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Ligneous conjunctivitis (LC) is a rare form of pseudomembranous chronic conjunctivitis caused by a deficiency in plasminogen activity. Due to its rarity, little is known about this disorder. We hereby report a case of ligneous conjunctivitis, describing the clinical findings, the biological diagnosis and the treatment of this rare disease.

Connective tissue dysplasia (CTD) is an urgent problem, especially in young and employable people. Damage to cardiovascular system and, in particular, aorta is predominant factor determining the incidence of various complications and mortality in patients with CTD. The authors report surgical treatment of aortic hypoplasia in an adolescent patient with connective tissue dysplasia syndrome and combined deficiency of coagulation factors.

Introduction: Postpartum haemorrhage (PPH) is the main cause of maternal morbidity and mortality globally, but it is far more important in non-developed countries. PPH represents 25% of all maternal deaths worldwide. Women with von Willebrand disease (VWD) and other inherited haemorrhagic disorders are at increased risk of PPH. Our aim was to establish a probable association of severe PPH in women with a history of haemostatic abnormalities., Methods: An observational, controlled study of adult women with a one or more episodes of severe PPH requiring treatment in an intensive care unit or >10 units of blood products during the 24-hour period after diagnosis and their controls. The tests performed were blood cell count, blood group, renal, viral, liver function and haemostatic tests, fibrinogen, activity of the plasma factors and specific test to diagnose and classify VWD., Results: We included 124 women with 133 PPH events and their controls. The median age at the first event was 25.5 years old. Results were significantly different between the groups in terms of fibrinogen concentration, VWF:Ag, VWF:RCo and FVIII. A specific diagnosis was established in 69 (55.6) and 4 (3.2%) patients in the PPH group and controls, respectively. Of 61 patients with VWD, 57 had type 1, two had type 2A, and another two had type 2B., Conclusion: Our results show a relationship between PPH and inherited haemostatic disorders. VWD was the most frequent diagnosis. Appropriate and opportune diagnosis before pregnancy of inherited haemostatic disorders may be important to effectively prevent and treat PPH., (© 2019 John Wiley & Sons Ltd.)

Background: Conventional coagulation assays (CCAs), prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (aPTT), detect clotting factor (CF) deficiencies in hematologic disorders. However, there is controversy about how these CCAs should be used to diagnose, treat, and monitor trauma-induced coagulopathy. Study objectives were to determine whether CCA abnormalities are reflective of deficiencies of coagulation factor activity in the setting of severe injury., Methods: Patients without previous CF deficiency within a prospective database at an ACS-verified Level I trauma center had CF activity levels, PT/INR, aPTT, and fibrinogen levels measured upon emergency department arrival from 2014 to 2017. Linear regression assessed how CF activity explained the aPTT and PT/INR variation. Prolonged CCA values were set as INR greater than 1.3 and aPTT greater than 34 seconds. CF deficiency was defined as less than 30% activity, except for fibrinogen, defined as less than 150 mg/dL., Results: Sixty patients with a mean age of 35.8 (SD, 13.6) years and median New Injury Severity Score of 32 (interquartile range, 12-43) were included; 53.3% sustained blunt injuries, 23.3% required massive transfusion, and mortality was 11.67%. Overall, 44.6% of the PT/INR variance and 49.5% of the aPTT variance remained unexplained by CF activity. Deficiencies of CFs were: common pathway, 25%; extrinsic pathway, 1.7%; and intrinsic pathway, 6.7%. The positive predictive value for CF deficiencies were: (1) PT/INR greater than 1.3:4.4% for extrinsic pathway, 56.5% for the common pathway; (2) aPTT greater than 34 seconds:16.7% for the intrinsic pathway, 73.7% for the common pathway., Conclusion: Almost half of the variances of PT/INR and aPTT were unexplained by CF activity. Prolonged PT/INR and aPTT were poor predictors of deficiencies in the intrinsic or extrinsic pathways; however, they were indicators of common pathway deficiencies., Level of Evidence: Prognostic, level III.

Introduction: Even though thrombotic events are rare in patients with coagulation deficiencies, several cases of both arterial and venous thromboses have been reported in patients with single coagulation factor defects and platelet defects. Thromboses have been described both in hemophilia A and B, von Willebrand disease as well as in many other rare congenital coagulation factor and platelet defects. Thromboses may also occur in patients with acquired hemophilia and in patients with severe thrombocytopenia due to hematological malignancies or intensive chemotherapy. Areas covered: We searched in the PubMed database to identify scientific publications describing patients with bleeding disorders and thromboses and published suggestions/guidelines for the treatment of thromboses in such patients. Expert commentary: The article gives a review of published case reports/studies of thromboses in these patients. Thromboses are rare in all these diseases. There is generally a lack controlled clinical studies for the use of anticoagulation therapy in such patients, and the article gives an overview of published suggestions and expert opinions based on the experience at large centers for treatment of thromboses in patients with congenital coagulation defects, acquired hemophilia and severe thrombocytopenia.

The deficiency of fibrinogen, prothrombin, factor V (FV), FVII, FVIII, FIX, FX, FXI, and FXIII, called rare coagulation disorders (RCDs), may result in coagulopathies leading to spontaneous or posttrauma and postsurgery hemorrhages. RCDs are characterized by a wide variety of symptoms, from mild to severe, which can vary significantly from 1 disease to another and from 1 patient to another. The most typical symptoms of all RCDs are mucosal bleedings and bleeding at the time of invasive procedures, whereas other life-threatening symptoms such as central nervous system bleeding and hemarthroses are mostly present only in some deficiencies (afibrinogenemia, FX, and FXIII). At variance with hemophilia A and B and von Willebrand disease, RCDs are much less prevalent, ranging from 1 case in 500 000 to 1 in 2 million in the general population. Their clinical heterogeneity associated with the low number of patients has led to a delay in the development of appropriate therapies. Indeed, a similar heterogeneity can also be found in the treatment products available, ranging from the specific recombinant proteins to treat FVII- and FXIII-deficient patients to the complete absence of specific products to treat patients with FII or FV deficiencies, for whom prothrombin complex concentrates or fresh frozen plasma are, to date, the only option. The recent development of novel hemostatic approaches for hemophilia, such as the use of nonsubstitutive therapy as RNA interference, anti-tissue factor pathway inhibitor, and the gene therapy aimed at improving the patient's quality of life may also have an important role in the treatment of patients with RCDs in the future., (© 2019 by The American Society of Hematology.)

Background: Congenital plasminogen deficiency is a rare autosomal recessive condition. Plasminogen deficiency is thought to result in an inability of fibrin breakdown and therefore accumulation of fibrin and formation of ligneous changes. Ligneous lesions can form on a number of mucosal membranes including the cervix and endometrium., Methods: We report the case of a 25-year-old woman with type 1 plasminogen deficiency with ligneous cervicitis and endometritis and her treatment and clinical course over the last few years. We then review the current literature of ligneous cases of the female genital tract and discuss available treatment options., Key Results: We found 30 reported cases of ligneous lesions affecting the female genital tract, with the cervix being the most affected part. A number of treatment options have been tried by our patient and other cases in the literature. These include use of the combined oral contraceptive pill, fresh frozen plasma infusion, topical plasmin and plasminogen and trial use of plasminogen concentrate., Conclusions: This is a chronic condition requiring a multidisciplinary approach. There is currently no definitive treatment for the condition, current trials with plasminogen concentrate replacement therapy may provide a promising option for these patients in the future., (© 2018 John Wiley & Sons Ltd.)

Objective: To explore the change of coagulation function and associated potential mechanisms and the relationship between coagulation disorders and deep venous thrombosis (DVT) after subarachnoid hemorrhage (SAH) within 3 days of onset., Methods: A total of 150 patients with SAH within 3 days of onset and 100 healthy individuals were recruited. Thrombelastography analysis and traditional laboratory tests were performed. Tissue factor (TF), tissue factor pathway inhibitor (TFPI) and activated protein C (APC) were tested by using enzyme-linked immunoassay kits. Extremities of patients with SAH were scanned by Doppler ultrasonography. Subgroup analysis was performed in patients with SAH based on the presence or lack of DVT., Results: Compared with control groups, R (an indicator of coagulation factor function in thrombelastography) was significantly decreased (4.32 ± 0.99 minutes vs. 6.00 ± 0.75 minutes; P < 0.001), especially in patients with DVT. TF was significantly increased (20.84 ± 4.15 pg/mL vs. 5.24 ± 1.86 pg/mL; P < 0.001). TFPI was decreased (50.42 ± 5.81 ng/mL vs. 64.10 ± 6.04 ng/mL). APC had no apparent changes. R was negatively correlated with TF (r = 0.358; P < 0.05) and positively correlated with TFPI (r = 0.325; P < 0.05) and APC (r = 0.162; P < 0.05). TF, TFPI, and APC had the same variation characteristics in the DVT subgroup compared with the no DVT subgroup. DVT was associated with R through association analysis (r = 0.369; P < 0.05). The R cutoff value for estimating the presence of DVT was 3.65 minutes., Conclusions: Coagulation factor hyperfunction may be mainly accompanied within 3 days of SAH onset and may induce DVT. This situation may be associated with TF-TFPI-APC imbalance. R = 3.65 minutes was a potential intervention point to prevent the risk of DVT in this population., (Copyright © 2017. Published by Elsevier Inc.)

Massive obstetric haemorrhage remains a major cause of maternal death attributable to hypofibrinogenaemia. Transfusion of large volumes of fresh frozen plasma (FFP) is required to normalise fibrinogen levels. We compared the efficacy of FFP (F group) with that of FFP plus fibrinogen concentrate (F + F group) in massive obstetric haemorrhage. In this retrospective study, we compared the medical charts (2004-2016) of 137 patients with <150 mg/dl fibrinogen treated with F + F (n = 47; after August 2009) or F (n = 56; before August 2009). Although fibrinogen concentrate was only administered in severe cases, the FFP/red blood cell concentrate (RCC) ratio was significantly lower in the F + F group than in the F group. A sub-group analysis of cases requiring ≥18 RCC units showed that the F + F group received significantly less FFP than the F group (40.2 ± 19.6 versus 53.4 ± 18.5 units; P = 0.047) and showed significantly less pulmonary oedema (24.0% vs 57.1%; P < 0.05) in the absence of any significant differences in pre-transfusion coagulation, estimated blood loss, or RCC transfusion volume. Administration of fibrinogen concentrate increased the rate of fibrinogen supplementation five-fold and reduced FFP dosage, the FFP/RCC ratio, and the incidence of pulmonary oedema.

Aim: Chronic subdural hematoma (CSDH) is typically in elderly and rarely in young people. To prevent complications and re-bleeding after surgical treatment of CSDH it is important to assess the risk factors as coagulation disorders especially in young patients (below 65 years) with no history of head trauma, alcohol abuse or anticoagulant therapy., Patients and Methods: This study consists of 16 patients (12 males, 4 females) with age ranging from 27 to 59 years (median 48,25 years) operated for CSDH. All patients are submitted to routine coagulation parameters pre-operatively and complete screening for unknown coagulation deficit in the follow-up., Results: Factor VII was altered in 6 out of 16 patients and one patient had the alteration of the Von Willebrand factor. Recurrence occurred in 4 out of 16 patients and all of these patients were positive for factor VII deficiency. Three pts were in therapy with ASA. No patients were alcoholists or suffered from hematological disease., Conclusion: In this study we documented that the decreased activity of VII factor may play a role in the pathophysiology and recurrence of spontaneous CSDH in young adults. We suggest that for young patients aged under 65 y.o. suffered from CSDH the screening of coagulation factors is useful to planning a safely and correct surgical therapy.

We report a first case of hypocomplementemic urticarial vasculitis of C2 fraction in a child, with cutaneous manifestation only, with no reports in scientific literature.

Pulmonary embolism is a complication of deep vein thrombosis. It occurs in the population with a normal clotting mechanism, but it may also occur in patients with congenital bleeding conditions. Here, we report on all cases of pulmonary embolism in congenital hemorrhagic disorders. All reported cases of pulmonary embolism in congenital coagulation disorders have been gathered by a time-unlimited PubMed search. Cross-checking of the references listed at the end of the single papers was carried out to avoid omissions. Seventy-two patients had an objectively demonstrated pulmonary embolism. The event occurred in patients with fibrinogen, factor V, factor VIII (FVII), FVIII, FIX, and FXI deficiency, and in those with von Willebrand's disease. No embolism was reported in FII, factor X, and FXIII deficiency. Thirty were women and 28 were men, whereas in the remaining 14 cases, sex was not reported. Age varied from 6 to 81 years (mean age 34.3 years). The management varied from only supportive to the administration of unfractionated heparin, low-molecular-weight heparin, and anti-vitamin K medications, accompanied by adequate replacement therapy. Evolution was fair or good in the majority of cases, but there were 10 fatalities. Risk factors were present in 61 patients. The most frequent of these were replacement therapy (35 cases), surgery (34), and old age (13). Some patients had more than one risk factor. Eleven patients had no risk factors. There are discrepancies in the prevalence of pulmonary embolism among different clotting disorders. The conditions most frequently affected are FVII deficiency and fibrinogen defects. The significance of the findings is discussed.

Background: Postoperative haemorrhage in neurosurgery is associated with significant morbidity and mortality. There is controversy whether or not factor XIII (FXIII) deficiency leads to bleeding complications after craniotomy. Decreased fibrinogen levels have been associated with an increased incidence of bleeding complications in cardiac and orthopaedic surgery. The aim of this study was to assess perioperative fibrinogen and FXIII levels in patients undergoing elective intracranial surgery with and without severe bleeding events., Methods: Perioperative FXIII and fibrinogen levels were prospectively assessed in 290 patients undergoing elective craniotomy. Patients were divided into two groups according to the presence or absence of severe bleeding requiring surgical revision. Coagulation test results of these groups were compared using Student's t-test., Results: The incidence of postoperative severe bleeding was 2.4%. No differences in FXIII levels were observed, but postoperative fibrinogen levels were significantly lower in patients suffering from postoperative haematoma compared with those without postoperative intracranial bleeding complications [237 mg dl(-1) (standard deviation, SD 86) vs 170 mg dl(-1) (SD 35), P=0.03]. The odds ratio for postoperative haematoma in patients with a postoperative fibrinogen level below 200 mg dl(-1) was 10.02 (confidence interval: 1.19-84.40, P=0.03)., Conclusions: This study emphasizes the role of fibrinogen as potentially modifiable risk factor for perioperative bleeding in intracranial surgery. Future randomized controlled trials will be essential to identify patients who might benefit from fibrinogen substitution during neurosurgical procedures., (© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Based on the premise that the capacity of plasma to generate thrombin in vitro is a comprehensive and precise functional test of the clotting system, we designed a cross-sectional, single-center study involving 83 patients with rare bleeding disorders (RBDs) to compare the usefulness of the thrombin generation (TG) assay versus conventional tests including prothrombin time (PT) and activated partial thromboplastin time (aPTT) in predicting bleeding risk in patients with RBD in southern Iran. The TG parameters consisted of endogenous thrombin potential, lag time, peak, time to peak (ttPeak), and start tail. The area under the receiver-operating characteristic (ROC) curve showed statistically significant associations between bleeding risk and lag time, ttPeak, and start tail. We determined cutoff values for these 3 TG parameters and obtained a negative predictive value of 86% to 90% in patients with RBD who had a bleeding score (BS) ≤13. The ROC curves for the association of PT and aPTT with BS did not indicate any significant association. Correlation analysis supported the results of ROC curve analysis, only lag time, ttPeak, and start tail showed significant positive correlations with BS (P < .05). Disease severity based on plasma factor activity was significantly associated with prolonged lag time and ttPeak and with prolonged PT (P <.05). We suggest that TG assay is a potentially more useful tool for predicting the bleeding risk in patients with RBD. However, the small sample size in different RBD subgroups precluded subgroup analysis. Prospective multicenter studies with larger numbers of patients are therefore advisable., (© The Author(s) 2013.)

This is a retrospective study on six multiple myeloma patients with upfront coagulopathy and bleeding. A detailed description and analysis of clinical characteristics, coagulation factor deficiencies, treatments and outcome of those six multiple myeloma patients are presented. All six patients presented with significant bleeding. One patient was detected with single factor X deficiency and another with single factor VII (FVII) deficiency, whereas four other patients had complex factor deficiencies. The time from symptom presentation to diagnosis ranged from 3 to 10 months. After correct diagnosis and coagulation factor supplementation, those patients were treated with bortezomib/adriamycin/dexamethasone (PAD) or melphalan/dexamethasone/thalidomide (MTD) regimen. It took 29-71 days (median time 46 days) to completely correct coagulation factor deficiencies since the start of therapy for multiple myeloma. Multiple myeloma patients with acquired bleeding disorders may present with large, deep and multiple sites of haematoma or other types of significant bleeding, which may affect bone marrow examination in some of the cases. Patients may be easily misdiagnosed. The routine examinations of erythrocyte sedimentation rate, serum immunoglobulins and blood urine light chain are the key to diagnosis, hence requiring the treating physician to think broadly and look for traits suggesting myeloma as the underlying cause.

Study Objective: To evaluate the incidence of hemostatic disorders in a population of adolescents with various patterns of abnormal uterine bleeding (AUB)., Design: Retrospective observational study., Setting: University hospital., Participants: One hundred thirteen adolescents with AUB; mean age at menarche and mean age at the onset of symptoms 12 ± 1.2 years and 13.5 ± 2.8 years, respectively., Main Outcome Measures: Data on menstrual history, bleeding symptoms, co-existing medical conditions, and medical therapies were assessed. All patients were screened for hemostatic disorders with laboratory testing. The incidence of the disorders was calculated. Subjects were further divided in 2 groups based on whether the AUB started in the first 2 years from menarche (group 1) or later (group 2). A statistical analysis was performed using a chi-square test to compare incidence of hemostatic disorders between the groups., Results: One hundred thirteen adolescents with AUB were identified. Overall, 54 (47.8%) patients had some underlying hemostatic disorder, of which a platelet dysfunction was the most common (17.7%). Von Willebrand disease was detected in 13.3% of cases and a deficiency of a coagulation factor in 12.4%. In 7.1% of patients an isolated increase of bleeding time was observed. When divided in 2 groups, 44.2% of patients in group 1 and 59.2% in group 2 had a coagulation disorders, with no statistically significant difference between the 2 groups (P = .17)., Conclusion: AUB in adolescents is frequently associated with an underlying disorder of hemostasis, most commonly a platelet function disorder. The results highlight the importance of screening for coagulation disorders in adolescents with AUB, independently from the gynecologic age at onset., (Copyright © 2013 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Epistaxis, superficial and deep hematomas, hemarthrosis, gastrointestinal bleeding, hematuria represent the most frequent hemorrhagic events in congenital coagulation disorders. Occasionally, bleeding manifestations occur in unusual sites or are peculiar. A clotting defect may alter the clinical aspect of skin conditions or infections (hemorrhagic scabies or varicella). Hemobilia may occur as a complication of transjugular liver biopsy in hemophilia or Bernard-Soulier syndrome. Hemarthrosis of small joints of feet and hands occur in patients with hemophilia treated with protease inhibitors. Intramedullary hematomas of long bones have been described in α2-plasmin inhibitor or fibrinogen deficiencies. Spleen fracture with consequent hemoperitoneum has been reported in patients with fibrinogen deficiency. Rectus muscle sheath hematoma may occur in patients with factor VII (FVII)or FX deficiency. Acute or subacute intestinal obstruction may be caused by intramural wall hematomas in hemophilia and von Willebrand (vW)-disease. Physicians should always keep in mind that a congenital hemorrhagic disorder may cause bleeding in any tissue of the body and therefore alter the normal clinical features of a given disease.

Background: Coagulopathic bleeding is a leading cause of in-hospital death after injury. A recently proposed transfusion strategy calls for early and aggressive frozen plasma transfusion to bleeding trauma patients, thus addressing trauma-associated coagulopathy (TAC) by transfusing clotting factors (CFs). This strategy may dramatically improve survival of bleeding trauma patients. However, other studies suggest that early TAC occurs by protein C activation and is independent of CF deficiency. This study investigated whether CF deficiency is associated with early TAC., Methods: This is a prospective observational cohort study of severely traumatized patients (Injury Severity Score ≥ 16) admitted shortly after injury, receiving minimal fluids and no prehospital blood. Blood was assayed for CF levels, thromboelastography, and routine coagulation tests. Critical CF deficiency was defined as ≤ 30% activity of any CF., Results: Of 110 patients, 22 (20%) had critical CF deficiency: critically low factor V level was evident in all these patients. International normalized ratio, activated prothrombin time, and, thromboelastography were abnormal in 32%, 36%, and 35%, respectively, of patients with any critically low CF. Patients with critical CF deficiency suffered more severe injuries, were more acidotic, received more blood transfusions, and showed a trend toward higher mortality (32% vs. 18%, p = 0.23). Computational modeling showed coagulopathic patients had pronounced delays and quantitative deficits in generating thrombin., Conclusions: Twenty percent of all severely injured patients had critical CF deficiency on admission, particularly of factor V. The observed factor V deficit aligns with current understanding of the mechanisms underlying early TAC. Critical deficiency of factor V impairs thrombin generation and profoundly affects hemostasis.

Background: Thrombophilias, both acquired and inherited, have been investigated in the etiopathogenesis of unexplained recurrent pregnancy loss., Aim: To study coagulation inhibitors and activated protein C resistance (APCR) in recurrent pregnancy losses (RPL) occurring in second and third trimesters., Materials and Methods: A total of 30 pregnant women (group A) with two or more recurrent unexplained fetal loses were evaluated for APCR, protein C deficiency, protein S deficiency, antithrombin deficiency, and antiphospholipid antibodies (APLA). Thirty age-matched controls were taken (group B) comprising of pregnant women with at least one live issue., Statistical Analysis: Comparisons between two group frequencies and group means were made using Chi square test and Student's t test, respectively., Results: Protein C and protein S levels were reduced in group A compared with group B and the difference was statistically significant (P=0.005 and P=0.032, respectively). The mean value of antithrombin was slightly reduced in group A compared with group B. APCR was observed in 16.6% cases and 3.3% controls. However, the difference was not statistically significant. APLA was observed in 20% cases and none of the controls. Of these, lupus anticoagulant was positive in 16.6% cases and anticardiolipin antibodies in 10% cases. Combined defects were seen in seven patients., Conclusion: There is a significant risk of RPL in pregnant women with thrombophilias. Therefore, screening for thrombophilias may be justified in pregnant women with unexplained recurrent fetal wastage, especially in second and third trimester.

Inherited antithrombin deficiency is estimated to carry a 50% risk of a venous thrombotic complication during each pregnancy and puerperium. We present a case of a female with heterozygous type I antithrombin deficiency who presented with a central nervous system transverse sinus thrombosis in the third trimester of pregnancy despite the use of therapeutic doses of low molecular weight heparin, as venous thromboembolic prophylaxis, since conception. A successful pregnancy outcome was achieved with the combined use of therapeutic anticoagulation and regular plasma-derived antithrombin concentrate infusions to normalize her antithrombin levels. This case lends further debate to the issue of whether antithrombin concentrate, in addition to anticoagulation, should be routinely administered for venous thromboembolic prophylaxis during pregnancy and the puerperium to women with inherited antithrombin deficiency. This point may become more relevant as further experience is gained with the use of recombinant human antithrombin., (Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Thrombotic manifestations occurring in patients with coagulation defects have drawn considerable attention during the last decade. It concerned mainly patients with hemophilia, vW disease or FVII deficiency. Occasional reports involved also the deficiencies of the contact phase of blood coagulation, mainly FXII deficiency. The purpose of the present study was to evaluate the comparative incidence of thrombosis in all reported patients with FXII, Prekallikrein and Kininogens deficiencies. Out of the reported 341 cases with these conditions that could be tracked there were 43 cases with thrombosis. More specifically, there were 32 patients with FXII deficiency who also had a thrombotic event (16 arterial and 16 venous). As far as Prekallikrein deficiency is concerned, there were nine cases with thrombosis (five arterial and four venous). Finally, two patients with Total or High molecular weight Kininogen deficiencies had also a thrombotic manifestation (one arterial and one venous). The thrombotic manifestations were M.I. 11 cases; ischemic stroke 9 cases; peripheral arteries 3 cases; deep vein thrombosis with or without pulmonary embolism 17 cases; thrombosis in other veins 3 cases. Congenital or acquired associated prothrombotic risk factors were present in 33 out of 36 cases. In three cases the existence of associated risk factors was excluded whereas in the remaining seven patients no mention is made in this regard. This study clearly indicates that the severe in vitro coagulation defect seen in these conditions does not protect from thrombosis.

The detection rate of perinatal stroke is rising due to improved neuroradiological imaging techniques, increased survival of neonates with severe underlying diseases and an increased awareness of the diagnosis by pediatricians. Its pathogenesis is multifactorial and includes a large variety of maternal and neonatal risk factors as well as prothrombotic coagulation factors. Although the relative risk of prothrombotic coagulation factors is still unknown, testing is recommended to design large studies in the near future. This article is an overview of studies of prothrombotic risk factors in both neonatal arterial ischemic stroke and cerebral sinovenous thrombosis. Although prothrombotic coagulation factors are present in more than half of the cases, we conclude that they most likely play a minor role in the pathogenesis of perinatal stroke. Current therapeutic guidelines focusing on thrombosis are based on expert opinion and recommend low molecular weight or unfractionated heparin for cardioembolic arterial ischemic stroke, antiplatelet or anticoagulant therapy for recurrent arterial ischemic stroke, and low molecular weight heparin or unfractionated heparin for sinovenous thrombosis without hemorrhage and/or when extension of the thrombotic process occurs.

Congenital dysfibrinogenemia is a rare disease characterised by inherited abnormality in the fibrinogen molecule, resulting in functional defects. Two patients, a 26-year-old woman and a 61-year-old man, both with history of thrombotic events, had abnormal coagulation test results. DNA sequencing showed the heterozygous gamma Y363N mutation (Fibrinogen Praha III) and the heterozygous Aalpha N106D mutation (Fibrinogen Plzen), respectively. Fibrin polymerisation, after addition of either thrombin or reptilase, showed remarkably delayed polymerisation in both cases. Fibrinolysis experiments showed slower tPA initiated lysis of clots. SDS-PAGE did not show any difference between normal and Praha III and Plzen fibrinogens. Both mutations had a significant effect on platelet aggregation. In the presence of either ADP or TRAP, both mutations caused the decrease of platelet aggregation. SEM revealed abnormal clot morphology, with a large number of free ends and narrower fibres of both fibrin Praha III and Plzen. Praha III mutation was situated in the polymerisation pocket "a". The replacement of the bulky aromatic side chain of tyrosine by the polar uncharged small side chain of asparagine may lead to a conformational change, possibly altering the conformation of the polymerisation pocket. The Plzen mutation is situated in the coiled-coil connector and this replacement of polar uncharged asparagine residue by polar acidic aspartate changes the alpha-helical conformation of the coiled-coil connector; and may destabilise hydrogen bonds in its neighborhood. Although both mutations are situated in different regions of the molecule, both mutations have a very similar effect on fibrinogen functions and both are connected with thromboses.

Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes, and cardiovascular system. The classic forms of PXE are due to mutations in the ABCC6 gene that encodes the ABCC6 protein, a putative transmembrane transporter expressed primarily in the liver and the kidneys. PXE-like clinical findings have been encountered in association with vitamin K-dependent coagulation factor deficiency, an autosomal recessive disorder that is due to mutations in either the GGCX or VKORC1 genes. In this study, we investigated a family with two siblings with characteristic features of PXE and vitamin K-dependent coagulation factor deficiency. Mutation analysis identified two GGCX mutations in the affected individuals (p. R83W and p.Q374X); however, no mutations in either ABCC6 or VKORC1 could be found. GGCX encodes a gamma-glutamyl carboxylase necessary for activation of both coagulation factors in the liver and matrix gla protein, which, in fully carboxylated form, is able to prevent ectopic mineralization. Analysis of skin by specific antibodies demonstrated that matrix gla protein was found predominantly in undercarboxylated form and was associated with the mineralized areas in the patients' lesional skin. These observations pathomechanistically suggest that, in our patients, reduced carboxylase activity results in a reduction of matrix gla protein carboxylation, thus allowing peripheral mineralization to occur. Our findings also confirm GGCX as the second gene locus causing PXE.

Ligneous gingivitis is a rare condition characterized by inflammation and nodular gingival enlargement secondary to fibrin deposits in the gingival that results from plasminogen deficiency. Several therapeutic approaches have been used with limited success. We report a case of a patient with homozygous plasminogen deficiency and ligneous gingivitis that was initially refractory to local care and systemic antibiotics, but later improved with the addition of warfarin.

We studied the prevalence of acquired and genetic thrombophilia in 198 women with recurrent fetal loss who were having three or more than three abortions. Seventy-nine women had only early pregnancy losses, that is, first trimester abortions, 30 women had only late pregnancy losses, that is, second and third trimester abortions whereas 89 had both early and late pregnancy losses. The control group included 100 age-matched fertile parous women who did not have any obstetric complications and had at least one normal healthy child. Several genetic and acquired thrombophilia markers were studied. The strongest association was observed with anticardiolipin (odds ratio 22.6, confidence interval 5.7-89, P = 0) followed by lupus anticoagulant, anti-beta2 glycoprotein-1, antiannexin. Association of antiphospholipid antibody syndromes was detected with the time of pregnancy loss in anticardiolipin, lupus anticoagulants, which was significantly associated with early pregnancy loss as compared with second and third trimester loss. In case of beta2 glycoprotein-1, antiannexin it was less significantly associated with early pregnancy loss as compared with second and third trimester loss. The risk of fetal loss with protein S deficiency was the highest risk observed for any heritable thrombophilia, followed by protein C, factor V Leiden, endothelial protein C receptor, antithrombin III deficiency and beta448 fibrinogen polymorphism. Modest risks were also observed with 5,10-methylenetetrahydrofolate reductase, plasminogen activator inhibitor 4G/4G polymorphisms and beta448 fibrinogen polymorphism. A combination of two or more than two genetic risk factors were observed in 55 (27.7%), whereas the genetic and acquired risk factors were observed in 107 (54%) of the cases. Thrombophilia is an important contributing factor for both early and late pregnancy losses; approximately two-thirds of our cases of unexplained fetal losses could be explained by acquired or heritable thrombophilia or both, which is in line with other western studies.

Henoch-Schonlein purpura (HSP) is the most common systemic vasculitis in children. Although long-term outcome is generally good, serious complications may occur. Thrombosis has been reported only as an extremely rare complication of HSP. Here, we describe a 15-year-old-boy with features of HSP, who developed left main iliac, external iliac and femoral vein thrombosis. Factor VIII (FVIII) and homocystein levels were found to be high. This suggests that HSP itself may lead to a prothrombotic state and increase the risk of developing thrombosis in patients who have any risk factors.

Type 1 plasminogen deficiency is an inherited and potentially life-threatening systemic disease in which patients develop pseudomembranous lesions of mucosal surfaces exposed to minor trauma. It is most commonly clinically encountered as ligneous conjunctivitis. We report the case of a 39-year-old woman with extensive involvement of the female genital tract. Microscopically, the vagina, cervix, endometrium, ovaries, and parametrial tissues showed innumerable deposits of paucicellular hyaline material with adjacent inflammation. Histochemical, immunofluorescent, and electron microscopic analyses revealed the amorphous material to be fibrin and collagen. In the plasma, functional plasminogen and plasminogen antigen levels were markedly decreased. Sequencing showed the patient to be a compound heterozygote for a missense and nonsense mutation in the plasminogen gene. Histologically, deposits in ligneous vaginitis are easily confused with amyloid or fibrinous debris. Recently, replacement therapy with plasminogen has been shown to significantly improve systemic symptoms, making ligneous mucositis a serious but treatable condition.

Whether severe coagulation factor deficiency can cause adverse pregnancy outcomes or recurrent fetal loss is not definitely known. We report here on five women with severe deficiency of coagulation factors (two factor X, one factor XI, one factor VII and one von Willebrand factor) who presented with history of unexplained fetal loss or with adverse pregnancy outcome. Detailed investigations of thrombophilia showed that four patients were positive for antiphospholipid antibodies, one of whom was also homozygous for the plasminogen-activator inhibitor-1 4G/4G polymorphism, and the fifth patient was deficient for protein C. Despite the concomitant presence of both coagulation factor defect and thrombophilia, fetal loss may be attributed to factor defect that in reality is a red herring, with underlying thrombophilia not being evaluated.

Background and Objectives: Mucocutaneous bleeding (MCB) is the main expression of inherited disorders of primary hemostasis. However, the relative prevalence of these disorders, their clinical differential diagnosis, and the proportion of patients with MCB of unknown cause (BUC) after an initial comprehensive laboratory testing are unknown., Design and Methods: We studied prospectively 280 consecutive patients with MCB and 299 matched controls, using strict inclusion and exclusion criteria. A single physician recorded the clinical data in a bleeding score and estimated the severity of bleeding in clinical categories. Laboratory criteria for the diagnosis of von Willebrand's disease (VWD) and platelet function defects were established from reference values derived from controls., Results: Fifty patients (17.9%) had VWD (type 1VWD=45, type 2=5). Platelet function defects and mild clotting factor deficiencies were found in 65 (23.2%) and 11 (3.9%) patients, respectively. Thirteen (11.5%) patients had combined defects. The remaining 167(59.6%) patients had BUC, with prolonged bleeding time in 18.6% as their only abnormality. All these disorders, including BUC, were clinically undistinguishable. Moreover, no relationship was found between the severity of bleeding and VWF/platelet function variables., Interpretation and Conclusions: The diagnostic efficacy of a first laboratory testing in patients with hereditary MCB is 40.4%. Most patients have a disease(s) of high prevalence but unknown pathogenesis. Concurrent bleeding disorders in the same patient are frequent. Our results support the proposal that low plasma VWF levels, but also platelet function defects, should be considered risk factors rather than unequivocal causes of hemorrhages.

The aim of the study was to assess the incidence and the cumulative probability of cytolytic and cholestatic hepatotoxicity during antiretroviral treatment in a group of HIV HCV haemophiliacs. We evaluated 47 patients that received 246 courses of antiretroviral treatment [98 courses of pre-highly active antiretroviral therapy (pre-HAART) and 148 HAART treatments]. Liver function tests were assessed at baseline of each treatment, after 1 month and at least every 4 months thereafter. Cytolytic and cholestatic hepatotoxicity was recorded. Of the 246 treatments, 28 (12.45%) were followed by cytolytic hepatotoxicity and 32 (13%) by cholestatic hepatotoxicity. Cytolytic hepatotoxicity was similar in HAART (16/148; 10.8%) and in pre-HAART treatment (12/98; 12.2%) and cholestatic hepatotoxicity was more frequent in HAART (29/148; 19.6%) than in pre-HAART treatment (3/98; 3.1%) (P < 0.001). The actuarial probability of developing cytolytic and cholestatic hepatotoxicity at 10 years of onset of antiretroviral treatments was 39% and 56%, respectively. Most enzyme elevations were asymptomatic, but in eight cases therapy was discontinued or changed and in one case a cirrhotic patient died of progressive liver failure. In HIV HCV haemophiliacs, the cumulative probability of developing hepatotoxicity during follow-up is high and although in the most cases the toxicity is mild, fatal cases can occur.

Pregnancies and deliveries represent important hemostatic challenges for congenital coagulation disorders. The same is true for the assumption of oral contraceptives. Available information mainly deals with von Willebrand's disease, factor XI (FXI) deficiency and carriers of hemophilia A. Data concerning patients with congenital prothrombin complex factor deficiencies are very scanty. In the present study, data of a total of 27 women are presented, 11 patients with homozygous or double heterozygous deficiencies of FII, FVII and FX, together with 16 cases of hemophilia B carriers. The patients with FII, FVII or FX defects had a total of 14 pregnancies and often needed transfusion therapy. Proper management resulted in a decrease in postpartum bleeding and satisfactory fetal outcome. Elective cesarean delivery seems indicated only in recent years. Carriers of hemophilia B had a total of 19 pregnancies but showed no bleeding and needed no substitutive therapy. Searching the literature, we discovered only 9 additional patients with prothrombin deficiency or FX deficiency, having a total of 16 pregnancies. On the contrary, there were at least 17 additional patients with FVII deficiency, with a total of 21 pregnancies. The management of the diseases has been variable, but in substantial agreement with the personal observations. Oral contraceptive therapy was administered in some of our patients and in a few additional cases described in the literature. Medication was always well tolerated and patients who took it for a long period of time showed a decrease in menometrorrhagia and an improvement in hematocrit levels. This led to a decrease in transfusional needs and to improved general conditions., (Copyright 2006 S. Karger AG, Basel.)

The Italian Association of Haemophilia Centres reviewed and finally approved in November 2004 the new Italian Guidelines for the diagnosis and treatment of patients with clotting factor inhibitors. The recommendations have been based on the identification of levels of clinical evidence derived from the systematic review carried out in 2003 by the School of Health and Related Research, the University of Sheffield, UK, and further integrated by clinical studies published from 2003 to 2004. The Italian guidelines consist of six major domains concerning inhibitor definition, epidemiology, risk factors, diagnosis, inhibitor eradication, management of bleeding episodes, in patients with congenital and acquired coagulation disorders, with 121 statements, 59 synthesis and 54 recommendations. We report here recommendations and open issues concerning the diagnosis and monitoring of inhibitors, inhibitor eradication and the management of bleeding in patients with haemophilia A and B.

Background: During surgical procedures, patients with bleeding disorders have a major risk of bleeding complications. To reduce the risk of bleeding it is necessary to provide pre-, peri- and postoperative antihaemorrhagic therapy. In less severe bleeding disorders, pharmacologic treatment may be sufficient, but in patients with severe bleeding disorders there is always a need for clotting factor concentrates., Materials and Methods: This study includes all patients with bleeding disorders admitted to Rikshospitalet University Hospital between 1997 and 2003 for surgical procedures during which therapy with clotting factor concentrates was mandatory., Results and Interpretation: Over the study period, 135 patients underwent a total of 255 different surgical procedures. In 47% of the patients there was a causal relationship between the need for surgery and the bleeding disorder. Our results show that patients with severe bleeding disorders, including patients with inhibitors, can be treated safely provided that the patients receive adequate treatment with clotting factor concentrates. However, substitution therapy with clotting factor concentrates is very expensive. Cost related to substitution therapy is the main determinant of how many patients with severe bleeding disorders can undergo elective surgery in our hospital each year.

Objectives: To study the effect of an intensive programme to modify life-style on levels of plasma fibrinogen in patients without cardiovascular pathology, with high fibrinogen and normal cholesterol levels. To analyse whether the effect on fibrinogen is independent, or otherwise, of the effect on lipids., Design: Randomised clinical trial with a control., Setting: 11 health districts in L'Hospitalet de Llobregat and Barcelona., Participants: 436 patients will be included, 218 individuals between 35 and 75 years old in each group, and without cardiovascular pathology (ischaemic cardiopathy, cerebral vascular accident or peripheral arteriopathy), with hyperfibrinogenaemia (fibrinogen > 300 mg/dL) and with plasma control < 250 mg/dL., Interventions: One group of patients will receive an intensive intervention (in frequency and intensity of counselling and treatment) for life-style changes, i.e. stopping smoking, low-calorie diet in case of overweight or obesity, and physical exercise. The follow-up of the intervention group will be every 2 months. The control group will follow customary treatments., Measurements: Levels of plasma fibrinogen. In addition, other relevant events will be recorded over a 2-year monitoring period: modification of risk factors, changes in quality of life, cardiovascular events or death., Discussion: The introduction of an intensive primary prevention intervention (life-style changes) in patients with hyperfibrinogenaemia could be a more effective measure than the habitual intervention for reducing plasma fibrinogen figures. In addition, these measures could be translated into a reduction of cardiovascular risk and an improvement in the patient s quality of life.

Combined deficiency of factor (F)V and FVIII (F5F8D) and combined deficiency of vitamin K-dependent clotting factors (VKCFD) comprise the vast majority of reported cases of familial multiple coagulation factor deficiencies. Recently, significant progress has been made in understanding the molecular mechanisms underlying these disorders. F5F8D is caused by mutations in two different genes (LMAN1 and MCFD2) that encode components of a stable protein complex. This complex is localized to the secretory pathway of the cell and likely functions in transporting newly synthesized FV and FVIII, and perhaps other proteins, from the ER to the Golgi. VKCFD is either caused by mutations in the gamma-carboxylase gene or in a recently identified gene encoding the vitamin K epoxide reductase. These two proteins are essential components of the vitamin K dependent carboxylation reaction. Deficiency in either protein leads to under-carboxylation and reduced activities of all the vitamin K-dependent coagulation factors, as well as several other proteins. The multiple coagulation factor deficiencies provide a notable example of important basic biological insight gained through the study of rare human diseases.

Although intracranial hemorrhage accounts for approximately 10 to 15% of all cases of stroke, it is associated with a high mortality rate. Bleeding disorders account for a small but significant risk factor associated with intracranial hemorrhage. In conditions such as hemophilia and acute leukemia associated with thrombocytopenia, massive intracranial hemorrhage is often the cause of death. The authors present a comprehensive review of both the physiology of hemostasis and the pathophysiology underlying spontaneous ICH due to coagulation disorders. These disorders are divided into acquired conditions, including iatrogenic and neoplastic coagulopathies, and congenital problems, including hemophilia and rarer diseases. The authors also discuss clinical features, diagnosis, and management of intracranial hemorrhage resulting from these bleeding disorders.

Of all the coagulation factor deficiencies, only deficiency of factor XIII (FXIII) and fibrinogen are associated with pregnancy loss. FXIII deficiency and a complete or partial deficiency of fibrinogen are associated with bleeding since childhood, impaired wound repair, and recurrent spontaneous abortions. Both FXIII and fibrinogen play an essential role in placental implantation and maintenance of pregnancy. The causes of miscarriages in FXIII or fibrinogen-deficient women is discussed and an appropriate treatment advocated.