PV is a chronic myeloproliferative disorder characterized by hyperplasia of the red lineage with hyperplasia of both the granulocytic and megakaryocytic lineages caused by the JAK2V617F mutation or the JAK2 exon 12 mutation. Primary myelofibrosis (PMF) is classified as a Bcr/abl-negative chronic myeloproliferative disease. It is characterized by a significant increase in red blood cell count and blood volume with elevated neutrophils and propulsion platelets, a series of signs and symptoms due to polycythemia and hyperviscosity, often accompanied by splenomegaly and pruritus, and an insidious onset and long course, with various transformations occurring in the late stages.
As early as 1892, Vaquz reported a case of persistent hematocytosis with cyanosis, and in 1904, Turk first suggested that PV was accompanied by proliferation of both granulocyte and megakaryocyte lineages in its early stages, and in 1951, Dameshek classified PV, ET, PMF and Chronic Myeloid Leukemia (CML) as a group of related diseases and called them chronic myeloproliferative disorders. They are called chronic myeloproliferative disorders.
I. Overview of the disease
PV is a rare disease, but not a rare disease, mostly occurs in the middle-aged and elderly, the average age of onset in 50-60 years old, more men than women, the onset of countries have, the incidence of more countries and regions are Israeli Jews, Nagasaki, Japan, and Gothenburg, Sweden. The incidence rate of Israeli Jews: 1.3/100,000 men and 0.5/100,000 women; Nagasaki, Japan: 1.6/100,000 men and 0.4/100,000 women; Gothenburg, Sweden: 1.4/100,000 people. It was first reported in China in 1957, and the average age of onset reported in the literature was 53 years, but due to the lack of census data of the disease, no incidence rate has been reported in China.
II. Etiology and pathogenesis
Although the etiology of PV is still unknown, numerous experimental data have shown that patients with PV have the following characteristics.
The initiating link of pathogenesis occurs at the level of pluripotent hematopoietic progenitors, and transformed hematopoietic progenitors predominate over non-transformed ones;
2. In the absence of specific stimulation, one or more types of blood cells can be overproduced;
3. The ability to form spontaneous colonies in vitro;
4. Extremely active bone marrow proliferation and active or poor megakaryocyte proliferation;
5. Major cytogenetic alterations involving chromosomes 1, 8, 9, 13 and 20;
6. The main causes of death in patients are hemorrhage and thrombosis; 7. Exuberant extramedullary hematopoiesis; 8. Tendency for spontaneous transformation to acute leukemia and myelofibrosis.
In 2005, four different international research groups reported the presence of JAK2V617F mutation in more than 90% of PV patients at almost the same time in different prestigious international medical journals, a “landmark” discovery that opened new horizons for the elucidation of the molecular mechanism of MPDS pathogenesis. The structural model of JAK2 suggests that residues V617 to E621 form a loop that links two beta chains protruding from the N terminus of the pseudokinase region, with C618 contacting the activation loop. The kinase activation loop moves from the inactivated conformation to the activated conformation (i.e., the V617 region plays a direct role in negatively regulating JAK2 signaling). The substitution of the large aromatic amino acid phenylalanine for valine is likely to disrupt this negative regulation, which could also explain on a molecular basis why erythroid progenitor cells from PV patients can spontaneously form colonies in culture in vitro, and why erythroid and myeloid progenitor cells from patients with myeloproliferative disorders are particularly sensitive to several different growth factors, but for the pathogenesis of JAK2V617F mutation-negative patients However, the molecular basis for the pathogenesis of JAK2V617F mutation negative patients needs to be further investigated.
Pathology
PV lesions mainly involve bone marrow, spleen and liver. There is a marked increase in red marrow in the bone marrow and relatively little adipose tissue. The bone marrow structure is still basically normal, the red lineage hyperplasia is extremely obvious, granular and megakaryocyte lineage often proliferate at the same time, but also one of the lineage hyperplasia, some patients only red lineage hyperplasia alone. Young erythrocytes proliferate in an island-like pattern next to the venous sinuses, granulocytes in all stages proliferate diffusely next to the trabeculae and around the vessels, and megakaryocytes proliferate in the intertrabecular area. Bone marrow proliferating cells were highly heterogeneous, with significant sinusoidal expansion. Bone marrow iron storage cells and iron granules were significantly reduced, and about 80% of patients had negative iron staining. Later in the course of the disease, fibroblasts and blood vessels are significantly proliferated, and large islands of red blood cells with immature granulocytes and heterogeneous megakaryocytes appear. Reticulofibrillar staining shows a high degree of reticulofibrillar hyperplasia, indicating transformation or associated myelofibrosis.
Based on bone marrow pathology, PV is divided into three phases: erythropoietic phase (this phase is characterized by active bone marrow hematopoiesis with excessive proliferation of red lineage cells accompanied by leukocytosis and thrombocytosis); stable phase (this phase maintains a normal range of whole blood cells; this change is not due to a normal transformation of the diseased bone marrow hematopoiesis, but is the result of the bone marrow being replaced by abnormally proliferating fibrous tissue and a decrease in bone marrow hematopoiesis compared to the previous one) The stage of bone marrow failure (during this period the proliferation of fibrous tissue in the bone marrow increases, reducing the intramedullary hematopoietic tissue and producing extramedullary hematopoiesis).
In early enlarged spleens, the splenic sinuses are significantly dilated and congested, and the red lineage is increased with a small number of infantile red blood cells. In late stages, triple lineage hematopoietic cells may appear, resembling myeloid metaplasia. In the enlarged liver, the hepatic sinusoids are also dilated and accompanied by myeloid metaplasia. These pathological changes in the liver and spleen are also the pathological basis for portal hypertension and frequent upper gastrointestinal bleeding. In case of thrombosis in the larger vessels, foci of infarction can be seen in the corresponding organs. Other organs usually have no obvious pathological changes.
IV. Clinical manifestations
The onset of the disease is insidious, and it is usually detected by chance during routine blood tests.
1. Neurological symptoms: including headache, dizziness, swelling and numbness of the extremities, sensory impairment, vision loss, tinnitus and OEMS syndrome. In severe cases, there is impaired consciousness and even dementia. The above symptoms are related to elevated blood viscosity, thrombocytosis and lacunar cerebral infarction.
2, polycythemia symptoms: manifested as conjunctival congestion, red face, purple lips, dark red tongue and anger of blood vessels. It is due to excessive red blood cells, high blood viscosity, slow blood flow and tissue hypoxia, resulting in microcirculation and systemic vascular congestion and dilation.
3. Bleeding: Gum bleeding and nasal bleeding are common, but skin bruising and gastrointestinal bleeding can also occur, and cerebral bleeding is a complication in a few patients. The causes of hemorrhage are: excessive vasodilation and blood stagnation leading to endothelial damage, abnormal platelet function, and inappropriate use of non-steroidal analgesic drugs leading to impaired platelet function.
4.Splenomegaly: usually mild to moderate enlargement, in advanced stage with myelofibrosis, splenomegaly can reach the pelvis.
5, thrombosis: the most common complication, occurring in about 1/3 of patients, with cerebral thrombosis being the most common, followed by coronary artery of the heart, deep veins of the lower extremities and splenic involvement a few may develop arterial thrombosis of the extremities. PV has been reported in the literature to be an important cause of hepatic vein thrombosis (Budd-Chiar syndrome), accounting for about 10% of cases. When platelets increase significantly, it can also be complicated by erythematous limb pain, and in severe cases, cyanosis of the extremities, and even gangrene.
6, skin pruritus: foreign report skin pruritus is an important clinical symptom of PV, the incidence of skin pain and itching up to 65.3%, the authors observed 38 cases of PV patients with 14 cases of skin pruritus symptoms, and there is no significant difference between PV with positive JAK2V617F mutation and PV with negative JAK2V61 7F mutation. PV-associated pruritus is often described as a generalized pruritic, numb, burning, or pins-and-needles sensation that occurs after skin contact with water and is often classified as aquagenic pruritus (AP). It can be triggered by a sudden change in temperature, fire, sweating after exercise, alcohol consumption, or use of hot bedding. The cause is due to the extensive infiltration of mast cells in the dermis, and some authors have suggested that PV-related AP is associated with iron deficiency and biogenic amines. The incidence of pruritus in PV patients with JAK2V617F mutation-positive purets has been reported to be as high as 69%.
The patients with PV have hyperuricemia due to accelerated nucleoprotein catabolism because of the hypermetabolic state of bone marrow cells, so clinical gout attacks are common.
V. Laboratory tests
1.Blood routine
The relative density of blood is 1.075~1.080. Red blood cells are ≥6~10×109/L, hemoglobin is ≥180~240g/L, hematocrit is 0.55~0.80, reticulocyte count is normal or slightly higher, and the size of red blood cells is different, multi-staining and nucleated red blood cells can be seen in late stage. In late stages, anomalous erythrocytes and a large number of teardrop-shaped erythrocytes can be seen, suggesting complicated myelofibrosis. The life span of erythrocytes is normal in the early stage and shortens later. 2/3 of patients have an increased white blood cell count, mostly 12-15×109/L, with a few exceeding 50×109/L. There is a left shift of the nucleus and a small number of intermediate and late granulocytes. Neutrophil NAP scores were elevated in 70% of patients, and granulocyte chemiluminescence in response to certain antagonists such as leukotrienes showed selective inhibition abnormalities. Platelet counts ranged from 450 to 800×109/L in half of the patients, and large and giant platelets were seen. Platelets responded abnormally to epinephrine-induced aggregation or were even deficient, and thromboxane A2 production and metabolic secretion were increased, but binding to platelet activating factor stimulation was diminished, and expression of platelet receptors was diminished.
2.Bone marrow picture
The bone marrow shows active or markedly active proliferation, mainly in the red lineage, often accompanied by proliferation of granulocyte and megakaryocyte lineages. The proportion of cells in each phase of the lineage is normal. Iron staining shows that both intracellular and extracellular iron are reduced or even absent. Bone marrow biopsy shows the aforementioned pathological changes, which helps in the diagnosis.
3.Red cell volume
The erythrocyte volume was measured by the nuclein 51Cr labeling method and was significantly elevated in patients with PV. This test is an important indicator to confirm the diagnosis of erythrocytosis with high repeatability. In case of concomitant portal hypertension, the increase in plasma volume can cause the illusion of normal RBC, Hb and HCT, and a similar phenomenon can occur in case of iron deficiency. In this case, the diagnosis can be confirmed by checking the red blood cell volume.
4.Chromosome
Bone marrow karyotype analysis about 25-35% of patients have various acquired abnormalities after chemotherapy, radiotherapy, or disease progression can appear 5q-, 7q- and other abnormalities. Those who have cytogenetic abnormalities at the time of diagnosis have poor prognosis.
5.Molecular biology
Almost all patients with PV have increased expression of anti-apoptotic factors such as Bcl-XL (B-cell leukemia-XL) and excessive activation of STAT3 or STAT5 in bone marrow juvenile red blood cells. Recent studies have shown that 95% of patients with PV have JAK2V617F mutation.
6.Other
Blood rheological examination shows a significant increase in blood viscosity and slowing of hematocrit. All coagulation and fibrinolytic indicators are mostly normal, but there are reports of decreased antithrombin, protein C, protein S, and protein C resistance, suggesting decreased anticoagulant activity. Serum vitamin B12 is significantly elevated in about 40% of patients due to increased release from granulocytes. Folic acid and ferritin are often decreased. Blood uric acid and LDH are elevated. Blood gas analysis shows normal oxygen saturation. Serum EPO levels are reduced. In vitro bone marrow stem cell culture, BFU-E growth is often without the presence of EPO. Echocardiography shows 77% of patients with PV have aortic or mitral valve pathology such as valve thickening and redundancy, which is one of the pathological bases of thromboembolic complications.