Polycythemia And Ploycythemia Vera  In Children

There are two forms of polycythemia in the post-neonatal period. Non-clonal polycythemia, which is typically a complication of other systemic illnesses; Clonal polycythemia, which is extremely rare
Polycythemia: Polycythemia is the term for an excess of red blood cells.

Neonatal Polycythemia

Neonate with venous hematocrit ≥65%;  said to be present if central venous blood Hb or Hct is >+2SD above mean for gestational age & postnatal age conversely,  Venous Hb ≥22g/dL 

Polycythemia is characterized by a rise in viscosity if the mass of red blood cells (RBCs) beyond a particular threshold. All of the clinical symptoms are actually caused by a hyperviscosity, or increase in viscosity. 

Aiims Protocol 2019

According to this definition, hyperviscosity is viscosity more than 14.6 centipoises at a shear rate of 11.5 s/s. RBC mass is greater by nature; RBC membrane is different in neonates,that is less pliable Dehydration
Low Oxygen significantly increase the impact of somewhat excessive viscosity

Key Points To Note

When examining a newborn for polycythemia: Polycythemia should be diagnosed using central Hb, venous blood rather than capillary (or heel stick) blood. Venous hematocrit is more significant and reliable than capillary hematocrit since the latter is often 10-15% higher than the former due to the deceptively high hematocrit result that capillary or heel stick blood might provide.

Hematocrit physiological changes: The hematocrit reaches a maximum of 71% at 2-3 hours of age. Because there is some fluid transudation from the intravascular space to the exterior during the first two hours of life, some people routinely develop a hematocrit of 71%. The hematocrit gradually decreases and, by the sixth hour of life, it has reached 68%. In the majority of term neonates, it stabilizes the level below 65% of the normal value within 12 to 24 hours.

Relationship Between Hematocrit And Viscosity

Up to a hematocrit of 65%, the connection between hematocrit and viscosity is linear. The viscosity increases disproportionately more with rising hematocrit at a hematocrit value > 65%. The value can be logarithmic at times. therefore, it is crucial to use the 65% cutoff to clinically diagnose polycythemia in patients because even a 1-2% rise in hematocrit above 65% may result in a viscosity change that is many times greater.

Epidemiology Of Neonatal Polycythemia

 It affects 1.5% to 4% of live newborns.  Greater prevalence or risk variables were seen in large for gestational age (LGA), small for gestational age (or) intrauterine growth restriction (SGA/IUGR). Babies born at higher elevations frequently have it. One risk factor is maternal smoking.  The hematocrit value of vaginal delivery is observed to be somewhat greater than that of LSCS.  Prolonged chord cutting.

Etiology

Epidemiology Of Neonatal Polycythemia

There are two types of reasons for neonatal polycythaemia:
1. The location of increased RBC production.
2. The newborn is simply getting more red blood cells; he is not creating more of them.

Also Read: Transfusion In Children">Platelet Transfusion In Children

Clinical Features Of Neonatal Polycythemia

The characteristics of polycythemia are not notable; up to 50% of cases are asymptomatic and 50% symptomatic. Minithrombi and microthrombi will form; essentially, there will be greater viscosity and tiny blood vessels. Due to hypoxia-induced tissue damage, sepsis and hypoxia will coexist in the observed characteristics. CNS: Seizures, jitters, lethargy, irritability, and early hypotonia.

Late-onset brain defects: reduced development scores, motor impairments. These kids will have poorer IQ scores later in life.
Hypoglycemia, hypocalcemia, and newborn jaundice (NNJ) are examples of metabolic characteristics. Tachycardia, tachypnea, respiratory distress, cyanosis, and plethora are examples of cardio-pulmonary characteristics; pulmonary plethora and cardiomegaly are seen on CXR. 

Pluria is not the same as pulmonary pluria. Pulmonary plethora will increase pulmonary vascular marking.  A infant with plethora will have a reddish-suffused face, similar to tomato skin. Among the symptoms of the GIT include poor eating, vomiting, and NEC. The onset of NEC is not always painful; often, there is distension of the abdomen and some feeding tolerance. It is typically reversible if you stop them, but because it progresses, necrotizing enterocolitis is the common outcome. 

Renal venal thrombosis (RVT) and oliguria, which can lead to renal cauterization, are two examples of renal involvement. A small percentage of indolent individuals will have hematological characteristics, such as moderate thrombocytopenia. Male testicular infarction, peripheral gangrene, and priapism are examples of incidental characteristics.

Clinical Features Of Neonatal Polycythemia 

Screening Protocol

Whom to screen?

Examine the infants who are either LGA or SGA.  Children whose mother has diabetes. Monochoronic twins, particularly the larger twin; infants exhibiting signs or physical characteristics suggestive of IUGR
For instance, if the head circumference (HC) is 3.4–5 cm greater than the chest circumference 

When to screen?

At two hours of life, the initial screening is conducted.  If results are abnormal, repeat after 6, 12, 24, and 48 hours.

How to screen?

Centrifuge venous blood in capillaries that have been heparinized. The blood will then revolve at 10,000–15,000 rpm for three to five minutes.
Capillary blood can also be utilized for screening if venous blood cannot be obtained. The use of capillary blood is permissible, but it is insufficient to initiate therapy on its own. Abnormal values will be replicated by measuring the venous hematocrit.

Point to note  

Therefore, automated hematology analyzers give lower and more accurate values than microcentrifuges. Automated hematology analyzers are superior than micro centrifuges. For analysis, venous blood is always preferable than capillary blood.

Management Algorithm

Rule out and treat dehydration in neonates with low venous hematocrits (Hct ≥ 65%). Dehydration is one of the most frequent causes of polycythemia in children. If the youngster appears to be dehydrated, a clinical and investigative evaluation will be conducted. It is usually advisable to screen for hemoconcentration, total leukocyte count, and other related parameters if the kid exhibits clinical characteristics such as a sunken anterior fontanelle, loose rugosities, and reduced urinary output. 

The therapy of dehydration entails providing the kid with sufficient fluids, either orally or parenterally. It is established if the child is asymptomatic or symptomatic if dehydration is checked out and the youngster has real polycythemia. Check this person's hematocrit levels if there are no symptoms. If the percentage is 65–69%, then just one person will keep an eye on the child.  There will be another test in a day or two. The infant will get hydration if the HCT is between 70 and 74 percent and there are no symptoms. 

It has been discovered that hydration therapy works well for managing these kids. Extra fluids can be administered parenterally or orally as part of hydration therapy, which consists of 20 milliliters per kilogram each day.  By giving the infant extra breast milk and fluids orally through a nasogastric tube, the child's feeding is boosted. If the parenteral route is used, milk cannot be administered; this will depend on the child's condition and level of stability.

Ringer's lactate can also be administered non-parenterally in the event that regular saline is not available. Conduct a partial exchange transfusion (PET) if the hemoglobin concentration (HCT) is greater than 75%, regardless of whether the patient is experiencing symptoms or not.

Pet- Partial Exchange Transfusion

 It is comparable to an exchange transfusion, which is given for infant jaundice. PET is fluid that replaces blood. In PET, a portion of the blood is extracted and replaced with regular saline in order to get the hematocrit down below the desired level of 55%. Although research has indicated that some individuals have utilized 5% albumin, colloids, or ringer lactate, normal saline is the most widely used amount in all protocols used in India. 

The volume to be exchanged can be calculated using the formula V=Blood vol.×(Observed HCT-Targets HCT).noted HC.
Term = 80–90 ml/kg
90–100 ml/kg is the preterm.
It is 80–90 ml/kg for term newborns; the exact amount varies on body weight.  In premature infants, the ratio is 90–100 ml/kg. If a preterm infant with polycythemia has an HCT value of 75%, you must ascertain whether the child exhibits symptoms or none at all. 

There will be a partial exchange if the HCT is 75%. The following calculation determines the blood volume to be used: If the child weighs 3 kg, then the blood volume of the infant will be calculated by taking the middle amount, or 85% multiplied by 3. Because the observed HCt was 75% and the target HCt was 55%, the result was 75-55%, or 20%. This indicates a dividend.

Rule of Thumb

The AIIMS states that the standard blood exchange volume is 20 milliliters per kilogram. Aim for 20 ml per kg, however other books offer 15–20 ml.

Peripheral Versus Umbilical Route For Pet

There are various methods for performing exchange transfusions. One option is to: Adopt the parenteral route exclusively. A tiny 5- to 10-ml portion of catheter, one cannula in the vein, and one in the artery can remove blood from one side and provide fluid from the other, completing a peripheral route. The utilization of umbilical vessels is the second method, known as the umbilical route. The third method involves using two vessels: one for injection or extraction, and the other for extraction or injection via an umbilical catheter.

The peripheral route is recommended above the umbilical route in most clinical situations, following AIIMS policy, because if using the umbilical route therefore, in polycythemia patients receiving PET, the peripheral route is favored over the umbilical route because to the increased risk of the patient having necrotizing enterocolitis (NEC) and the kid acquiring multiple infections. 

Partial Exchange Transfusion For Polycythemia: What Is The Evidence?

According to a Cochrane review (2010), there is no difference in infant mortality when utilizing PET (one research, RR 5.23, RR5.23, 95% CL 0.66, 41.26). The developmental delay is the same in four low-quality studies (RR 1.45, 95%CL 0.83). Two trials found that infants receiving PET had a higher incidence of NEC (RR 11.18, 95%C 11.49, 83.64).
There is no variation in the short-term side effects, such as thrombocytopenia (one research) and hypoglycemia (two studies).
Despite the strong evidence, the children will be deprived of certain measures that will keep them from developing hypoxia if PET is not administered. The majority of surviving newborns were not evaluated for developmental outcomes, and the Cochrane review's low-quality studies made it difficult to determine the actual risks and benefits of PET. It is generally agreed upon that not all children with polycythemia will need this type of testing. Children will only require PET if they have severe symptoms or a value of about 75%.

Recommendation

The AIIMS protocol recommends restricting PET in symptomatic newborns with HCt of >65% and in asymptomatic neonates with HCt of >75% due to the uncertainty surrounding the long-term effects.

Q. A term neonate at 2 hours of life was found to have a HCT of 72% on capillary blood centrifugation; what is the next step in management?

Ans. As capillary blood needs to be checked by centrifugation rather than an automated analyzer, the therapy is to repeat the test on venous blood. However, this should not be the basis for starting the treatment.
Repeat the test on venous blood if the patient exhibits abnormal capillary blood hematocrit readings but no symptoms are reported. 

An automated analyzer ought to be used to analyze it preferentially.
It's okay if it's not accessible, but venous blood should be used instead.
It is referred to as real newborn polycythemia and will be treated according to protocol if the Hct ≥ 65%. Rerunning the test on venous blood is the next step in the management process.

Definition Of Polycythemia In Post Neonatal Age 

There are several definitions put out in this contentious field.  Increased red blood cell mass (RBC mass) more than 30 milliliters per kilogram of body weight, assuming dehydration is not the cause commonly used Hb >17 g/dl or HCT ≥50% throughout childhood.  Postpubertal children; RBC Mass > 25% above mean; or, if dehydration is checked out, Hb >18.5g% in men and Hb >16.5g% in females.

Major Causes Of Polycythemia

Relative Erythrocytosis-hemoconcentration secondary to dehydration, diuretics, ethanol abuse, androgens, or tobacco abuse.

Chuvash Polycythemia

The von Hippel- Lindau gene (VHL), a negative regulator of hypoxia sensing, is homozygously mutated in Chuvash polycythemia, a hypoxia-sensing illness. This mutation is found globally and is indigenous to the Chuvash population of Russia, yet it originated from a single ancient occurrence. 

Indicates AR inheritance. Even in situations where oxygen levels are normal, the condition causes a rise in the hypoxia inducible factors HIF-1 and HIF-2 as well as an elevation of the hypoxic response. Consequently, elevated levels of EPO-producing polycythemia are observed. 

Approach To Polycythemia

Polycythemia Vera (PV)

More often observed in adults, it is an acquired clonal myeloproliferative condition that is uncommon in children. Clonal denotes the multiplication of single lines. While erythrocytosis, or an increase in red blood cell mass, is the main symptom, many patients also experience thrombocytosis and leukocytosis. When it comes to adults, JAK-2 gene mutations are the most frequent causes overall. Thus, the JAK-2 gene is experiencing a rise in mutations.

Just 30% of children have mutations in the JAK-2 gene, compared to almost 90% of adults. Mutations in the calreticulin or TPO receptor gene are present in young infants without involvement in the JAK-2 gene. These mutations arise from improper functioning and indirectly cause erythrocytosis proliferation as well as stimulation of the EPO receptors, which in turn activates the erythroid series which occurs due to abnormal functioning due to mutations. Serum EPO levels are either normal or low, and the patients' erythropoietin (EPO) receptors were shown to be normal.

Clinical Features

These are older children who will develop headache, tinnitus, peripheral gangrene, priapism, and even stroke-like syndromes as a result of increased RBC mass and hyperviscosity.  Additionally, hepatosplenomegaly (HSM), which is present in more than 60% of cases, is discovered in many of these patients. 

There will also be thrombocytosis. They will have abnormal bleeding or thrombosis if thrombocytosis is present. As a result, paradoxical thrombosis or hemorrhage can both have. When it comes to granulocytosis, they will discover that a portion of these people can experience severe or refractory pruritus, which could keep them awake at night because of histamine release.

Management

The RBC count must be maintained on the lower side for managerial purposes. As a result, monthly recurring phlebotomy is first required; after the RBCs have stabilized, this will eventually change to every three to four months. These recommendations are based on adult guidelines.
When it comes to children, personalized therapy is necessary. There will be secondary supportive therapy provided. 

These patients have an increased risk of thrombosis when receiving secondary supportive therapy. As a result, it is advised that children take low-dose aspirin or other antiplatelet medications to reduce their risk of thrombosis. For adults, the rules are different, though. Antiplatelets should not be used in adults. Aside from any noticeable improvement, there are occasions when it can have unintended consequences.
Furthermore, medications such as hydroxyurea, interferon alpha, or anagrelide may be used to severe individuals if there is refractory pruritus or an inadequate response to phlebotomy. There is no polycythemia in the study conducted on children, although rare diseases are more prevalent in adults. Leukemia can advance to adulthood frequently, but children are less likely than adults to get this type of disease.

New Drug In PV

A novel treatment for polycythemia vera  JAK-2 inhibitor, such as rufinib. There is no proof that youngsters are using it, despite the fact that it is available and approved for use in adults. 

Fact To Remember

Every 1,000 meters (3,300 feet) of elevation gain causes the hemoglobin level to rise by about 4%. Hemoglobin M disease is an autosomal dominant condition that produces methemoglobinemia and can result in polycythemia. Cyanosis and polycythemia can be brought on by congenital methemoglobinemia, which is caused by an autosomal recessive cytochrome b5 reductase deficiency. 

Also Read: Marfan Syndrome : Signs, Diagnosis, Management and Prognosis

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