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 Table of Contents  
Year : 2021  |  Volume : 12  |  Issue : 3  |  Page : 167-171

Cerebral venous thrombosis in nucleophosmin gene-mutated acute myeloid leukemia: A rare case report

1 Department of Hematology, HCG Manavata Cancer Centre, Nashik, Maharashtra, India
2 Department of Academics, HCG Manavata Cancer Centre, Nashik, Maharashtra, India
3 Department of Surgical Oncology, HCG Manavata Cancer Centre, Nashik, Maharashtra, India

Date of Submission25-Nov-2020
Date of Decision23-Jun-2021
Date of Acceptance26-Jun-2021
Date of Web Publication21-Oct-2021

Correspondence Address:
Dr. Sudarshan Pandit
Department of Haematology, HCG Manavata Cancer Centre, Nashik - 422 011, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joah.joah_224_20

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Association of cancer and thrombotic complications in acute leukemia is not uncommon. The underlying mechanism involved in thrombus formations is largely unknown with limited published data. Our patient was presented with complaints of continuous headache and persistent projectile vomiting. After initial tests, a magnetic resonance imaging of the brain performed revealed cerebral venous sinus thrombosis. Anticoagulant and anticonvulsant prophylaxis was initiated, and further treatment was planned. In such rare cases, early diagnosis and management are desirable. The role of clinicians in identifying the clinically suspicious signs and symptoms can help in identifying such rare conditions before developing severe thromboembolic complications. In the present study, we report a rare case of cerebral venous thrombosis, its associated treatment, and complications in a patient diagnosed with nucleophosmin gene-mutated acute myeloid leukemia.
Similar Cases Published: None.

Keywords: Acute myeloid leukemia, cerebral venous thrombosis, nucleophosmin

How to cite this article:
Pandit S, Wasekar N, Badarkhe G, Ramesh YV, Nagarkar R. Cerebral venous thrombosis in nucleophosmin gene-mutated acute myeloid leukemia: A rare case report. J Appl Hematol 2021;12:167-71

How to cite this URL:
Pandit S, Wasekar N, Badarkhe G, Ramesh YV, Nagarkar R. Cerebral venous thrombosis in nucleophosmin gene-mutated acute myeloid leukemia: A rare case report. J Appl Hematol [serial online] 2021 [cited 2023 Sep 30];12:167-71. Available from: https://www.jahjournal.org/text.asp?2021/12/3/167/328722

  Introduction Top

Association of cancer and thromboembolism was first described in 1865, by Trousseau, as migratory superficial thrombophlebitis, which is also called as Trousseau's syndrome.[1] Cancer-associated thrombosis is a common complication in patients with malignancies.[2] Thrombotic complications are well-established fact in solid tumors and acute leukemias (ALs).[2],[3],[4] In AL patients, the incidence and risk of thrombosis were largely varied from 1% to 37% compared to the general population and patients with other cancers.[5]

In AL, patients are typically prone to hemorrhagic complications or infections as a result of alterations in hemostasis, which was proven to be life-threatening in many patients.[6] The possibility of venous thromboembolism (VTE) in AL was observed to be high in patients with acute lymphoid leukemia (ALL) over acute myeloid leukemia (AML). This might be due to ALL and its associated multiple influencing factors such as treatment with L-asparaginase, usage of steroids, prothrombotic changes, and thrombophilic mutations.[7],[8] However, the risk of thrombosis, especially the risk of cerebral venous thromboembolism (CVT) in nucleophosmin (NPM1) gene-mutated AML (NPAML) of AML, was observed to be very rare with limited available published data causing a paucity in knowledge related to its preventive or therapeutic strategies in the patients affected. The aim of the present study was to report such a rare case, describing the events associated with CVT in NPAML patient for better understanding of the condition.

  Case Report Top

A 45-year-old female was presented to our outpatient department with complaints of headache and vomiting for 1 week. Physical examination was unremarkable. Laboratory investigations showed abnormal levels of hemoglobin - 7.8 g/dL, total leukocyte count - 16,600/cu.mm, and platelet count - 132,000/mL. Peripheral blood smear has shown 90% blasts [Figure 1], suggestive of AL. Immunophenotyping by flow cytometry was performed [Figure 1], where the reports have shown a cluster of cells (72.83%), extending to blast window with moderate scatter of CD45 and expression of markers CD33, CD36, CD117, CD11b, and cyMPO. Immature markers such as CD38, HLA-DR, and CD34 were negative, suggestive of AML. Fluorescence in situ hybridization analysis revealed negative status for AML1/ETO: t (8;21) (RUNX1/RUNX1T1), PML RARA: t (15;17), MLL: t (11q23) gene rearrangement, and CBFß:inv (16) in 100% of interphase cells analyzed. Cytogenetics analysis revealed negative status for FMS-like tyrosine kinase 3 mutation detection and CCAAT/enhancer-binding protein alpha mutation detection, respectively. However, c. 863_864insTCTG (p.W288fs*12) mutation was detected in NPM1 gene. Chromosomal analysis Giemsa Banding (GTG)-Banding with 400 band resolution) followed by standard unstimulated cell culture technique was also done, where microscopic evaluation revealed an apparently normal female karyotype in all the metaphases analyzed.
Figure 1: (a) Flow cytometry histogram showing 72.83% cells in Progen/Blast gate (shown in red color). (b) Flow cytometry histogram showing blasts cells (shown in red color) are CD34 negative. (c) Flow cytometry histogram showing blasts cells (shown in red color) are CD117 and CD11b positive flow cytometry histogram showing blasts cells (shown in red color) are CD33 positive. (d) Flow cytometry histogram showing blasts cells (shown in red color) are HLA-DR negative and CD36 positive. (e) Flow cytometry histogram showing Blasts cells (shown in red color) are cyMPO positive. (g-i) Peripheral blood smear picture showing blast cells (pointed with arrowhead)

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In view of patient complaining of continuous headache and persistent projectile vomiting, magnetic resonance imaging (MRI) of the brain was performed [Figure 2]. MRI brain has shown altered signal intensity in the right transverse sinus, sigmoid sinus, and internal jugular vein with the corresponding absence of flow-related enhancement in these sinuses on magnetic resonance venography with a possibility of cerebral venous sinus thrombosis. No focal lesions were identified in brain parenchyma. No focal neurological deficit was seen. Power normal reflexes and other neurological examinations were all normal. Based on the initial findings, the patient was started on anticoagulant and anticonvulsant prophylaxis, respectively. A decrease in vomiting and severity of headache was noted.
Figure 2: Magnetic resonance imaging brain images showing altered signal intensity in right transverse sinus (star marked – a, b, c, h, i), sigmoid sinus (star marked – d, e, h, i) and internal jugular vein (star marked – g, h, i) with corresponding absence of flow related enhancement in these sinuses on magnetic resonance venography images most likely s/o cerebral venous sinus thrombosis. No focal lesion was seen in the brain parenchyma

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Based on the flow cytometric results, AML was confirmed and induction phase treatment was initiated on standard 7 + 3 (cytarabine and daunorubicin) chemotherapy protocol.

On day 12, the patient had developed continuous fever with persistent tachycardia. Two-dimensional echocardiography was repeated, showing mild fluid overload and mild pericardial effusion with an ejection fraction of 35%–40%. N-terminal pro b-type natriuretic peptide values were found to be >35,000 pg/ml, suggestive of cardiac problems. Ultrasonography of the abdomen and pelvis was performed, revealing hepatomegaly, diffuse edematous wall thickening of the colon wall with a maximum thickness of approximately 14 mm, suggesting colitis. Small bowel loops were observed to be normal with no evidence of obstruction. Mild free fluid was seen.

Patient's final diagnosis was confirmed as NPM1-positive NPAML with cortical cerebral venous thrombosis. The patient was succumbed during the induction phase itself because of sepsis and cytopenia.

  Discussion Top

Leukemia is classified based on the disease progression (acute or chronic) and the type of white blood cells affected. Leukemia of lymphocytic origin is called as lymphoid leukemia. However, leukemia developed in other than lymphocytes is called as myeloid leukemia.[4] AL is further classified morphologically as acute ALL or AML.

According to the WHO classification of hematopoietic and lymphoid tissue 2016, AML was classified into various subtypes based on morphology and genetic abnormalities. AML is a group of hematological diseases, with a diminished capacity for differentiation. In this condition, accumulation of myeloblasts and immature myeloid cells in the bone marrow, peripheral blood, or other tissues was observed. AML represents ~20% of AL cases in children and ~80% in adults.[9] Treatment strategies are also largely varied, and they are different for both acute promyelocytic leukemia (APML) and non-APML of AML. The major concern and cause for morbidity and mortality during AML induction phase treatment were mostly due to infection and bleeding. Risk factors for infections include the number of skin-penetrating venous catheters, the degree of hemorrhagic diathesis of skin and mucosal tissue, severe mucositis, impaired cellular and humoral immunity caused by the underlying disease, and profound neutropenia.

Thrombosis was also observed to be a common complication in patients with AL. The risk factors for such thrombosis in children include the use of concomitant steroids, use of Escherichia coli L-asparaginase, presence of central venous lines, and hereditary thrombophilic abnormalities. However, as of date, information related to pathogenesis, risk factors, and clinical outcome of thrombosis in adult patients with (ALL) Acute Lymphocytic Leukemia and AML is limited. Among these thromboembolisms, the occurrence of CVT in ALL and APML patients was found to be normal due to treatment-related prothrombotic state, hyperleukocytosis, and increased expression of tissue factor in leukemic cells.[2]

However, CVT was observed to be a very rare occurrence in patients with non-APML of AML category.[10] In a study conducted by Mohren et al., the rate of thrombosis in 455 patients with ALL was found to be 12%, occurring mostly during the induction phase of the treatment due to central venous catheters, with equal risk in ALL and AML patients.[6] De Stefano et al. have also confirmed the thrombosis as a rare event at diagnosis; in their study, only 3.2% of patients were identified to have non-APML. However, none have reported CVT.[2]

Treatment of thromboembolism in AML and APL patients is very challenging, because of the hemorrhages due to coagulation, severe thrombocytopenia, and fibrinolysis abnormalities due to abnormally high levels of annexin A2 on APL cells.[11],[12] Thrombosis and the risk of very rare CVT are the extremely underestimated complications, especially in APL and non-APML patients. Due to nonspecific manifestations associated with CVT, the clinical diagnosis was also observed to be very difficult because of the largely varied signs and symptoms.[11],[12] The exact underlying mechanism responsible for CVT is still unknown. In many patients, brain CT findings were observed to be normal and later found to have CVT on performing cerebral venography. Hence, it is “highly recommended to perform cerebral venography in highly suspicious cases of CVT even in the presence of normal brain CT findings.”[11]

Therefore, it has become very important and essential to identify the etiology and treat the underlying cause before the treatment initiation using standard anticoagulation drug therapy protocol. Patients with hematological malignancies undergoing chemotherapy are mostly immunocompromised and thrombocytopenic. It is always a debate on the safety of treating such a subset of patients with anticoagulation therapy. In a study conducted in patients with solid tumors for 6 months, low-molecular-weight heparin (LMWH) was proved superior and safe over warfarin in VTE recurrence. Imberti et al. have also conducted a similar study in patients with hematological malignancy and VTE. They have also reported that LMWH as a safe and attractive choice over warfarin.[13] However, in recent times, unfractionated heparin (UFH) is preferred over LMWH in clinically unstable patients because of its short half-life and potential reversibility. As of date, no comparative studies were found between LMWH and UFH in treating thromboembolisms. Such studies are encouraged in the future for a better understanding of the disease and its prognosis.

From previously reported studies and current recommendations, it was suggested that patients with a platelet count of above 50 × 109/l, LMWH can be given normally, whereas in patients with a platelet count of below 50 × 109/l, the therapeutic dose should be adjusted to below 50% than normal and it can be temporarily discontinued if the platelet count continues to fall further.[11]

In our patient, LMWH is withheld whenever the thrombocyte count is <50 × 109/l. No bleeding or recurrent thrombotic episodes have been observed. As of date, no standard guidelines were recommended for the treatment of CVT in hematological malignancies. Only left out option in the current scenario is the use of UFH for the first few days of the therapy and then switching to LMWH once the patient is clinically stable, by closely monitoring the platelet count and hemorrhagic symptoms.

  Conclusion Top

The underlying mechanism involved in the formation of CVT is still unknown, and the published data remain scant. The role of clinicians in identifying the clinically suspicious signs and symptoms can help in identifying such rare conditions before developing severe thromboembolic complications. It is always recommended, not to overlook the risk of thrombotic events in these AML patients. Anticoagulants can play a vital role as a safe and feasible form of therapy options in treating thromboembolic complications. However, large prospective trials are warranted for providing conclusive results.

Guidelines statement

The present case report was prepared as per the CARE guidelines.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.


The authors would like to thank Dr. Yasam Venkata Ramesh from HCG Manavata Cancer Centre, Centre for Difficult Cancers, Nashik, India, for his medical writing assistance.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Trousseau A. Phlegmatia Alba Dolens. 2nd ed., Vol. 3. Paris, France: J.-B. Baillière Et Fils; 1865. p. 654-712.  Back to cited text no. 1
De Stefano V, Sorà F, Rossi E, Chiusolo P, Laurenti L, Fianchi L, et al. The risk of thrombosis in patients with acute leukemia: Occurrence of thrombosis at diagnosis and during treatment. J Thromb Haemost 2005;3:1985-92.  Back to cited text no. 2
Semrad TJ, O'Donnell R, Wun T, Chew H, Harvey D, Zhou H, et al. Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg 2007;106:601-8.  Back to cited text no. 3
Types of Leukemia: Common, Rare and More Varieties | CTCA. Available from: https://www.cancercenter.com/cancer-types/leukemia/types. [Last accessed on 2020 Oct 12].  Back to cited text no. 4
Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715-22.  Back to cited text no. 5
Mohren M, Markmann I, Jentsch-Ullrich K, Koenigsmann M, Lutze G, Franke A. Increased risk of venous thromboembolism in patients with acute leukaemia. Br J Cancer 2006;94:200-2.  Back to cited text no. 6
Goyal G, Bhatt VR. L-asparaginase and venous thromboembolism in acute lymphocytic leukemia. In: Future Oncology. Vol. 11. London: Future Medicine Ltd.; 2015. p. 2459-70.  Back to cited text no. 7
Mitchell L, Lambers M, Flege S, Kenet G, Li-Thiao-Te V, Holzhauer S, et al. Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: Results of a multicenter cohort study. Blood 2010;115:4999-5004.  Back to cited text no. 8
Estey E, Döhner H. Acute myeloid leukaemia. Lancet 2006;368:1894-907.  Back to cited text no. 9
Runde V, Aul C, Heyll A, Schneider W. All-trans retinoic acid: Not only a differentiating agent, but also an inducer of thromboembolic events in patients with M3 leukemia. Blood 1992;79:534-5.  Back to cited text no. 10
Tang AS, Yeo ST, Law WC, Chew LP. Cerebral venous thrombosis as an initial manifestation of acute myeloid leukemia. Oxf Med Case Rep 2019;2019:32-4.  Back to cited text no. 11
Crespo-Solís E. Thrombosis and acute leukemia. Hematology 2012;17 Suppl 1:S169-73.  Back to cited text no. 12
Imberti D, Vallisa D, Anselmi E, Moroni CF, Bertè R, Lazzaro A, et al. Safety and efficacy of enoxaparin treatment in venous thromboembolic disease during acute leukemia. Tumori 2004;90:390-3.  Back to cited text no. 13


  [Figure 1], [Figure 2]


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