Clinical Case Report: A 65-Year-Old Presenting with Disseminated Intravascular Coagulation as a Rituximab Infusional Reaction

Introduction

Rituximab is a monoclonal antibody that targets the CD20 antigen on B cells and subsequently recruits immune effector functions to mediate their lysis.[1] It is approved in the European Union for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, autoimmune diseases,[1] and it is also used in multiple off-label conditions. Although not considered myelosuppressive, hematological alterations are present in a few patients; ≥grade 3 neutropenia, anemia, and thrombocytopenia were only observed in 4.2, 1.1, and 1.7% of the patients, respectively.[1]

A pharmacovigilance study using the World Health Organization's database (Vigibase) showed that, although many widely used medicines may be associated with disseminated intravascular coagulation (DIC), the most frequently reported as potential causal agents were heparin, methotrexate, paracetamol, vincristine, and cytarabine.[2] Coagulation disorders after rituximab administration are considered uncommon.[1] Nevertheless, a few reports of DIC-like reactions after rituximab and obinutuzumab infusion have been published.[3] [4] [5] [6] [7] However, the rechallenge with anti-CD20 agents following DIC-like episodes has rarely been studied.

This article was prepared following the CARE Guidelines,[8] and it was reviewed by the local Ethics Committee (Hospital Universitario Puerta de Hierro Majadahonda), which determined that formal approval was not required in accordance with local regulations.

Case Report

We present a case of a 65-year-old white male with long-standing epilepsy well controlled with three antiepileptic drugs (AEDs) (valproic acid, carbamazepine, and phenobarbital). He was diagnosed seven years ago with marginal zone lymphoma with peripheral expression and was initially managed with watchful waiting. Over the years, he developed progressive lymphocytosis (>10 × 10³/μL). He also underwent a computed tomography scan, which revealed splenomegaly measuring 24 cm. Based on these findings, monotherapy with rituximab was started at a dose of 375mg/m² in accordance with international clinical practice guidelines.[9] [10] Physical examination and baseline blood tests were unremarkable aside from the lymphocytosis.

Approximately 3.5 hours into the first rituximab infusion, the patient developed fever (38.7°C), desaturation down to 92%, and generalized tonic–clonic (GTC) seizures followed by a decreased level of consciousness. The patient was transferred to the emergency department and experienced another two GTC seizure episodes. Brivaracetam was then initiated. It was confirmed with the patient's family that he had missed his usual morning AEDs.

Six hours after rituximab infusion, blood tests revealed alarming results with acute thrombopenia and lymphopenia, increased prothrombin time, hypofibrinogenemia, and D-dimer elevation. No schistocytes were observed in the peripheral blood smear. Coagulation factors showed a generalized decreased activity. Antithrombin activity was normal (76%). Despite there was a low suspicion of thrombotic thrombocytopenic purpura, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was tested, and it was found to be normal (67.3%). The patient did not present a bleed or thrombosis at any time. Cerebral scanner and video electroencephalogram were normal. A diagnosis of DIC was made, based on the International Society on Thrombosis and Haemostasis (ISTH) criteria (score of 6, consistent with overt DIC).[11] Intensive treatment with fibrinogen supplements and vitamin K was initiated. After 48 hours, coagulation was almost normalized, with platelets and lymphocytes progressively ascending. After 3 days of admission to the hematology department, the patient was discharged. Complete blood test results from the first infusion of rituximab are presented in [Table 1].

Table 1 Analytical parameters before and after the first infusion of rituximab

	2 h before infusion	6 h after infusion	48 h after infusion
Hemoglobin (g/dL)	12.1	10.6	9.3
Leucocytes (×103/μL)	15.67	5.80	11.43
Neutrophiles (×103/μL)	3.0	4.6	3.2
Lymphocytes (×103/μL)	10.5	0.8	6.4
Platelet (×103/μL)	126	15	57
Prothrombin time (s)	NA	19.3	13.5
Prothrombin activity (%)	NA	45.0	73.0
INR	NA	1.80	1.25
Fibrinogen (mg/dL)	NA	101.0	223
D-dimer (ng/mL)	NA	246500	2458
Factor II (%)	NA	44.1	55.0
Factor V (%)	NA	8.9	61.4
Factor VII (%)	NA	57.3	60.3
Factor VIII:C (%)	NA	77.3	96.4
Factor X (%)	NA	55.3	69.9
Functional plasminogen	NA	49.0	NA
LDH (U/L)	NA	352	177
Total bilirubin (mg/dL)	0.4	0.3	0.3

Abbreviations: INR, international normalized ratio; LDH, lactate dehydrogenase.

Note: Previous LDH and coagulation values before infusion were normal.

One month later, a supervised administration of rituximab second dose was conducted. On that occasion, the dose and speed of infusion were reduced to 100 mg and 20 mL/h, respectively. Standard premedication was administered, and it was confirmed that AEDs had been taken correctly. After the administration of 45 mL, the patient developed fever (40.2°C) and tachycardia (120 bpm). Rituximab was discontinued, and analgesics were started with poor clinical response. Hydrocortisone was subsequently administered, leading to significant improvement. No seizures were observed at that time.

At that time, blood tests showed acute reduction of lymphocytes, mild thrombocytopenia, modest elevation of lactate dehydrogenase (LDH), and slight coagulopathy, which required one dose of vitamin K. The patient recovered and was discharged after 48 hours with normalized blood parameters. [Table 2] shows blood test results from the second rituximab administration. The Clinical Pharmacology Department conducted a causality assessment using the Spanish Pharmacovigilance System algorithm, which comprises multiple dimensions.[12] Considering the compatible temporal sequence, the cases reported in the literature, the patient's improvement after rituximab withdrawal, the positive rechallenge and the exclusion of other causes, the final causality was established as a defined adverse reaction.

Table 2 Analytical parameters before and after the second infusion of rituximab

	4 h before second infusion	During second dose infusion	6 h after discontinuing second dose infusion	32 h after second dose infusion
Hemoglobin (g/dl)	11.4	11.1	10.0	9.5
Leukocytes (×103/μL)	18.14	5.63	9.74	11.65
Neutrophiles (×103/μL)	4.0	4.1	5.6	2.9
Lymphocytes (×103/μL)	12.3	1.3	3.3	7.1
Platelet (×103/μL)	159	111	126	122
Prothrombin time (s)	12.7	14.0	14.2	13.1
Prothrombin activity (%)	80.0	69.0	68.0	77.0
INR	1.17	1.29	1.31	1.21
Fibrinogen (mg/dL)	362	349	344	286
LDH (U/L)	178	283	259	183
Total bilirubin (mg/dL)	0.4	0.3	0.3	0.3

Abbreviations: INR, international normalized ratio; LDH, lactate dehydrogenase.

Eight months later, the patient resumed the watchful waiting strategy, presenting stable anemia (11.0 g/dL) and recurrence of lymphocytosis (21.0 × 10³/μL).

Discussion

This case report presents a rare adverse effect of rituximab: a DIC-like reaction, with successful but attenuated symptoms upon rechallenge. Even though the patient initially presented a GTC seizure, it was considered secondary to the febrile infusion reaction and not as an independent adverse reaction since, the patient was a known epileptic and had not taken his AED medication. While DIC-like reactions are not listed as adverse events in the Summary of Product Characteristics for rituximab, few cases are available in the literature.[3] [4] [5] [6] Evidence that obinutuzumab may cause nonovert DIC also exists.[7]

Two main hypotheses have been proposed regarding the origin of this adverse event. The first suggests that the DIC-like reaction may be triggered by cytokine release syndrome (CRS),[4] [13] a theory supported by several published case reports in which patients exhibited both CRS and a DIC-like reaction.[4] [6] CRS arises from the massive activation of effector cells, followed by the release of proinflammatory cytokines (including IL-6, TNF-α, and IP-10), after the rapid lysis of CD20-positive B cells; this process is particularly pronounced in patients with a high tumor burden or splenomegaly, as observed in our patient.[14]

However, since some reported cases did not develop CRS,[3] [5] a second hypothesis proposes that DIC may instead result from systemic fibrinolysis induced by rituximab-mediated cytolysis of CD20-positive malignant cells.[5] Our patient presented features suggestive of a CRS in both infusions (fever, hypoxia, acute cytopenias, LDH elevation) and, although coagulopathy can be observed in CRS,[14] this hypothesis does not fully explain the marked consumption of fibrinogen and the pronounced elevation of D-dimer levels. These findings are more consistent with systemic fibrinolysis triggered by the release of cytolytic products resulting from the destruction of malignant B lymphocytes.[15] [16]

Moreover, a high disease burden may have amplified the cytolytic response to rituximab, thereby contributing to the development of coagulopathy. This is consistent with the findings of Byrd et al.,[17] who reported a correlation between greater disease burden and an increased risk of infusion-related adverse events. In our case, the patient exhibited markedly elevated lymphocyte counts prior to each rituximab infusion. Therefore, patients with a high disease burden may be at increased risk of developing a DIC-like reaction following an anti-CD20 therapy, likely due to more extensive tumor cell cytolysis and CRS. Similar associations have been described with obinutuzumab and in other reports of early-onset DIC-like reactions in high disease burden.[4] [5] [6] [7] However, one published case described a patient with nephrotic syndrome who developed a DIC-like reaction 11 days after rituximab infusion despite the absence of any malignancy.[3]

According to the EudraVigilance database (accessed 16 July), 139 suspected DIC-like cases were reported for rituximab, 24 for obinutuzumab, 1 for ofatumumab, and none for ocrelizumab, although two coagulopathy cases without further specification were recorded for the latter.[18] DIC-like cases do not seem to be related exclusively to rituximab but could be a class effect for anti-CD20 agents, as suggested by findings in the pharmacovigilance database.[18]

Unlike previous reports, we documented how coagulation factors descended after the rituximab infusion, showing an intense factor V reduction. Furthermore, our case generates data about rituximab reexposure, a piece of information that is often missing. In the already published cases two patients passed away after the first infusion,[3] [6] in one case data are missing,[5] and the obinutuzumab publication does not mention second dosing.[7] Only one published case describes a rituximab rechallenge without further complications.[4]

After the rechallenge, our patient developed only mild CRS and coagulopathy, which resolved with infusion discontinuation and symptomatic treatment. The milder reaction was likely related to the lower dose and slower infusion rate, as seen in previous studies.[14] This suggests that higher rituximab doses may increase the risk of DIC due to both a greater CRS and a more intense cytolysis of malignant cells. Therefore, rechallenge at reduced dosage and speed appears reasonable after a first infusion complicated by DIC, in cases where, after careful consideration, the individual's benefit–risk for receiving a second dose is deemed positive.

Even though this case report may offer new perspectives on DIC-like reactions caused by anti-CD20 agents, it is important to acknowledge its limitations. This case report alone may not provide sufficient evidence to be generalized to all patients, although it can contribute to generating safety signals that may be studied in further detail by regulators. In both episodes, vitamin K supplement was initiated as part of the DIC treatment. Although vitamin K is not part of standard DIC management, it was added because the patient showed mild deficiencies in vitamin K–dependent coagulation factors, which could have contributed to the coagulopathy alongside the DIC-like process. Considering that some patients may present a nonovert DIC, which could be asymptomatic,[19] mild cases might also not be detected unless a blood test is performed after the infusion of an anti-CD20 agent. Finally, the information from the pharmacovigilance databases does not allow for a comprehensive study of the suspected adverse reaction, since they only include information limited to the medical term of the suspected adverse reaction and drug names.

Conclusion

This case report presents how DIC-like cases after administration of anti-CD20 agents are infrequent but potentially life-threatening and should be ruled out when acute thrombocytopenia is observed after their infusion. Patients with high disease burden may be more predisposed to developing a DIC-like reaction. A careful and individualized benefit–risk assessment is needed if the reintroduction of the suspect medicine is considered in the context of oncohematological disorders with limited treatment alternatives.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 27 August 2025

Accepted: 15 October 2025

Article published online:
10 November 2025