X-linked thrombocytopenia, also referred to as XLT or thrombocytopenia 1, is an inherited clotting disorder that primarily affects males. It is a ''WAS''-related disorder, meaning it is caused by a mutation in the

Wiskott–Aldrich syndrome Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczem ...

(''WAS'') gene, which is located on the short arm of the

X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...

. ''WAS''-related disorders include Wiskott–Aldrich syndrome, XLT, and X-linked congenital

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

(XLN). Of the ''WAS''-related disorders, X-linked thrombocytopenia is considered to be the milder

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

. Between 1 and 10 per million males worldwide are affected with this disorder. Females may be affected with this disorder but this is very rare since females have two X chromosomes and are therefore typically carriers of the mutation.

Symptoms and signs

X-linked thrombocytopenia is typically diagnosed in infancy. The disease presents as a bleeding disorder with easy bruising, mucosal bleeding, such as nosebleeds, and mild to severe anemia.

Anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

is a condition in which there is an insufficient number of red blood cells to carry adequate levels of oxygen to the body's tissues. X-linked thrombocytopenia is considered to be the milder phenotype of the ''WAS''-related disorders. As age increases, the severity of symptoms tends to decrease. However, individuals with X-linked thrombocytopenia have an increased risk for life-threatening brain hemorrhages and spontaneous bleeding.

Causes

X-linked thrombocytopenia is inherited on the

. Females that are carriers will have a 50% chance of passing the ''WAS'' gene mutation on to their male offspring. Female offspring also have a 50% chance of receiving the mutated gene from their mothers and are considered carriers in that event. Males with X-linked thrombocytopenia will not pass the condition to their sons since they pass their Y chromosome on to any male offspring. However, any daughters males with this condition have will be carriers.

Mechanism

X-linked thrombocytopenia primarily affects the circulatory system, specifically the

platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

in the blood. Platelets are cell fragments in the blood that aid in clotting. Platelets are produced in the

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

. Normal platelet counts range from 150,000 to 450,000 platelets per µL of blood. Individuals with XLT usually have drastically reduced platelet counts, typically less than 70,000 platelets per µL of blood. Not only are there fewer platelets circulating, but individuals with XLT also have smaller platelets. Fewer and smaller platelets causes the efficacy of the clotting mechanism in the body to be seriously compromised, which can lead to bruising and bleeding. X-linked thrombocytopenia is caused by a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

of the ''WAS'' gene. This mutation causes the decreased, absent, or altered Wiskott–Aldrich syndrome protein (WASp). Normal WASp is involved in relaying signals from the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

to the actin

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

. If WASp is decreased, absent, or altered, then the

hematopoietic Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...

cells it is found in will show signaling and cytoskeleton abnormalities. This form of thrombocytopenia is inherited on X chromosome, thus individuals with this disorder are typically males. In regards to the sex chromosomes, males have one X chromosome and one

Y chromosome The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abse ...

while females have two X chromosomes. Because males only have one X chromosome, if they receive an X chromosome with a ''WAS'' gene mutation from their mother, then they will show phenotype of the condition. Females can be carriers for this disorder, which means that they have one normal X chromosome and one X chromosome with the ''WAS'' gene mutation. Females that are carriers do not show any signs or symptoms of X-linked thrombocytopenia. Males with X-linked thrombocytopenia are also susceptible to severe infections, bleeding,

autoimmune diseases An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

and malignancies.

Diagnosis

Aside from observing the symptoms characteristic of X-linked thrombocytopenia in infancy (easy bruising, mild anemia, mucosal bleeding), molecular genetic testing would be done to confirm the diagnosis. Furthermore,

flow cytometry Flow cytometry (FC) is a technique used to detect and measure physical and chemical characteristics of a population of cells or particles. In this process, a sample containing cells or particles is suspended in a fluid and injected into the flo ...

or western blotting would be used to test for decreased or absent amounts of WASp. Family history would also assist in diagnosis, with specific attention to maternally related males with ''WAS''-related disorders. Because ''WAS''-related disorders are phenotypically similar, it is important to confirm the absence of the diagnostic criteria for Wiskoff-Aldrich syndrome at the outset. These diagnostic criteria include

eczema Dermatitis is inflammation of the Human skin, skin, typically characterized by itchiness, erythema, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become lichenification, thick ...

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...

, autoimmune disorder, recurrent bacterial or viral infections, family history of maternally related males with a ''WAS''-related disorder, and absent or decreased ''WASp''. X-linked congenital neutropenia can be diagnostically distinguished from XLT with persistent

, arrested development of the bone marrow, and normal ''WASp'' expression.

Treatment

Treatment for individuals with X-linked thrombocytopenia is typically focused on managing symptoms of the disorder. Splenectomy has been shown to improve platelet counts but also significantly increases the risk of life-threatening infections for patients with XLT. Therefore, these individuals must take antibiotics for the rest of their life to avoid fatal

bacteremia Bloodstream infections (BSIs), which include bacteremias when the infections are bacterial and fungemias when the infections are fungal, are infections present in the blood. Blood is normally a sterile environment, so the detection of microb ...

. In the event of significant bleeding, platelet transfusions should be administered. Circumcision should be avoided for infant males with XLT due to the risk of bleeding and infection. Regular follow ups to track blood counts should be utilized as well as confirming that any medications, over the counter or prescription, will not interfere with platelet functioning.

Prognosis

Recent studies have found that the life expectancy of males with XLT is not significantly affected.Albert MH, Bittner TC, Nonoyama S, Notarangelo LD, Burns S, Imai K, Espanol T, Fasth A, Pellier I, Strauss G, Morio T, Gathmann B, Noordzij JG, Fillat C, Hoenig M, Nathrath M, Meindl A, Pagel P, Wintergerst U, Fischer A, Thrasher AJ, Belohradsky BH, Ochs HD. X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options. Blood. 2010;115:3231–8. Individuals with XLT typically experience milder symptoms than those with other ''WAS''-related disorders. For this reason, the long term prognosis for individuals with XLT is generally positive as long as symptoms are managed appropriately. Enhanced treatment methods in the past two decades have significantly improved the prognosis as well.

Recent research

Recent research has suggested that hematopoietic stem cell transplantation may be a treatment option for patients with XLT despite associated risks. Other studies have shown that treatment with

corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involve ...

or intravenous

immunoglobulin An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

in any dose or duration may have a beneficial impact on platelet counts, although transiently.Zhang, X., et al. " linical characteristics and treatment responses of X-linked thrombocytopenia" Zhonghua er ke za zhi. Chinese journal of pediatrics 52.12 (2014): 890-895. Furthermore, research has shown that splenectomy may not be a good treatment option for patients with XLT as it increases the risk of severe infections. This same research showed that patients with XLT have a high overall survival rate but they are at risk for severe life-threatening complications associated with this disorder, such as serious bleeding events and malignancies.

References

External links

NCBI GeneReviews WAS-Related Disorders

Genetics Home Reference WAS gene

Genetic Testing Registry X-linked Thrombocytopenia

Genetics Home Reference X-linked Thrombocytopenia
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