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Rare bleeding disorders


Table 1: Data from successive WFH Global Surveys 2004


2005 Haemophilia A + B


Von Willebrand disease Other bleeding disorders


National registries (% global population)


120,812 43,334 11,384


40/96 (85%)


2006


131,264 135,475 45,001 16,735


48,901 19,689


49/98 (88%)


56/99 (87%)


2007


146,612 52,662 18,811


59/105 (89%)


2008


148,971 52,330 21,510


61/108 (91%)


2009


153,251 62,158 27,030


NA/105 (92%)


2010


162,781 65,100 29,301 106


(94%)


Total number of patients with bleeding disorders reported in the World Federation of Haemophilia annual surveys, showing the rare disorders (other) in comparison to haemophilia A and B, and von Willebrand Disease from 2004 when data on the rare disorders were first requested, to 2010. NA = Not available.


investigation of bleeding symptoms at any age. The most severe of these are Glanzmann thrombasthenia (GT) – the platelet count is normal but platelets are missing an essential functional receptor – and Bernard-Soulier syndrome (BSS), where the platelet count is low and the platelets have reduced function because the receptor that links platelets to the vessel wall is missing. There are many other rare and less well-defined platelet disorders that will not be considered here, and many drugs affect platelet function. In addition to the important general measures considered above, in a serious bleeding situation or for major surgery, two main options are considered: the use of recombinant activated factor VII (rVIIa) and/or platelet concentrates. Platelet concentrates should only be used if absolutely necessary because of the risk of development of alloantibodies against the missing receptor in GT or BSS. If these antibodies develop, future management may be very difficult. Women who develop such antibodies are at risk from the development of neonatal alloimmune thrombocytopenia in pregnancy (the antibodies cross the placenta and attack the fetal platelets), which may be associated with serious bleeding in the foetus/neonate. The risk of sensitisation is reduced by using HLA-matched platelets; therefore, individuals with these disorders should have their HLA type (tissue type) recorded at diagnosis, although it may not be possible to get matched platelets in an emergency. The use of rVIIa is well described for GT5


but less evidence is available for use in BSS. 16


Multiple factor deficiencies Two specific multiple coagulation factor deficiencies have been well described: ● FV with FVIII deficiency – this is caused by mutations affecting a protein that moves these two large factors across the cell (cargo protein). Affected individuals usually present with bleeding after surgery and the


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severity is related to the residual levels of the factors, but it is generally less severe. Treatment is with sources of both FVIII (concentrates) and FV (PI-FFP) and is generally only required for surgery or accidents.


● Deficiencies of all four vitamin K-dependent factors (FII, FVII, FIX and FX) can occur together when there are mutations in the vitamin K pathway. Few families are described and this disorder must be considered when the investigation of bleeding and bruising leads to a deficiency of all four factors in the absence of vitamin K deficiency or antagonists. Many of these patients can be managed with large doses of vitamin K but may need four-factor concentrates for accidents or surgery (prothrombin complex concentrates containing factors II, VII, IX and X).


Factor XI deficiency


This is a mild bleeding disorder that usually does not present with spontaneous bleeding, even in those with absent FXI. FXI has a secondary role in haemostasis, continuing to trigger the intrinsic pathway once coagulation has begun. The deficiency is particularly common in Ashkenazy Jews, where the carrier rate is about 1 in 12, but it is found in all racial groups. The bleeding is related to injury or surgery, particularly in areas of the body where there is increased fibrinolysis, such as the nose and throat, and the genitourinary tract. The bleeding risk is very poorly related to the factor level and may well be related to additional factors – in some cases the presence of associated mild von Willebrand disease or a platelet defect – but this has not been completely unravelled.6


Elevated levels of FXI are associated with thrombosis.


In addition to the general measures above, specific FXI replacement may be required for surgery. FXI concentrates are available in some countries and are used


carefully in order to avoid high FXI levels which can be associated with thrombosis. Other options include PI-FFP and more recently the use of low-dose rVIIa, particularly in those who develop anti-FXI antibodies. These antibodies are most likely to develop in people homozygous for null mutations, that is, who produce no FXI at all (for example, those homozygous for one of the most common mutations in Jewish people, the Type II mutation) and therefore are more likely to ‘see’ any transfused FXI as foreign. However, it should be noted that this agent is not licensed for this indication at present.


Future developments


There are many factors that influence the balance of haemostasis in normal individuals, such as blood group (reduced thrombotic risk with blood group O and increased with A) and age (increase in several coagulation factors with age, particularly fibrinogen, von Willebrand factor and FVIII). The balance of these factors, rather than simple levels of individual factors, may increase or decrease bleeding after surgery. There is renewed interest in FXI or FXII inhibitor development for use as antithrombotic agents in normal people, as deficiency of FXI is associated with a mild bleeding risk and FXII with no bleeding risk.7 ●


References 1. Bolton-Maggs PH et al. The rare coagulation disorders-review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation. Haemophilia 2004;10:593–628.


2. Peyvandi F et al. Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity. J Thromb Haemost 2012;10:1938–43.


3. Pike GN, Bolton-Maggs PH. Factor deficiencies in pregnancy. Hematology/oncology clinics of North America 2011;25:359–78,viii–ix.


4. Bolton-Maggs PH et al. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol 2006;135:603–33.


5. Poon MC et al. Glanzmann’s thrombasthenia treatment: a prospective observational registry on the use of recombinant human activated factor VII and other hemostatic agents. Semin Hematol 2006;43:S33–6.


6. Bolton Maggs P. Factor XI deficiency - resolving the enigma? American Society of Hematology Education Program Book 2009:97–105.


7. Muller F, Gailani D, Renne T. Factor XI and XII as antithrombotic targets. Current Opinion in Hematology 2011;18:349–55.


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