Overview

Blood is arguably one of the most important components of our body. Blood circulation keeps us alive, helps to remove waste products, and provides our cells with nutrients. Blood also contains many other components that help protect us from illness, transport molecules, and regulate temperature.

One of the lesser-known abilities of blood is its capacity to clot. After a skin injury, you may notice a scab forming as part of the wound-healing process. Platelets play a key role in initiating this process. In this article, we will explore what happens when our body does not produce enough functional platelets, resulting in a condition known as familial platelet disorder.

What is familial platelet disorder with associated myeloid malignancy?

Familial platelet disorder with associated myeloid malignancy (FPD/MM) is an inherited genetic blood disorder in which individuals can experience prolonged bleeding. This can be evident with frequent nosebleeds, bleeding gums and bruising easily. The name of the disorder refers to its nature of being an inherited (familial) condition, and the lack of functional platelets in the blood, which causes excessive bleeding.

This disorder was first reported in medical literature in 1999, and in 2016, FMD/MM was added to the World Health Organisation database of blood cancers.^1,4 This disorder is very rare, with only 130 individuals reported having the disorder in medical literature.^2,5

What are the symptoms of FPD/MM?

Symptoms of this disorder mainly appear as physical characteristics and become apparent after certain activities: 

Bruises

The affected individual could have many unexplained bruises that could indicate they are afflicted with this disorder. These bruises can appear quite easily, even without a known injury. 

Excess bleeding

After brushing teeth, flossing, or dental appointments, the affected individual may have excessive bleeding around the gums. Similarly, the individuals may experience very frequent or prolonged nosebleeds or experience heavy menstrual bleeding. Around 90% of individuals with FPD/MM will experience symptoms of excess bruising and bleeding.³

Eczema

Individuals with FPD/MM may have broken, itchy, or dry patches of skin. In a study of 31 patients with FPD/MM, 29 patients showed signs of allergic diseases, including eczema, suggesting that having this disorder increases one's risk of developing these types of diseases.^2,4 

Gut issues

There have been some reports of individuals with FPD/MM experiencing gut issues. Some may have difficulty swallowing (dysphagia), acid reflux, or vomiting. In the same study of patients with a confirmed diagnosis of FPD/MM, 24 of 30 patients experienced gastrointestinal issues with acid reflux being the most common ailment.^2,4

Blood cancer

The risk of developing a type of blood cancer (also known as myeloid malignancies) can increase by 44% for those afflicted with FPD.^3,5 Therefore, FPD is frequently described as in association with myeloid malignancies (FPD/MM). Such malignancies include an increased risk of having acute myeloid leukaemia, myelodysplastic syndrome, and T-cell acute lymphoblastic leukaemia/lymphoma.⁵ 

It's important to note that FMD/MM manifests very differently between individuals. Some people may have mild bleeding, minimal bruising, and develop a blood cancer later in life, whilst others may show excessive bruising but not develop a myeloid malignancy. A family history of unusual bleeding/bruising can help with a diagnosis of FPD/MM, however, a genetic test can also help to confirm a diagnosis.

What causes the symptoms of FPD/MM?

The role of platelets in FPD/MM

Platelets, or thrombocytes, are a component of our blood that helps with blood clotting and wound healing. Platelets are derived from megakaryocyte cells in the bone marrow. Around 90% of individuals with FPD/MM have a low number of platelets in their blood (thrombocytopenia) or have abnormally shaped megakaryocyte cells.³

The reduced number of platelets or dysfunctional platelet production explains the easy bruising and excessive bleeding observed in FPD/MM.

What is the genetic basis behind FPD/MM?

Mutations in genes can disrupt the production of proteins necessary for normal body functions. In FPD/MM, mutations in the RUNX1 gene interfere with normal platelet production. Genes often encode transcription factors, which help control when and how proteins are produced. RUNX1 encodes a transcription factor that activates bone marrow stem cells, leading to the production of various blood cells, including megakaryocytes.

Normally, individuals inherit two copies of each gene, one from each parent. For those with FPD/MM, they only have one functional copy of the RUNX1 gene. The other copy of the RUNX1 gene is mutated, impairing blood cell production. The result is a low number of circulating platelets, causing the characteristic symptoms of the disorder.

What are associated myeloid malignancies?

Having FPD can increase one's risk of developing a myeloid malignancy in their lifetime by 44%, with an average onset age of 33 years.⁵ Myeloid refers to the bone marrow tissue, the site of blood cell production. A malignancy, or a tumour, describes an abnormal growth of cells that can spread around the body. Therefore, a myeloid malignancy is another way to describe the blood cancers. 

There are many types of blood cancers, depending on where the malignancy originates. Those with FPD have an increased risk of developing certain types of leukaemia, lymphoma and blastomas. The most common types are:

Acute myeloid leukaemia (AML) 

AML is one of the most common types of blood cancers and manifests from faulty myeloid cells. Myeloid cells are stem cells found in the bone marrow which eventually form into mature immune cells and red blood cells. If these stem cells are faulty, it results in less functional blood cells in the body, which can lead to bruising and bleeding, common symptoms for those with FPD/MM. 

In addition, as the bone marrow stem cells are non-functional, there are fewer immune cells circulating in the blood, which explains why allergenic and autoimmune diseases are common comorbidities seen in individuals with FPD/MM.

Myelodysplastic syndrome (MDS)

MDS describes bone marrow cells (myeloid cells) as being dysplastic or abnormally shaped. This prevents these cells from becoming mature, functioning blood cells (including platelets), which can contribute to the symptoms of FPD/MM. 

MDS can progress into AML, with a 15% risk of transformation after 3-5 years.⁶ Therefore, having regular checkups and bone marrow biopsies are very important to manage the progression of the disease.

T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL)

T-ALL is a cancer of both the bone marrow and lymphatic system, so it can be described as both a leukaemia and a lymphoma. The lymphatic system allows lymph to circulate around the body. Lymph fluid plays an important role in our immune system and is composed of many immune cells, including T-cells. 

T-cells, a type of lymphoblast, originate in the bone marrow and become mature in the lymphatic system. T-cells play a key role in recognising and activating our immune system to produce antibodies. In T-ALL, too many abnormal immature T-cells are circulating in the body. 

A faulty RUNX-1 gene could be responsible for the poor development of T-cells, therefore having FPD could increase one's risk of developing T-ALL, however, documented cases of this are very rare. 

Summary

Familial platelet disorder with associated myeloid malignancy (FPD/MM) is a rare inherited genetic disorder in which the faulty RUNX1 gene is responsible for a low number of platelets circulating in the blood. Platelets are needed for blood to clot, therefore, individuals with FPD/MM can experience frequent bleeding and bruising. 

As blood and immune cells originate in the bone marrow, individuals with FPD/MM may also develop allergic conditions and gastrointestinal symptoms. Furthermore, FPD/MM increases the risk of developing myeloid malignancies, such as acute myeloid leukaemia, myelodysplastic syndrome, and T-cell acute lymphoblastic leukaemia/lymphoma. Early diagnosis, regular health check-ups, and careful monitoring are crucial to managing the condition and improving outcomes.