A. M. Lombardi

The occasional venous thromboses seen in patients with severe (homozygous) FXII deficiency are probably due to associated risk factors: a study of prevalence in 21 patients and review of the literature.

According to our personal experience and to the study of the literature, 11 cases of venous thrombosis have been described as sporadic reports in patients with severe (homozygous) factor XII (FXII) deficiencies. In every cases but 4, associated risk factors were found to be present (pregnancy, post-partum period, surgery, trauma, in dwelling catheter, AT deficiency, heterozygous factor V Leiden, Burgers disease). In some instances more then one condition was present. The four patients for whom no information is supplied, were cases gathered from old and logically incomplete files and therefore the existence of associated risk factors cannot be excluded.The papers which investigated the presence of venous thrombosis in cohorts of patients with homoxygous FXII deficiency demonstrated the occurrence of venous thrombosis in 2 additional cases out of a total of 63 patients investigated. In these latter cases thrombosis occurred during pregnancy. This brings the total number of patients with FXII deficiency who showed a venous thrombosis to 13. Only a few of these patients were investigated for the presence of concomitant congenital prothrombotic conditions.The conclusion of the study seem to suggest that the role played by FXII deficiency in the pathogenesis of venous thrombosis is minor, if any.

Myocardial Infarction and Arterial Thrombosis in Severe (Homozygous) FXII Deficiency: No Apparent Causative Relation

Twenty-one patients (12 female and 9 male) with severe (homozygous) factor XII (FXII) deficiency and 58 (32 female and 26 male) with heterozygous FXII deficiency were observed for an average 16.2 years. No patient with homozygous FXII deficiency experienced myocardial infarction or any other arterial thrombosis. The same was true for heterozygotes. The cases of FXII deficiency and arterial thrombosis reported in the literature were evaluated. In every instance, associated risk factors were present that could justify the arterial thrombosis. Dyslipidemia, hypertension, smoking, and diabetes mellitus were the most frequent findings. The examination of the few papers that dealt with the prevalence of arterial thrombosis in patients with severe FXII deficiency showed that only 1 patient of 61 experienced myocardial infarction. In conclusion, it seems that the role of FXII deficiency in the pathogenesis of arterial thrombosis is minor.

Pregnancy and oral contraceptives in factor V deficiency: a study of 22 patients (five homozygotes and 17 heterozygotes) and review of the literature

Summary.  Information on the effect of pregnancy or oral contraceptives (OC) in congenital factor V (FV) deficiency is scanty. The personal investigation of five homozygous and 17 female heterozygous showed that patients with severe deficiency bleed considerably at the time of delivery. However, bleeding can be controlled properly by administration of fresh frozen plasma with excellent foetal outcome. The safe level for adequate haemostasis seems around 25% of normal. On the contrary, heterozygote patients show no significant postpartum bleeding and therefore need no substitution therapy. Oral contraceptives were taken and well tolerated by four of our homozygous patients and appear to be beneficial because they cause a decrease in menometrorrhagies thereby improving the anaemia and decreasing transfusional needs. One patient took hormonal replacement therapy with no undue effects. No thrombosis was noted in the propositae during oral contraceptive therapy. The review of the literature has allowed the gathering of information on 20 additional pregnancies. The foetal outcome was satisfactory in every instance. Excessive bleeding was noted in 11 pregnancies. In seven of the remaining pregnancies, no undue bleeding was noted thanks to appropriate substitution therapy. In the remaining two pregnancies no bleeding was noted and no substitution therapy was given. No data are apparently available in the literature about the use of OCs in FV deficiency.

Pregnancies and oral contraceptive therapy in severe (homozygons) FXII deficiency: a study in 12 patients and review of the literature.

Twelve women with severe Factor XII (FXII) deficiency were under observation for an average period of about 16 years. During this time, these women had 19 pregnancies without any bleeding or thrombotic complications. The evaluation of the literature has shown that three patients manifested deep vein thrombosis during pregnancy. Five women also showed mild bleeding at delivery .The significance of these findings is not clear since thrombotic and bleeding complications may occur occasionally even in normal women. Five of our patients took oral contraceptive therapy during their fertile life for a variable period of time (2–10 years). No thrombosis was noted in any of these patients. From the scanty data gathered, in this respect, from the literature, it was shown that only three women with severe FXII deficiency took oral contraceptives and no thrombosis was noted. Altogether these results seem to indicate that the FXII deficiency does not play any significant role in the pathogenesis of bleeding and of thrombotic complications in pregnancy. However, the occurrence of deep vein thrombosis in 3 out of the 64 patients for whom sufficient data could be gathered indicates the need for further studies. This is more so if one considers that 3 out of the 6 cases of venous thromboses described altogether in the literature for females with severe FXII deficiency occurred during pregnancy or puerperium.

Comparison of three different immunoassays in the diagnosis of heparin-induced thrombocytopenia.

Abstract Background: Heparin-induced thrombocytopenia (HIT) is caused by platelet activating antibodies that recognize platelet factor 4/heparin (PF4/H) complexes. Laboratory testing plays a key role in the diagnosis of HIT. As functional assays are unfeasible for most clinical laboratories, antigen binding assays are commonly used in routine testing. However, their low specificity leads to overdiagnosis of HIT. Therefore, it is advisable to improve screening tests in this setting. Methods: Blood samples from 114 patients in whom HIT was suspected were investigated using a chemiluminescence test (HemosIL® AcuStar HIT-IgG), a PF4/H IgG enzyme immunoassay (Lifecodes PF4 IgG), an IgG-specific lateral flow immunoassay heparin-induced thrombocytopenia (LFI-HIT, STic Expert® HIT) and the heparin-induced platelet aggregation (HIPA) test. Results: Twenty-nine (25.4%) out of 114 subjects with suspected HIT had a positive HIPA test. None of patients with a 4Ts score <4 were positive at HIPA. HemosIL® AcuStar HIT-IgG showed the best performance in term of sensitivity and specificity when used as single test. Receiver operating characteristic (ROC) analysis showed optimization of sensitivity and specificity using a cut-off of 1.13 U/mL (0.95 and 0.98, respectively). As an alternative approach, a strategy based on screening samples by STic Expert® HIT and then retesting positive results by Lifecodes PF4 IgG (cut-off 1 OD) or HemosIL® AcuStar HIT-IgG (cut-off 1.3 U/mL) showed a performance compared to a single test approach by HemosIL® AcuStar HIT-IgG. Conclusions: The HemosIL® AcuStar HIT or a combinatorial approach with the STic Expert® HIT and the PF4/H IgG enzyme immunoassay provide an accurate diagnosis of immune HIT.

Persistent validity of a classification of congenital factor X defects based on clotting, chromogenic and immunological assays even in the molecular biology era.

Summary.  An adequate classification of congenital bleeding disorders is of great importance in clinical practice. This is true also for factor X (FX) deficiency. This defect is classified in two forms: type I (cases with low activity and antigen) and type II (cases with low activity and variable levels of antigen). The introduction of molecular biology techniques has allowed a classification based on the site of mutation (propeptide, Gla‐domain, catalytic domain etc.) or on the type of mutation (missense, nonsense, deletion etc.). However, with a partial exception for defects in the Gla‐domain, no site or type of mutation yields a constant and/or typical phenotype. Due to these difficulties, a classification based on clotting, chromogenic or immunological assays is still the most suited for clinical purposes. A satisfactory classification that takes into account recent advances of FX deficiency could read today as follows:

Unexplained discrepancies in the activity--antigen ratio in congenital FX deficiencies with defects in the catalytic domain.

Studies on molecular biology have considerably enhanced our understanding of congenital coagulation disorders but have failed so far to supply tools for an adequate classification of defects. In fact, mutations in the same domain may give rise to different phenotypes. Conversely, mutations in different domains, controlled by different exons, may cause similar patterns. The 37 kindreds with congenital factor X (FX) deficiency, known to have a defect in the catalytic domain, have been evaluated in an attempt to investigate the genotype—phenotype relation. Discrepant results were obtained because about half kindreds showed a type I pattern, namely a concomitant decrease in FX activity and antigen. The other half showed a type II pattern, namely a decrease in FX activity with a normal or near normal FX antigen. In a few instances, the allocation of the kindred either to type I or to type II defect could not be reached, due to the lack of information about the antigen. The comparison of the kindreds in which the same mutation has been discovered by different investigations is not always possible also for lack of information. The study analyzes the need to have a multipronged approach to the study of congenital FX deficiency. The indication of a mutation in a given domain does not provide clear information about the phenotype.

Comparable levels of activity and antigen in factor XII deficiency: a study of 21 homozygotes and 58 heterozygotes.

Results of coagulation studies on 21 homozygote patients with factor XII (FXII) deficiency revealed that all of them had no cross-reacting material (CRM) in their plasma. The 58 heterozygotes had in every instance an antigen level comparable to that of clotting activity namely, approximately 50% of normal. An analysis of all pertinent literature also showed that the presence of CRM is very rare in FXII deficiency. CRM is present in approximately 5% of homozygote patients. More precisely, seven of 145 patients. Only in one case, the antigen level was normal (FXII Washington). This prevalence appears lower than that observed for another contact phase factor (prekallikrein). The significance of blood abnormal forms of FXII has not been completely clarified yet. Their study appears useful in the attempt of clarifyng the structure-function relation of factor XII.

The impact of blood coagulability on atherosclerosis and cardiovascular disease: a rebuttal

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Homozygous FVII deficiencies with different reactivity towards tissue thromboplastins of different origin.

Abstract The reagents most frequently used for FVII activity assay are obtained by rabbit brain or human placenta. In recent years, human recombinant thromboplastins have received great attention. FVII activity in FVII deficiency is usually low, regardless of the thromboplastin used. There are a few exceptions to this rule. These are represented by FVII Padua (Arg304Gln), FVII Nagoya (Arg304Trp), and FVII (Arg79Gln). In these three instances, clear discrepancies were noted in the FVII activity depending on the thromboplastin used. This indicates that at least two areas of FVII are involved in tissue binding, namely an epidermal growth factor domain of the light chain (Arg79Gln) and the catalytic domain (Arg304), controlled by exons 4 and 8, respectively. Since these three variants are cross reactive material positive, namely they are Type 2 defects, all other variants with normal antigen should be investigated by a panel of at least three tissue thromboplastins (rabbit brain, human tissue or human recombinant, and ox brain derived) in order to obtain a satisfactory classification.