Each coagulation factor deficiency must be analysed separately, as they all have their own specific characteristics. But for each of them, the people concerned will need regular follow-up with a specialist treatment centre. Therapeutic education, i.e. personalised support to help you live better with the disease, is possible. The Association française des hémophiles can also help you with any questions you may have, working closely with the healthcare network.
Summary
Rare coagulation factor deficiencies are inherited coagulation abnormalities that occur when one or more coagulation factors (factors I, II, V, V+VIII, VII, X, XI or XIII) are absent or do not function properly. Although haemorrhagic symptomatology is at the forefront, each coagulation factor deficiency has its own biological and clinical characteristics, which must be taken into account when establishing a therapeutic strategy.
General
There are several coagulation factors, often referred to by number and sometimes by name (factors I or fibrinogen, II or prothrombin, V, VII, VIII or antihaemophilic A, IX or antihaemophilic B, X, XI, XII, XIII). The rare coagulation factor deficiencies found in constitutional haemorrhagic diseases are inherited anomalies that occur when one or more of these factors are absent or do not function properly. Generally speaking, and due to their rarity, these deficiencies are often poorly understood and under-diagnosed, which can lead to delays in treatment. Although also rare, haemophilia A and B and von Willebrand factor deficiency are not included in the particularly rare coagulation factor deficiencies and are therefore not described in this chapter.
Little is known about the epidemiology, i.e. the frequency, of rare coagulation factor deficiencies (see table 1). Their transmission is usually autosomal recessive (both parents must carry the defective gene in order to pass it on), but autosomal dominant transmission of the defective gene by a single parent is possible for certain deficiencies (e.g. hypofibrinogenemia or dysfibrinogenemia). These modes of transmission mean that these deficiencies can occur in both men and women.
Symptoms, i.e. haemorrhagic signs, are variable and generally correlated with the level of the deficiency factor. However, for some deficiencies (e.g. factor XI deficiency) such a correlation is not evident (see table 1). Paradoxically, certain deficiencies may be associated with an increased risk of thrombosis (i.e. blood clots).
Treatment consists, as far as possible, of providing the patient with the coagulation factor deficiency (Table 2). These clotting factor concentrates are produced from human plasma and treated to eliminate viruses such as HIV and hepatitis B and C. Recombinant factor VIIa can also be prepared in the laboratory without using human plasma. Other therapeutic options include the administration of prothrombin complex concentrates (PCC) containing factors II, VII, IX and X, or the administration of fresh frozen plasma (FFP), preferably viro-inactivated, which contains all the coagulation factors. Anti-fibrinolytics such as tranexamic acid can also be used to limit bleeding by inhibiting the fibrinolysis stage (dissolution of the fibrin clot). These medicines are used in particular in certain specific clinical situations (e.g. dental treatment or excessive menstrual bleeding). In the event of menorrhagia, hormonal treatment with oral contraception is proposed. Local haemostasis using adhesives should be encouraged in the event of trauma or surgery.
Fibrinogen deficiency
Symptomatology is highly heterogeneous and depends on the subtype of fibrinogen abnormality and the fibrinogen level. In the case of afibrinogenemia (complete absence of fibrinogen), bleeding is frequent, often from birth, and sometimes very serious, such as central nervous system haemorrhage. These patients may also experience delayed healing and spleen complications. Patients suffering from hypofibrinogenemia (low fibrinogen levels) do not usually experience spontaneous bleeding, but rather bleeding secondary to trauma or surgery. In dysfibrinogenemia (fibrinogen present in sufficient quantity but abnormal), haemorrhagic complications are generally mild, mainly in the mucous membranes, and many patients are asymptomatic. In the case of afibrinogenemia and certain dysfibrinogenemias, patients are at risk of venous or arterial thrombosis. Treatment in the event of haemorrhage or risk of haemorrhage consists of administration of a fibrinogen concentrate, particularly in the event of pregnancy in afibrinogenemic patients, who cannot carry a pregnancy to term without an external supply of fibrinogen.
Factor II deficiency
This is a very rare deficiency due either to a quantitative anomaly (drop in prothrombin levels) or a qualitative anomaly (prothrombin in sufficient quantity but abnormal). Haemorrhagic symptoms correlate with factor II levels, but are unusual in qualitative abnormalities. Bleeding generally occurs in the mucous membranes or joints, and central nervous system haemorrhages are rare. The two products available to treat factor II deficiency are Prothrombin Complex Concentrate (PCC) or Fresh Frozen Plasma (FFP).
Factor V deficiency
Haemorrhagic symptoms are generally mild or absent and mainly affect mucous membranes (nose or mouth bleeds, bruising). However, bleeding from the central nervous system has been observed and severe deficits can appear as early as the neonatal period. In the event of haemorrhagic complications, the treatment consists of administering PFC. A concentrate containing only factor V has been developed and could be marketed in the near future. Transfusions of platelet concentrates, which contain factor V, are an option in some cases.
Combined factor V and VIII deficiency
This coagulation anomaly results from a concomitant drop in factors V and VIII. It is due to a defect in the passage of factors V and VIII into the circulation and not to a synthesis defect. Haemorrhagic symptoms are generally moderate and rarely spontaneous. Treatment consists of administering a factor VIII concentrate or PFC (containing both factor VIII and factor V). Desmopressin is sometimes an alternative. This synthetic hormone induces an increase in factor VIII levels.
Factor VII deficiency
This is the most common coagulation factor deficiency. Haemorrhagic symptomatology is heterogeneous, ranging from the absence of symptoms to severe spontaneous haemorrhage. Factor VII levels only imperfectly predict the risk of bleeding. When necessary, treatment consists of administering recombinant factor VII or factor VII concentrate.
Factor X deficiency
Haemorrhagic symptoms depend on factor X levels. Severe deficiencies present haemorrhagic complications from birth, such as bleeding from the umbilical cord or haemorrhage from the central nervous system. The usual treatment is a PCC or FFP, but there is a factor IX concentrate which contains factor X in known quantities. A factor X concentrate is about to be marketed.
Factor XI deficiency
It is a rare deficiency, although its prevalence can be high in certain populations. There is very little correlation between factor XI levels and the risk of haemorrhage; in fact, even severe deficiencies can be asymptomatic. Haemorrhagic symptoms mainly occur in tissues with increased fibrinolytic activity (for example, the urinary system or the ENT tract). Post-operative bleeding is common. Treatment consists mainly of administering antifibrinolytic agents and sometimes factor XI concentrate. Factor XI substitution must be carried out with caution, as thrombotic complications have been reported.
Factor XIII deficiency
This is a very rare deficit. Haemorrhagic symptoms are severe, with frequent umbilical cord bleeding at birth and haemorrhage into the central nervous system in cases of major deficiency. Problems with healing and foetal loss have been reported, as in the case of afibrinogenemia. Treatment (often primary prophylaxis) consists of administering a factor XIII concentrate.
Combined deficiency of vitamin K-dependent factors
Combined vitamin K-dependent factor deficiency is a very rare deficiency due to a simultaneous anomaly in factors II, VII, IX and X. Symptoms are heterogeneous, but in the case of severe deficiency, there is an increased risk of bleeding from birth and central nervous system haemorrhage. In some children, this deficit may be associated with skeletal anomalies or hearing loss. Elderly patients suffer mainly from bleeding from the skin and mucous membranes. Treatment consists of administering vitamin K or, where appropriate, PCCs containing the four vitamin K-dependent factors.