Coagulation Abnormalities in Patients with Noonan Syndrome - a Single Centre Case Series.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1035-1035
Author(s):  
Jayson M. Stoffman ◽  
Bernard N. Chodirker ◽  
Sara J. Israels
Keyword(s):  
Platelet Aggregation ◽  
Noonan Syndrome ◽  
Case Series ◽  
Protein S ◽  
Bleeding Tendency ◽  
Thrombin Time ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Coagulation Abnormalities ◽  
Von Willebrand

Abstract Noonan syndrome (NS) is an autosomal dominant disorder that includes short stature, characteristic facies, congenital heart defect, webbed neck, and developmental delay. A mutation in the PTPN11 gene can be identified in 50% of patients. A bleeding tendency is included in the phenotypic spectrum, with factor XI deficiency and platelet abnormalities described most frequently. At Winnipeg’s Health Sciences Centre, 24 patients with features typical of NS have been studied by the Special Haemostasis Laboratory. Four patients in whom the diagnosis was suspected but not considered definite are also included in this analysis. Clinical complaints included easy bruising (9), epistaxis (2), menorrhagia (1), and a family history of bleeding problems (3). Sixteen patients were referred for investigation following the diagnosis of NS. All 28 patients had coagulation screening tests: 16 patients had an abnormal PT and 12 had an abnormal aPTT. Thrombin time was slightly prolonged in 6 of 23 patients. Reptilase time was normal in 8 patients, and fibrinogen concentration was normal in 20 patients. Factor XI levels were measured in 14 patients, with a mean value of 62% (range 32–99%). Only 2 patients had levels below the normal range. One of 13 patients evaluated for FXII levels was deficient (FXII 25%), and 2 of 19 patients evaluated for FIX levels had mild FIX deficiency (FIX 40 and 49%) without symptomatic bleeding. No other factor deficiencies were identified. Twenty-four patients had determinations of von Willebrand Factor antigen and activity; 2 had results consistent with mild Type 1 von Willebrand Disease. Platelet aggregation studies were done in 22 patients. A variety of abnormalities were noted, with the most frequent being abnormal aggregation with epinephrine (7/22). Dense granule number was decreased in 2 of 7 samples studied by electron microscopy. Lupus anticoagulants were detected in 3 of 13 patients screened. Thrombophilia investigations in 4 patients detected decreased protein S in one patient who had been diagnosed previously with protein S deficiency. This unselected case series, the largest reported to date in the literature, illustrates the heterogeneity of coagulation abnormalities that may occur in NS. Symptoms, when present, were mild, and often did not correlate with laboratory abnormalities. Non-specific platelet aggregation defects were the most commonly identified abnormalities. In contrast to the literature, factor XI deficiency was not prevalent. A specific etiology for the variable bleeding tendency has not yet been identified in NS.

The Effect of Combined Factor XI Deficiency with von Willebrand Factor Abnormalities on Haemorrhagic Diathesis

1990 ◽  
Vol 63 (01) ◽  
pp. 036-038 ◽  
Author(s):  
Shulamith Tavori ◽  
Benjamin Brenner ◽  
llana Tatarsky
Keyword(s):  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Haemorrhagic Diathesis ◽  
Von Willebrand’S Factor ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor

SummaryTo account for the lack of correlation between the level of factor XI (FXI) in deficient patients and haemorrhagic manifestations, we correlated the prevalence of combined FXI and von Willebrand’s factor (vWF) deficiency in 212 FXI-deficient patients. Fifty-four patients had a combined FXI and vWF deficiency: 16 patients had severe and 38 patients had mild FXT deficiency. In a group of 28 patients with comparably mild FXI deficiency, 14 bleeders had significantly lower mean vWF, Ag, ristocetin cofactor and ristocetin induced platelet aggregation than 14 non-bleeders selected on the basis of comparable FXI levels. These findings suggest that the combination of FXI and vWF deficiency is common and may affect the bleeding tendency in mild FXI deficiency.

The Association Between SHP-2 Mutations and Platelet Function in Noonan Syndrome.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1239-1239
Author(s):  
Jayson M. Stoffman ◽  
Archibald Mcnicol ◽  
Teresa Zelinski ◽  
Bernard N. Chodirker ◽  
Sara J. Israels
Keyword(s):  
Platelet Aggregation ◽  
Phosphatase Activity ◽  
Platelet Function ◽  
Noonan Syndrome ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Variable Expression ◽  
Factor Xi Deficiency ◽  
Ptpn11 Mutation ◽  
Platelet Aggregometry

Abstract Noonan syndrome (NS) is an autosomal dominant disorder characterized by variable expression of multiple defects including short stature, facial dysmorphias, congenital heart defects, developmental delay, and hematological abnormalities. A bleeding tendency has been variably described in patients with NS; Factor XI deficiency and platelet function abnormalities are reported most frequently. Recently, germline missense mutations in the PTPN11 gene have been identified in up to 50% of individuals with NS. PTPN11 encodes the ubiquitously expressed cell-signaling mediator SHP-2, a non-transmembrane protein tyrosine phosphatase involved in the normal activation of the Ras-MAPK signaling cascade. SHP-2 has a pivotal role in cell proliferation, differentiation, and survival, but also modulates platelet responses to some stimuli. Some PTPN11 mutations lead to altered SHP-2 phosphatase activity, and have been shown to impact cardiac development in a mouse model of NS. This study examined the potential association among PTPN11 mutations, platelet function abnormalities, and platelet SHP-2 activity in patients with NS. Eighteen patients with a clinical diagnosis of NS were studied: 14 (78%) were female and the mean age was 20.7 years (range 4–56 years). A validated bleeding questionnaire was administered to each participant, and platelet aggregometry was performed on platelet-rich plasma according to standard clinical practice. SHP-2 was isolated by immunoprecipitation from agoniststimulated platelets and phosphatase activity measured spectrophotometrically. PTPN11 mutations were identified by dHPLC and defined by DNA sequencing in each participant to characterize the presence and the precise nature of a mutation associated with their NS. Seven (39%) participants were classified as bleeders on the basis of the questionnaire; of these, four had no hemostasis abnormality identified. One participant had mild Factor XI deficiency. Seven participants had abnormalities of platelet aggregation, and four participants had decreased platelet dense granule numbers and ATP release. PTPN11 mutations were identified in 12 (67%) participants: seven were the commonly described mutation in Exon 8; four members of a three-generation family had a previously described Exon 3 mutation; and one individual had a mutation in Exon 12 which is usually associated with LEOPARD syndrome. Mutations in other genes associated with NS were not evaluated in this study. Six patients with PTPN11 mutations were clinically classified as bleeders, but no correlation was found between PTPN11 mutation and agonist-induced platelet aggregation or SHP-2 phosphatase activity. Three patients with platelet function abnormalities had no PTPN11 mutation identified. Not all patients with NS have a clinical bleeding profile or platelet function abnormalities. Neither clinical bleeding history nor platelet function abnormalities correlated with PTPN11 mutations, suggesting that additional factors may be required for a bleeding phenotype associated with PTPN11 mutations. Mutations in other NS-associated genes may contribute to a bleeding phenotype. Abnormalities in platelet aggregometry could not be explained on the basis of SHP-2 activity, although it is possible that changes in enzyme activity downstream in the Ras-MAPK pathway may impact platelet function in some patients with NS. Ultimately, the identification of a molecular basis for the frequently observed platelet aggregation defects could provide a means to predict the risk of bleeding in patients with NS.

Definition of the Bleeding Tendency in Factor XI-Deficient Kindreds–A Clinical and Laboratory Study

1995 ◽  
Vol 73 (02) ◽  
pp. 194-202 ◽  
Author(s):  
P H B Bolton-Maggs ◽  
D A Patterson ◽  
R T Wensley ◽  
E G D Tuddenham
Keyword(s):  
Convincing Evidence ◽  
Factor Vii ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Excessive Bleeding ◽  
North West ◽  
Factor Xi Deficiency ◽  
History Analysis ◽  
Definition Of ◽  
Von Willebrand

SummaryIndividuals with severe factor XI deficiency are prone to excessive bleeding after injury or surgery, but the existence of a haemorrhagic tendency in partial factor XI deficiency is controversial. In this study, 172 members of 30 kindreds (20 non-Jewish) transmitting factor XI deficiency in North West England were interviewed and a bleeding history questionnaire completed. Blood was taken for coagulation assays. The questionnaires were categorised independently by two assessors to determine presence or absence of a bleeding tendency, in the absence of information about the factor XI level or family history. Analysis shows that 48% of heterozygotes have a bleeding tendency. Eighteen (60%) families came to attention because of bleeding problems in heterozygotes. Comparison of histories between partially deficient and non-deficient individuals demonstrated a higher incidence of menstrual problems, an increase in significant bruising, and an increased likelihood of excessive bleeding after tonsillectomy and dental extractions.The incidence of von Willebrand’s disease was not increased, but individuals with heterozygous factor XI deficiency who were bleeders tended to have lower levels of factor VIIIc and von Willebrand factor, and were more commonly of blood group 0. These features may contribute to the bleeding tendency. There was no evidence of alteration in factor VII activity (as defined by the ratio of activity to antigen) between the bleeders and non-bleeders.This is convincing evidence for abnormal bleeding in factor XI deficiency which is not confined to severely deficient patients.

Von Willebrand Factor Antigen and Factor XI Activity Levels As Predictors of Bleeding Tendency in Israeli Patients with Von Willebrand's Disease

1995 ◽  
Vol 1 (4) ◽  
pp. 260-264 ◽  
Author(s):  
Benjamin Brenner ◽  
Tamar Stemberg ◽  
Arieh Laor ◽  
Shulamit Tavori ◽  
Ilana Tatarsky ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Activity Levels ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Von Willebrand Factor Antigen ◽  
Von Willebrand ◽  
Induced Aggregation ◽  
Willebrand Factor ◽  
Factor Antigen

Previous preliminary data and case reports have suggested an association of von Willebrand's disease (vWD) with factor XI deficiency and platelet abnormalities. We have analyzed the prevalence of factor XI deficiency and thrombocytopathy in a cohort of Israeli patients with vWD. Decreased factor XI levels (<67 U/dl) were documented in 35 of 63 (36%) vWD subjects; factor XI levels were <30 U/dl in five of 60 (8%). A significant decline in ADP-induced platelet aggregation (<30% of control) was found in 48% of vWD patients. Likewise, epinephrine-induced aggregation was reduced in 41%, and collagen-induced aggregation was decreased in 7% of vWD patients. Logistic regression analysis showed that while Ivy bleeding time, ristocetin cofactor, and ristocetin-induced platelet aggregation did not predict bleeding, both von Willebrand factor antigen and factor XI activity levels predict bleeding in patients with vWD. These findings suggest that mild factor XI deficiency and thrombocytopathy are common in Israeli subjects with vWD and that associated factor XI deficiency can result in clinical bleeding in these patients. Key Words: Von Willebrand' s disease—Factor XI deficiency—Thrombocytopathy.

scholarly journals Hematological findings in Noonan syndrome

2003 ◽  
Vol 58 (1) ◽  
pp. 5-8 ◽  
Author(s):  
Débora R. Bertola ◽  
Jorge David A. Carneiro ◽  
Élbio Antônio D'Amico ◽  
Chong A. Kim ◽  
Lilian Maria José Albano ◽  
...  
Keyword(s):  
Platelet Count ◽  
Noonan Syndrome ◽  
Coagulation Factor ◽  
Invasive Procedure ◽  
Clinical Findings ◽  
Thrombin Time ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
And Function

OBJECTIVE: Noonan syndrome is a multiple congenital anomaly syndrome, and bleeding diathesis is considered part of the clinical findings. The purpose of this study was to determine the frequency of hemostatic abnormalities in a group of Noonan syndrome patients. METHOD: We studied 30 patients with clinical diagnosis of Noonan syndrome regarding their hemostatic status consisting of bleeding time, prothrombin time, activated partial thromboplastin time and thrombin time tests, a platelet count, and a quantitative determination of factor XI. RESULTS: An abnormal laboratory result was observed in 9 patients (30%). Although coagulation-factor deficiencies, especially factor XI deficiency, were the most common hematological findings, we also observed abnormalities of platelet count and function in our screening. CONCLUSIONS: Hemostatic abnormalities are found with some frequency in Noonan syndrome patients (30% in our sample). Therefore, we emphasize the importance of a more extensive hematological investigation in these patients, especially prior to an invasive procedure, which is required with some frequency in this disorder.

Glycoprotein Ib Has a Partial Role in Platelet-von Willebrand Factor Collagen Interaction

1988 ◽  
Vol 60 (02) ◽  
pp. 182-187 ◽  
Author(s):  
Morio Aihara ◽  
Ken Tamura ◽  
Ryuko Kawarada ◽  
Keizou Okawa ◽  
Yutaka Yoshida
Keyword(s):  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Ricinus Communis ◽  
Protein S ◽  
Platelet Membrane ◽  
Membrane Glycoprotein ◽  
Normal Plasma ◽  
Ricinus Communis Agglutinin ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe adhesion of human fixed washed platelets (FWP) to collagen was decreased after treatment with Serratia marcescens protease (SP), which removed 95% of the glycocalicin from platelet membrane glycoprotein (GP) lb. However, the diminished adhesion of SP treated FWP to collagen could still be increased in the presence of purified von Willebrand factor (vWF). This ability of vWF to increase FWP adhesion to collagen is defined as collagen cofactor (CCo). The adhesion of FWP to collagen was not affected by a monoclonal antibody (MAb) to GP Ilb/IIIa (10E5), that inhibits ADP and collagen induced platelet aggregation. On the other hand, it was decreased by 50% by a MAb to GP lb (6D1), that inhibits ristocetin induced platelet aggregation. Adhesion of FWP in buffer to collagen was completely inhibited by Ricinus communis agglutinin I or concanavalin A, while Lens culinalis agglutinin and wheat germ agglutinin showed 50% inhibition. The FWP adhesion to collagen in the presence of vWF (normal plasma) was unaffected by MAbs to GP Ilb/IIIa (10E5, P2, HPL1) but was decreased to 32-38% by MAbs to GP lb (6D1, AN51, HPL11). A MAb to vWF (CLB-RAg 35), that inhibits ristocetin induced binding of vWF to platelets, decreased the CCo of normal plasma by 70%. The MAb, CLB-RAg 201, that inhibits the binding of vWF to collagen, completely inhibited the CCo of normal plasma. In conclusion, our data suggest that (1) GP lb has a partial role in FWP adhesion to collagen; (2) the binding of vWF to collagen is required for the expression of CCo; (3) CCo is partly mediated through GP lb; but (4) other platelet membrane protein(s) besides GP lb or GP Ilb/IIIa must also be involved in FWP-vWF-collagen interactions.

EFFECT OF DDAVP ON PRIMARY HEMOSTASIS WITH CONGENITAL AFIBRINOGENEMIA

1987 ◽  
Author(s):  
M Taki ◽  
M Inagaki ◽  
T Miura ◽  
N Saito ◽  
T Meguro ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Retention Rate ◽  
Platelet Membrane ◽  
Bleeding Tendency ◽  
Primary Hemostasis ◽  
Prolonged Bleeding Time ◽  
Before And After ◽  
Congenital Afibrinogenemia ◽  
Von Willebrand ◽  
Platelet Functions

It has been reported recently that DDAVP might be an useful tool in the therapy and prevention of bleeding in patients with congenital afibrinogenemia (CA).To study the mechanism of its efficacy, changes in the platelet functions of a patient with CA were examined prior to, and one hour after, the infusion of DDAVP (0.4 μg/Kg). A patient with Glanzmann's thrombasthenia (GT) was also examined, to allow a study of the role of platelet membrane glycoprotein IIb/IIIa (GP IIb/IIIa), a deficient platelet in GT, in the resulting effects of the drug. When both patients were infused with DDAVP, the level of plasma von Willebrand factor (vWF) increased two- to fourfold, accompanied by an enhancement of ristocetin-induced platelet agglutination. The level of plasma fibrinogen was never changed.The prolonged bleeding time observed was markedly improved only in the CA patient, remaining unchanged in the GT patient, after the infusion of DDAVP. This indicates that DDAVP is effective in diminishing the bleeding tendency in CA, but not in GT. Among the platelet functions tested, only the platelet retention rate on glass beads, ADP-induced platelet aggregation and collagen-induced platelet aggregation improved in CA, each remaining unchanged in GT. In particular, collagen-induced platelet aggregation was markedly improved in the CA patient. However, the platelet adhesion to collagen (50 μg/ml)-Sepharose remained normal, both before and after the infusion of DDAVP in CA.These results suggest that an increase in the plasma vWF level and the existence of platelet membrane GPIIb/IIIa may be necessary for the improvement of primary hemostasis, after the infusion of DDAVP. The vWF-mediated platelet aggregation by collagen or ADP may produce this effect in the CA patient.

The Use of Factor XI Concentrates (Hemoleven, LFB) in Patients with Congenital Factor XI Deficiency and a Known Bleeding Tendency.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1796-1796
Author(s):  
Vickie McDonald ◽  
Savidge F. Geoffrey ◽  
Savita Rangarajan ◽  
Mike Mitchell
Keyword(s):  
Fresh Frozen Plasma ◽  
Incidence Rates ◽  
Treatment Modalities ◽  
Bleeding Tendency ◽  
Normal Range ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Unit Dose ◽  
The Mean ◽  
Congenital Factor

Abstract Traditional treatment modalities for FXI deficiency (UK prevalence 400 cases) include antifibrinolytics, desmopressin, fresh frozen plasma (FFP) and FXI concentrates but there has been reluctance to use FXI concentrates because of reported incidence rates of thrombosis up to 10%. Concerns over the safety and efficacy of FFP, with additional viral inactivation steps possibly leading to reduced FXI recoveries, have led us to increase our use of FXI concentrates. We aimed to assess the indications, dosage, recovery, efficacy and safety of Hemoleven, a plasma derived, purified and virally inactivated FXI concentrate, which also contains heparin and antithrombin, in patients with congenital factor XI deficiency. A retrospective study was performed using hospital notes and laboratory records of all patients who had received Hemoleven over a 2-year period. Eleven patients (6 male, 5 female) had been treated with a median age of 38 years (range 7–74) and mean baseline FXI:C levels of 25.4U/dl (3–50). All patients received Hemoleven as prophylaxis for surgery or dental work and had all previously had excess bleeding when surgically challenged. One patient died of a condition unrelated to FXI treatment. Pre- and post-FXI:C levels were available for a total of 60 treatment episodes of which 25 were 1000-unit doses and 35 were 2000-unit doses. The mean increase in FXI:C per 1000-unit dose was 25.4 U/dl (12.4–43.9) while the mean increase in FXI:C per 2000-unit dose was 50.5 U/dl (11.8–106.5). This is consistent with the manufacturer’s data. Ten minute post infusion FXI:C levels were above the normal range (73–133 U/kg) in 8% of patients given 1000 units and 11% of patients given 2000 units but below the normal range in 24% of patients who received 1000 units and 20% of patients who received 2000 units. 90% of treatment episodes led to FXI:C levels above the usual treatment target of 65 U/dl. Genetic analysis of 9/11 patients showed that 2 were homozygous (one type II and one type III), 6 were heterozygous for other recognised mutations and one had no mutation identified but apparent absence of RNA from one allele demonstrated in a relative by qRT-PCR. No excess bleeding or inhibitor development was recorded even in one patient who had had a poor haemostatic response with FFP. There were no episodes of arterial or venous thrombotic complications within this group and no clinical or laboratory evidence of DIC following treatment. In summary, treatment with factor XI concentrates gave consistent increments in FXI:C at the doses given and achieved good haemostasis with no episodes of thrombosis in this study, even in patients over the age of 60y. While the risk of prion transmission is still unknown, use of FXI concentrates is not associated with the risks of fluid overload and TRALI that are seen with FFP. We acknowledge that the study includes small numbers of patients however the cohort of patients with a bleeding diathesis in this condition is small. We conclude that Hemoleven appears to be an effective and reliable treatment for patients with FXI:C deficiency but should be given in the context of FXI:C level monitoring in order to detect those patients who may develop high levels and possible thrombosis.

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