The first report of a JAK2 V617F‑positive myeloproliferative neoplasm with initial manifestation as a rare pampiniform venous plexus thrombosis and review of the literature
Jeremy Jacobs1 · Deva Sharma1,2 · Cindy Vnencak‑Jones3
Accepted: 29 June 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
1 Division of Transfusion Medicine, Department of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
2 Division of Hematology-Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
3 Department of Pathology, Microbiology, & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Abstract
Pampiniform venous plexus (PVP) thrombosis is exceedingly rare, with fewer than 25 cases described. Thus, the etiology and pathophysiology remain largely unknown. A 38-year-old male with no known risk factors incidentally noted a 10-day history of right testicular discomfort prompting evaluation. Findings included extensive right PVP thrombus, critically elevated hematocrit, and a JAK2 V617F gene variant. Despite no treatment guidelines, conservative management was initi- ated with therapeutic apixaban, and therapeutic phlebotomy and hydroxyurea for newly diagnosed primary polycythemia vera (PV), sparing exploratory genitourinary surgery. This represents the first reported case of PVP thrombosis as the initial manifestation of a JAK2 V617F positive PV and the first documented report of PVP thrombosis associated with an acquired hypercoagulable state. Of the 8 previous cases with hypercoagulable testing performed, 2 involved inherited hypercoagulable states, suggesting hereditary and acquired prothrombotic disorders should be considered as predisposing factors. Testing for the JAK2 V617F variant in patients with mesenteric, cerebral, and splanchnic venous thromboses is currently recom- mended, but testing patients with venous thromboses in other anatomical locations remains controversial. We reviewed all previously described cases to expound upon this diagnosis, potential association with hypercoagulable disorders, treatment options, and observed clinical outcomes. This case adds to the minimal literature and supports genetic testing all patients with spontaneous PVP thrombosis for the JAK2 V617F variant and other hypercoagulable conditions. Additionally, conservative management with therapeutic anticoagulation and treatment of the underlying precipitating disease state may be acceptable in select patients, following exclusion of surgical emergencies.
Keywords Janus kinase 2 · Myeloproliferative neoplasm · Thrombophilia · Thrombosis · Venous thrombosis · Pampiniform venous plexus thrombosis
Highlights
• Pampiniform venous plexus (PVP) thrombosis is rare, with fewer than 25 cases described.
Jeremy Jacobs [email protected]
• We describe the first case of a PVP thrombosis with a
JAK2 variant and review the literature.
• JAK2 V617F variant testing should be considered in patients with PVP thrombosis.
• Conservative management of PVP thrombosis with thera- peutic anticoagulation may be acceptable.
• Natural history studies and a rare disease registry would be beneficial to further elucidate etiology and best man- agement strategies for patients with PVP thrombosis.
Background
Spontaneous pampiniform venous plexus (PVP) throm- bosis is rare, with fewer than 25 reports since the first comprehensive description by McGavin in 1935 [1]. Most cases involve the left venous plexus because of anatomical differences in the vasculature between the left and right gonadal veins, resulting in greater propensity for left-sided venous stasis [2–5].
Hypercoagulable states may also be predisposing factors, with two published cases of patients with inherited throm- bophilias [3, 6, 7]. Association with acquired thrombophilia has not previously been reported. To our knowledge, PVP thrombosis has not been described in association with a Janus Kinase (JAK) 2 gene variant, or in the setting of a myeloproliferative neoplasm (MPN). We present the first known case of a PVP thrombosis as the initial presentation of primary polycythemia vera with a JAK2 V617F variant. We review the literature and analyze the association between PVP thrombosis and hypercoagulable disorders, pathophysi- ology, diagnosis and observed clinical outcomes.
Methods
Diagnostic strategies for unusual thromboses
The JAK2 V617F variant has been associated with devel- opment of venous thromboses in “unusual” locations, with many authors recommending JAK2 V617F variant test- ing in patients with splanchnic, mesenteric, and cerebral venous thrombosis, given the frequency of this variant in this patient population [8–10]. Conversely, the evidence is more controversial regarding the association between this variant and thromboses in other sites, with some authors arguing against JAK2 V617F variant testing in patients with unexplained venous thrombosis outside of the mes- enteric and splanchnic regions [10, 11].
Given the rarity of a PVP thrombosis with less than 25 reported cases in the medical literature, there is insufficient data to recommend for or against testing for the JAK2 V617F variant. However, in cases where other laboratory findings are suggestive of a MPN, such as elevated hemoglobin and hematocrit, platelet count, and/or WBC count without a known secondary etiology, testing for this acquired hyperco- agulable variant may be informative. Our testing algorithm for these patients includes molecular genetic testing for vari- ants including JAK2 V617F, variants in the CALR and MPL genes, and FISH for the t(9; 22) translocation. If these tests are nondiagnostic, we assess for mutations in exon 12 of the JAK2 gene and consider NGS testing.
For patients with normal hematologic parameters, and for those patients in which the aforementioned testing is unre- vealing, we perform additional testing for underlying ger- mline hypercoagulable disorders. This includes testing for factor V Leiden, the prothrombin G20210A mutation, pro- tein C and protein S deficiency, and antithrombin deficiency.
We also test for antiphospholipid antibody syndrome, par- ticularly when there is a personal or family history of arterial thromboses or recurrent miscarriages, as these results may affect the selection of anticoagulation therapy. The results of this testing may also influence the duration of anticoagula- tion and provide useful information about thrombotic recur- rence risk in patients with these hypercoagulable disorders.
Molecular genetic testing
Molecular diagnostic methods were utilized to evaluate for potential underlying genetic abnormalities as part of routine clinical care. To assess for the presence or absence of the JAK2 V617F variant, qualitative allele-specific polymerase chain reaction (PCR) with a fluorescently tagged primer coupled with capillary electrophoresis (CE) was performed. To detect hot spot variants in the MPL gene, exon 10 was amplified by PCR and purified PCR products were subjected to bidirectional fluorescent Sanger sequencing. To screen for commonly observed deletions or insertions in exon 9 of the CALR gene [52 base pair (bp) deletion, 5 bp insertion, or any other sized deletion or insertion involving exon 9], PCR using a fluorescently tagged primer, CE and fragment analysis was utilized to detect changes in the size of the PCR product corresponding to the presence of a deletion or insertion in this region. To assess for the presence of other less common genetic alterations that could be present in this patient, Next Generation Sequencing (NGS) using a 37-gene myeloid specific panel was performed on DNA extracted from the diagnostic bone marrow specimen.
Cytogenetic testing
Fluorescence in situ hybridization (FISH) was performed on a peripheral blood sample to evaluate for the presence of the t(9;22)(q34;q11) translocation using a dual-color dual-fusion technique. 200 interphase cells were analyzed using a probe for the BCR gene on chromosome 22q11.2 and a probe for the ABL1 gene on chromosome 9q34.
Case presentation
Informed consent was obtained from the patient. A 38-year-old man without personal or family history of venous or arterial thrombosis or hypercoagulability pre- sented for a routine examination. He endorsed 10 days of right testicular discomfort. Scrotal ultrasound revealed extensive right PVP thrombosis, prompting evaluation.
Initial laboratory studies were significant for elevated white blood cell count (WBC), hemoglobin, and hemato- crit (Table 1). Repeat WBC, hemoglobin, and hematocrit remained abnormal with elevated reticulocyte count and decreased serum erythropoietin (Table 1).
Computed tomography (CT) of the abdomen and pel- vis demonstrated splenomegaly (22.3 cm) and a right PVP thrombus. Evaluation for masses, lymphadenopa- thy, hepatobiliary and germ cell malignancies was nega- tive. Portal vein thrombosis and inferior vena cava (IVC) anatomical abnormalities were not identified. Secondary causes of polycythemia including cigarette use, obstruc- tive sleep apnea, testosterone use, high altitude living, and cyanotic heart and lung disease were excluded.
The abnormal labs concerning for autonomous white and red blood cell (RBC) production by the bone marrow and concurrent thrombosis at an unusual site prompted cytogenetic and molecular testing to assess for a poten- tial underlying MPN and concurrent prothrombotic state. Bone marrow biopsy findings were significant for a hypercellular marrow (95% cellularity) with erythroid- predominant trilineage hyperplasia, consistent with poly- cythemia vera. Therapy included apixaban for a minimum of 3 months, cytoreductive therapy with hydroxyurea, anti-platelet therapy with aspirin, and phlebotomy to maintain hematocrit below 45%.
Testing of DNA extracted from a peripheral blood specimen revealed JAK2 variant c.1849G > T (p.V617F) with a variant allele frequency of 83% identified by NGS. No deletions or insertions of DNA were detected in exon 9 of the CALR gene, and exon 10 sequencing of the MPL gene revealed no variants. Fluorescence in-situ hybridiza- tion (FISH) using a BCR/ABL1 probe was negative for the t(9;22)(q34;q11) translocation.
Discussion
This is the first description of a PVP thrombosis associated with a JAK2 V617F variant and only the third documented case of an isolated right-sided PVP thrombosis. The litera- ture regarding the etiology, pathophysiology, and treatment of PVP thrombosis is sparse. We reviewed reported cases of PVP thrombosis, their association with hypercoagulabil- ity, as well as clinical outcomes and associated therapeutic interventions (Table 2).
Risk factors for PVP thrombosis
Almost all reported cases of PVP thrombosis involve the left venous plexus, with only 2 prior reports of isolated right- sided thrombosis [6, 17]. This may be related to normal ana- tomical differences between the right and left-sided vascular structures [2]. Other causes such as tumor obstruction, val- vular insufficiency, or anatomical defect may also contribute to select cases [4].
In addition to anatomical risk factors, there are 2 pub- lished cases of PVP thrombosis in patients with underlying inherited hypercoagulable states (protein C deficiency and factor V Leiden variant [c.1691G > A (p.R506Q)] heterozy- gosity) [6, 7]. In contrast, acquired thrombophilias have not been observed in any previously reported case of PVP thrombosis, although hypercoagulable evaluation was only documented in 8 of 24 patients.
JAK2 V617F variant and hypercoagulable states
Both hyperviscosity from increased RBC mass and the JAK2 V617F variant contribute to the hypercoagulability in polycythemia vera. This genetic variant causes the acti- vation of hemostatic factors and prothrombotic cytokines, leading to platelet activation and transient microvascu- lar thromboses [25, 26]. Hobbs et al. demonstrated that thrombus formation is increased in the setting of a JAK2 V617F gene variant, with platelets showing greater sen- sitivity to collagen-related peptide and thrombin, and thus, increased reactivity, aggregation, and spreading [27]. Additional studies have shown that platelets from patients with JAK2 variants have increased expression of P-selectin on their surface, indicating a more activated state [28]. Furthermore, the presence of the JAK2 V617F variant correlates with elevated, more reactive immature platelets [28, 29].
Table 1 Hematological laboratory parameters of patient case
Laboratory value Initial laboratory evalua- tion at presentation
Subsequent evaluation following admission to hospital
WBC count (reference: 3900–10,700/uL) 16,500/uL 17,500/uL Hemoglobin (reference: 14–18.1 g/dL) 24.3 g/dL 24.4 g/dL
Hematocrit (reference: 41–49%) 76% 73% Platelet count (reference 135,000–371,000/uL) 336,000/uL 386,000/uL Reticulocyte count (reference 0.5–1.8%) N/A 2.0%
Serum erythropoietin (reference: 4–27 mU/mL) N/A 1 mU/mL
WBC white blood cell
The effects of the JAK2 V617F variant are not limited to platelets. De Grandis et al. demonstrated that this vari- ant induces phosphorylation of certain glycoproteins on the surface of RBCs [30]. This phosphorylation leads to increased adhesion between RBCs and endothelial cells [30]. This increased adhesion capability results in greater predilection to thrombosis, particularly in anatomical regions with a high propensity for venous stasis.
Conclusion
Thrombosis of the PVP is rare, with minimal data in the literature describing the etiology or pathophysiology of this entity. Despite the rarity, the present case highlights the potential association between acquired hypercoagulable states such as the JAK2 V617F gene variant and thromboses in this unusual anatomic location.
Author contributions JJ designed the manuscript, analyzed and inter- preted data, and wrote the manuscript. DS provided supervision, ana- lyzed and interpreted data, edited the manuscript, and approved the final version. CV-J provided supervision, analyzed and interpreted data, edited the manuscript, and approved the final version.
Funding The authors received no funding support for this research.
Declarations
Conflict of interest The authors declare that they have no conflicts of interest relevant to the manuscript submitted to the Journal of Throm- bosis and Thrombolysis.
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