Female Hemophilia Research Articles

Congenital Bleeding Disorders in Karachi, Pakistan

To determine the frequency of inherited bleeding disorders, its complications, and treatment modalities available for its treatment. Cross-sectional study. Patients with a history of bleeding tendency were tested for confirmation of the diagnosis. History and clinical findings were recorded. Laboratory analysis included prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time (BT), and fibrinogen assay. Patients with prolonged APTT were tested for factors VIII (FVIII) and IX (FIX). If FVIII was low, von Willebrand factor: antigen (vWF:Ag) and von Willebrand factor:ristocetin cofactor (vWF:RCo) were performed. When PT and APTT both were prolonged, FV, FX, and FII were tested. Platelet aggregation studies were done when there was isolated prolonged BT. Urea clot solubility test was done when all coagulation tests were normal. All patients with hemophilia A and B were evaluated for inhibitors. Of the 376 patients, inherited bleeding disorder was diagnosed in 318 (85%) cases. Median age of patients was 16.4 years. Hemophilia A was the commonest inherited bleeding disorder that was observed in 140 (37.2%) followed by vWD 68 (18.0%), platelet function disorders 48 (12.8%), and hemophilia B in 33 (8.8%) cases. We also found rare congenital factor deficiencies in 13 (3.4%), low VWF in 11 (3.0%) participants and 5 (1.3%) in female hemophilia carriers. Hemarthrosis was the most frequent symptom in hemophilia A and B (79.7%) involving knee joint. Inhibitor was detected in 21 (15%) cases. Fresh frozen plasma/cryoprecipitate were the most common modality of treatment. In 58 patients, no abnormality was detected in coagulation profile. Hemophilia A and vWD are the most common congenital bleeding disorders in this study. Hemarthrosis involving knee joint was the most common complication. Inhibitor was detected in a significant number of patients. Plasma is still the most common modality of treatment.

Case Report on a Female Patient with Congenital Haemophilia a and An Acquired Type-2 Inhibitor to FVIII

Only rare cases of female haemophilia have been reported. Moreover, no case of congenital haemophilia A associated with an acquired type-2 inhibitor to FVIII in a female child has been described in literature yet. We report the case of a 15-year old girl, diagnosed with severe haemophilia A (FVIII:C <1%) at the age of 13 months. Her father suffered from severe haemophilia A (FVIII:C <1%) due to an intron 22 inversion. In the girl both an intron 22 inversion and a non-random X-inactivation were found. At 3 years the girl received prophylactic treatment, and recombinant FVIII (3 × 40 IU/kg/week) from 6 years of age. Bleeding episodes were rare. Aged 13 she developed two large spontaneous haematomas. In-depth analysis confirmed decreased FVIII-recovery, –half-life and an inhibitor titre of 7.6 BU following type-2 kinetics (haemophilic autoantibodies). All of the few reported children with an aquired FVIII inhibitor presented with other autoimmune diseases or had used penicillin. Our patient showed none of this, but interestingly experienced menarche 4 weeks after inhibitor detection. This lets us speculate that the ethiology of the inhibitor formation in our patient at the time of hormonal change might be similar to that in pregnant or postpartum women.Taking into account the recommendations of Ma et al. (2006) regarding inhibitor development during pregnancy in healthy women, we initiated a modified ITI with 75 IU/kg rFVIII concentrate (4,000 IU per infusion) every other day without additional immunosuppressive therapy. After 6 weeks of ITI, inhibitor titres declined and became negative after 8 months, resulting in a normal FVIII half-life till now.

Female haemophilia A caused by skewed X inactivation

Female haemophilia A caused by skewed X inactivation

Rapid identification of female haemophilia A carriers with deletions in the factor VIII gene by quantitative Real-Time PCR analysis

Large deletions of the factorVIII gene account for approximately 5% of severe haemophilia A patients. Although deletions are readily detectable in males, the identification of heterozygosity in possible carriers of these families still constitutes a challenge. In order to identify a deleted allele over the background of the normal allele in these carriers, we developed a rapid real-time quantitative PCR approach by means of LightCycler technology and SYBR green I for monitoring product formation. The method was applied to families with independent deletions (one in exon 14 and the other in exons 23-24) of the Factor VIII gene, thereby allowing a reliable determination of carrier or non-carrier status. The method is extremely versatile and can be adapted to other deletions within the factorVIII gene as well as to other diseases whose molecular pathology consists of deletions or duplications.

Somatic mosaicism and compound heterozygosity in female hemophilia B

Sequencing the complete factor IX gene of 2 sisters with hemophilia B with different phenotypes and no family history of hemorrhagic diathesis revealed a common 5′ splice site mutation in intron 3 (T6704C) in both and an additional missense mutation (I344T) in one. The presence of dysfunctional antigen in the latter strongly suggested that these mutations are in trans. Neither mutation was found in leukocyte DNA from the asymptomatic parents, but the mother was in somatic mosaicism for the shared splice site mutation. This case illustrates the importance of defining the phenotype and considering somatic mosaicism in sporadic cases. It underlines the limitations of complete gene sequencing for the detection of mosaicism and has implication for genetic counseling.

Somatic mosaicism and compound heterozygosity in female hemophilia B

AbstractSequencing the complete factor IX gene of 2 sisters with hemophilia B with different phenotypes and no family history of hemorrhagic diathesis revealed a common 5′ splice site mutation in intron 3 (T6704C) in both and an additional missense mutation (I344T) in one. The presence of dysfunctional antigen in the latter strongly suggested that these mutations are in trans. Neither mutation was found in leukocyte DNA from the asymptomatic parents, but the mother was in somatic mosaicism for the shared splice site mutation. This case illustrates the importance of defining the phenotype and considering somatic mosaicism in sporadic cases. It underlines the limitations of complete gene sequencing for the detection of mosaicism and has implication for genetic counseling.

The revised classification of von Willebrand disease including the previously masqueraded female hemophilia A (type 2N)

The revised classification of von Willebrand disease was proposed by the working committee (Chairperson: J.E. Sadler) and approved by the Scientific and Standardization Committee/the International Society on Thrombosis and Hemostasis in 1993. It consists of three major types; type 1 with decreased level of normal von Willebrand factor (VWF) and type 3 with complete deficiency of VWF as quantitative abnormality, and type 2 with qualitative anomaly of VWF subcategorized into 2A, 2B, 2M and 2N, respectively, depending on the functional abnormalities (decrease of GPIb binding with defect of VWF large multimers, increase of GPIb binding, decrease of GPIb binding with VWF large multimers, decrease of FVIII binding). This classification is frequently quoted in the USA and Europe. We introduce this classification and review again the structural abnormalities of VWF, including the previously masqueraded female hemophilia A (type 2N).

Female Hemophilia A in a Saudi Family: Family Study and Review of the Literature

Female Hemophilia A in a Saudi Family: Family Study and Review of the Literature

Female haemophilia A in a family with seeming extreme bidirectional lyonization tendency: abnormal premature X‐chromosome inactivation?

We studied a female child with mild classical haemophilia A, presenting with a F VIII deficiency similar to that detected in her maternal grandfather. Investigations on several occasions showed that the obligate carrier mother of the proposita had normal VIII:C activity, whereas her likewise obligate carrier sister had a typical carrier VIII:C/vWf:Ag pattern. The child was a phenotypically normal female with normal karyotype. Her father had no clinical or biochemical signs of haemophilia A. RFLP-analysis using DX13 and St14 probes each elicited one allele (5.8 and 3.4 kb, respectively) segregating along with the affected F VIII gene from the hemizygous grandfather to both his daughters and further to the haemophilic female child. The paternity of the child was analyzed using various red cell and HLA antigens and RFLP by p29C, a probe detecting polymorphic hypervariable TaqI and PstI fragments in the pseudoautosomal areas of the X- and Y-chromosomes. All results obtained were concordant with the declared paternity. RFLP-analysis, using single (Pst I) and double digestion (Pst I/Hha I) of DNA and a PGK probe, revealed a remarkable difference in hybridization fragments, strongly suggesting hypermethylation, and in consequence, preferential X-chromosome inactivation in the proposita. This points to extreme lyonization as the most plausible explanation for haemophilia A in this female child. A familial tendency to abnormal premature X-chromosome inactivation is speculated.

Haemophilia A in a Female: Study of a Family Using Intragenic and Extragenic Restriction Site Polymorphisms

Restriction fragment length polymorphisms (RFLPs) were studied in a large Algerian family which includes 6 haemophiliacs and a previously described case of female haemophilia A. The female propositus is 66 years old with a normal karyotype. Her parents are first cousins. Her 3 sons are haemophiliacs and her 3 daughters with affected children are obligate carriers. The proband has an excessive bleeding tendency and markedly reduced levels of F.VIII (VIII C 0.03 U/ml, VIII Ag 0.01 U/ml) with elevated vWF Ag (2.30 U/ml), similar to the levels observed in affected males from the family. Four RFLPs can be identified by Southern blotting after digesting genomic DNA with the restriction enzymes Bcl I, Bgl I, Kpn I/Xba I and Taq I and hybridization with a 647 bp Stu I/Sca I F.VIII genomic probe, a 1.8 Kb EcoRI F.VIII cDNA probe, a 1.0 Kb EcoRI/Sst I fragment of intron 22 and the extragenic probe ST 14, respectively. With these four RFLPs, the propositus was found to be homozygous for the alleles segregating in this family with the abnormal X-chromosome. The carrier status was proven in a granddaughter and excluded in another. In conclusion, this RFLP linkage analysis is another argument to suggest that the propositus, a rare case of female haemophilia, is homozygous for the abnormal gene.

Australian hemophiliac recipients of voluntary donor blood products longitudinally evaluated for AIDS. A clinical and laboratory study, 1983-1986.

One hundred and sixty-one Australian patients with hereditary bleeding disorders comprising hemophilia A (120), hemophilia B (18), von Willebrand's disease (16), and seven symptomatic female hemophilia A or B carriers were screened for clinical and serological evidence of exposure to HTLV-III/LAV/ARV/HIV infection. During the previous five years (1979-1984) they had been treated almost exclusively with blood products derived from Australian voluntary donors. The prevalence of HTLV-III antibodies in 1985 was 45%, with the highest frequency being in those with severe hemophilia A (78%) and the lowest in patients with hemophilia B (6%). Antibody positivity correlated with a reduced absolute T helper (T4) cell numbers and/or an inverted T4:T8 ratio. Lymphadenopathy was detected in 23 subjects but only 13 had an abnormal T cell ratio. Comparison of seropositivity and T4:T8 ratios in 32 patients studied in 1983 and again in 1985 suggested that T4 cell deficiency reflected HTLV-III exposure rather than being a predisposing factor for infection with the virus. Individual patients showed considerable fluctuation in T cell subsets over a 12 month period of follow-up, but as a population there was a slight trend with time towards diminishing T4:T8 ratio only in the antibody positive hemophilia A patients of mild to moderate severity. Three (2%) of the 161 patients screened to date have developed confirmed AIDS with fatal outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

血液疾患における口こう出血管理に関する研究 ２０ ＤＤＡＶＰによる女性血友病Ａ患者の止血管理について

Haemophilia A is a bleeding disorder that usually seen in males and is inherited as a sex-linked recessive trait. The disorder has been reported in females in several families with male haemophiliacs. However about 20% of female haemophiliacs are described as sporadic type.On the other hand, resently a synthetic vasopressin DDAVP (1-deamino-8-D-arginine vasopressin) was used for haemostatic control of haemophiliacs. The haemostatic mechanism of DDAVP in haemophilia A and von Willebrand's disease is understandable because of the increment of factor VII activity.Scaling was performed in a female haemophilia A (VII: C 7%) and then DDAVP (0.4 μg/kg) was administered for haemostatic treatment. DDAVP infusion (iv) induced the increment of factor VII activity. This procedure resulted in effective haemostasis without factor VII replacement therapy.

A Girl with Hemorrhagic Diathesis in a Family of Mild Hemophilia B (Female Hemophilia B?)

Female carriers of hemophilia are usually asymptomatic. Female hemophilia B or symptomatic carriers of hemophilia B are extremely rare and so far only 16 cases have been reported.We report a girl with hemorrhagic diathesis in a family of mild hemophilia B, who was suspected female hemophilia B. The patient was referred to KCMC at the age of 8 years because of easy bruising, which had first been noted at the age of 3 years. The family history showed that father and brother were mild hemophilia B, whose factor IX activity was 36% (4.5%) and 15%, and that her material paternal grandmother, uncle and her cousin had mild bleeding tendency. Mother had no bleeding tendency with normal activity of factor IX, but she was suspected a carrier of hemophilia B because her son was mild hemophilia B. The coagulation findings were as follows: Prothrombin time; 11.9sec., Kaolin activated PTT; 55-63.5sec., Factor IX activity; 4-16%, Factor II, V, VII, VIII, X, XI, XII activity and Fibrinogen level were normal.Platelet function tests: Bleeding time; 3min. 30sec., Platelet retention test; 24%, and Platelet aggregation tests (ADP, Collagen and Ristocetin induced) were normal. The karyotype was found to be 46, XX, although sex chromatin was 4%.If mother is a silent carrier, it is possible for this patient to be female hemophilia B. If mother is not a carrier, we must postulate hemophilia B transmitted by autosomal dominant pattern of inheritance or new disease with low activity of factor IX.We will study on immunological determination of factor IX and more precise family history.

Severe factor VIII and factor IX deficiency in females

A survey of 11 hemophilia centers produced data concerning 28 females with extremely low levels of factor VIII or IX coagulant activity. Ten of the 28 have hemophilia A, six have hemophilia B, and 12 have severe von Willebrand's disease. The 16 females who have severe factor VIII or factor IX deficiency as an isolated defect exemplify several of the possible genetic explanations for the occurrence of hemophilia in females. All 16 bruise excessively, and several have had recurrent hemarthroses. Three of these girls, ages five, 10 and 23 years, have evidence of chronic hemophilic arthropathy. The 12 females with severe von Willebrand's disease are either homozygous for von Willebrand's disease or severely affected heterozygotes. All 12 have mucous membrane bleeding. In addition, five of the 12 have recurrent hemarthroses and three have evidence of chronic joint disease. However, the major problem in the adult females with von Willebrand's disease has been extreme menorrhagia. One of the seven adults underwent irradiation sterilization and another had a hysterectomy because of menorrhagia. The others have been managed with anovulatory drugs or plasma infusions and EACA. Despite menorrhagia, five pregnancies and deliveries have been uneventful in three of these women.

629 SEVERE FACTOR VIII AND FACTOR IX DEFICIENCY IN FEMALES

A survey of eleven hemophilia centers participating in the NHLBI-sponsored “cooperative study of Factor VIII inhibitors developing in hemophiliacs”, produced data concerning 27 females with extremely low levels of factor VIII or IX. Ten of the 27 have hemophilia A, 5 hemophilia B, and 12 have severe von Wille-brand's disease (vWD). The 15 females who have severe F. VIII or F. IX deficiency as an isolated defect exemplify several of the possible genetic explanations for the occurrence of hemophilia in females (dominant inheritance, mosaic Turner's syndrome, abnormality involving X-chromosome, and extreme Lyonization). All 15 bruise excessively and several have had recurrent hemarthroses. Two of these girls, ages 5 and 10 years, have evidence of chronic hemophilic arthropathy and one has twice undergone synovectomy. All twelve females with severe vWD have mucous membrane bleeding. In addition, 5 of the 12 have recurrent hemarthroses and 3 have evidence of chronic joint disease. However, the major problem in the post pubertal females with vWD has been extreme menorrhagia. While one underwent hysterectomy because of this problem the others have been managed with anovulatory drugs or plasma infusions and EACA. Despite menorrhagia, 4 pregnancies and deliveries have been uneventful in two of these women. No unusual bleeding occurred at the time of childbirth; however, when menses began again bleeding was again extreme. This interesting phenomenon may reflect increased levels of F. VIII activity, antigen and ristocetin cofactor activity during pregnancy.

Hemophilia A in a phenotypically normal female with XX/XO mosaicism.

HEMOPHILIA in females has been the subject of a number of reports in recent years.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Excluding patients who conform to the classic sex-linked mode of transmission and are truly homozygous for the hemophilia gene,5 , 9 , 11 , 12 , 14 , 17 a residual group of apparent females who exhibit varying degrees of clinical disease remains. The deficiency of antihemophilic globulin (AHG, factor VIII) in these persons who are assumed to be heterozygotes has generally been explained on the basis of mutation in the normal X chromosome. Five such persons have had chromosome analyses performed,4 , 6 , 8 , 10 , 16 and in only 110 was an abnormal karyotype detected. It is the purpose . . .

Hemophilia A in a phenotypically normal female with XX/XO mosaicism

HEMOPHILIA in females has been the subject of a number of reports in recent years.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Excluding patients who conform to the classic sex-linked mode of transmission and are truly homozygous for the hemophilia gene,5 , 9 , 11 , 12 , 14 , 17 a residual group of apparent females who exhibit varying degrees of clinical disease remains. The deficiency of antihemophilic globulin (AHG, factor VIII) in these persons who are assumed to be heterozygotes has generally been explained on the basis of mutation in the normal X chromosome. Five such persons have had chromosome analyses performed,4 , 6 , 8 , 10 , 16 and in only 110 was an abnormal karyotype detected. It is the purpose . . .