Coagulation Factor Deficiency Clinical Trial
Official title:
Cross-sectional Study on Prevalence of Coagulation Factors Deficiency in Children Attending Assiut University Children Hospital ( a One Year Study)
Blood coagulation is a complex mechanism that is required for the rapid establishment of a stable fibrin clot. A series of interdependent enzyme-mediated reactions translate the molecular signals that initiate blood coagulation into the formation of the fibrin clot. Congenital coagulopathies result when there is a deficiency of protein co factors and enzymes implicated in blood coagulation
The most frequent inherited coagulation disorders are haemophilia A and B, due to the
deficiency of factor VIII and IX. Haemophilia A and B are clinically indistinguishable from
each other and occur in mild, moderate and severe forms (with plasma factor levels of 6-30%,
2-5% and 1% or less respectively). Inherited as X-linked traits, haemophilia A and B are
prevalent in the general population of approximately 1 in 10 000 and 1 in 50 000, with no
significant racial difference. Other deficiencies of coagulation factors that cause a bleeding
disorder, such as afibrinogenaemia, hypoprothrombinaemia, deficiencies of factors V and
combined factor V and VIII, VII, X, XI and XIII are inherited as autosomal recessive traits
and are generally much rarer than the haemophilias, wich are prevalent in the general
population varying between 1 in 500 000 and 1 in 2 000 000. As a consequence of the rarity of
these deficiencies, which are expressed clinically only in homozygotes or compound
heterozygotes, the type and severity of symptoms, the underlying molecular defects and the
actual management of bleeding episodes are not well established as for haemophilia A and B.
Inherited deficiencies are described for all of the known coagulation factors. In addition,
there are people with an abnormal bleeding tendency for whom no cause has yet been
identified. The concept of overall hemostatic balance is increasingly recognized, that it is
not solely the level of a single factor that matters, but the overall control of hemostasis
that may determine the bleeding risk. This may explain why the bleeding risk cannot be
predicted from a single factor level alone as in, for example, factor VII or factor XI
deficiency in particular. The rare factor deficiencies have several common properties: they
are inherited in an autosomal manner, although bleeding symptoms have been described in
heterozygous partially deficient individuals. These rare deficiencies are more common in
populations and countries where cousin marriages are frequent and therefore there is
considerable geographic variation in the incidence, in contrast to hemophilia and von
Willebrand disease types I or II which occur with the same incidence in different countries.
Clinical manifestations:
In their most severe form, the deficiencies present with serious hemorrhage in the neonatal
period; intracranial hemorrhage is a significant presentation of severe deficiency of FXIII,
factor VII, factor X or fibrinogen (afibrinogenaemia). Bleeding from the umbilical stump can
occur with any of these disorders as it can with severe hemophilia. It is important for
caregivers to be aware that any unusual bleeding manifestation must prompt appropriate
investigation so that diagnosis is not delayed, and appropriate replacement therapy is given
as soon as possible. A history of consanguinity of the parents and their ethnic origin are
relevant.
Diagnosis should be straightforward but there are pitfalls in testing. Difficult
venepunctures in infants in an emergency may give erroneous results due to tissue factor
contamination. Coagulation samples do not travel well, so if plasma samples are sent to
another laboratory they must be properly transported, generally frozen and sent on dry ice.
It may be helpful to test both parents because, apart from the two truly recessive disorders
detailed below, the parents will usually have evidence of partial deficiency. It is important
for each laboratory to establish its own normal range, and to ensure that the possibility of
genetic carriage of a disorder is fully discussed with parents irrespective of the blood
results as the birth of more children with a serious bleeding disorder is a great emotional
and social burden especially in countries and communities with poor health resources.
Fibrinogen deficiency
Fibrinogen deficiency is heterogeneous and two main phenotypes can be distinguished. In
afibrinogenaemia, plasma and platelet levels of the protein are unmeasurable or very low when
using assays that measure clottable and immunoreactive protein, whereas in dysfibrinogenaemia
low clottable fibrinogen contrasts with normal or moderately reduced fibrinogen antigen.
Clinical manifestations:
Whereas most patients with dysfibrinogenaemia do not bleed at all, afibrinogenaemic patients
have a bleeding tendency.
Among severe bleeding symptoms that are dangerous for life and for the musculoskeletal
function, umbilical cord and joint bleeding is relatively frequent (in 75% and 50% of
patients), whereas muscle hematomas and bleeding in the gastrointestinal tract and central
nervous system are less common.
Milder symptoms such as epistaxis and menorrhagia are also frequent. Post-partum bleeding
occurs when no prophylactic replacement therapy is given. Excessive blood loss and impaired
wound healing in about one-third of the patients often accompany circumcision and other
surgical maneuvers. There is no increased prevalence of recurrent miscarriages. Central
nervous system bleeding is rare.
Factor V deficiency Congenital factor V deficiency (also known as labile factor or
proaccelerin) is a rather uncommon [1:1000,000] inherited coagulopathy (autosomal recessive
inheritance).
Affected patients become symptomatic in early childhood with spontaneous or post- traumatic
bleeding complications
Factor VII deficiency
Factor VII deficiency is the most common autosomal recessive coagulation disorder (1 per 500
000 population). Factor VII circulates in plasma at a concentration of approximately 0.5
μg/mL (10 mmol/L). Plasma levels of factor VII coagulant activity (FVII:C) and FVII antigen
(FVII: Ag) are influenced by a number of genetic and environmental factors (sex, age,
cholesterol and triglyceride levels). The majority of patients have concomitantly low levels
of factor VII functional activity and antigen, but several cases are characterized by normal
or low borderline levels of factor VII antigen, contrasting with lower levels of functional
activity. Most gene knockout mice made experimentally deficient in factor VII develop
normally but some suffer fatal perinatal bleeding.
Clinical manifestations:
The severity of symptoms of factor VII deficiency is variable and generally reported to be
poorly correlated with plasma levels. Some patients do not bleed at all after major
challenges of haemostasis, and even cases of thrombosis have been described. life- or
limb-endangering bleeding manifestations are relatively rare, the most frequent symptoms
being epistaxis and menorrhagia. However, the prevalence of haemarthroses and soft-tissue
bleeding was less than that found in other large series. The risk of central nervous system
bleeding in infants with severe factor VII deficiency is high in some series.
Factor VIII & factor IX deficiency:
The hemophilias are X-linked congenital bleeding disorders, and the two major categories are
hemophilia A (factor VIII deficiency, seen in 1 in 5,000 male births) and hemophilia B
(factor IX deficiency, seen 1 in 30,000 male births) Prophylaxis for children with severe
hemophilia consists of infusion of a factor concentrate two or three times a week in order to
keep blood levels of factor VIII or IX high enough to prevent bleeding. On-demand therapy
involves infusion of a factor concentrate immediately after bleeding starts in an effort to
prevent joint or muscle damage
Factor XI deficiency Factor XI deficiency is characterized by a decrease of the functional
activity of this plasma protein, usually accompanied by correspondingly low levels of factor
XI antigen. Most of cases reported in the literature are of Ashkenazi Jewish origin, the
frequency of heterozygosity for factor XI deficiency being as high as 8% in this population.
In knockout mice, the loss of the gene coding for this factor is compatible with life, with
no tendency for spontaneous bleeding.
Clinical manifestations:
The relationship between the residual factor XI levels in plasma and the bleeding tendency is
not as clear-cut as for other coagulation factor deficiencies. Usually, patients with severe
factor XI deficiency (1% or less) are mildly affected and have bleeding symptoms only after
trauma or surgery. Surprisingly patients with low but detectable levels of factor XI are also
mild bleeders, severe or moderate deficiency (factor XI < 1-5%) and in patients with mild
deficiency (6-30%). All patients were mild bleeders, but those symptoms that define the
severity of the bleeding tendency, such as muscle hematomas and hemarthroses, showed a
similar frequency in the two groups of deficient patients (approximately 25%). The most
frequent symptoms were oral and post-operative bleeding, which occurred in more than 50% of
patients.
Differential diagnosis :
Causes of congenital bleeding disorders
The most common include:
Von Willebrand Disease Hemophilia A (Factor Viii Deficiency) Hemophilia B(Factor Ix
Deficiency)
Less Common :
Factor 1(Fibrinogen Deficiency) Factor II (Prothrombin Deficiency or Dysfunction) Factor V
Deficiency Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor XIII
Deficiency Platelet Disorders Congenital Aplastic Anemia
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