been reported in the literature previously, was given to the three cases with EBV-HLH, and our results showed that after treatment with protamine, the coagulopathy and bleedings in these patients were improved rapidly. Unfortunately, the three patients relapsed soon and died despite intensive treatment. However, these cases suggest that protamine may serve as a potential treatment option for coagulation associated with EBV-HLH. Besides, the study helps us improve the understanding of the EBV-HLH related coagulation disorders, and provide a potential strategy for future treatment of the disease.
Keywords: Hemophagocytosis, Epstein–Barr virus, Treatment, Protamine, Coagulopathy
Introduction
Hemophagocytic lymphohistiocytosis (HLH), also called as hemophagocytic syndrome, is a rare immune-mediated but life-threatening disease. In adult HLH, Epstein–Barr virus (EBV) infection is one of the important triggers for the disease. Among EBV-related HLH (EBV-HLH) patients, the clinical course of the disease varies from mild to aggressive and often has fatal outcomes [1–6]. It has been reported that the development of EBV-HLH is related to severe systemic inflammation, and the uncontrolled inflammatory response is capable of causing serious tissue injury and multiple organs failure rapidly in patients with EBV-HLH [1, 4]. Besides, coagulopathy and hemorrhages are shown to be two common severe complications in EBV-HLH patients [6, 7]. Generally, it is believed that high levels of cytokines contribute to the red blood cell phagocytosis, liver dysfunction, and coagulation factors consumption, which could further result in severe coagulopathy [1], and are associated with a high mortality rate in patients with EBV-HLH [2–4].
Prompt introduction of appropriate therapy is necessary for the survival of patients with EBV-HLH [8–10]. Given the rarity of EBV-HLH, there was not enough data to guide therapy decisions, and until now, no ideal treatment for EBV-HLH has been established. Although the chemotherapeutic regimens, including HLH-94 and HLH-2004 protocols, which based on etoposide and dexamethasone therapy, and blood transfusion, have been reported to be effective in the disease, most of the patients still experienced a relapse and death [11, 12]. Therefore, it is essential to develop novel approaches to treat EBV-HLH. Here, we report the effect of protamine treatment on three cases with severe EBV-HLH. The results showed that after treatment with protamine, the coagulopathy and bleedings in these patients were improved rapidly. The finding from our study could improve the understanding of the EBV-HLH related coagulation disorders, and provide a potential strategy for future treatment of the disease. In addition, the study protocol was approved by the ethics committee of Peking University Shenzhen Hospital, China. Informed consent was obtained from each patient.
Case 1
A 45-year-old female was diagnosed with chronic active EB virus infection in XX Hospital in August 2017. At that time, the patient had no fever or hypocytosis. In December 2018, a surgery was performed to remove the right ovarian solid mass, and the postoperative pathological diagnosis of ovarian solid was NK/T cell lymphoma, in which the EBV-encoded small RNA (EBER) was positive. Unknown fever, thrombocytopenia, and abnormal coagulation appeared before the surgery. Atypical NK cells with the phenotype of CD3−CD4−CD8−CD56−CD5−CD7−CD16+ were found in both bone marrow and peripheral blood. The level of EBV-DNA was detected at the 1.57 × 107 copies/mL in the peripheral blood of the patient. In addition, hemophagocyte was present in the bone marrow. Based on the clinical symptoms and laboratory testing, the diagnosis of EBV associated NK/T cell lymphoproliferative disorder (EBV-T/NK-LPD) and EBV-HLH was given. HLH-94 treatment was applied to the patient following the surgery (the clinical parameters before and after HLH treatment were shown in Table 1). Chemotherapy with GemOX (Gemcitabine, Oxaliplatin) was further given 1 week later. Hyperthermia was repeated during chemotherapy without any infection. One week after completing chemotherapy, HLH symptoms were aggravated with high fever, abnormal blood coagulation, liver dysfunction (as shown in Table 1) in the patient, and next, she started the treatment with etoposide (VP16), hormone therapy, plasma exchange and continuous renal replacement therapy (CRRT). During the treatment of HLH symptoms, the patient underwent the puncture and drainage of pleural effusion. Local bleeding occurred during and after the operation. The extravasation blood volume was about 200 mL per day and the blood pleural effusion was 1200 mL. In addition to the treatment above, blood transfusions were actively executed and factor VIIα was used, but the blood coagulation was abnormally persisted. Further examination showed that the activated partial thromboplastin time (aPTT) was not corrected, thrombin time (TT) protamine neutralization test was positive and lupus anticoagulant was negative. All these coagulation tests were repeatedly reviewed and iatrogenic heparin contamination was excluded. Protamine was then administered at 7 mg/h and coagulation disorders improved after 12 h. Two days later, TT decreased to the normal level, aPTT was close to normal and the bleeding stopped (Fig. 1). The patient then received DEP chemotherapy and other treatments successively. She was readmitted for prolonged aPTT and TT and recovered after re-use of protamine. However, the patient eventually failed in HLH treatment and died 70 days after admission.
Table 1.
Clinical and laboratory characteristics of Case 1 before and after HLH and GemOX treatment
| Indicators | Before HLH-94 | 1 week after HLH treatment | 1 week after GemOX treatment |
|---|---|---|---|
| WBC (109/L) | 4.6 | 2.5 | 1.3 |
| HB (g/L) | 90 | 79 | 87 |
| PLT (109/L) | 92 | 58 | 92 |
| FERR (ng/mL) | >2000 | 1973 | 15,794 |
| IL-6 (pg/mL) | 32.3 | 19.4 | 666.1 |
| PT (s) | 18.5 | 15.2 | 18.4 |
| APTT (s) | 99.7 | 77.8 | 88.8 |
| TT (s) | 55 | 14.7 | 18 |
| FIB (g/L) | 0.92 | 4.42 | 1.52 |
| ALT (U/L) | 133 | 27 | 246 |
| T-BIL (umol/L) | 55.5 | 35.8 | 58.5 |
| D-BIL (umol/L) | 32.0 | 20.3 | 35.4 |
WBC, white blood cell; HB, hemoglobin; PLT, platelet; FERR, ferritin; IL-6, interleukin-6; PT, prothrombin time; APTT, activated partial thromboplastin time; TT, thrombin time; FIB, fibrinogen; ALT, alanine transaminase; T-BIL, total bilirubin; D-BIL, direct bilirubin
Fig. 1.
Trend of aPTT and TT before and after protamine treatment in Case 1
Case 2
A 17-year-old male presented with fever for 18 days. He was observed to have thrombocytopenia, liver dysfunction, ferritin with 8492 ng/mL, coagulation disorder, and hemophagocyte in the bone marrow sample. The bone marrow aspirate revealed an accumulation of atypical lymphocytes (CD3+CD8+TVRa+TCRVbeta3+CD4−), and the EBER was positive based on the detection with in situ hybridization. EBV-DNA load was found at the 1.03 × 107 copies/mL in peripheral blood. Molecular genetic analysis demonstrated there was no mutation in genes associated with familial HLH. He was diagnosed with EBV-T-LPD and EBV-HLH, started with HLH-94 treatment, and followed by DEP and Ruxolitinib chemotherapy. During the treatment, the patient’s coagulation abnormality did not improve, and blood transfusion was given because of persistent prolonged PT and aPTT (Table 2). Protamine was then administered at 7 mg/h and PT, and aPTT and TT were normalized 2 days after the treatment (Table 2). Furthermore, aPTT and TT were normal even on day 10 of the treatment. In addition, lupus anticoagulant and anti-cardiolipin antibody were negative. All of these were repeatedly reviewed and excluded from iatrogenic heparin contamination. Unfortunately, the patient relapsed soon with severe pneumonia, sepsis, and died of multiple organ failure on hospital day 37.
Table 2.
Changes in coagulation parameters during treatment in Case 2
| Indicators (normal range) | Before HLH-94 protocol | Before protamine treatment | Two days after protamine treatment |
|---|---|---|---|
| PT (s) (11.0–15.0) | 16.3 | 15.7 | 13.0 |
| aPTT (s) (28.0–43.0) | 58.9 | 65.6 | 39.4 |
| TT (s) (14.0–21.0) | 24.7 | 35.9 | 18.8 |
| FIB (g/L) (2.0–4.0) | 1.01 | 0.92 | 1.46 |
PT, prothrombin time; aPTT, activated partial thromboplastin time; TT, thrombin time; FIB, fibrinogen
Case 3
A 51-year-old male, presented with persistent fever for 1 month, was diagnosed with EBV-T-LPD and EBV-HLH. He was found to have hepatosplenomegaly, liver and kidney dysfunction, elevated ferritin of > 40,000 ng/mL, coagulation disorder, pancytopenia, bilateral pleural effusions, and type II respiratory failure. EBV-DNA was detected at the 5.6 × 107 copies/mL in peripheral blood. The bone marrow aspirate revealed an accumulation of atypical lymphocytes (CD3+CD8+CD4−CD16−CD56−CD7+TCRa+TCRVbeta3+). Based on in situ hybridizations, EBER was found to be positive. Hemophagocyte was present in the bone marrow. After diagnosed with EBV-T-LPD and EBV-HLH, he was started with HLH-94 protocol, coupled with CRRT, plasma exchange, and assist ventilation. After these treatments, the ferritin level was decreased to 2550 ng/mL, body temperature was dropped to normal, and liver function was also improved. However, coagulation disorder was persisted with prolonged aPTT (120 s) and TT (36 s). Correction tests showed that aPTT could be partially corrected, and TT could correct to normal. These results indicated a heparin-like anticoagulant appeared in the patient. All of these clinical parameters were repeatedly reviewed and iatrogenic heparin contamination was excluded. Protamine was then administered at 7 mg/h, and aPTT and TT were improved at 1 day after the treatment (45 s and 25 s respectively). The patient delayed further therapy and his condition worsened 1 week later. Unfortunately, he developed hepatic and renal failure, severe pneumonia complicated with respiratory failure and died 2 weeks after admission.
Discussion
EBV is a ubiquitous herpes virus that has been shown to infect up to 90% of the population worldwide. The virus can infect lymphocytes with different types (B, T, and natural killer cells) as well as epithelial cells. EBV infected lymphocytes could develop into a lymphoproliferative disorder (LPD), the clinical conditions of which was characterized by persistent EBV infection and excessive lymphoid proliferation of T and/or natural killer cells [2, 4]. EBV-associated LPD often has the features of HLH, a syndrome with severe life-threatening hyperinflammation.
At present, HLH is diagnosed with the presence of at least five of eight criteria: (1) fever lasts > 7 days (temperature > 38.5 °C); (2) splenomegaly; (3) cytopenias (affecting at least two of three lineages in the peripheral blood: Hemoglobin < 90 g/L, platelets < 100 × 109/L, neutrophils < 1.0 × 109/L with non-myeloid hematopoietic function); (4) hypertriglyceridemia and/or low fibrin (fasting triglyceride ≥ 3.0 mmol/L, fibrinogen ≤ 1.5 g/L); (5) hemophagocyte was found in bone marrow, spleen or lymph nodes, no evidence of malignant tumor; (6) low or absent NK-cell activity; (7) ferritin level ≥ 500 μg/L; and (8) soluble IL-2 receptor (sCD25) ≥ 2400 U/mL [3]. In addition, EBV-T-LPD is defined with the clonal proliferation of EBV-infected T cells, and EBV infection is defined when more than 100 copies/mL of EBV antigens detected by polymerase chain reaction (PCR) [4]. The diagnostic standard of EBV associated HLH in this study was based on the above criteria. All three patients presented persistent fever, splenomegaly, pancytopenia, ferritin exceeding 2000 μg/L, fibrinogen less than 1.5 g/L, hemophagocyte presented in bone marrow, abnormal T lymphocytes, EBER positive in the pathological examination and serum EBV-DNA more than 107 copies/mL, and all of these met the diagnostic criteria of EBV-HLH.
In addition to fever, splenomegaly, cytopenia, respiratory failure, and liver dysfunction, more than half of patients with EBV-HLH have abnormal coagulation [5]. It’s now believed that the appearance of coagulopathy is an important feature of severe EBV-HLH [6, 7]. It is generally believed that coagulopathy in HLH is mainly related to the activation of the fibrinolytic system, which is produced by macrophages to produce a plasminogen activator. In addition, disseminated intravascular coagulation (DIC) and decreased synthesis of coagulation factors, which caused by infiltrating macrophages, are also related to this disorder [6, 13]. In addition, an individual patient may have cerebral hemorrhage [8, 14]. Despite our understanding of this disease is deepening, the underlying mechanisms of coagulopathy in the HLH are still not fully clarified, and deserved further investigated.
The HLH-94 and HLH-2004 protocols are the current standards of care for patients with HLH [11, 12]. HLH-94 is based on etoposide, dexamethasone, and in selected patients with intrathecal methotrexate. Besides, the drugs of HLH-2004 protocol consists of etoposide, dexamethasone, and cyclosporin A. In the present study, to achieve clinical remission, and keep the patients alive and stable, the initial therapy with the HLH-94 treatment protocol, were given to the three patients. Although the three patients were temporarily improved after treatment following the HLH-94 protocol, TT and aPTT were not improved. Even more, with the aggravation of HLH, coagulopathy got worse, and severe bleeding appeared. These results indicated that, at this time, apart from etoposide and dexamethasone therapy, more effective and fast treatment was warranted.
Until now, the treatment of HLH-related coagulopathy is still challenging, because of the unclear pathogenesis of the disease. The coagulopathy is manifested as significant prolongation of aPTT, TT and hypofibrinogenemia. aPTT prolongation is usually seen under the following situations: (1) endogenous coagulation factor deficiency; (2) the appearance of coagulation inhibitor, including antibody of a coagulation factor and antiphospholipid antibodies; and (3) the application of heparin [15–23]. TT prolongation generally indicates an increase in anticoagulant with decreased fibrinogen or increased fibrinogen degradation products. In all the three patients enrolled in the study, aPTT was significantly prolonged and was not corrected to normal after treatment with HLH-94 protocol, suggesting that there was no deficiency in endogenous coagulation factors. TT prolongation, combined with the exclusion of the iatrogenic heparin contamination, suggested the presence of anticoagulants in these patients. TT protamine neutralization test was positive, together with the negative result in lupus-like anticoagulant test, further implied that the existence of heparin-like anticoagulants in patients with EBV-HLH. Under pathological conditions, overproduction and release of heparin-like anticoagulants have been reported to could cause abnormal and fatal bleeding, in patients with hematological malignancies or solid tumors, or in patients with systemic candidiasis or asthma (Table 3). When complexed with antithrombotic, endogenous heparin and heparin-like anticoagulants could inhibit plasma serine proteases thrombin (factor IIα), factor Xα, factor IXα, factor Xiα, and XIIα, and further suppress the thrombosis [11].
Table 3.
Classification of diseases with heparin-like anticoagulants
| Etiology | References |
|---|---|
| Hematological malignances | |
| Systemic or cutaneous mastocytosis | Sucker et al. [11], Hansen et al. [13] |
| Multiple myeloma | Torjemane et al. [12], Llamas et al. [14], Willner et al. [15], Tefferi et al. [22] |
| Chronic lymphocytic leukemia | Llamas et al. [14] |
| Precursor T cell leukemia | Llamas et al. [14] |
| Solid tumors | |
| Breast carcinoma | Hill et al. [16] |
| Small cell bronchial carcinoma | Garnier et al. [17] |
| Bladder carcinoma | Tefferi et al. [22] |
| Infections | |
| Systemic candidiasis | Horne et al. [18] |
| Rheumatism disease | |
| Systemic lupus erythematosus | Ratti et al. [19] |
| Allergy | |
| Asthma | Lasser et al. [20] |
| Pregnancy | Cassese et al. [21] |
Protamine has been reported to could neutralize the heparin-like anticoagulant activity and stop bleeding [12]. In the study, we treated EBV-HLH patients with protamine to explore whether the reagent has an effect on coagulopathy. Our results showed that protamine could correct coagulopathy and shorten TT more than 5 s in EVB-HLH patients. These results implied that the heparin-like anticoagulants appeared in HLH patients and induced the disorder of coagulation. The response to protamine treatment for EBV-HLH patients indicated that heparin could interact with these heparin-like anticoagulants to correct coagulopathy.
To our knowledge, this is the first report of the use of protamine in treating severe coagulopathy and bleedings in EBV-LPD with HLH. The prompt response in TT, aPTT, and bleeding after protamine administration, especially reuse in case 1 patient, indicates that protamine is the effective and fast treatment for coagulopathy in EBV-LPD with HLH. It should be noteworthy that, with the prolong of the period of treatment with protamine, the continuous improvement to inhibit coagulopathy was not observed in our enrolled patients, and these results implied that, as the disease continues to advance, other types of anticoagulants, which could not interact with protamine, maybe appear in the body of HLH patients and further worsen the disease. Besides, sustained production of heparin-like anticoagulation in EBV-HLH patients may be another reason for inhibiting the long-term in-effectivity of protamine. Further investigations of heparin-like anticoagulant production in EBV-HLH patients are needed. In case 1, abnormal NK cells were detected in peripheral blood, but the levels of TT were normal, suggesting that heparin-like anticoagulants may be produced by over-activated T cells or macrophages, but not abnormal NK cell lymphoma in HLH.
In summary, our report indicated that heparin-like anticoagulants should be taken into consideration when aPTT and TT prolongation in EBV-HLH. We found the protamine treatment is fast and effective in improving coagulation disorders and severe bleeding associated with EBV-HLH. The symptoms of the three patients improved upon treatment with the HLH-94 protocol, but unfortunately died of multiple organ failure. However, this experience suggests that protamine may serve as a potential treatment option for coagulation associated with EBV-HLH. At present, the mechanisms of coagulopathy in patients with EBV-HLH are still obscure, and future studies are warranted to determine the role and associated mechanisms of protamine in this disease.
Funding
This study was supported by Clinical research of safety and effectiveness of anti CD19 chimeric antigen receptor T cell immunotherapy in relapsed and refractory B cell lymphoma (SZXJ2018081) and Sanming Project of Medicine in Shenzhen (SZSM201612004).
Availability of data and material
The datasets used or analysed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflict of interest
None.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Footnotes
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Data Availability Statement
The datasets used or analysed during the current study are available from the corresponding author on reasonable request.