Multiple Coagulation Factor Deficiency Research Articles

Causal Effects of COVID-19 on the Risk of Thrombosis: A Two-Sample Mendel Randomization Study.

Coronavirus disease 2019 (COVID-19) and thrombosis are linked, but the biomolecular mechanism is unclear. We aimed to investigate the causal relationship between COVID-19 and thrombotic biomarkers. We used two-sample Mendelian randomization (MR) to assess the effect of COVID-19 on 20 thrombotic biomarkers. We estimated causality using inverse variance weighting with multiplicative random effect, and performed sensitivity analysis using weighted median, MR-Egger regression and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods. All the results were examined by false discovery rate (FDR) with the Benjamin and Hochberg method for this correction to minimize false positives. We used R language for the analysis. All COVID-19 classes showed lower levels of tissue factor pathway inhibitor (TFPI) and interleukin-1 receptor type 1 (IL-1R1). COVID-19 significantly reduced TFPI (odds ratio [OR] = 0.639, 95% confidence interval [CI]: 0.435-0.938) and IL-1R1 (OR = 0.603, 95% CI = 0.417-0.872), nearly doubling the odds. We also found that COVID-19 lowered multiple coagulation factor deficiency protein 2 and increased C-C motif chemokine 3. Hospitalized COVID-19 cases had less plasminogen activator, tissue type (tPA) and P-selectin glycoprotein ligand 1 (PSGL-1), while severe cases had higher mean platelet volume (MPV) and lower platelet count. These changes in TFPI, tPA, IL-1R1, MPV, and platelet count suggested a higher risk of thrombosis. Decreased PSGL-1 indicated a lower risk of thrombosis. TFPI, IL-1R, and seven other indicators provide causal clues of the pathogenesis of COVID-19 and thrombosis. This study demonstrated that COVID-19 causally influences thrombosis at the biomolecular level.

Combined factor VIII and IX deficiency: An exceptional case

Familial multiple coagulation factor deficiencies are a group of rare inherited disorders that are characterized by the simultaneous decrease in the levels of two or more coagulation factors. Common synchronous deficiencies are factors VIII and IX and combined deficiency of Vitamin K-dependent coagulation factors (factors II, VII, IX, and X). Here, we report a case of synchronous dual deficiency of factor VIII and IX, which is an extremely rare occurrence and no case report has been mentioned so far to the best of our knowledge. Recognizing such a dual deficiency is very important for proper management of patients.

Solvent/detergent treated pooled human plasma can decrease the recurrence of allergic transfusion reactions in pediatric, adolescent, and young adult patients.

Octaplas is a solvent/detergent (S/D)-treated pooled human plasma indicated for the treatment of thrombotic thrombocytopenic purpura (TTP) as well as multiple coagulation factor deficiency in patients with liver disease or undergoing liver transplantation or cardiac surgery. We aimed at providing pediatric, adolescent, and young adult evidence for the decrease in allergic transfusion reactions (ATRs) with S/D-treated plasma. A single-center retrospective review of patient records was performed from January 2018 through July 2022 for patients who received S/D treated plasma (Octaplas™; Octapharma). A total of 1415 units of S/D-treated plasma were transfused to nine patients at our institution. Patient ages ranged from 13 months to 25 years old. The reason to initiate transfusion with S/D treated plasma in six patients was mild to severe ATR to plasma-containing products and the need for therapeutic plasma exchange (TPE) or plasma transfusions (PTs). TPE or PT was performed for various clinical indications. Average S/D treated plasma volume per TPE or PT ranged from 200 to 1800 mL per event. During the study period, since initiating transfusions with S/D treated plasma, there have been no allergic or other transfusion reactions reported among these patients. We have successfully utilized S/D treated plasma over the last 4.5 years for pediatric, adolescent, and young adult patients who otherwise would have suffered ATR due to necessary TPE or PT. S/D treated plasma is an additional tool that can be utilized by transfusion services, including pediatrics, to safely transfuse their patients.

Function-guided selection of salivary antigens from Ornithodoros erraticus argasid ticks and assessment of their protective efficacy in rabbits

The identification of new protective antigens for the development of tick vaccines may be approached by selecting antigen candidates that have key biological functions. Bioactive proteins playing key functions for tick feeding and pathogen transmission are secreted into the host via tick saliva. Adult argasid ticks must resynthesise and replace these proteins after each feeding to be able to repeat new trophogonic cycles. Therefore, these proteins are considered interesting antigen targets for tick vaccine development. In this study, the salivary gland transcriptome and saliva proteome of Ornithodoros erraticus females were inspected to select and test new vaccine candidate antigens. For this, we focused on transcripts overexpressed after feeding that encoded secretory proteins predicted to be immunogenic and annotated with functions related to blood ingestion and modulation of the host defensive response. Completeness of the transcript sequence, as well as a high expression level and a high fold-change after feeding were also scored resulting in the selection of four candidates, an acid tail salivary protein (OeATSP), a multiple coagulation factor deficiency protein 2 homolog (OeMCFD2), a Cu/Zn-superoxide dismutase (OeSOD) and a sulfotransferase (OeSULT), which were later produced as recombinant proteins. Vaccination of rabbits with each individual recombinant antigen induced strong humoral responses that reduced blood feeding and female reproduction, providing, respectively, 46.8%, 45.7%, 54.3% and 31.9% protection against O. erraticus infestations and 0.7%, 3.9%, 3.1% and 8.7% cross-protection against infestations by the African tick, Ornithodoros moubata. The joint protective efficacy of these antigens was tested in a second vaccine trial reaching 58.3% protection against O. erraticus and 18.6% cross-protection against O. moubata. These results (i) provide four new protective salivary antigens from argasid ticks that might be included in multi-antigenic vaccines designed for the control of multiple tick species; (ii) reveal four functional protein families never tested before as a source of protective antigens in ticks; and (iii) show that multi-antigenic vaccines increase vaccine efficacy compared with individual antigens. Finally, our data add value to the salivary glands as a protective antigen source in argasids for the control of tick infestations.

Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories.

Coagulation factors, anticoagulants, and fibrinolytic proteins are important for hemostasis, and mutations affecting these proteins causes some rare inherited bleeding disorders that are particularly challenging to diagnose. This review provides current information on rare inherited bleeding disorders that are difficult to diagnose. A review of the literature was conducted for up to date information on rare and difficult to diagnose bleeding disorders. Some rare bleeding disorders cause an inherited deficiency of multiple coagulation factors (F), such as combined FV and FVIII deficiency and familial vitamin K-dependent clotting factor deficiency. Additionally, congenital disorders of glycosylation can affect a variety of procoagulant and anticoagulant proteins and also platelets. Some bleeding disorders reflect mutations with unique impairments in the procoagulant/anticoagulant balance, including those caused by F5 mutations that secondarily increase the plasma levels of tissue factor pathway inhibitor as well as THBD mutations that increase functional thrombomodulin in plasma or cause a consumptive coagulopathy due to thrombomodulin deficiency. Some bleeding disorders accelerate fibrinolysis due to loss-of-function mutations in SERPINE1 and SERPINF2 or in the case of Quebec platelet disorder, a duplication mutation that rewires PLAU and selectively increases expression in megakaryocytes, resulting in a unique platelet-dependent gain-of-function defect in fibrinolysis. Current information on rare and difficult to diagnose bleeding disorders indicates they have unique clinical and laboratory features, and pathogenic characteristics to consider for diagnostic evaluation. Laboratories and clinicians should consider rare inherited disorders, and difficult to diagnose conditions, in their strategy for diagnosing bleeding disorders.

Separate roles of LMAN1 and MCFD2 in ER-to-Golgi trafficking of FV and FVIII.

Mutations in lectin, mannose-binding 1 (LMAN1) and multiple coagulation factor deficiency protein 2 (MCFD2) cause the combined deficiency of factor V (FV) and FVIII (F5F8D). LMAN1 and MCFD2 form a protein complex that transports FV and FVIII from the endoplasmic reticulum (ER) to the Golgi. Although both proteins are required for the cargo receptor function, little is known about the specific roles of LMAN1 and MCFD2 in transporting FV/FVIII. We used different LMAN1 and MCFD2 deficient cell lines to investigate the LMAN1/MCFD2-dependent FV/FVIII secretion pathway. LMAN1 deficiency led to more profound decreases in FV/FVIII secretion in HEK293T and HepG2 cells than in HCT116 cells, suggesting that regulation of cargo transport by the LMAN1/MCFD2 pathway varies in different cell types. Using these cell lines, we developed functional assays to accurately assess the pathogenicity of recently reported potential LMAN1 and MCFD2 missense mutations. LMAN1 with mutations abolishing carbohydrate binding can still partially rescue FV/FVIII secretion, suggesting that N-glycan binding is not essential for FV/FVIII transport. Surprisingly, overexpression of either wild-type or mutant MCFD2 is sufficient to rescue FV/FVIII secretion defects in LMAN1 deficient cells. These results suggest that cargo binding and transport are carried out by MCFD2 and that LMAN1 primarily serves as a shuttling carrier of MCFD2. Finally, overexpression of both LMAN1 and MCFD2 does not further increase FV/FVIII secretion, suggesting that the amount of the LMAN1-MCFD2 receptor complex is not a rate-limiting factor in ER-Golgi transport of FV/FVIII. This study provides new insight into the molecular mechanism of F5F8D and the intracellular trafficking of FV and FVIII.

Vitamin E-induced coagulopathy in a young patient: a case report

BackgroundHigh-dose vitamin E intake is known to inhibit vitamin K-derived coagulation factor synthesis, which can cause serious bleeding events such as gastrointestinal bleeding and intracranial hemorrhage. We report a case of coagulopathy induced by marginally increased levels of vitamin E.Case presentationA 31-year-old Indian man presented with oral bleeding, black tarry stools, and bruising over his back. He had been taking non-steroidal anti-inflammatory drugs for low backache and vitamin E for hair loss. He had mild anemia with normal platelet count, thrombin time, and prolonged bleeding time, activated partial thromboplastin time, and prothrombin time. Serum fibrinogen was slightly raised. Mixing studies with pooled normal plasma, aged plasma, and adsorbed plasma were suggestive of deficiency of multiple coagulation factors due to acquired vitamin K deficiency. Serum phylloquinone was normal, while prothrombin induced by vitamin K absence-II level was increased. Serum alpha-tocopherol was slightly raised. Upper gastrointestinal endoscopy showed multiple gastroduodenal erosions. A final diagnosis of vitamin E toxicity-related coagulopathy was made. The patient responded well to pantoprazole, vitamin K supplementation, multiple fresh frozen plasma transfusions, and other supportive treatments besides the discontinuation of vitamin E supplementation. The coagulation parameters normalized, and the patient was discharged with complete resolution of symptoms and remained asymptomatic during the follow-up for 6 months.ConclusionsVitamin E-related inhibition of vitamin K-dependent factors with coagulopathy may occur even at marginally increased levels of serum vitamin E. This risk becomes significant in patients receiving other drugs that may increase the risk of bleeding.

Fatal acquired coagulation factor V deficiency after hepatectomy for advanced hepatocellular carcinoma as a possible immune checkpoint inhibitor-related adverse event: a case report

BackgroundAtezolizumab plus bevacizumab therapy was recently introduced as the first line for unresectable advanced hepatocellular carcinoma (HCC), but immune-related adverse events (IrAEs) due to atezolizumab are a great concern. Here, we report the case of a patient who developed fatal acquired coagulation factor deficiency after hepatectomy for HCC, treated with atezolizumab and bevacizumab before surgery.Case presentationA 70-year-old man received right trisegmentectomy of the liver with hepaticojejunostomy for advanced HCC with bile duct invasion, after atezolizumab and bevacizumab therapy. The patient suffered the sudden onset of severe multiple coagulation factor deficiency (II, V, VII, VIII, IX, X, XI and XII) immediately following reoperation for anastomotic leakage of hepaticojejunostomy, 7 days after hepatectomy. The coagulation factor deficiency did not reverse even with intensive treatment, and the patient died of uncontrollable bleeding 32 days after hepatectomy. An IrAE due to atezolizumab was suspected because the patient had developed the possible IrAE of enthesitis of the right gastrocnemius muscle before surgery, and specific inhibitors against factor V and anti-factor V autoantibodies were detected, leading to an ultimate diagnosis of autoimmune FV/5 deficiency (AiF5D).ConclusionSevere acquired coagulopathy should be recognized as a possible life-threatening IrAE when using atezolizumab and bevacizumab for HCC.

"Familial Multiple Coagulation Factor Deficiencies of FXI and FXII in an Asymptomatic Saudi Woman".

Factor XI deficiency (FXI) is the third most common coagulation factor deficiency after hemophilia A and B, ie, in the hierarchy after factors VIII and IX, taking into account von Willebrand's factor deficiency, as bleeding disorders are higher than in hemophilia C. Factor XII deficiency (FXII) is a congenital condition, inherited in the vast majority of cases in an autosomal recessive manner, more often associated with thromboembolic complications. A combination of both factor deficiencies has been found very rarely, and it can be familial multiple coagulation factor deficiency (FMCFD). This study reports the case of a 39-year-old woman from Saudi Arabia who had the combination of FXI and FXII deficiencies, known to be on treatment for hypothyroidism and was referred to a hematology clinic with an incidental finding of prolonged activated partial thromboplastin time (aPTT). Although there was no history of bleeding tendency, her siblings had a family history of an unknown type of bleeding disorder. On physical examination, the patient did not show any bruising, petechiae, or ecchymosis. The aPTT was 69 seconds (27-38) with normal use of other hemostatic agents and was corrected after a 50:50 mixing study. Intrinsic coagulation factors were evaluated, and they revealed severe FXI and moderate FXII deficiencies. Due to a strong family history, the patient was diagnosed with FMCFD. In conclusion, familial combined multiple clotting factor deficiency (FCMFD) is a rare condition that requires attention and reporting. The management strategy in such cases has not been well studied, especially in the long-term symptomatic patient with severe but asymptomatic combined FXI and FXII deficiencies, which is an area for review and further study.

A novel circRNA-miRNA-mRNA network reveals hsa-circ-0040039 as a biomarker for intervertebral disc degeneration.

ObjectiveAlterations in the structure and function of intervertebral discs by multifaceted chronic processes can result in intervertebral disc degeneration (IDD). The mechanisms involved in IDD are still unknown.MethodsWe investigated the possible mechanisms underlying IDD using a bioinformatics analysis of publicly available microarray expression datasets and built a circular RNA–microRNA–mRNA (circRNA–miRNA–mRNA) network based on the results. Datasets GSE67566 and GSE116726 were downloaded from the Gene Expression Omnibus (GEO) and analyzed using the limma package in R. The CircInteractome database was used to detect miRNAs related to circRNA, and TargetScan, miRDB, and miRTarBase were used to predict target mRNAs. Key target genes were annotated using Gene Ontology terms.ResultsThe circRNA hsa-circ-0040039 was found to have the top log fold-change score. Analysis using Metascape showed that the associated genes were enriched mainly in the cell cycle. The Cytoscape plugin MCODE predicted that two members of the RAS oncogene family—RAB1A and RAB1B—and multiple coagulation factor deficiency (MCFD2) may play key roles in IDD.ConclusionOur results suggested that hsa-circ-0040039 and the related network may be potential biomarkers for IDD.

Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a Large Cohort of Patients-A Single-Center Experience in Genetic Diagnosis.

Background: Familial multiple coagulation factor deficiencies (FMCFDs) are a group of inherited hemostatic disorders with the simultaneous reduction of plasma activity of at least two coagulation factors. As consequence, the type and severity of symptoms and the management of bleeding/thrombotic episodes vary among patients. The aim of this study was to identify the underlying genetic defect in patients with FMCFDs. Methods: Activity levels were collected from the largest cohort of laboratory-diagnosed FMCFD patients described so far. Genetic analysis was performed using next-generation sequencing. Results: In total, 52 FMCFDs resulted from coincidental co-inheritance of single-factor deficiencies. All coagulation factors (except factor XII (FXII)) were involved in different combinations. Factor VII (FVII) deficiency showed the highest prevalence. The second group summarized 21 patients with FMCFDs due to a single-gene defect resulting in combined FV/FVIII deficiency or vitamin K–dependent coagulation factor deficiency. In the third group, nine patients with a combined deficiency of FVII and FX caused by the partial deletion of chromosome 13 were identified. The majority of patients exhibited bleeding symptoms while thrombotic events were uncommon. Conclusions: FMCFDs are heritable abnormalities of hemostasis with a very low population frequency rendering them orphan diseases. A combination of comprehensive screening of residual activities and molecular genetic analysis could avoid under- and misdiagnosis.

Crystallographic snapshots of the EF-hand protein MCFD2 complexed with the intracellular lectin ERGIC-53 involved in glycoprotein transport.

The transmembrane intracellular lectin ER-Golgi intermediate compartment protein 53 (ERGIC-53) and the soluble EF-hand multiple coagulation factor deficiency protein 2 (MCFD2) form a complex that functions as a cargo receptor, trafficking various glycoproteins between the endoplasmic reticulum (ER) and the Golgi apparatus. It has been demonstrated that the carbohydrate-recognition domain (CRD) of ERGIC-53 (ERGIC-53CRD) interacts with N-linked glycans on cargo glycoproteins, whereas MCFD2 recognizes polypeptide segments of cargo glycoproteins. Crystal structures of ERGIC-53CRD complexed with MCFD2 and mannosyl oligosaccharides have revealed protein-protein and protein-sugar binding modes. In contrast, the polypeptide-recognition mechanism of MCFD2 remains largely unknown. Here, a 1.60 Å resolution crystal structure of the ERGIC-53CRD-MCFD2 complex is reported, along with three other crystal forms. Comparison of these structures with those previously reported reveal that MCFD2, but not ERGIC-53-CRD, exhibits significant conformational plasticity that may be relevant to its accommodation of various polypeptide ligands.

Low factor V level ameliorates bleeding diathesis in patients with combined deficiency of factor V and factor VIII

AbstractCombined factor V (FV) and FVIII deficiency (F5F8D) is a rare autosomal-recessive bleeding disorder caused by mutations in lectin mannose binding-1 (LMAN1) and multiple coagulation factor deficiency-2 (MCFD2). Six causative homozygous mutations (5 in LMAN1 and 1 in MCFD2) were identified in 6 patients with F5F8D. A thrombin-generation assay, triggered with tissue factor (1 pM) in F5F8D plasma, paradoxically exhibited enhanced thrombin generation compared with normal plasma. Significantly lower free tissue factor pathway inhibitor (fTFPI) was found in F5F8D patients compared with healthy controls (P < .01). Normalizing tissue factor pathway inhibitor α (TFPIα) in F5F8D plasma greatly delayed and reduced thrombin generation. Increasing FV concentrations by adding plasma FV to F5F8D plasma only caused a gradual decrease in thrombin generation, suggesting that low levels of TFPIα and FV cocontributed to the elevated thrombin generation by reducing anticoagulant effects. On the contrary, thrombin generation in F5F8D platelet-rich plasma (PRP) was significantly lower than in normal controls (P < .05); however, it was fully corrected by normalizing FVIII or after 1-deamino-8-d-arginine vasopressin (DDAVP) infusion, indicating that the hypocoagulable state of F5F8D patients is associated with low FVIII levels. In addition, plasma and platelet FV in F5F8D PRP were sufficient to support normal thrombin generation, and low TFPIα may have no effect on thrombin generation. DDAVP infusion induced a complete response in 5 F5F8D patients and a partial response in the remaining patient. Based on our findings, we suggest that DDAVP may be considered a potential substitute for FVIII concentrates, and fresh-frozen plasma (FFP) infusion may not be necessary for F5F8D patients with minor bleeding challenges.

Pancytopenie, panhypopituitarizmus a jaterní cirhóza: rozbor složité kazuistiky

Panhypopituitarism following craniopharyngioma resection has systemic impact with potential influence on physio-logical hematopoiesis. There is a growing body of evidence of liver fibrosis/cirrhosis risk development due to altered metabolism and lipid accumulation. The authors present a case report of a woman with a history of craniopharyngioma resection followed by aggravating pancytopenia with suspected indolent lymphoproliferative disorder and possible acquired bone marrow aplasia syndrome due to paroxysmal nocturnal hemoglobinuria. A complex hemostasis disorder with deficiency of multiple coagulation factors (FXII, FXI, FX, FIX, FVII, FX, FV, FXIII, antitrombin, protein C, protein S) was accidentally detected. Despite normal sonographic liver imaging, all possible causes of chronic liver disease were systematically excluded (viral hepatitis, hemochromatosis, Wilson´s disease, &#945;-1-antitrypsin deficiency); anti-LKM-1 and anti-ENA antibodies were detected. Finally, the magnetic resonance imaging confirmed image of liver cirrhosis - with signs of portal hypertension.

Multiple coagulation factor deficiency protein 2 as a crucial component in metastasis of human oral cancer

Multiple coagulation factor deficiency protein 2 (MCFD2), a binding partner of lectin mannose binding 1 (LMAN1), causes combined deficiencies of coagulation factors V and VIII. MCFD2 function in inherited hematologic disorders is well elucidated; however, little is known about its role in human tumorigenesis. The aim of the current study was to investigate the states of MCFD2 in oral squamous cell carcinoma (OSCC). The expression of MCFD2 was up-regulated significantly in all cell lines examined. Evaluation of the cellular functions associated with tumoral metastasis showed that MCFD2 knockdown (shMCFD2) cells exhibited significantly lower cellular invasiveness and migration and higher cellular adhesion compared with shControl cells. Of note, shMCFD2 cells also showed weak immunoreactivity of LMAN1 and a lower secretion level of galactoside-binding soluble 3 binding protein (LGALS3BP). In addition to in vitro validation, clinical data on 70 patients with OSCC indicated that state of MCFD2 expression level is associated with regional lymph node metastasis. Altogether, we have demonstrated that MCFD2 promotes cancer metastasis by regulating LMAN1 and LGALS3BP expression levels. Hence, MCFD2 may represent a promising candidate for a novel therapeutic target for patients with metastatic OSCCs.

Redox Status, Procoagulant Activity, and Metabolome of Fresh Frozen Plasma in Glucose 6-Phosphate Dehydrogenase Deficiency.

Transfusion of fresh frozen plasma (FFP) helps in maintaining the coagulation parameters in patients with acquired multiple coagulation factor deficiencies and severe bleeding. However, along with coagulation factors and procoagulant extracellular vesicles (EVs), numerous bioactive and probably donor-related factors (metabolites, oxidized components, etc.) are also carried to the recipient. The X-linked glucose 6-phosphate dehydrogenase deficiency (G6PD-), the most common human enzyme genetic defect, mainly affects males. By undermining the redox metabolism, the G6PD- cells are susceptible to the deleterious effects of oxidants. Considering the preferential transfusion of FFP from male donors, this study aimed at the assessment of FFP units derived from G6PD- males compared with control, to show whether they are comparable at physiological, metabolic and redox homeostasis levels. The quality of n = 12 G6PD- and control FFP units was tested after 12 months of storage, by using hemolysis, redox, and procoagulant activity-targeted biochemical assays, flow cytometry for EV enumeration and phenotyping, untargeted metabolomics, in addition to statistical and bioinformatics tools. Higher procoagulant activity, phosphatidylserine positive EVs, RBC-vesiculation, and antioxidant capacity but lower oxidative modifications in lipids and proteins were detected in G6PD- FFP compared with controls. The FFP EVs varied in number, cell origin, and lipid/protein composition. Pathway analysis highlighted the riboflavin, purine, and glycerolipid/glycerophospholipid metabolisms as the most altered pathways with high impact in G6PD-. Multivariate and univariate analysis of FFP metabolomes showed excess of diacylglycerols, glycerophosphoinositol, aconitate, and ornithine but a deficiency in riboflavin, flavin mononucleotide, adenine, and arginine, among others, levels in G6PD- FFPs compared with control. Our results point toward a different redox, lipid metabolism, and EV profile in the G6PD- FFP units. Certain FFP-needed patients may be at greatest benefit of receiving FFP intrinsically endowed by both procoagulant and antioxidant activities. However, the clinical outcome of G6PD- FFP transfusion would likely be affected by various other factors, including the signaling potential of the differentially expressed metabolites and EVs, the degree of G6PD-, the redox status in the recipient, the amount of FFP units transfused, and probably, the storage interval of the FFP, which deserve further investigation by future studies.

Coagulation Abnormalities and Hemostatic Surgical Outcomes in 142 Patients with Noonan Syndrome

Background: Noonan syndrome, characterized by dysmorphic facies, webbed neck, short stature, chest deformity, developmental delay and congenital heart defects, occurs as a result of mutations affecting the RAS-MAPK signaling pathway. A wide range of coagulation abnormalities are observed in these patients including: thrombocytopenia, platelet dysfunction and coagulation factor deficiencies. Screening for coagulation defects is recommended in childhood and especially prior to surgical procedures. Data available is limited and the extent of the hemostatic evaluation needed is not clearly defined. We carried out this study to outline the spectrum of coagulation abnormalities seen in patients with Noonan syndrome and their impact on surgical outcomes.Methods: In this retrospective cohort study, the electronic medical record system was queried for patients with Noonan syndrome seen at Mayo Clinic between 2000 and 2016. A detailed chart review was undertaken.Resultsi) Phenotypic correlates: 142 patients (58% male) met our study criteria, median age 21 years (range 14 days to 68 years). The referral specialty for initial evaluation was: cardiology 69 (49%), endocrinology 10 (7%), urology 10 (7%), neurology 8 (6%), pulmonary 6 (4%), orthopedic surgery 3 (2%), gastroenterology 2 (1%), psychiatry 2 (1%) and other specialties 4 (3%). Ten patients (7%) were referred for developmental delay, 13 (9%) for dysmorphism and 4 (3%) after having a family member diagnosed with Noonan syndrome. One patient (1%) presented with hematochezia. Twenty-seven (52%) of the 52 patients screened with genetic testing had a Noonan-associated gene defect. Bleeding was reported by 22 patients (15%) with a median International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) score of 2 (range 1-8). Of those tested, 11/121 (9%) patients had thrombocytopenia (platelets < 150 x 10^9/L). Screening coagulation tests were done in 58 (41%) patients, and included PT/aPTT in 43 (74%) and extended coagulation panels (including platelet function studies) in 15 (26%). Of the 22 patients with history of bleeding, 20 (90%) had screening coagulation testing. Twenty-two (38%) of patients screened had one or more coagulation laboratory abnormality. Ten (66%) patients with clinically suspected platelet dysfunction had normal platelet function analyzer (PFA)-100 testing and normal light transmission aggregometry, while 5 (33%) had decreased platelet aggregation with epinephrine. Four patients (7%) (including 2 siblings) had low vWF levels consistent with type 1 vWD, 9 (16%) had mild clotting factor deficiencies ( FIX- 3, FXII-2 and multiple clotting factors-5) and 4 (7%) had a prolonged baseline PT and/or aPTT without additional coagulation factor assessment (Table 1). Thirteen patients (9%) had both a bleeding phenotype and abnormal coagulation laboratory results.ii) Surgical outcomes: A total of 274 surgical procedures were performed in 89 patients (63%). These included: cardiac 118 (43%), orthopedic 30 (11%), ENT 27 (10%), neurosurgical 26 (10%), abdominal 17 (6%), urologic 17 (6%), gynecologic 12 (4%) thoracic 8 (3%), ophthalmologic 7 (3%), plastic surgery 5 (2%), maxillofacial 4 (1%) and lymph node dissection 3 (1%). Platelets were utilized in 26 procedures (10%), fresh frozen plasma in 19 (7%) and cryoprecipitate in 7 (3%). Two procedures were performed in patients with type 1 vWD using vWF concentrates. Abnormal intra or postoperative bleeding was seen in 5/274 procedures (1.8%) performed in 4 patients. One patient had a known functional platelet disorder, one had normal PT and aPTT and two were not screened for coagulation defects. Bleeding was managed with transfusional supportive care in 3 (60%) surgical cases, while in 2 (40%) cases patients required re-intervention to achieve surgical hemostasis (bleeding from femoral access site and pacemaker pocket hematoma). There was no mortality related to the excess perioperative bleeding.Conclusion: Varying hemostatic abnormalities are seen in patients with Noonan syndrome, ranging from thrombocytopenia to multiple coagulation factor deficiencies. Frank bleeding manifestations however are uncommon and when present are usually mild. Clinical evaluation focused on the bleeding history and basic coagulation screening allows for successful perioperative hemostatic support and good surgical outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Combined factor V and VIII deficiency in a young woman with abundant bleeding after tooth extraction.

TO THE EDITOR: Combined factor V and VIII deficiency, a rare autosomal recessive coagulopathy, was first defined by Oeri et al. in 1954 [1]. Although it is seen worldwide, Mediterranean countries have higher prevalence rates [2]. The presentation varies from mild to serious bleeding symptoms such as easy bruising, menorrhagia, epistaxis, gingival bleeding, intramuscular bleeding, and post-operation or tooth extraction bleeding. Plasma levels of the two factors vary between 5% and 30% [3]. Bleeding episodes are treated with factor V replacement by using fresh frozen plasma, desmopressin, and factor VIII replacement with special factor VIII concentrates [4]. A 20-year-old woman consulted our outpatient clinic with a complaint of continuous bleeding after tooth extraction. The patient's history revealed that she had been having long-lasting bleeding episodes after a minor trauma, easy bruising, and menorrhagia after menstruation. She did not have other signs of bleeding such as melena, hematochezia, hemoptysis, hemarthrosis, petechiae, and ecchymosis. Her parents were not related, and her physical examination results and vital signs were normal. The total blood count was normal. Prothrombin time (PT) and activated partial prothrombin time (aPTT) were measured twice (18–20 sec and 65–68 sec, respectively; Table 1; normal reference range for PT, 10.4–13.4 sec; aPTT, 20–34 sec). Bleeding time was normal. aPTT and PT values were also normal after mixing the patient's plasma with a healthy plasma in a 1:1 ratio. Fibrinogen, factor VII, factor IX, factor X, and factor XI and von Willebrand factor levels were all normal. Factor V and VIII levels were measured twice, and both measured levels were low (11.7–10.2% and 28–25%, respectively; Table 1). According to these findings, the patient was diagnosed as having a combined factor V and VIII deficiency. Table 1 Hemostatic parameters. Combined factor V and VIII deficiency is known to be rare in the general population (1:1,000,000). However, it is seen more often in areas where consanguineous marriages are common [4]. The incidence of the disease was estimated to be 1 case per 100,000 individuals in the Middle Eastern Jewish and non-Jewish Iranian populations [5]. It is an autosomal recessively inherited disease and characterized by low levels of both factors V and VIII (generally between 5% and 20%) [6]. It is primarily caused by defects of the factor V and VIII coagulation secretion pathways, including lectin mannose-binding protein type 1 (LMAN1), which was previously called ERGIC-53, and multiple coagulation factor deficiency 2 (MCFD2) [7]. In these patients, the severity of hemorrhagic symptoms was found to be similar to that in patients with isolated factor V deficiency. Therefore, it can be suggested that combined factor V and VIII deficiency does not worsen bleeding severity [5]. Mild symptoms such as easy bruising, epistaxis, and gingival bleeding are frequently observed in these patients. Moreover, bleeding after tooth extraction, surgery, trauma, and menorrhagia and postpartum hemorrhage in females are not rare [5,8]. Gastrointestinal and central nervous system hemorrhages were reported in a few cases [2,8]. In our case, the patient was admitted with continuous bleeding after tooth extraction, and she had easy bruising, long-lasting bleeding after a minor trauma, and excessive bleeding during menstruation. Factor V and VIII deficiency is characterized by normal platelet count and bleeding time but with prolonged PT and aPTT [9]. Similarly, the total blood count of our patient was normal, double measurements revealed prolonged PT and aPTT (18–20 sec and 65–68 sec, respectively), and bleeding time was normal. In combined factor V and VIII deficiency, regular prophylaxis is not required during bleeding episodes, and the patient is generally treated only when required. However, in case of recurrent hematoma and hemarthrosis, prophylaxis should be preferred [10]. The treatment of the bleeding is replacement of factor V and VIII. While factor V replacement therapy is administered by using fresh frozen plasma, factor VIII replacement therapy is administered by using special factor VIII concentrates (either plasma-originated or recombinant factor VIII products). Desmopressin can be administered in case of mild bleeding [4]. In our case, the patient was given fresh frozen plasma, and her bleeding stopped.

Pseudoxanthoma Elasticum-Like Disorder with Multiple Coagulation Factor Deficiency in a Patient with Crohn’s Disease

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Retinitis Pigmentosa, Cutis Laxa, and Pseudoxanthoma Elasticum–Like Skin Manifestations Associated with GGCX Mutations

Gamma-glutamyl carboxylase (GGCX) mutations have been reported in patients with a pseudoxanthoma elasticum (PXE)-like phenotype, loose redundant skin, and multiple vitamin K-dependent coagulation factor deficiencies. We report on the clinical findings and molecular results in 13 affected members of two families who had a uniform phenotype consisting of (PXE)-like skin manifestations in the neck and trunk, loose sagging skin of the trunk and upper limbs, and retinitis pigmentosa confirmed by electroretinographies in 10 affected individuals. There were no coagulation abnormalities. Molecular investigations of the ATP-binding cassette subfamily C member 6 did not yield causative mutations. All 13 affected family members were found to be homozygous for the splice-site mutation c.373+3G>T in the GGCX gene. All tested parents were heterozygous for the mutation, and healthy siblings were either heterozygous or had the wild type. We suggest that the present patients represent a hitherto unreported phenotype associated with GGCX mutations. Digenic inheritance has been suggested to explain the variability in phenotype in GGCX mutation carriers. Consequently, the present phenotype may not be explained only by the GGCX mutations only but may be influenced by variants in other genes or epigenetic and environmental factors.