Dubin Johnson Syndrome associated with defective ristocetin – induced platelet agglutination

Background: This is the first reported case of platelet aggregation defect in association with Dubin-Johnson Syndrome. Case presentation: We reported a 14 months old female infant with recurrent attacks of mild to moderate ear and nose bleeding and moderate amount of subarachnoid hemorrhage with ristocetin induced platelet agglutination other than Von Willebrand Factor disease and Bernard–Soulier syndrome. The patient also had fluctuating bilirubin level (Maximum of 15 mg/dl) and remaining liver function tests were normal; the patient diagnosed as Dubin Johnson Syndrome by liver biopsy. Conclusions: Dubin-Johnson Syndrome may be associated with platelet aggregation defect.

Platelet Dysfunction in Noonan and 22q11.2 Deletion Syndromes in Childhood

Introduction An underlying thrombocytopathy seems to be responsible for hemorrhagic symptoms in patients diagnosed with 22q11.2 deletion syndrome (22q11DS) or Noonan syndrome (NS). In 22q11DS, it is explained by a defect in the membrane glycoprotein (GP) complex Ib-V-IX. The cause of thrombocytopathy in NS remains unclear. Aim The objective is to study the incidence of thrombocytopathy in pediatric patients diagnosed with 22q11DS or NS assessing the utility of ISTH-BAT questionnaire and laboratory techniques. Materials and Methods Prospective study between March and December 2018 in children (2–18 years old) diagnosed with 22q11DS or NS. Hemorrhagic symptoms using ISTH-BAT score, total cell blood count, platelet indices, PFA-200 closure times, and platelet aggregation were evaluated in all patients and membrane GP expression in 22q11DS patients. Results Nearly 70% of NS patients (n = 22) had a platelet aggregation defect without thrombocytopenia. A defect of platelet aggregation with adenosine diphosphate (ADP) and epinephrine was the most frequent pattern. A statistically significant inverse correlation between closure times and aggregation with arachidonic acid (p = 0.049, p = 0.043) and epinephrine (p = 0.021, p = 0.035), and ADP (p = 0.117, p = 0.05) was found. Total 5 out of 29 patients diagnosed with 22q11DS had macrothrombocytopenia; more noteworthy in older patients. Twenty-six patients showed an impairment in ristocetin-induced platelet aggregation that correlated with prolonged collagen/epinephrine (p = 0.034) and collagen/ADP (p = 0.01). A significant association between ISTH-BAT score >3 and closure times (p = 0.022, p = 0.002) and aggregation defect with ristocetin (p = 0.043) was also demonstrated. Conclusion Most NS and 22q11DS patients show an impairment of platelet aggregation that correlates with closure times. In 22q11DS patients, these results were also related to hemorrhagic symptoms.

Systemic Levels of 6-Keto-Prostaglandin F1α Following Administration of Inhaled Aerosolized Prostacyclin

A case is described where systemic levels of prostacyclin metabolite were measured during inhaled aerosolized prostacyclin (IAP) therapy for severe hypoxaemia in a patient with the acute respiratory distress syndrome. Comparable levels of prostacyclin metabolite have been associated with a marked platelet aggregation defect in vitro. A platelet aggregation defect was also demonstrated in vivo in this patient. Haemodynamic and gas exchange data during the IAP therapy are described.

Effect of Low Concentrations of Prostacyclin on Platelet Function in Vitro

The study was performed to determine the possible direct effects of low concentrations of prostacyclin that might spill over into the systemic circulation during the administration of inhaled aerosolized prostacyclin. Platelet aggregation in response to adenosine diphosphate and collagen, as well as measurement of the maximum amplitude of the thrombelastograph (TEG), was undertaken in vitro using venous blood exposed to low concentrations of prostacyclin (0, 10, 100 and 500 pg/ml) from eight healthy volunteers. There were statistically significant reductions in parameters of platelet aggregation in response to the agonists adenosine diphosphate (1 μmol/l and 8 μmol/l) and collagen (10 μmol/l) following exposure to as little as 10 pg/ml of prostacyclin. The maximum amplitude of the TEG was unchanged over the entire range of prostacyclin concentrations studied. The results indicate that low concentrations of prostacyclin or prostacyclin metabolite such as may be observed during inhaled aerosolized prostacyclin therapy are likely to be associated with a marked platelet aggregation defect. This defect was not detected by the TEG.

Comparative Effects of Recombinant Staphylokinase and Streptokinase on Platelet Aggregation

SummaryRecombinant staphylokinase (RSTA) has been shown to offer promise as a thrombolytic agent. In contrast to streptokinase (SK), few studies have been devoted to possible effects of RSTA on platelets. We have compared the capacity of RSTA and SK to trigger platelet aggregation and to modify ADP (2.5 µM) response in platelet-rich plasma (PRP) of 25 healthy subjects. Thus, exposure of PRP to SK (40 to 50 µg/ml) induced platelet aggregation in 6 out of 25 subjects. However, under the same conditions, RSTA failed to induce platelet aggregation in all cases (25 out of 25 subjects). In contrast to RSTA, SK (0.4 to 50 µg/ml) greatly reduced ADP-induced platelet aggregation in 12 out of 25 subjects. Preincubation of plasma with SK is associated with a decrease in the fibrinogen concentration. Furthermore, there was a good correlation between SK-induced fibrinogenolysis and SK- induced platelet aggregation defect (r2 = 0.9; p = 0.001). No fibrino genolysis was observed when different amounts of RSTA (0.4 to 50 µg/ml) were incubated in plasma for one min. However, there was a marked decrease in fibrinogen level (about 50%) when the plasma was incubated for five min with a very high concentration of RSTA. SK markedly enhanced the platelet response to ADP in 13 out of 25 subjects. In PRP of 6 out of 25 subjects, SK induces platelet aggregation and potentiates platelet response to ADP, however in PRP of 7 out of 25 subjects, SK caused only the increase of platelet response to ADP. The monoclonal antibody anti-FcγRIIal, IV-3 (2 [µ/ml), abolished SK-induced platelet aggregation and SK-enhanced ADP-induced platelet aggregation. In all cases (25 out of 25 subjects), RSTA failed to potentiate platelet response to ADP.These findings confirm that RSTA has a lesser fibrinogenolytic ability than SK and suggest its negligeable effect on platelet function.

SEVERE VON WILLEBRAND'S DISEASE WITH ABNORMAL PLATELET AGGREGATION

A 17-year-old boy with a life long history of easy bruising, epistaxis, subcutaneous hematoma and prolonged bleeding time from minor injuries, was initially diagnosed as having von Willebrand's disese, when he presented epistaxis at 2 years of age. Since his initial diagnosis, he has been treated with cryoprecipitate on many occasions to correct his bleeding tendency. The laboratory findings in the patient and his family are summarized in the table. The patient's mother, father and one brother have not complained any bleeding tendency.Multimeric analysis of vWF using SDS agarose gels showed absence of large multimer in the patient's plasma, decreased large multimer in mother's and brother's plasma. When the patient's PRP was tested for aggregation and release of ATP by ADP, epinephrine and collagen, using lumi aggregometer, platelet aggregation was abnormal as shown by disaggregation and almost no ATP activity was detectable in the supernatant. ATP contents of patient's and father's platelet was about 50% of normal platelets. Washed platelets of the patient in normal plasma did not aggregate normally, but washed normal platelets in the patient's plasma aggregate normally. No inhibitor of vWF could be demonstrated in the patient's plasma. Clot retraction was normal. These findings suggest that our patient has inherited vWD from materal side and the platelet aggregation defect, probably a kind of storage pool disease, from the paternal side of the family.