Hereditary Pyropoikilocytosis

Hereditary pyropoikilocytosis (HPP) is a disease emanating from a defect in spectrin, which is the major peripheral protein of the red blood cell (RBC) membrane. This blood disorder is characterized by an RBC morphology similar to that seen in patients suffering from extensive burns—hence the term pyropoikilocytes.

HPP is considered a subtype of the more common disorder hereditary elliptocytosis (HE). HPP is characterized by an abnormality in both horizontal (spectrin self association defect) and vertical (spectrin deficiency) RBC membrane protein interaction. This results in severe hemolytic anemia as the RBC's lipid membrane destabilizes and loses its abilty to withstand intravascular shear stress.

Hereditary pyropoikilocytosis (HPP) is subtype of hereditary elliptocytosis (HE), a red blood cell (RBC) membrane disorder that results from mutations in the genes encoding α-spectrin (SPTA1), β-spectrin (SPTB), or protein 4.1R (EPB41). HE is caused by monoallelic (heterozygous) mutations and inherited in an autosomal dominant fashion, while HPP has an autosomal recessive inheritance and is typically caused by biallelic (homozygous or compound heterozygous) mutations.[1]

Hereditary pyropoikilocytosis (HPP) is a rare cause of severe hemolytic anemia. Up to a third of family members of patients with HPP have hereditary elliptocytosis (HE).

HPP is mostly observed in people of African descent, but it has been documented in people of European and Arab descent. It has no gender predominance. The disorder is usually discovered in infancy or early childhood when the affected person presents with severe hemolytic anemia. These patients can present with classic HE later in life.

Prognosis is related to the number of transfusions needed to maintain adequate hemoglobin levels for a growing child and the ability to treat or to prevent life-threatening infections after splenectomy. Most complications are related to extended severe anemia with multiple resultant transfusions and iron toxicity to major organs. Complications similar to those of the more common disorder hereditary spherocytosis (HS) are generally related to chronic hemolysis and include the following:

• Gallstones
• Hemolytic crisis
• Aplastic crisis

Patients who have undergone splenectomy are susceptible to infection with encapsulated organisms, but such infections are rare in patients who have been immunized against pneumococcus, Haemophilus influenzae, and meningococcus.

For patient education information, see Blood Transfusion. Discuss with the patient's parents the possibility that they could bear another child with the same disease.

Hereditary pyropoikilocytosis (HPP) is considered the most severe type of hereditary elliptocytosis (HE) and manifests during infancy. HP is generally recognized when an infant or young child presents with a transfusion-dependent hemolytic anemia. The family history typically includes nonhemolytic hereditary elliptocytosis in a parent or sibling. The other parent likely has a previously undiagnosed spectrin deficiency. Most patients are of African origin, though cases have been reported in people of Arabian or Caucasian descent.

Physical examination is remarkable for signs of anemia. Prolonged neonatal jaundice has been reported.[2, 3, 4]  Signs of extramedullary hematopoiesis such as frontal bossing and splenomegaly could be appreciated. Affected children can have growth retardation. The chronic hemolytic disease can be complicated by gallbladder disease. 

The diagnosis of HPP relies on identifying abnormal red blood cell (RBC) morphology on peripheral blood smear and identifying characteristic membrane biomechanical properties using osmotic gradient ektacytometry.[5, 6] The blood smear is characterized by elliptocytes, as seen in hereditary elliptocytosis, together with the following:

• Microcytic red cells
• Polychromasia
• Bizarrely shaped cells with fragmentation, poikilocytes, pyknocytes, and microspherocytes

The increasingly recognized genetic heterogeneity of RBC membrane disorders underlines the problem of a very complex differential diagnosis. Expanding from limited studies of candidate genes to wider panels of genes has become possible with targeted next-generation sequencing (t-NGS). Recent studies have established t-NGS as a comprehensive and invaluable diagnostic tool that can provide a correct diagnosis, allowing clinicians to proceed with careful management of these patients.[7]

One of the most important aspects of the use of t-NGS gene panels in clinical practice is their ability to be easily upgradable in view of novel discoveries. Despite their wide use in clinical practice, the major drawback of current NGS applications is the difficulty in determining the pathogenicity of the numerous identified variants. One of the ways to overcome this limitation is the simultaneous evaluation of all family members, which helps establish the inheritance pattern of the identified variants and thus to delineate their pathogenetic role, although functional characterizations are often necessary.[1]

The International Council for Standardization in Haematology (ICSH) has established guidelines for the diagnosis of nonimmune hereditary red cell membrane disorders, including hereditary pyropoikilocytosis (HPP). The guidelines note that diagnosis can often be made by reviewing the patient's clinical/family history, blood count results, reticulocyte count, red cell morphology, and chemistry results, together with tests available through hematology laboratories.[5]

A complete blood count and a peripheral blood smear are the most important studies to obtain when testing for HPP.  The peripheral blood smear of a patient with HPP demonstrates bizarre forms, anisocytosis, fragments, micropoikilocytosis, microspherocytosis, and budding red blood cells.[6] See the image below.

Peripheral smear that shows evidence of hereditary pyropoikilocytosis.

A reticulocyte count and, possibly, other markers of hemolysis may be of use in these cases. Reticulocytosis should occur, depending on how well the patient's bone marrow is able to respond. The mean corpuscular volume (MCV), reported in femtoliters, may be as low as 25-55 fL.

Further testing through a hematology laboratory can provide further confirmation of the diagnosis. Results in hereditary pyropoikilocytosis include the following[5] :

• Increased osmotic fragility
• Decreased acid glycerol lysis time
• Marked decrease in the maximum value of the deformability index (DI _max), with a distorted trapezoidal profile, on osmotic gradient ektacytometry
• Markedly decreased fluorescence on the eosin-5′-maleimide (EMA) binding test

In addition, thermal sensitivity testing shows fragmentation of the red blood cells at temperatures as low as 45°C.

Molecular analysis of membrane protein genes can be performed, but generally does not add extra information in cases where the patient's family is already known to have the red cell disorder. However, DNA sequencing may be warranted in some cases (eg, cases of suspected de novo mutation).[5]

Ektacytometry

Osmotic gradient ektacytometry has been the reference technique for diagnosis of RBC membrane disorders, but its limited availability has severely restricted its use.[8] An ektacytometer is a laser-diffraction viscometer in which deformability is measured as a continuous function of the osmolality of the suspending medium. 

On ektacytomettry, the Omin point is the osmolality at which the minimum deformability index is reached and is related to the surface area–to-volume ratio of the cell. The Hyper point is the osmolality at which the minimum deformability index reaches half of its maximum value. The Hyper point is related to the internal viscosity of the cell and to its mechanical properties.[9]

In hereditary elliptocytosis, ektacytometry shows decreased maximum deformability characterized by a trapezoidal curve with normal Omin and Hyper points. In hereditary pyropoikilocytosis, the maximum deformability is decreased and the Omin and Hyper points are shifted towards the left.[1]

Evaluate the ratio of spectrin to band 3 to determine the spectrin level so that this entity can be differentiated from homozygous hemolytic elliptocytosis.

Ultrasound of the biliary tract may show gallstones, especially in patients with symptomatic cholelithiasis. If ultrasonography is nondiagnostic, a nuclear scan can be done to work up gallbladder disease.

In the setting of  severe hemolytic anemia with hereditary pyropoikilocytosis, transfusion of packed red blood cells is necessary. Folate supplementation is also necessary in chronic hemolytic disease. In the acute care setting, supportive measures (eg, intravenous fluids, oxygen, monitoring of blood counts) are provided according to the needs of the individual patient.

No specific medications are used to treat patients with hereditary pyropoikilocytosis. The need for treatment with medications is patient-specific and based on individual complications. Folic acid is often used to prevent folic acid deficiency, which may occur as a result of increased erythropoiesis. Iron chelation therapy may be necessary in patients who develop significant iron overload from red blood cell transfusions.

The spleen is the primary site of red cell sequestration and contribute to the severity of anemia in patients with HPP. Splenectomy has been advocated by some experts for severe hemolytic anemia refractory to or complicated by chronic blood trasnfusion. Splenectomy has been reported to improve the severity of anemia, symptoms and incidence of gallstones.[10]

Provide routine outpatient care and monitor hemoglobin levels if symptoms occur. Maintain high suspicion for early development of gallbladder disease. Iron chelation therapy may be required to prevent irreversible end-organ damage due to transfusion-induced hemosiderosis. Monitor the number of transfusions performed and the iron status of the patient to determine if and when this therapy is needed.

Routine vaccination against pneumococcal and meningococcal disease and Haemophilus influenzae prior to splenectomy is important in preventing morbidity from these pathogens.

No specific medications are used to treat hereditary pyropoikilocytosis. Other related conditions can arise that may require treatment with medications specific to the situation, but medications do not affect the underlying disorder. Folic acid is often used because of the relative or absolute folate deficiency that often occurs in patients with chronic hemolysis and increased erythropoiesis by the bone marrow.

Class Summary

A folate deficiency can develop because of the high turnover rate in the erythroid line and subsequent use of substrate. Replacement is often necessary. This is easily accomplished with an oral dose of 1 mg/d.

Folate (Folvite)

Important cofactor for enzymes used in production of red blood cells. A folate deficiency can develop because of the high turnover rate in the erythroid line and subsequent use of substrate.