Associated prothrombotic conditions are probably responsible for the occurrence of thrombosis in almost all patients with congenital FVII deficiency. Critical review of the literature.

The occasional occurrence of thrombosis in patients with congenital bleeding disorders has received considerable attention during the past decade. Myocardial infarction, ischemic strokes and venous thromboembolism have been reported in hemophilia A or B patients, in von Willebrand disease and, also, in rare coagulation disorders, especially in factor VII (FVII) deficiency. To explain the relatively high frequency of thrombotic phenomena, mainly venous, seen in the last condition, it was speculated that a special form or variant of FVII deficiency could exist. The presence of associated prothrombotic risk factors has been occasionally reported to be present in these patients but the matter has never been duly evaluated and emphasized. The purpose of the present paper was to evaluate if the clinical setting in which thrombosis appeared in these patients could explain the occurrence of the thrombosis. All reported cases of thrombosis seen in patients with FVII deficiency have been analyzed and the presence of associated risk factors recorded. Out of a population of 33 documented cases, the presence of prothrombotic risk factors was reported in 30 instances. In two of the remaining cases, no mention is made about associated risk factors. In the last case they were explicitly excluded. The critical evaluation of the literature suggests that the occurrence of thrombosis in FVII deficiency may be due to common prothrombotic risk factors. As a consequence it may be only stated that FVII deficiency does not protect from thrombosis.

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.

Hemospermia in patients with congenital coagulation disorders: a study of three cases.

Hemospermia is usually a symptom of urological relevance, however it may have also a medical and hematological significance and has been reported in congenital or acquired bleeding disorders. Because of this symptom's negative psychological impact on the patient, it is likely that the condition is underplayed and therefore underdiagnosed. During the years 1967-2003 we had the opportunity to see 3 patients with hemospermia on a congenital bleeding disorder: a patient with hemophilia A, another with prothrombin deficiency and finally a patient with von Willebrand disease type I. All patients were heterosexual. In all instances the course was benign since it required administration of substitution therapy on only 2 occasions. Rest and abstinence from sexual activity appeared to be helpful. The first patient had other signs and symptoms compatible with the diagnosis of urethritis due to Escherichia coli and he underwent a course of antibiotic therapy. The other 2 cases appeared to be idiopathic since no associated condition was found. Urinary cytology, rectal examination, prostate sonography and prostate-specific antigen were normal in all cases. The rarity of hemospermia in congenital bleeding disorders remains unexplained, although the strong perineal and sphincter muscles may exercise a compressive hemostatic effect which could prevent or reduce bleeding.

Congenital bleeding disorders of the vitamin K-dependent clotting factors.

Congenital bleeding disorders of the vitamin K-dependent coagulation factors represent only about 15-20% of all congenital bleeding disorders. However, they played an important role of the history of blood coagulation. Prothrombin was the first entity dealt with. Subsequently, in the late 1940s or early 1950s, the discovery of factor IX allowed the separation of hemophilia into two groups, A and B. In the 1950s, the discovery of factors VII and X allowed the formulation of a logic and plausible explanation for the clotting mechanism. The subsequent discovery of vitamin K-dependent proteins with an inhibitory effect on blood coagulation has further enhanced the importance of the vitamin K-dependent clotting factors. Recently, the study of families with multiple defects of the prothrombin complex has spurred the interest in vitamin K metabolism and the gamma-carboxylation system. The relevance of these studies had also an important role in the understanding the mechanism of action of other noncoagulation-related proteins. The vitamin K-dependent clotting factors represent a homeostatic mechanism at the basis of the hypercoagulability (thrombosis)-hypocoagulability (hemorrhagic) system, namely, to a mechanism that is vital for survival. The different bleeding condition will be dealt with separately, namely, prothrombin or Factor II, Factor VII, Factor IX (hemophilia B), and Factor X deficiencies. An additional heading deals with the combined defect of the prothrombin complex, namely, combined deficiency of Factor II, Factor VII, Factor IX, and Factor X. Since, sometimes, a hemorrhagic role has been attributed to Protein Z deficiency, another vitamin K-dependent protein, this defect will also be dealt with, even though briefly. Each deficiency has been approached in a global manner, namely, with adequate reference to history, background, prevalence, classification, hereditary pattern, biochemistry and function, molecular biology, clinical picture, updated laboratory diagnosis, prognosis, and therapy. Particular emphasis has been placed on the significance of cases with "true" deficiency [cross-reacting material (CRM negative)] and cases with abnormalities (CRM positive). The genetic, clinical, and laboratory implications of these two forms have been extensively discussed in every instance. The importance of a multiple, combined diagnostic approach that has to include whenever possible clotting, chromogenic, immunological, and molecular biology studies has been underlined. Clotting tests have to be carried out using different activating agents since results may vary, thereby indicating a different reactivity of the abnormal protein. Molecular biology techniques, alone, are unable to supply plausible diagnostic conclusions. In fact the genotype-phenotype relation has not been clarified so far for most of these bleeding conditions. Recent progress in management such as the use of recombinant factor concentrates, results of liver transplantation, and attempts at genetic therapy has been discussed. Potential complications of therapeutic measures have also been discussed. A section dealing with future putative aims of research in this field will close the chapter.

Congenital FX deficiency combined with other clotting defects or with other abnormalities: a critical evaluation of the literature.

The presence of more than one congenital clotting defect in a given patient is a rare event but not an exceptional one. Combined defects of factor X (FX) are very rare because congenital isolated FX deficiency is by itself very rare. A perusal of personal files and of the literature has yielded 12 families with FX deficiency in which an association with another clotting factor deficiency was found. The associated defects were factor VII (FVII) or factor VIII (FVIII) or factor XII (FXII) deficiency. By far the most frequently associated was with FVII. Two forms of this association were found. In the first form there is casual association of both FVII and FX deficiency in the proband with independent recessive segregation of the two defects in other family members. The second form is because of abnormalities in chromosome 13 (deletions, translocations and so on) involving both FX and FVII genes. These genes are known to be very close and located on the long arm of chromosome 13 at about 13q34. In this form the hereditary pattern is autosomal dominant. Isolated FX deficiency and, more frequently, combined FX + FVII deficiency appear also associated with coagulation-unrelated abnormalities (carotid body tumours, mitral valve prolapse, atrial septal defect, ventricular septal defect, thrombocytopenia absent radius (TAR) syndrome, mental retardation, microcephaly and cleft palate). Diagnosis of a combined clotting defect could be difficult on the basis of global tests. For example, both isolated FX deficiency and combined FX + FVII deficiency yield a prolongation of basal PTT and PT. Only specific assays could allow one to reach the correct diagnosis. In cases of casual association with other defects, it is also important to study family members, as the two defects should segregate independently.

The management of feto-maternal alloimmune thrombocytopenia: report of three cases.

We report herein three cases of severe fetal thrombocytopenia due to anti-human platelet antigen (HPA)- 1a maternal antibodies. The first and the third cases were diagnosed on the basis of previously affected siblings and treated successfully by maternal intravenous human immunoglobulins and corticosteroids. In the second case an unexpected neonatal thrombocytopenia was found after birth without previously affected siblings and treated subsequently with intravenous immunoglobulins. Our experience supports a switch from an invasive management, including early FBS (fetal blood sampling) and platelet transfusions, to a more cautious approach. Also in severe HPA-1a alloimmunization and in 'high risk' fetuses, prenatal maternal treatment could be performed, without previous FBS, only on the basis of a risk score defined by sibling history and parents' genotypes.

Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review.

A thorough review of the literature and of personal files has allowed the gathering of 81 patients with rare congenital bleeding disorders and thrombotic phenomena. Sixteen of these patients had congenital afibrinogenemia, eight involved factor V deficiency, 20 factor VII defects, 33 factor XI deficiencies and only one, a factor XIII defect. Altogether 42 patients showed arterial thrombosis (myocardial infarction [MI] in 28 cases; ischemic stroke in 4; arterial occlusion in 8; 2 patients with disseminated intravascular coagulation (DIC)). Ages varied between 13 and 74. Twenty-two patients were males and 16 females. In four cases, sex was not reported. There were three fatalities: two after a MI and one because of heart failure. With regard to venous thrombosis: 9 patients had pulmonary embolism, 15 patients had deep vein thrombosis, 9 patients had both pulmonary embolism and deep vein thrombosis; 1 patient had superficial vein thrombosis, whereas, 5 cases had an unusual site venous thrombosis (two portal systems, two cerebral sinuses, one inferior vena cava) for a total of 39 cases. Age varied between 3 and 86. In this case, 20 patients were males and 17 were females. In two cases, sex was not reported. There were three fatalities: two because of pulmonary embolism and one because of inferior vena cava thrombosis. The fact that thrombosis has never been described in patients with factor II or factor X seems to underscore the central antithrombotic role that these two factors have in the coagulation system.

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

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.

Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia.

BACKGROUND: As reported by major clinical series in the literature, about 2% of patients receiving unfractionated heparin (UFH) develop immune-mediated (type II) heparin-induced thrombocytopenia (HIT) that may be complicated in 30-75% of cases by a paradoxical thrombotic syndrome (HITTS), either arterial or venous. HITTS carries relevant rates of mortality and morbidity, amongst which cerebral and/or myocardial infarction and limb amputations. It is unclear as yet why some patients suffer from isolated thrombocytopenia (HIT), whilst others have HITTS. The aim of the present study was to look for clinical and laboratory features related to the occurrence of HITTS. PATIENTS AND METHODS: We retrospectively analysed the clinical records of 56 patients with proven HIT, as diagnosed on clinical grounds and by in vitro demonstration of immunoglobulin (IgG)/IgM against the PF4/heparin complex. Thirty-four patients (61%) had HITTS (19 venous thrombosis, seven arterial thrombosis, five arterial and venous thrombosis, two skin necrosis, one diffuse intravascular coagulation), whereas 22 had uncomplicated HIT. Amongst HITTS patients, two had limb amputation, five had recurrent thrombosis and seven died. Amongst HIT patients three died from causes unrelated to HIT. RESULTS: No significant difference in sex, age, previous exposure to heparin, UFH route of administration or dose, duration of therapy, time of onset of thrombocytopenia and platelet count recovery, nor antiheparin/PF4 antibodies subtype (IgG or IgM) was detected when comparing HIT and HITTS. In contrast, in the HITTS group a higher prevalence of orthopaedic surgery (15 of 34 vs. 2/22; P=0.01), a significantly lower platelet count nadir (43 +/- 32 vs. 75 +/- 63 x 109/L; P=0.01) and a significantly higher titre of antiheparin/PF4 antibodies, expressed as optical density of enzyme-linked immunosorbent assay (ELISA); (1989 +/- 1024 vs. 1277 +/- 858; P=0.009), were observed in comparison with the HIT group. Amongst HITTS patients, the prevalence of venous thrombosis was significantly higher in orthopaedic patients and in those being treated for venous thromboembolism (18/24 vs. 1/9 patients, chi2 8.4, P=0.004), whilst arterial thrombosis (ART) occurred more often in heparin treatment for arterial disease (3/4 vs. 4/29 patients, chi2 4.6, P=0.03). CONCLUSIONS: Orthopaedic surgery, the severity of thrombocytopenia and high antiheparin/PF4 antibodies titre are adverse prognostic or concurrent factors in the development of HITTS.

Indirect study of thrombopoiesis (TPO, reticulated platelets, glycocalicin) in patients with hereditary macrothrombocytopenia.

Chronic isolated hereditary macrothrombocytopenia (CHMT) is a congenital form of macrothrombocytopenia that seems to be due to defective production secondary to a disturbance in megakaryocyte fragmentation. To better understand the pathogenesis of thrombopoiesis in this hereditary thrombocytopenic disorder, we determined the percentage of reticulated platelets (RP), plasma glycocalicin (GC) and thrombopoietin (TPO) levels in 29 patients with CHMT, 23 patients with immune thrombocytopenic purpura (ITP), and 17 patients with thrombocytopenia secondary to decreased bone marrow megakaryocytes (hypoplasia). The % RP was similar in CHMT (2.27 +/- 1.33) and hypoplasia (1.98 +/- 1.35) patients and markedly lower than that in ITP patients (8.80 +/- 7.97; p <0.001), suggesting that the production of new platelets is reduced in CHMT. Plasma GC was within the normal range (0.84 +/- 0.16 microg/mL) both in patients with CHMT (0.63 +/- 0.20 microg/mL) and ITP (0.82 +/- 0.90 microg/mL), while it was significantly decreased in patients with hypoplasia (0.16 +/- 0.04 microg/mL; p < 0.001). When the GC value was normalized for platelet count, the GC index was normal in CHMT patients (2.05 +/- 1.1) and in patients with hypoplasia (0.85 +/- 0.10) while it was significantly increased in ITP patients (10.88 +/- 18.00; p<0.001); thus, patients with CHMT seem to have a normal platelet turnover. TPO was significantly increased in CHMT (195 +/- 72 pg/ml) as compared with normal (80 +/- 53 pg/ml; p < 0.002); however, the mean level was not as high as in ITP patients (345 +/- 167 pg/mL; p < 0.001). This finding suggests that CHMT syndrome is not secondary to a defective production of TPO and that megakaryocyte mass is nearly normal.

[The visual fixation test in the study of visual-vestibular interactions. General aspects and results in normal subjects and patients]. / II test di fissazione visiva nello studio delle interazioni visivo-vestibolari. Generalità e risultati in soggetti normali e patologici.

Whenever we need to study visual-vestibular interactions, our method of choice among the ones based on thermal stimulation is the visual suppression test. In the vestibular laboratory of the II E.N.T. Clinic of the University of Parma the V.S.T. has been employed since 6 years systematically in all patients undergoing Electronystagmography. Our study was based on 10 normal patients and on 30 patients suffering from different pathologies. These patients were divided into groups according to the site of the lesion. The results we obtained are interesting: this test gives us important clinic data that we cannot obtain using other methods and allows us to discriminate the central or the peripheral site of the vestibular system lesion.

Closed versus open technique in the management of labyrinthine fistulae.

A labyrinthine fistula is the most common complication of cholesteatomatous chronic ear disease. Its treatment remains a controversial subject. The present paper reports our approach to the management of this complication. Operations were performed on 1,226 cases of chronic otitis media with cholesteatoma between January 1971 and December 1985. A labyrinthine fistula was detected in 158 cases. We favor intact canal wall tympanoplasty even in the presence of medium or large fistulas: in the latter case, the matrix is not removed but is trimmed to cover only the bony defect and it is left in place. Open procedures with the preservation of the matrix over the fistula are done in an only-hearing ear with fistula, in ears with a wide defect of the posterior canal wall, and in ears with multiple labyrinthine fistulas. The management of the matrix over the fistula and the anatomic and functional results following each type of procedure are presented and discussed.

The surgical management of childhood cholesteatoma.

The results of treatment of 124 cases of childhood cholesteatoma are reported in the present study and compared with an adult group of patients. Intact canal wall tympanoplasty was performed in over 90 per cent of cases in children and the procedure was staged in nearly 80 per cent of cases. The children had a 43.8 per cent incidence of residual cholesteatoma and an 8.8 per cent incidence of recurrent cholesteatoma in intact canal wall tympanoplasty cases. Intact canal wall tympanoplasty remains the technique of choice in our hands for the treatment of childhood cholesteatoma; pre-planned staging of the operation is mandatory for the detection and elimination of residual cholesteatoma which occurs more frequently in children.

Prevention of recurrent cholesteatoma in closed tympanoplasty.

Recurrent cholesteatoma in a series of 534 staged intact canal wall tympanoplasties performed over a 10-year period has been reviewed for the present study. Overall detected incidence of recurrent cholesteatoma is 5.2% (28 of 534 operated ears). A steady decrease of recurrent cholesteatoma was found, however, in the second period of our surgical experience (1978 to 1982) when prevention techniques were adopted in all operations, resulting in a 1.07% incidence (four of 373 operated ears). Our present policy for prevention of recurrent cholesteatoma in intact canal wall tympanoplasties with mastoidectomy includes the use of plastic sheeting with thick Silastic, the repair of bony sulcus defects with cartilage shavings, staging of the operation with preplanned reexploration of the middle ear and mastoid, and transtympanic ventilation tube insertion in cases of refractory tubal insufficiency.

[Anesthesiologic management in scleroderma patients. Presentation of a clinical case]. / Condotta anestesiologica nel paziente sclerodermico. Presentazione di un caso clinico.

The scleroderma (literally, hard skin), or progressive systemic sclerosis (PSS), is a multisystem disease and can present various anaesthetic problems. The anaesthesist should be aware of the difficulty in opening mouth wide enough for laryngoscopy and intubation, the possibility that cardiopulmonary changes may be present and the probability of lesions in oesophagus, bowel, kidneys, skin and joints. In this article the authors describe the anesthetic management of a patient with Thibierge-Weissenbach syndrome (scleroderma with calcinosis cutis) and explore potential problems that should be anticipated by the anesthesiologist.