Bleeding Disorders
Bleeding Disorders
At Haemophilia NI, we’re dedicated to supporting people across the UK and beyond who are living with bleeding disorders. Through our work, we raise awareness, offer support, and advocate for better care and understanding. This page shares a simple introduction to what bleeding disorders are and how they can affect day-to-day life — from managing treatment to coping with physical and emotional challenges. Whether you're newly diagnosed or supporting a loved one, you're not alone.
What are bleeding disorders?
‘Bleeding disorders’ is an umbrella term for a group of conditions that impair the blood’s ability to clot properly. These include haemophilia A and B, von Willebrand Disease (VWD), and other rare bleeding disorders (RBDs), which can present in mild, moderate, or severe forms depending on the individual.
With proper care and access to effective treatment, many individuals living with bleeding disorders can lead full, healthy lives. However, where treatment is limited or unavailable, the consequences can be serious. Uncontrolled bleeds — especially those occurring in critical areas such as the brain — can be life-threatening or lead to long-term disability if not managed appropriately.
All bleeding disorders fall under the European Union’s definition of rare diseases, meaning they affect fewer than 1 in 2,000 people. Despite this rarity, conditions like haemophilia and VWD are among the more recognised and better-managed rare conditions. Diagnostic tools and a variety of treatments are available for many of these patients, putting them ahead in comparison to other lesser-known rare diseases.
Nonetheless, challenges persist. Access to specialist care is often limited, with treatment centres concentrated in only a few locations across each country. The high cost of therapies further complicates consistent care. Across the UK and wider European region, significant disparities remain in access to treatment, resulting in unequal outcomes and quality of life for those affected.
The Clotting Process
Clotting factors are specialised proteins found in the blood that help control bleeding. When a blood vessel is damaged, its walls contract to reduce blood flow to the affected area. At the same time, platelets — small blood cells — are activated and begin to adhere to the injury site, spreading across the surface of the vessel to begin forming a barrier.
These platelets release chemical signals from small internal sacs, which draw additional platelets to the area. This process results in the formation of a platelet plug — the body’s first line of defence against bleeding.
Meanwhile, a series of complex chemical reactions — known as the coagulation cascade — takes place on the surface of the activated platelets. During this cascade, various clotting factors work together to create a fibrin clot, a mesh-like structure that stabilises the plug and halts the bleeding.
Clotting factors normally circulate through the bloodstream in an inactive state. When injury occurs, the coagulation process activates each factor in a precise sequence, ultimately resulting in clot formation. These factors are named using Roman numerals (such as Factor I or FI), although the order in which they act does not follow numerical order.
How coagulation disorders affect an individual
One of the most significant impacts of bleeding disorders on individuals is the damage they cause to joints — particularly the hips, knees, ankles, wrists, and shoulders. These joints contain a high concentration of blood vessels, making them especially vulnerable to internal bleeds.
When bleeding occurs within a joint, the synovium — the lining of the joint — attempts to absorb and clear the blood. However, iron from the blood builds up in the synovium, which is believed to cause thickening of this tissue. As the synovium thickens, it develops more blood vessels, increasing the likelihood of further bleeding. Over time, this cycle can lead to a condition similar to arthritis.
Repeated joint bleeds cause progressive damage. Eventually, the joint may deteriorate to the point where movement is severely limited or even lost entirely. This not only results in long-term disability but can also be extremely painful. If left untreated or poorly managed, joint bleeds can take several weeks to heal, potentially requiring prolonged hospital stays and preventing individuals from participating in education, employment, or social activities.
For this reason, preventing joint bleeds is considered more effective than simply treating them once they occur. Currently, prophylactic treatment — regular administration of clotting factor to prevent bleeding — is regarded as the most effective strategy. While this approach is sometimes seen as costly, in the long term it may actually be more efficient.
Rather than waiting for a bleed to occur and then using large doses of clotting factor to manage it, individuals on prophylaxis often end up using a comparable — or even smaller — amount of factor over the course of a year. Investing in preventative care not only helps preserve joint function but also improves overall quality of life for those living with bleeding disorders.
Factor I (Fibrinogen) Deficiency
Rare inherited coagulation disorders characterised by bleeding symptoms ranging from mild to severe resulting from reduced quantity and/or quality of circulating fibrinogen. Afibrinogenemia (complete absence of fibrinogen) and hypofibrinogenemia (reduced plasma fibrinogen concentration) correspond to quantitative anomalies of fibrinogen while dysfibrinogenemia corresponds to a functional anomaly of fibrinogen. Hypo- and dysfibrinogenemia may be frequently combined (hypodysfibrinogenemia).
Estimated
Prevalence 1-9/1,000,000
Affected Factor Factor I (1)
Afibrinogenemia
Prevalence 1/1,000,000
Hypofibrinogenemia
Prevalence 1-9/1,000,000
Dysfibrinogenemia
Prevalence 1-9/1,000,000
Fibrinogen Deficiency: Overview
Epidemiology
Afibrinogenaemia is an extremely rare bleeding disorder, with an estimated prevalence of 1 in 1,000,000 individuals. In contrast, hypofibrinogenaemia and dysfibrinogenaemia occur more frequently. Both males and females are equally affected. While fibrinogen deficiency can be identified at any age, afibrinogenaemia typically presents in early childhood — often during the neonatal period.
Clinical Presentation
Individuals with afibrinogenaemia may experience a range of symptoms, with common signs including bleeding from the umbilical cord at birth, nosebleeds (epistaxis), joint bleeds (haemarthrosis), gastrointestinal bleeding, excessive menstrual bleeding (menorrhagia), and bleeding following injury or surgery. Rarely, life-threatening intracranial haemorrhage may occur. Recurrent spontaneous miscarriages are also reported among women with this condition.
Those with hypofibrinogenaemia tend to experience milder and less frequent bleeding episodes, usually triggered by trauma or surgical procedures. Most individuals with dysfibrinogenaemia are asymptomatic — approximately 60% show no symptoms — while others may suffer from bleeding (28%) or, less commonly, thrombotic events (20%).
Genetic Causes
Congenital fibrinogen deficiencies arise from mutations in one of three genes: FGA, FGB, or FGG. Afibrinogenaemia follows an autosomal recessive inheritance pattern, while both hypofibrinogenaemia and dysfibrinogenaemia are typically inherited in an autosomal dominant manner.
Diagnosis
Diagnosis involves a combination of blood clotting tests. Prolonged activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time, and reptilase time are commonly observed. Fibrinogen levels are assessed through both functional (Clauss method) and immunological assays to determine the extent and nature of the deficiency.
Differential Diagnosis
Fibrinogen deficiency must be distinguished from other inherited clotting disorders, including deficiencies in clotting Factors II, V, VII, VIII, IX, X, XI, and XIII. Acquired fibrinogen deficiencies, such as those resulting from disseminated intravascular coagulation or liver failure, should also be considered. In cases presenting with thrombosis, other hereditary or acquired thrombophilias should be ruled out, including antithrombin deficiency, protein C or S deficiency, Factor V Leiden, lupus anticoagulant, and prothrombin G20210A mutation.
Antenatal Testing
Prenatal diagnosis for afibrinogenaemia is possible if the specific mutations have previously been identified within the family. Genetic counselling and testing can assist prospective parents in understanding the risk of transmission.
Management and Treatment
Fibrinogen deficiency is typically managed with fibrinogen concentrates, which effectively control bleeding episodes. If unavailable, fresh frozen plasma may be used. In women with afibrinogenaemia, prophylactic treatment early in pregnancy can help prevent recurrent miscarriages.
Prognosis
With early diagnosis and proper treatment, the outlook for afibrinogenaemia is generally good, despite the risk of serious bleeds such as intracranial haemorrhage. Individuals with hypo- or dysfibrinogenaemia usually have mild symptoms and a favourable prognosis.
Factor II (Prothrombin) Deficiency
A rare inherited bleeding disorder due to reduced activity of factor II (FII, prothrombin) and characterised by mucocutaneous and soft tissue bleeding symptoms
Estimated
Prevalence <1/1,000,00
Affected Factor Factor II (2)
Congenital Factor II Deficiency
Prevalence 1/1,000,000
Epidemiology
Factor II deficiency is the most rare coagulation factor deficiency. Prevalence of homozygous forms is estimated at 1/2,000,000. Both sexes are equally affected.
Clinical description
Congenital FII deficiency can manifest at any age, with severe forms of the disease manifesting early in life. Common clinical signs include epistaxis, menorrhagia, oral cavity bleedings, mucosal bleeding, soft tissue bleeding, haemarthrosis, easy bruising, and prolonged bleeding after tooth extraction, trauma or surgery. Severe forms may present intracranial haemorrhage. The severity of the bleeding manifestations correlates with the FII levels. Thromboembolic manifestations have been described in case of dysprothrombinemia.
Etiology
Inherited FII deficiency is caused by mutations in the F2 gene (11p11-q12) encoding prothrombin.
Diagnostic methods
Diagnosis is based on prolonged prothrombin and activated partial thromboplastin times (PT, aPTT) and on low FII coagulant activity measured using a PT based assay. Molecular testing is available, but is unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include deficiencies of factors V, VII, X, VIII, IX, XI, XIII or acquired deficiencies in FII (lupus anticoagulant).
Antenatal diagnosis
Prenatal diagnosis is available for the most severe forms.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Prothrombin Complex Concentrates (PCCs) or fresh frozen plasma (if PCCs are not available) are usually used to treat hemorrhagic episodes.
Prognosis
Prognosis is good with early diagnosis and adequate treatment.
Congenital factor V deficiency
An inherited bleeding disorder due to reduced plasma levels of factor V (FV) and characterised by mild to severe bleeding symptoms.
Estimated
Prevalence 1/1,000,000
Affected Factor Factor V (5)
Congenital Factor
Deficiency
Prevalence 1-9/1,000,000
Epidemiology
Prevalence of homozygous forms is estimated at 1/1,000,000. Both sexes are equally affected.
Clinical description
Congenital FV deficiency can manifest at any age, with the most severe forms manifesting early in life. Common clinical signs include epistaxis, bruising, mucosal bleeding, soft tissue bleeding, and hemarthrosis. Excessive and prolonged bleeding during or following surgery, delivery or trauma are frequent. Women may present with menorrhagia. In severe forms of the disease, there can be a risk of intracranial, pulmonary or gastrointestinal bleedings. The severity of the bleeding manifestations correlates with the FV levels.
Etiology
Congenital FV deficiency is caused by mutations in the F5 gene (1q23) controlling the production of plasma FV.
Diagnostic methods
Diagnosis is based on prolonged prothrombin and activated partial thromboplastin times (PT, aPTT) and on low FV levels measured using a PT based assay. The bleeding time (BT) may be prolonged. Molecular testing is available, but unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include factor VIII deficiency, and combined deficiency of factor V and factor VIII (see these terms).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Fresh frozen plasma (FFP) is the only treatment as FV concentrates are not available. In acute cases of severe bleeding, the addition of platelet concentrates may be helpful.
Prognosis
Prognosis is good with early diagnosis and adequate treatment.
Combined Factor V and
Factor VIII Deficiency
A rare inherited bleeding disorder due to the reduction in activity and antigen levels of both factor V (FV) and factor VIII (FVIII) and characterised by mild-to-moderate bleeding symptoms.
Estimated Between1/100,00
Prevalence and 1/1,000,000
Affected Factor Factor V (5) + Factor VIII (8)
FV and FVII Combined
Deficiency
Prevalence 1-9/1,000,000
Epidemiology
Prevalence is estimated between 1/100,000 and 1/1,000,000. The condition is more prevalent in the Mediterranean area and in areas where consanguineous marriages are common.
Clinical description
Combined FV and FVIII deficiency can manifest at any age. Epistaxis, easy bruising, post-surgical or post partum bleeding and menorrhagia are the most common symptoms. Hemarthrosis and muscular hematomas may occur. The symptoms are usually mild.
Etiology
Combined deficiency of factor V and factor VIII is caused by mutations either in the LMAN1 gene (chromosome 18; 18q21) or in the MCFD2 gene (chromosome 2; 2p21). LMAN1 encodes ERGIC-53, a transmembrane lectin, while MCFD2 is an EF-hand-containing protein. The ERGIC-53/MCFD2 protein complex functions as a cargo receptor that facilitates the transport of coagulation factors V and VIII from the endoplasmic reticulum to the Golgi apparatus. Mutations in LMAN1 account for approximately 70% of cases and include only null mutations. Mutations in MCFD2 account for approximately 30% of cases and include both null and missense mutations.
Diagnostic methods
Diagnosis is based on the measurement of factor V and factor VIII levels and on the detection of prolonged activated partial thromboplastin and prothrombin times. Levels of factor V and factor VIII range from as low as 1% to as high as 46%, but generally fall between 5% and 30%.
Differential diagnosis
Differential diagnosis includes co-inheritance of both FV deficiency (chromosome 1) and FVIII deficiency (chromosome X).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management aims at controlling the bleeding and includes treatments with fresh frozen plasma, FVIII concentrates and desmopressin administration.
Prognosis
The prognosis is favorable for moderate forms of the disease. Management of patients with more severe forms should be carried out at a specialised center.
Factor VII Deficiency
A rare, genetic, congenital vitamin K-dependant coagulation factor deficiency disorder characterized by decreased levels or absence of coagulation factor VII (FVII), resulting in bleeding diathesis of variable severity.
Estimated
Prevalence 1-9/1,000,000
Affected Factor Factor VII (7)
Congenital Factor VII
Deficiency
Prevalence 1-9/1,000,000
Epidemiology
European point prevalence appears to be close to 1/300,000, but may be markedly higher in countries where consanguineous marriage is frequent.
Clinical description
Clinical expression of this disorder is highly variable and no consistent relationship has been found between the severity of the hemorrhagic syndrome and the residual levels of FVII activity. The clinical picture can be very severe, with early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, may be moderate with cutaneous/mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by surgery or trauma. Finally, numerous subjects are completely asymptomatic despite a very low FVII level.
Etiology
FVII deficiency is caused by mutations in the F7 gene (13q34) coding for FVII. Typically, only homozygotes or compound heterozygotes develop a hemorrhagic syndrome; heterozygotes are usually asymptomatic. More than 250 mutations and six common variants are known to be associated with increased or decreased FVII plasma levels. Large genomic rearrangements have been reported in the literature and in the different locus-specific databases but they are rare. Genetic rearrangements have also been demonstrated, resulting in total or partial deletion of the F7 gene. The proximity and implication with the F10 gene (13q34) might also be the cause of combined deficits.
Diagnostic methods
Diagnosis is suspected with isolated prothrombin time and further confirmed by chronometric assays revealing a FVII activity level below that of pooled normal plasma (with values usually being between 70 and 140%). The deficiency is usually symptomatic only for values below 30%.
Differential diagnosis
Differential diagnoses include hepatocellular insufficiency, hypoavitaminosis K, acquired FVII deficiency associated with severe sepsis and, more rarely, the presence of autoantibodies against FVII.
Antenatal diagnosis
Due to the marked heterogeneity of the phenotypes (including asymptomatic individuals), access to prenatal diagnosis depends on the clinical repercussions of the disease in the family being considered. Only the existence of a first child with the very severe form may lead the medical team to propose prenatal diagnosis at the time of a subsequent pregnancy.
Genetic counseling
The disease is transmitted in an autosomal recessive manner. Due to the wide phenotypic heterogeneity of the disorder, with many asymptomatic patients, genetic counseling tends to differ depending on the clinical features specific to a family.
Management and treatment
At present, the main treatment consists of recombinant activated FVII (eptacog alfa). Concentrated prothrombinic or plasmatic Factor VII may be used as a second choice and frozen plasma as a last resort. However, indications remain difficult to establish prior to surgery in subjects with few or no symptoms. In 2008, recombinant coagulation factor VIIa (rFVIIa) got an Orphan designation in the USA.
Prognosis
Congenital FVII deficiency usually has good prognosis. Nevertheless, disease remains very disabling, or even fatal, in patients who cannot benefit from long-term replacement prophylaxis and which present the most severe forms (intracerebral hemorrhage and repeated hemarthroses).
Factor VIII Deficiency
(Haemophilia A)
A rare genetic haematological disorder characterised by spontaneous or prolonged haemorrhages due to factor VIII deficiency.
Estimated
Prevalence 1-9/100,000
Affected Factor Factor VIII (8)
Normal Range
Percentage of normal factor activity
in blood
50% - 150%
Number of international units (IU) per
milliliter (ML) of whole blood
0.50- 1.5 IU
Mild Haemophilia
Percentage of normal factor activity
in blood
5% - 40%
Number of international units (IU) per
milliliter (ML) of whole blood
0.05- 0.40 IU
Moderate Haemophilia
Percentage of normal factor activity
in blood
1% - 5%
Number of international units (IU) per
milliliter (ML) of whole blood
0.01- 0.05 IU
Severe Haemophilia
Percentage of normal factor activity
in blood
Less than 1%
Number of international units (IU) per
milliliter (ML) of whole blood
Less than 0.01 IU
Hemophilia A is the most common form of haemophilia. Prevalence is estimated at around 1 in 6,000 males. It primarily affects males, but females may also be symptomatic with a generally milder clinical picture.
Clinical description
In general, onset of bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with haemophilia are at risk of intra- or extracranial haemorrhage and other bleeding complications. The severity of clinical manifestations depends on the extent of factor VIII deficiency in both males and females. If the biological activity of factor VIII is below 1 IU/dL, haemophilia is severe and manifests as frequent spontaneous haemorrhages and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe haemophilia A). If the biological activity of factor VIII is between 1 and 5 IU/dL, haemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous haemorrhage is rare (moderately severe haemophilia A). If the biological activity of factor VIII is between 5 and 40 IU/dL, haemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous haemorrhage does not occur (mild haemophilia A). Patients may also be labeled as having mild haemophilia A if they have a FVIII >40 IU/dL and a DNA change in the F8 gene and one of the following: (i) a family member with the same DNA change and FVIII of <40 IU/dL, and the DNA change is found in <1% of the population; and (ii) the international databases list the DNA change as being associated with haemophilia A and <40 IU/dL FVIII. Bleeding most often occurs in joints (ahemarthroses) and muscles (haematomas), but any site may be involved following trauma or injury. Spontaneous haematuria is a frequent and highly characteristic sign of the disorder.
Etiology
Hemophilia A is caused by mutations in the F8 gene (Xq28) encoding coagulation factor VIII.
Diagnostic methods
Diagnosis is suspected based on prolonged coagulation times (activated partial thromboplastin time, aPTT) and can be confirmed by measuring factor VIII activity and antigen levels.
Differential diagnosis
Differential diagnosis includes von Willebrand disease (VWD), including type 2N VWD and other coagulation anomalies leading to prolonged coagulation times, in particular combined factor V and factor VIII deficiency.
Antenatal diagnosis
Prenatal diagnosis on chorionic villi or amniocytes is rapid and informative when the familial, causative mutation is known. Knowing the familial mutation status in the fetus allows for preparation of delivery and early newborn medical management.
Genetic counseling
Inheritance is X-linked recessive and genetic counseling is recommended for affected families. For a female carrier, there is a 50% risk that male offspring will be affected and a 50% risk that each female offspring will be carriers. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with hemophilia and a 25% risk that the baby will be a heterozygous female offspring.
Management and treatment
Management is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor VIII is the most straight forward treatment approach, using plasma-derived or recombinant factor VIII concentrates. Treatment may be administered after a hemorrhage or prophylactically, to prevent bleeding. The most frequent complication is the production of inhibitory antibodies against the administered coagulation factor. Bioengineered prolonged half-life factor VIII products and non-factor therapeutics as well as gene therapy are also available in Europe.
Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialised centers.
Prognosis
Left untreated, the disease course is severe in severe haemophilia A. Insufficient or incorrect treatment of recurrent haemarthroses and haematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications and prognosis is favoyrable. Haemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death.
Having haemophilia means that an individual’s body cannot naturally stop the bleeding that occurs once a blood vessel is damaged. These bleeds can be caused both by trauma and stress. If the bleed is not stopped and properly managed it can result in damages to the joints (such as ankles, hips and knees), which can cripple an individual (to the extreme an individual is at risk of losing limbs such as legs and arms) and limit his or her range of movements. Furthermore, intracranial bleeds can be both debilitating and fatal. In recent years, we have still seen reports of deaths in Europe due to untreated intracranial bleeds.
It is important to understand that besides being debilitating and life-threatening, bleeds are also extremely painful. This is why people with haemophilia need to have access to proper pain management.
Haemophilia has a greater impact on people affected by its severe form. This patients’ population needs to constantly have access to treatment and to specialised healthcare services. People with moderate and mild haemophilia may need treatment only if they injure themselves or if they undergo a great deal of stress. They may also need specialised services for dental care and other types of surgery, however in general they are not as affected by the disorder as people with severe haemophilia and are able to live a fairly normal life.
Living with severe haemophilia means that individuals with this condition need to infuse their treatment product several times a week when they are on prophylaxis. The missing factor is administered intravenously either by a medical professional or by the patient him- or herself. Although in most European countries home treatment is possible (this means that individuals can infuse their treatment without the supervision of a medical professional), it is still a time-consuming activity that may have an impact on an individual’s ability to travel, work and take part in social activities.
Finally, it is also important to know that at the moment approximately 30 per cent of the haemophilia population will develop an inhibitor to their treatment. This means that the body will reject the treatment, leaving the haemophiliac with no treatment solutions. For further information on this, please consult the inhibitors’ section.
Inhibitors
People with bleeding disorders are treated with what is called replacement therapy. This means that the missing clotting factor is infused in their body on a regular basis so that the clotting process can occur normally. Unfortunately, some people develop antibodies, called inhibitors, that neutralise the replacement clotting factor.
This means that the body induces an immune response to the treatment and therefore prevents the infused clotting factor from functioning normally. In this case, bleeds become very hard to control and can lead to permanent joint or muscle damage, making people with inhibitors disabled.
Treatment of inhibitors is the biggest challenge in haemophilia care today. It is possible to get rid of inhibitors using a technique called Immune Tolerance Induction (ITT). However, this type of treatment requires specialised medical expertise, is expensive and takes a long time. Drugs called bypassing agents can be used to work around inhibitors and help blood clot.
In haemophilia, inhibitors occur more often in individuals with the severe form than those with moderate or mild haemophilia. It is estimated that approximately 30% of patients with haemophilia A and 1.5% to 3% of patients with haemophilia B develop inhibitors to factor VIII and factor IX concentrates, respectively. For rare bleeding disorders, figures are unclear due to the limited patient population and the lack of treatment.
Inhibitors typically occur in the first 75 exposures to the treatment, this is why it is important that people with bleeding disorders receive their first treatment under medical supervision in a treatment centre where the right medical facilities and expertise are available in case of inhibitor development or other allergic reactions. In fact, allergic reactions may amplify when treatment is given over time.
Ideally, children and adults who are newly diagnosed with haemophilia should be tested regularly for inhibitors between first (1) and fiftieth (50) day of treatment. Even after the 50 day of treatment, they should be checked at least twice a year until they have received 150-200 doses and at least once a year after that. Testing for inhibitors should also be done before any major surgery.
Some studies have shown that people who receive regular treatments with factor concentrates to prevent bleeds (prophylaxis or prophylactic treatment) have a lower chance of developing inhibitors in their lifetimes. Little is known about whether the type of factor concentrates (recombinant or plasma-derived) that is used plays a role, but there are ongoing studies to shed light on this matter.
Factor IX Deficiency
(Haemophilia B)
A rare haematological disorder characterised by spontaneous or prolonged haemorrhages due to factor IX deficiency.
Estimated
Prevalence 1-9/100,000
Affected Factor Factor IX (9)
Normal Range
Percentage of normal factor activity
in blood
50% - 150%
Number of international units (IU) per
milliliter (ML) of whole blood
0.50- 1.5 IU
Mild Haemophilia
Percentage of normal factor activity
in blood
5% - 40%
Number of international units (IU) per
milliliter (ML) of whole blood
0.05- 0.40 IU
Moderate Haemophilia
Percentage of normal factor activity
in blood
1% - 5%
Number of international units (IU) per
milliliter (ML) of whole blood
0.01- 0.05 IU
Severe Haemophilia
Percentage of normal factor activity
in blood
Less than 1%
Number of international units (IU) per
milliliter (ML) of whole blood
Less than 0.01 IU
Epidemiology
Prevalence is estimated at around 1 in 30,000 males. Hemophilia primarily affects males, but a symptomatic form of hemophilia B in female carriers has also been described with a generally milder clinical picture.
Clinical description
In general, onset of the bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with hemophilia are at risk of intra- or extracranial hemorrhage and other bleeding complications. The severity of the clinical manifestations depends on the extent of the factor IX deficiency, both in males and in females. If the biological activity of factor IX is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia B). If the biological activity of factor IX is between 1 and 5 IU/dL, hemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia B). If the biological activity of factor IX is between 5 and 40 IU/dL, hemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia B). Bleeding most often occurs in joints (hemarthroses) and muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a frequent and highly characteristic sign of the disorder.
Etiology
Hemophilia B is caused by mutations in the F9 gene (Xq27) encoding coagulation factor IX.
Diagnostic methods
Diagnosis is suspected on the basis of coagulation tests revealing prolonged blood coagulation times (activated partial thromboplastin time – aPTT) and can be confirmed by specific measurements of factor IX activity and antigen levels.
Differential diagnosis
The differential diagnosis should include hemophilia A, von Willebrand disease, and other coagulation anomalies leading to prolonged blood coagulation times.
Antenatal diagnosis
Prenatal diagnosis performed on chorionic villi or amniocytes is rapid and informative when the familial, causative F9 mutation is known. Knowing the familial F9 mutation status in the fetus allows for preparation of delivery and early newborn medical management.
Genetic counseling
Inheritance is X-linked recessive and genetic counseling is recommended for affected families. For a female carrier, there is a 50% risk that male offspring will be affected and a 50% risk that each female offspring will be carriers. Female carriers may express mild to moderate symptoms. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with hemophilia and a 25% risk that the baby will be a heterozygous female offspring.
Management and treatment
Treatment is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor IX (plasma-derived or recombinant factor IX concentrates) is the usual treatment approach. Recently, bioengineered prolonged half-life factor IX products were approved for the treatment of hemophilia B and significantly improve the quality of life of patients. Treatment may be administered after a hemorrhage (treatment on demand) or to prevent bleeding (prophylactic treatment). The most serious complications are production of inhibitory antibodies against the administered coagulation factor and anaphylactic shock in response to factor IX therapy. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers.
Prognosis
Left untreated, the disease course is severe and in, severe hemophilia B, is generally fatal. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications and the prognosis is favorable. Hemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death in patients with hemophilia.
Having haemophilia means that an individual’s body cannot naturally stop the bleeding that occurs once a blood vessel is damaged. These bleeds can be caused both by trauma and stress. If the bleed is not stopped and properly managed it can result in damages to the joints (such as ankles, hips and knees), which can cripple an individual (to the extreme an individual is at risk of losing limbs such as legs and arms) and limit his or her range of movements. Furthermore, intracranial bleeds can be both debilitating and fatal. In recent years, we have still seen reports of deaths in Europe due to untreated intracranial bleeds.
It is important to understand that besides being debilitating and life-threatening, bleeds are also extremely painful. This is why people with haemophilia need to have access to proper pain management.
Haemophilia has a greater impact on people affected by its severe form. This patients’ population needs to constantly have access to treatment and to specialised healthcare services. People with moderate and mild haemophilia may need treatment only if they injure themselves or if they undergo a great deal of stress. They may also need specialised services for dental care and other types of surgery, however in general they are not as affected by the disorder as people with severe haemophilia and are able to live a fairly normal life.
Living with severe haemophilia means that individuals with this condition need to infuse their treatment product several times a week when they are on prophylaxis. The missing factor is administered intravenously either by a medical professional or by the patient him- or herself. Although in most European countries home treatment is possible (this means that individuals can infuse their treatment without the supervision of a medical professional), it is still a time-consuming activity that may have an impact on an individual’s ability to travel, work and take part in social activities.
Finally, it is also important to know that at the moment approximately 30 per cent of the haemophilia population will develop an inhibitor to their treatment. This means that the body will reject the treatment, leaving the haemophiliac with no treatment solutions. For further information on this, please consult the inhibitors’ section.
Inhibitors
People with bleeding disorders are treated with what is called replacement therapy. This means that the missing clotting factor is infused in their body on a regular basis so that the clotting process can occur normally. Unfortunately, some people develop antibodies, called inhibitors, that neutralise the replacement clotting factor.
This means that the body induces an immune response to the treatment and therefore prevents the infused clotting factor from functioning normally. In this case, bleeds become very hard to control and can lead to permanent joint or muscle damage, making people with inhibitors disabled.
Treatment of inhibitors is the biggest challenge in haemophilia care today. It is possible to get rid of inhibitors using a technique called Immune Tolerance Induction (ITT). However, this type of treatment requires specialised medical expertise, is expensive and takes a long time. Drugs called bypassing agents can be used to work around inhibitors and help blood clot.
In haemophilia, inhibitors occur more often in individuals with the severe form than those with moderate or mild haemophilia. It is estimated that approximately 30% of patients with haemophilia A and 1.5% to 3% of patients with haemophilia B develop inhibitors to factor VIII and factor IX concentrates, respectively. For rare bleeding disorders, figures are unclear due to the limited patient population and the lack of treatment.
Inhibitors typically occur in the first 75 exposures to the treatment, this is why it is important that people with bleeding disorders receive their first treatment under medical supervision in a treatment centre where the right medical facilities and expertise are available in case of inhibitor development or other allergic reactions. In fact, allergic reactions may amplify when treatment is given over time.
Ideally, children and adults who are newly diagnosed with haemophilia should be tested regularly for inhibitors between first (1) and fiftieth (50) day of treatment. Even after the 50 day of treatment, they should be checked at least twice a year until they have received 150-200 doses and at least once a year after that. Testing for inhibitors should also be done before any major surgery.
Some studies have shown that people who receive regular treatments with factor concentrates to prevent bleeds (prophylaxis or prophylactic treatment) have a lower chance of developing inhibitors in their lifetimes. Little is known about whether the type of factor concentrates (recombinant or plasma-derived) that is used plays a role, but there are ongoing studies to shed light on this matter.
Factor X Deficiency
A rare haematological disorder characterised by spontaneous or prolonged haemorrhages due to factor IX deficiency.
Estimated
Prevalence 1-9/1,000,000
Affected Factor Factor X (10)
Congenital Factor X
Deficiency
Prevalence 1-9/ 1,000,000
Epidemiology
Prevalence of homozygous forms is estimated at 1/1 000 000. Both sexes are equally affected.
Clinical description
Congenital FX deficiency manifests at any age but in general, severe forms of the disease manifest early in life. Patients may experience severe umbilical cord stump bleeding, recurrent epistaxis, soft-tissue hemorrhages, menorrhagia, easy bruising, intra cranial hemorrhages, hematuria, hemarthroses and excessive bleeding during or following surgery or delivery or trauma.
Etiology
Inherited congenital FX deficiency is caused by mutations in the F10 gene (13q34) controlling the production of plasma FX. The severity of the bleeding manifestations correlates with the FX level.
Diagnostic methods
Diagnosis is based on prolonged prothrombin, activated partial thromboplastin, and Russell viper venom times (PT, aPTT, RVVT), and on reduced levels of FX. Molecular testing is available, but unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include deficiencies of factors II, V, VII, VIII, IX, XI, XIII or acquired deficiencies in FX (amyloidosis).
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Heterozygote patients most often remain asymptomatic.
Management and treatment
Prothrombin Complex Concentrates (PCCs) or fresh frozen plasma (if PCCs are not available) are usually used to treat hemorrhagic episodes. A plasma-derived FX concentrate is now available.
Prognosis
Prognosis is good with early diagnosis and adequate treatment.
Factor XI Deficiency
A rare inherited bleeding disorder characterised by reduced levels and/or activity of factor XI (FXI) resulting in moderate bleeding symptoms, usually occurring after trauma or surgery.
Estimated
Prevalence 1-9/1,000,000
Affected Factor Factor XI (11)
Affected Factor Factor XI (11)
Congenital Factor XI
Deficiency
Prevalence 1-9/1,000,000
Epidemiology
Prevalence of homozygous forms is estimated at 1/1,000,000. The disease is more frequent in the Ashkenazy Jewish population where the frequency of partial deficiency is 8%. The disease affects both sexes.
Clinical description
Bleeding may manifest at any age, usually occuring after circumcision, dental extractions, trauma, or surgery (in particular surgery in the otorhinological and urogenital areas). Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate. Undiagnosed and untreated patients can develop significant hematomas after a surgical procedure.
Etiology
Congenital FXI deficiency is caused by mutations in the F11 gene (4q35.2) controlling the production of plasma FXI. Unlike in most factor deficiencies, the severity of the bleeding manifestations is poorly correlated with the FXI level.
Diagnostic methods
Diagnosis is based on a prolonged activated partial thromboplastin time (aPTT), and on reduced levels of FXI. FXI levels are < 20 IU/dL in severe defects and range between 20 and 60 IU/dL in partial deficiencies. Molecular testing is available, but unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses include deficiencies of factors II, V, VII, X, VIII, IX, XIII, combined deficiency of factor V and factor VIII, von Willebrand disease and platelet function disorders.
Genetic counseling
Transmission is mainly autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected, homozygous child at each pregnancy. Heterozygous patients with bleeding symptoms have also been observed, which suggests an autosomal dominant mode of transmission with variable penetrance.
Management and treatment
Patients may require treatment when dental extraction or surgery is planned. Factor XI concentrates or fresh frozen plasma is usually used. Low doses recombinant factor VIIa have been also used. Antifibrinolytics (aminocaproic acid, tranexamic acid) are also helpful as FXI deficiency leads to a hyperfibrinolytic state.
Prognosis
Prognosis is good, as bleeding symptoms are usually moderate.
Factor XIII Deficiency
An inherited bleeding disorder due to reduced levels and activity of factor XIII (FXIII) and characterised by hemorrhagic diathesis frequently associated with spontaneous abortions and defective wound healing. Factor XIII deficiency is one of the most rare coagulation factor deficiencies.
Estimated
Prevalence <1/1,000,000
Affected Factor Factor XIII (13)
Congenital Factor XIII
Deficiency
Prevalence <1/1,000,000
Epidemiology
Prevalence of homozygous forms is estimated at around 1/2,000,000. Both sexes are equally affected.
Clinical description
Congenital FXIII deficiency can manifest at any age, but diagnosis is often made during infancy. Umbilical stump bleeding manifests in up to 80% of patients. Other common signs include intracranial hemorrhage (25-30%), soft tissue bleeding, bruising, hemarthroses (20%), and recurrent spontaneous abortions. In most cases, hemorrhages are delayed (12-36hr) after trauma or surgery. Patients may have poor wound healing. Acquired forms of the disease have also been reported in association with hepatic failure, inflammatory bowel disease (see this term), and myeloid leukemia.
Etiology
Congenital FXIII deficiency is usually caused by mutations in the F13A1 gene (6p24.2-p23) encoding the catalytic A subunit, but mutations have also been found in the F13B gene (1q31-q32.1) encoding the B subunit. Transmission is autosomal recessive. The phenotype is less severe when the F13B gene is mutated.
Diagnostic methods
Diagnosis is based on quantitative FXIII activity measurement and antigen assays. Common clotting assays such as activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) are normal and cannot be used for the screening. The clot solubility test may also be used (clot is stable for more than 24 hours in case of FXIII deficiency). Molecular testing is available, but unnecessary for diagnosis.
Differential diagnosis
Differential diagnoses mainly include the other congenital coagulation factor deficiencies: fibrinogen, factors II, V, VII, X, XI, VIII, IX (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible if the causal mutations have previously been identified in the family.
Management and treatment
Factor XIII concentrates or fresh frozen plasma (when FXIII concentrates are not available) is usually used for the treatment of bleedings. Prophylactic therapy with FXIII concentrate should be indicated to prevent recurrent bleedings such as intracranial haemorrhage.
Prognosis
Intracranial haemorrhage can be life threatening, but prognosis is favourable if adequate treatment is provided.
von Willebrand Disease (VWD)
A rare, inherited bleeding disorder characterised by defective platelet adhesion and secondary coagulation defect that manifests as abnormal bleeding of variable severity occurring either spontaneously or in association with an invasive procedure. Three main subtypes are defined based on the type of von Willebrand factor defect: partial (type 1) or total (type 3) deficiency, and qualitative/functional anomalies (type 2).
Estimated
Prevalence 1-5/10,000
(All types) and 1/ 1,000,000 (Type 3)
Affected Factor
von Willebrand Factor
Type 1
Prevalence:
1-5/10,000
Inheritance:
Autosomal Dominant
Age of onset:
All ages
Bleedings:
None- Severe
Type 2
Prevalence:
1-9/1,000,000
Inheritance:
Autosomal Dominant (Common),
Autosomal recessive (Uncommon)
Age of onset:
All ages
Bleedings:
Moderate- Severe
Type 3
Prevalence:
1-9/1,000,000
Inheritance:
Autosomal recessive (Uncommon)
Age of onset:
Infancy, Neonatal
Bleedings:
Severe
The prevalence of Von Willebrand disease (VWD) in the general population is estimated at between 0.6 and 1.3% (including all forms) depending on the study, but the prevalence of symptomatic VWD that requires specific treatment is approximately 1/10 000. Type 3 VWD is much more rare (1/1 000 000).
Clinical description
Age of onset varies, with earlier onset being associated with more severe VWF deficiency. The disease manifests as abnormal bleeding of variable severity occurring either spontaneously or in association with an invasive procedure. The bleeding anomalies are generally characterized by mucocutaneous hemorrhage (epistaxis, menorrhagia, bleeding from minor wounds, etc.) but hematomas and hemarthrosis may occur in more severe forms.
Etiology
VWD is caused by mutations in the VWF gene (12p13.3) encoding the multimeric VWF protein. The VWF protein has an intraplatelet, endothelial and plasmatic localization and plays essential roles both in the interaction of platelets with the injured vessel wall and in the transport and stabilization of factor VIII (FVIII).
Diagnostic methods
Diagnosis relies on laboratory tests involving functional and immunological assays of VWF and FVIII levels. Determination of the type of VWD requires other specific tests such as studies of the distribution of VWF multimers.
Differential diagnosis
Measurements of VWF levels (antigen and functions) generally allow VWD to be distinguished from hemophilia A. However, these tests do not allow differentiation of type 2N VWD, which requires more specific assays. Differentiation between acquired von Willebrand syndrome (AVWS), which occurs in association with another underlying pathology, and inherited VWD is more problematic. The fact that individuals in the general population belonging to blood group O may also have moderately lower levels of VWF should also be taken into consideration in the differential diagnosis.
Antenatal diagnosis
In at risk pregnancies, the identification of underlying VWF mutations may be used for prenatal diagnosis of type 3 VWD.
How do you get VWD?
VWD is usually inherited. It is passed down through the genes from either parent to a child of either sex. However, sometimes VWD occurs due to a spontaneous change in the VWD gene before the baby is born. The figure below shows the inheritance of VWD.
VWD Types 1 and 2 are usually inherited in what is known as a ‘dominant’ pattern. This means that a parent who has VWD has a one in two (50 per cent) chance of passing a VWD gene on to each of his or her children.
Type 3 VWD, however, is usually inherited in a ‘recessive’ pattern. This type occurs when the child inherits the gene from both parents. Even if both parents have mild symptoms or no symptoms at all, their child may be severely affected.
Genetic counseling
VWD is most often transmitted in an autosomal dominant manner, however, the mode of inheritance is autosomal recessive for type 3 VWD and for some of the type 2 subtypes. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks, and to allow screening for detection of other affected family members. For couples at risk of having a child with type 3 disease, genetic counseling may be best discussed in a specialized multidisciplinary center.
Management and treatment
Management depends on the type of VWD. Desmopressin is generally an effective preventative or curative treatment for abnormal bleeding in type 1 VWD. In patients with type 2 disease, the response to desmopressin is variable and substitution therapy with purified human VWF is often required. Desmopressin does not constitute an effective treatment for patients with type 3 disease, and thus these individuals require substitution therapy with purified human VWF associated, at least for the first injection, with FVIII.
Prognosis
For patients managed within specialised haemostasis hospital centers, the prognosis is favourable, even for those with the most severe forms of the disease.
Bernard-Soulier Syndrome
A rare, inherited platelet disorder characterised by mild to severe bleeding tendency , macrothrombocytopenia, and absent ristocetin-induced platelet agglutination.
Estimated
Prevalence <1/1,000,000
Affected Factor Factor XIII (13)
Percentage of normal
factor activity in blood:
<1/1,000,000
Inheritance:
Autosomal Dominant, Autosomal Recessive
Age of onset:
All ages
Bernard-Soulier syndrome
is a platelet function disorder caused by an abnormality in the genes for glycoprotein Ib/IX/V. These genes code for a group of linked proteins normally found on the surface of platelets, the glycoprotein Ib/IX/V receptor (also called the von Willebrand factor or VWF receptor). Because this receptor is absent or is not working properly, platelets do not stick to the injured blood vessel wall the way they should and it is difficult for the normal blood clot to form.
Glanzmann Thrombasthenia
Glanzmann thrombasthenia (GT) is a bleeding syndrome characterised by spontaneous mucocutaneous bleeding and an exaggerated response to trauma due to a constitutional thrombocytopenia.
Estimated
Prevalence Unknown
Affected Factor Platelet
Prevalence:
Unknown
Inheritance:
Autosomal Recessive
Age of onset:
Infancy, Neonatal
Glanzmann thrombasthenia
a platelet function disorder that is caused by an abnormality in the genes for glycoproteins IIb/IIIa. These genes code for a group of linked proteins normally found on the surface of platelets, the glycoprotein IIb/IIIa receptor (also called the fibrinogen receptor). Because this receptor is absent or is not working properly, platelets do not stick to each other at the site of injury and it is difficult for the normal blood clot to form.
Storage Pool Deficiencies
Estimated
Prevalence Unknown
Affected Factor Platelet
Gray Platelet Syndrome:
Prevalence: <1/ 1,000,000
Inheritance:
Autosomal Recessive, Autosomal Dominant
Age of onset:
Childhood
Quebec Platelet Disorder
Prevalence: Unknown
Inheritance:
Autosomal Dominant
Age of onset:
Adult
Alpha Delta Granule Deficiency
Prevalence: Unknown
Inheritance:
Autosomal Dominant, Autosomal Recessive
Age of onset:
Unknown
Storage Pool Deficiencies
are a group of disorders caused by problems with platelet granules. Granules are little sacs inside the platelet in which proteins and other chemicals important to its function are stored. There are two types of granules: alpha granules and dense granules.
Some storage pool deficiencies (PSDP) are caused by a lack of granules, but the most common ones are caused by a failure of the platelets to empty the contents of the granules into the bloodstream (this is called the secretory or release mechanism).
There are four major inherited forms of PSDPs: Dense Body Deficiency, Gray Platelet Syndrome, Quebec Platelet Disorder, and Mixed Alpha-Granule/Dense-Body Deficiency. Each form has a wide variety of symptoms, and even within each type, symptoms can be very different.
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Release defects are a diverse group of disorders caused by a problem with the secretory mechanism. Even though the granules are present within the platelets, their contents are not emptied into the bloodstream properly.
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Delta storage pool deficiency is a platelet function disorder caused by a lack of dense granules and the chemicals normally stored inside them. Without these chemicals, platelets are not activated properly and the injured blood vessel does not constrict to help stop bleeding. This type of bleeding problem can be a feature of other inherited conditions (such as Hermansky-Pudlak syndrome and Chediak-Higashi syndrome).
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Grey platelet syndrome is a very rare platelet function disorder caused by a lack of alpha granules and the chemicals normally stored inside them. Without these proteins, platelets cannot stick to the blood vessel wall, clump together the way they should, or repair the injured blood vessel.
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Combined alpha-delta platelet storage pool deficiency is a rare hemorrhagic disorder due to a constitutional platelet anomaly characterised by moderate to severe deficiency in both platelet alpha-granules and dense bodies, resulting in impaired platelet function and decreased aggregation responses. Patients present increased bleeding tendency with symptoms like easy bruising, or menorrhagia.
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Quebec Platelet Disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and storage of urokinase plasminogen activator (uPA) by megakaryocytes. QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors.