​Kembara Xtra - Medicine - Polycythemia Vera

​Kembara Xtra - Medicine - Polycythemia Vera  
The myeloproliferative clonal stem cell condition polycythemia vera (PV) is characterized by excessive erythroid, myeloid, and megakaryocytic elements in the bone marrow and enhanced red blood cell production (erythrocytosis).
The main causes of morbidity and mortality are problems from blood hyperviscosity, which can result in thrombosis development and malignant transformation. Patients who go untreated may live for six to eighteen months. Life may be extended by more than 10 years with proper care.
Myelofibrosis (MF), which can proceed into hepatosplenomegaly, can form in the bone marrow.
Synonyms include primary polycythemia, Vaquez-Osler illness, PV rubra, polycythemia, splenomegalic, and maladie de Vaquez disease. 

Predominant age range: 50 to 75 years; nevertheless, cases have been reported in young adults and children. Predominant sex: male > female (slightly). ● United States incidence in 2012: Men make up 2.8 per 100,000 people while women make up 1.3 per 100,000; the highest rate is for men aged 70 to 79, who make up 23.5 per 100,000 people annually. Prevalence
Estimates for the number of instances per 100,000 patients in the United States in 2010 ranged from 45 to 57.

Pathophysiology and Etiology 

Associated with clonal proliferative disease is the JAK2 V617F mutation. Genetics Tyrosine kinase JAK2 V617F mutation: >97% of PV patients have this activating mutation, which aids in distinguishing PV from secondary erythrocytosis. Compared to heterozygotes, homozygote carriers will experience more symptoms like pruritus, but not more disease.

Risk Factors Compared to other Europeans or Asians, Jews of Eastern European heritage may have a somewhat higher prevalence of PV.
Familial histories are uncommon.


Budd-Chiari syndrome, ischemic digits, mesentery artery thrombosis, myocardial infarction, cerebrovascular accident or transient ischemic attack, venous thromboembolism, and pulmonary embolism are among the conditions that are associated with it.

Diagnosis Patients may be asymptomatic or present with general complaints such as weakness, malaise, weariness, and weight loss.
 Erythromelalgia (burning pain in the hands or feet that is sometimes accompanied by erythema, pallor, cyanosis, or paresthesias)  Aquagenic pruritus, which is a type of itch, especially after bathing  Vascular and arterial occlusive occurrences  Headaches Cloudy or blind areas in the vision Tinnitus, vertigo, and lightheadedness; spontaneous bleeding or bruising; and peptic ulcer disease (caused by changes in the blood supply to the gastrointestinal mucosa). Early satiety brought on by an enlarged spleen; rib and sternum pain; gout; insomnia; and depression

clinical assessment 
Blood pressure (46%)
 Palpable spleen (36%) and splenomegaly (75%).  (30%) Hepatomegaly
Skin excoriations from severe pruritus; ruddy cyanosis on the face; bone soreness, especially in the ribs and sternum; gouty tophi or arthritis; injection of the conjunctival tiny arteries and/or engorgement of the veins in the optic fundus 

Secondary erythrocytosis and essential thrombocytopenia are the differential diagnoses:
- Smoking cigarettes - Emphysema - Sleep apnea
Stenosis of the renal arteries with carbon monoxide poisoning
Erythropoietin (EPO), diuretics, and testosterone replacement therapy - Hemoglobinopathy - Ectopic EPO synthesis - Fake polycythemia


Laboratory Results 
CBC; if suspicion is high, get an EPO level and get your JAK2 V617F gene tested.
● A CBC should be performed again if the only sign of PV is an elevated hemoglobin (Hgb)/hematocrit (Hct) level. If the Hgb/Hct revert to normal, no additional testing is required.
Initial examinations (lab, imaging)
The 2016 World Health Organization diagnostic criteria calls for either the first two major criteria and the minor criterion, or all three major criteria.
- Major requirements include a Hgb level of at least 16.5 g/dL for men and 16.0 g/dL for women, a Hct level of at least 49% for men and 48% for women, or increased cell mass (>25% above mean normal predictive value).  A bone marrow biopsy reveals hypercellularity for one's age, trilineage growth (panmyelosis), substantial erythroid, granulocytic, and megakaryocytic proliferation, as well as mature megakaryocytes that are pleomorphic (having different sizes), in the bone marrow.  The JAK2 V617F mutation or another comparable mutation, such as the JAK2 exon 12 mutation - Minor requirements
Serum EPO levels that are below normalIn cases with significant absolute erythrocytosis, criterion number 2 (bone marrow biopsy) may not be necessary. If major criteria 3 and a minor criterion are satisfied, Hgb >18.5 g/dL in men (Hct, 55.5%) or >16.5 g/dL in women (Hct, 49.5%) will be the result. However, bone marrow biopsy is the sole way to identify early MF (occurring in up to 20% of points); this discovery may indicate a quicker progression to overt MF (post-PV MF).
 Additional lab results that are typical yet vague -
Hypercholesterolemia and Hyperuricemia
Low plasma volume causes prolonged PT and aPTT, prolonged thrombocytopenia (>400,000 platelets/mm3), and leukocytosis (>12,000/mm3). Elevated serum vitamin B12 levels are also a factor.
- Leukocyte alkaline phosphatase (100,000 U when no fever or illness is present).  Although not necessary for diagnosis, splenomegaly can be assessed with a CT or US.  Carboxyhemoglobin (COHb) and arterial oxygen saturation (92% SaO2) Bone marrow biopsy is not required. For this illness, there is no standard staging scheme.

Other/Diagnostic Procedures

If conducted, a bone marrow aspiration reveals erythroid, granulocytic, and megakaryocytic line hypercellularity, or MF.
 Test Interpretation for Cytogenetic Testing (JAK2 V617F)
 PV is excluded if testing for the JAK2 V617F mutation is negative and the EPO level is normal or high; look into the other causes of secondary erythrocytosis.
Other causes of erythrocytosis, such as ectopic EPO production from a renal tumor, hypoxia from chronic lung disease, or cyanotic heart disease, can be excluded with low or undetectable serum EPO level and normal oxygen saturation. JAK2 V617 mutation in exon 14 is a distinguishing feature versus secondary polycythemia but is not specific to PV as it can also be present in essential thrombocytopenia and primary MF.

Management 
Patients over 60 with a history of thrombosis are at a higher risk. Intermediate risk individuals are those under 60 with high platelets (>150,000) but no history of thrombosis. Low risk characteristics include age 60, normal platelets, and no previous thrombosis.
All patients should begin treatment with phlebotomy and low-dose aspirin; current PV therapy, though not curative, can ease symptoms and extend survival.
Phlebotomy reduces blood hyperviscosity, improves platelet function, restores systemic pressures, and lowers the risk of thrombosis. If secondary PV, address the etiology: aggressive treatment of obstructive sleep apnea, COPD (especially smoking cessation), and renal disease.
Phlebotomy: Lower Hct to 45% to greatly lower the rate of serious thrombosis and cardiovascular mortality- Phlebotomies of 250 to 500 mL (1 unit—500 mL) are performed initially as frequently as every 2 to 3 days until normal Hct is obtained; this should reduce Hct by 3 percentage points. In older individuals or patients with cerebrovascular illness, reduce to 250–350 mL.
- To prevent postural hypotension in frail individuals, volume replacement should be done using saline solution.
- Cytoreductive therapy is indicated when a patient has an elevated platelet count or a high risk of thrombosis.
- Phlebotomy complications include chronic iron shortage (symptoms include pica, angular stomatitis, and glossitis), potential muscle weakness, and extremely rare dysphagia brought on by esophageal webs. Other treatments include hydration maintenance.
- Treatment for pruritus includes interferon -2b, SSRIs, H1 and H2 blockers, oatmeal baths, and - Uric acid lowering medication


First Line of Medicine
Primary treatments:
- When combined with phlebotomy, low-dose aspirin (81 mg PO) has been shown to statistically not significantly lower the incidence of fatal thrombotic events without worsening bleeding complications. People who have acquired von Willebrand disease or other contraindications shouldn't use aspirin.
- Patients with splenomegaly and hepatomegaly, as well as those who are at high risk for thrombosis (age >60 or history of thrombotic event), should consider using hydroxyurea.
Standard initial doses range from 500 to 1,500 mg PO daily, titrating to manage platelet count and Hct. Be advised that using hydroxyurea increases your risk of developing a skin ulcer, myelosuppression, and leukemic transformation (5)[A].
- For patients with refractory PV or hydroxyurea intolerance, roxolitinib is approved.
By eliminating hyperactive marrow cells, radioactive phosphorus (32P) may be able to regulate platelet count and Hgb levels.
could take up to three months before cells are affected. Take into account patients who are unable to tolerate or adhere to hydroxyurea or who have a low chance of survival because of its propensity for mutation.
- Pegylated interferon-2a is beneficial in reducing erythrocytosis, though dosage is typically restricted due to unpleasant side effects; it is typically advised for younger patients (40 years old) and women who may become pregnant. For more information on dosage and instructions, consult a hematologist or oncologist.
Symptomatic or adjectival
- Allopurinol 300 mg PO daily for lowering uric acid
- H2 receptor blockers or antacids for GI hyperacidity; cimetidine is also used for pruritus. - Cyproheptadine 4 to 16 mg PO daily as needed for pruritus.
- Low-dose aspirin is also used to treat erythromelalgia and pruritus. Paroxetine and fluoxetine are SSRIs that have shown some promise in reducing pruritus. Pruritus might be alleviated by ultraviolet light therapy.

Next Line
Chlorambucil or busulfan are viable options for older individuals with advanced PV who are resistive to or intolerable of other medications such hydroxyurea and interferon, however a substantial rate of transformation was shown with busulfan at 2 to 4 mg daily.


Referral 

sending a patient to a hematologist for help with diagnosis and treatment 

Alternative Therapies 
Osteopathic manipulative treatment to increase blood flow

Admission DVT prevention should be administered.

Patient Follow-Up Monitoring
To keep Hct at the desired level, often monitor it and phlebotomize as necessary.


Avoid iron supplements as a permissive chronic condition of iron shortage can aid limit blood production. Diet: Avoid high-sodium diets as they can increase fluid retention.

Modification of Lifestyle 

Exercise your ankles and legs to prevent blood clots. Continued education about potential consequences. Seeking treatment as soon as symptoms alter or become more severe. 

PV has a poor prognosis but can be managed with medication.
With treatment, survival is more than 15 years.
Patients have a higher chance of developing malignant transformation and postpolycythemic MF (PPMF).

Complications 
Vascular thrombosis (the leading cause of death) (20%), splenomegaly or hepatomegaly, Budd-Chiari syndrome, acute leukemia (5%)  Conversion to MF (10%) Hemorrhage, peptic ulcer, uric acid stones, secondary gout, increased risk of surgical complications, and mortality. Before undergoing any elective surgery, weigh the risks and advantages and guarantee the best possible disorder control.

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