Essential thrombocythemia with (type2) calreticulin presented as stuttering priapism case report and review of literature

Abstract Priapism is a rare presentation and complication of ET that might be underreported. In ET, priapism can present as an ischemic or stuttering type. These patients are more likely to be anemic and have a high platelet count.


| BACKGROUND
Essential thrombocythemia is a myeloproliferative neoplasm (MPN), characterized by clonal proliferation of myeloid cell line with a significant increase in platelet count. Diagnosis is made by meeting the 2016 WHO criteria with four major or three major and one minor criterion after excluding secondary causes of thrombocytosis. It usually an asymptomatic disease or presents with hemorrhagic or thrombotic complications. Priapism is a prolonged penile erection not related to sexual stimulation. The longer the duration of priapism, the higher the risk for penile fibrosis and erectile dysfunction, which have a devastating outcome on male fertility. Priapism is seen more commonly in hematological conditions, that is, sickle cell anemia. In myeloproliferative neoplasms, it is relatively more common with chronic myeloid leukemia and is rarely reported with essential thrombocythemia, polycythemia Vera, or primary myelofibrosis. We are reporting a case of a 51-year-old man with persistent thrombocytosis diagnosed as essential thrombocythemia with CALR (Type 2). The patient developed priapism with the onset of rising in platelets count. This is the first report in the literature of CALR type 2 essential thrombocythemia presenting with priapism. The case sheds light on rare or underreported complication and reviewing our current knowledge concerning such rare complication.
Priapism is a persistent erection of the penis that is not associated with sexual stimulation or desire lasting more than 4 hours. 1 Priapism can be classified as ischemic, nonischemic, or stuttering. Stuttering priapism is defined; recurrent priapism lasting less than 4 hours. 2 Commonly, no cause is identified; secondary causes include medications, especially intracorporal injections or medical conditions such as hematological diseases, particularly sickle cell disease. But it is uncommon to be seen with essential thrombocythemia (ET). It adversely affects the quality of life, sexual function (SF), and physical wellness of the affected patients, 3 besides the risk of penile fibrosis and permanent erectile dysfunction. 2,4 The underlying pathophysiology is not clearly understood; several mechanisms have been postulated. This includes disturbed nitrous oxide (NO), phosphodiesterase enzyme activity, and disturbed autoregulation of the penile circulation. 1,5 There are few reported cases of priapism as the presenting feature of ET.
The peripheral blood smear showed increased numbers of platelets with some large and few giant forms. Chromosomal analysis revealed normal Karyotype: 46,XY. US Abdomen showed normal liver and spleen, no ascites, and no organomegaly. After the diagnosis of ET, the patient was counseled regarding the recurrence of priapism. He was started on aspirin 75 mg daily and is following with urology for priapism. He did not require any urological intervention for priapism.

| DISCUSSION
This patient platelet count was normal up to the time of presentation with priapism, as shown in (Figure 1). His only previous conditions were infertility and sleeve gastrectomy. The majority of patients with essential thrombocythemia are asymptomatic, discovered accidentally by chance during routine blood work or investigation for another reason. 6 Others present with vasomotor symptoms, thrombotic, or hemorrhagic complications. 7 Priapism is a rare medical condition incidence in the United States is 0.73 per 100 000 men per year. 8 It is rare for ET to present as priapism. Our literature search revealed 11 reported cases with ET who developed or presented with priapism.
The most common type of priapism is ischemic (low flow), while nonischemic is much rare and related to trauma. 9 Stuttering priapism results and can lead to ischemic priapism, and they share similar causes. 9 It thought that the initial insult results in defective penile circulation due to loss of phosphodiesterase type 5 (PDE5) regulatory function which in turn result in altered NO and cyclic guanosine monophosphate signaling mechanisms. 10,11 The major hematological cause for ischemic priapism is sickle cell anemia. In ET, the mechanism is probably related to high platelet count and platelets sludging in the corpora cavernosa, similar to RBC sludging in sickle cell disease and WBC sludging in leukemia. 12 Subsequent stasis and disturbed NO and cyclic guanosine monophosphate signaling. This might be precipitated by increased viscosity due to dehydration or release of free hemoglobin 13 secondary to hemolysis similar to sickle cell anemia, as many patients had low hemoglobin levels, as seen in (Table 1). The table shows that most of hemoglobin levels are in the low to lower normal limits, but no patient had high hemoglobin levels, opposite to what can be expected that F I G U R E 1 Shows previously normal platelet count until the time of presentation on April 30, 2019 polycythemia might increase the viscosity of the blood and enhance thrombosis. This is supported by observing patients with other myeloproliferative neoplasms who developed priapism. In one study 430 patients with chronic myeloid leukemia, those who developed priapism at diagnosis (8 patients) had lower hemoglobin levels compared to chronic myeloid leukemia patients who did not develop priapism. 14 In the same study, the mean hemoglobin level in patients with priapism was 8.4 ± 2.3 g/dL, compared to a hemoglobin level of 10.8 ± 2.5 g/dL in chronic myeloid leukemia patient's control who did not develop priapism. The age and platelet count did not have a significant effect on priapism in these patients with chronic myeloid leukemia. To the best of our knowledge, there are no reports of cases of adults with polycythemia Vera who devolved priapism, which might indicate that anemia has a sort of synergistic effect with leukocytosis in the pathogenesis of priapism in CML patients. And it might affect the type of priapism as most CML type is ischemic. But it is difficult to generalize this observation to ET. The effect of hemoglobin level on essential thrombocythemia with priapism is not clear, and it is not clear if the hemoglobin level itself is related to the type of priapism due to incomplete information. However, anemia can enhance thrombosis and the risk of thromboembolism. 15 This effect is not related to reactive thrombocytosis and might be linked to an increase in plasminogen inhibitors or the levels of clotting factors. 16,17 In the table, the WBC count is variable but at a high level for most patients. From (Table 1), it is noted that some patients presented after years from the onset of priapism. This may indicate the complaint of priapism is underreported, especially for patients with stuttering priapism who develop erection for a shorter duration of time and subsides spontaneously as with our case. While patients with painful ischemic priapism have prolonged, painful erection usually seeks medical attention from the first time. This can be the reason that chronic myeloid leukemia reports of priapism are relatively more common 1.7% compared to ET 18 because CML type is predominantly ischemic. At the same time, ET can be ischemic or stuttering.
Penile tissue composes of two spongy erectile tissue called corpora cavernosa and another spongy tissue in the ventral side of the penis called the corpus spongiosum. Priapism usually involves the cavernosal tissue; less commonly, it can affect the spongiosum and glans penis. 19,20 After 4-6 hours of erection, tissue damage can be detected at a microscopic level. 21 And with more prolonged erection, there is a high risk of permanent damage and fibrosis. If it persists more than 24 hours, the risk of permanent erectile dysfunction is more than 90% 22 and a drastic effect on male fertility.
Most of these cases are reported a long time ago, and few are reported after the 2008 WHO criteria for ET, which explains why no genetic studies were done for the cases before 2008. Two cases were Jak2 +, and our case is the first case with CALR type 2 ET to present with priapism. Usually, the platelet count is higher with CALR mutation than Jak2 mutation 23 but with fewer thrombotic or hemorrhagic complications than Jak2. Due to the limited numbers of reported cases, it is not clear if the priapism is related to Jak 2 mutation over CALR mutation. As Jak2 mutation is more common, it is expected to be seen more with Jak2 than CALR mutation. Other ET patients who developed priapism also had high platelet count (830-4100) ( Table 1). Some patients had splenomegaly. Splenomegaly is seen in up to 51% of ET patients by using ultrasonography. 24 In table, 6/11 had splenomegaly or splenectomy. This ratio is close to ET patients without priapism. The effect of age is ill-defined, as it was reported in children 25 as well in a patient aged 71 years 26 ; it seems that age plays a minor role, if any. Additionally, priapism pathophysiology is not clear, and ET presented with different types of priapism stuttering and ischemic, 26,27 which makes the underlying mechanism of such priapism more debatable.
Generally, stuttering priapism management depends on the situation at presentation. If the patient is in acute priapic even, priapism will be managed as Ischemic priapism. 9 If the patient is not in a priapic state, then the aim is to prevent the recurrence of the condition. 28 Management starts with patient counseling regarding early measures to control priapism-like physical activity, urination, ejaculation, fluid intake, and cold baths. 29 Various medications had shown benefits. Intracavernosal injection of α-agonists like phenylephrine or oral-like pseudoephedrine is used to contract the smooth muscles allowing detumescence. 30 Other modalities include the use of hormonal therapy to suppress testosterone-like goserelin acetate, leuprolide, and ketoconazole. Additional effective medications include phosphodiesterase 5 inhibitors, gabapentin, 31 and terbinafine. 30

| CONCLUSION
Priapism is a rare presentation and complication of ET. It can present as ischemic or stuttering types. Stuttering priapism might be underreported which explains the fewer reports in ET compared to CML because in CML priapism is mostly low flow type. The main risk factors are not well-understood due to the old and few reported cases. Splenomegaly, age, and type of mutation appear to have little impact. However, the distinctive feature is the high platelet count with or without anemia but no polycythemia. Early diagnosis and rapid management of such cases could lead to favorable prognosis and better outcome preserving the erectile ability of corpora cavernosa.

ACKNOWLEDGMENTS
I wish to show my gratitude to the Internal medicine residency program, to Dr Dabia Hamad Almohanadi, and I would like to thank the patient for allowing us to share his case. Open Access funding provided by the Qatar National Library.

CONFLICT OF INTEREST
None declared.

AUTHOR CONTRIBUTIONS
EAA: concept, writing, editing and approval of final manuscript. MAY: concept, writing, editing and approval of final manuscript. AJN: writing, editing, and approval of final manuscript.

CONSENT
The consent for publication was obtained.

DATA AVAILABILITY STATEMENT
All data generated during this published case report are not publicly available. However, it is available up on request from the corresponding author with permission.