201/223. Dysfunctional platelet glycoprotein IIb/IIIa associated with a platelet release defect: a family study. We are reporting on a 36-year-old white female with a bleeding history attributed to dysfunctional platelet glycoprotein IIb/IIIa (GPIIb/IIIa) and a coexisting platelet release defect. platelet aggregation studies (PAS) revealed markedly diminished to absent responses to ADP, epinephrine, collagen and arachidonic acid; the ristocetin response was normal. ATP content was normal with poor release to the agonists as measured by luminescent technique. DDAVP infusion shortened bleeding time from 13.5 min to 8.0 and 12 min (at 1 and 2 hours). Flow cytometry and immunoblotting revealed normal amounts of GPIIb and diminished GPIIIa (50% of control). Using a previously reported ELISA which measures the binding of GPIIb/IIIa to immobilized fibrinogen, the patient's platelet extract showed no binding to fibrinogen. Both the father and mother were found to have decreased PAS responses and normal amounts of GPIIb/IIIa determined by both Western blot and flow cytometry. However, the ELISA showed decreased binding of their GPIIb/IIIa to fibrinogen (71% and 62% as compared to controls, respectively). The patient's dysfunctional fibrinogen receptor was clearly demonstrated by the ELISA. The parents had moderately reduced GPIIb/IIIa function in this assay, but they did not demonstrate a reduced GPIIIa as was noted in the patient. The parents' PAS indicated a platelet release defect. These findings suggest an inherited platelet release defect and a dysfunctional GPIIIa. The partial response to DDAVP would be compatible with the presence of a platelet release defect. ( info) |
202/223. Functional studies on platelets of a patient with an acquired disorder of platelet function associated with autoantibodies against membrane glycoprotein IIB/IIIA complex. Platelet functions have been studied of a 63 year old woman with a severe acquired thrombopathy. The platelets did not adhere to siliconized glass. Aggregation could not be induced by either ADP (1 microM) nor collagen (2 micrograms/ml), no release of serotonin was found under these conditions. Thrombin caused only a weak aggregation response. Quantitative analysis of platelet actin revealed a very low total actin content (473 micrograms/10(9) platelets) and an extremely low F-actin value (3% of total actin). Stimulation of platelets with 0.1 U/ml thrombin for 3 min resulted in an increase of only 5% F-actin, whereas ADP and collagen did not induce any actin polymerization. Ca2 movement in the patient's platelets is severely impaired after ADP and collagen stimulation, whereas a normal Ca2 movement was obtained by 0.1 U/ml thrombin. The inhibition of the functions of normal platelets (aggregation and actin polymerization) by addition of patient's serum (5-10% final concentration) points to receptor blockade by platelet autoantibodies in the patient's serum. The antibody was purified by adsorption on Protein-A-sepharose. Addition of IgG-suspension (5% final concentration) to washed control platelets resulted in similar effects on aggregation and actin polymerization compared to the effects of patient's serum. ( info) |
203/223. Epidural analgesia in a preeclamptic parturient after normalization of a prolonged bleeding time with DDAVP. BACKGROUND AND OBJECTIVES. Despite several advantages to the use of epidural analgesia for the management of labor pain in preeclamptic parturients, this procedure is withheld from many such patients owing to associated thrombocytopenia and platelet dysfunction. methods. A preeclamptic parturient with mild thrombocytopenia and platelet dysfunction manifested by a prolonged bleeding time received intravenous DDAVP (0.3 microgram/kg) in an attempt to correct her coagulation abnormality. RESULTS. The patient's bleeding time was normalized with DDAVP administration, allowing her to receive epidural analgesia. CONCLUSIONS. Preeclampsia-induced platelet dysfunction might be corrected with DDAVP. A controlled study is required before its routine use can be advocated. ( info) |
204/223. Bernard-Soulier-like functional platelet defect in myelodysplastic syndrome and in acute myeloblastic leukemia associated with trilineage myelodysplasia. Platelet function was studied in a child with myelodysplastic syndrome (MDS: refractory anemia with an excess of blasts) and a child with acute myeloblastic leukemia (AML-M6) associated with trilineage myelodysplasia (TMDS). An acquired Bernard-Soulier-like platelet defect was considered in both patients with the findings of prolonged bleeding time and abnormally large platelets that failed to aggregate in response to ristocetin. In contrast to findings in von Willebrand's disease, the abnormal response of platelets to ristocetin could not be corrected by the addition of normal flesh plasma. The detection of abnormal platelet aggregation response to ristocetin may be a useful diagnostic finding for clonal disorders causing impaired platelet function in MDS and coexistent TMDS associated with AML. Further studies of ristocetin-induced platelet aggregation in a large number of these patients are required. ( info) |
205/223. Studies on the haemostatic defect in a complicated syndrome. An inverse Scott syndrome platelet membrane abnormality? The Stormorken syndrome is a multifacetted syndrome including a bleeding tendency. No deviations were found in the coagulation- or fibrinolytic systems. Platelet number was low normal, and size abnormal, whereas EM findings were unremarkable. survival time was half normal. clot retraction was initially rapid, but clearly decreased, whereas prothrombin consumption was also initially rapid, but complete. Membrane GP's were normal, so was AA metabolism, PI-cycle, granule storage and secretion, and c-AMP function, whereas 5-HT uptake and storage was decreased. Optical platelet aggregation was low normal with all physiological agonists. The only clearly abnormal finding was that coagulant activity was present on non stimulated platelets at the same level as kaolin-stimulated normal platelets. This indicated a platelet abnormality which should lead to a thrombogenic, not to a haemorrhagic trait. This paradox may have its origin in rheology, because when challenged with in vivo shear rates in an ex vivo perfusion chamber, platelet cohesion was abnormally low. Further studies to better delineate the membrane abnormality are underway. ( info) |
206/223. Linkage of a familial platelet disorder with a propensity to develop myeloid malignancies to human chromosome 21q22.1-22.2. Linkage analysis was performed on a large pedigree with an autosomal dominant platelet disorder and a striking propensity in affected family members to develop hematologic malignancy, predominantly acute myelogenous leukemia. We report the linkage of the autosomal dominant platelet disorder to markers on chromosome 21q22. Four genetic markers completely cosegregate with the trait and yield maximum logarithm of difference scores ranging from 4.9 to 10.5 (theta = .001). Two flanking markers, D21S1265 and D21S167, define a critical region for the disease locus of 15.2 centimorgan. Further analysis of this locus may identify a gene product that affects platelet production and function and contributes to the molecular evolution of hematologic malignancy. ( info) |
207/223. Deficiency of p-selectin in a patient with grey platelet syndrome. Patient B.G. is a 29-yr-old female with a lifelong bleeding disorder characterized clinically by a highly increased bleeding time, menorrhagias, long-lasting bleeding after cuts and tooth extractions and large post-traumatic haematomas. Her coagulation tests were within normal range, platelet count was 140,000-160,000 per microliters, but platelet function was impaired as demonstrated by the absence of collagen-induced aggregation, although no abnormalities were detected in aggregation response to ADP and ristocetin. Morphologically her platelets were characterized by gigantic size-average profile area was about 2.5 times higher than that of control donors, and severe deficiency of alpha-granules-only 16% of their number in control donors. These features taken together indicated the diagnosis of grey platelet syndrome. As has been shown by quantitative immunoblotting, patient's platelets contained small amounts of alpha-granule membrane protein p-selectin-about 15% of that in control donors. The content of plasma membrane glycoproteins IIb-IIIa and Ib was not reduced, suggesting the specific deficiency of alpha-granule membrane protein. Thus, B.G. is the second patient described in the literature (see also Lages et al, J Clin Invest 1991: 87: 919-929) with combined deficiency of alpha-granules and p-selectin. ( info) |
208/223. Pathogenetic analysis of five cases with a platelet disorder characterized by the absence of thromboxane a2 (TXA2)-induced platelet aggregation in spite of normal TXA2 binding activity. Five patients with mild bleeding tendencies characterized by defective thromboxane a2 (TXA2)-induced platelet aggregation are reported. The platelets of all the patients had the ability to bind exogenous TXA2. bleeding time was markedly prolonged in one patient. In three of the five patients, synthetic TXA2 mimetic (STA2)-induced platelet responses, including IP3 formation, Ca2 mobilization, phosphatidic acid formation and GTPase activities were selectively defective, suggesting impaired coupling between the TXA2 receptor and phospholipase C activation. However, in the remaining two patients, these responses were all within normal limits. This suggests that the defective site of this type of platelet disorder is heterogenous and that signaling mechanisms other than the TXA2 receptor-phospholipase C pathway are also involved in TXA2-induced platelet aggregation. ( info) |
209/223. Gastrointestinal angiodysplasia in congenital platelet dysfunction. We herein report three cases of repeated massive bleeding from the stomach and small bowel. One patient suffered from both thrombasthenia (type II) and von Willebrand disease (type 1) simultaneously. Two others had Bernard-Soulier's syndrome (BSS). One patient with BSS had bleeding from gastric angiodysplasia and was treated endoscopically by clipping. The other patients had massive bleeding from the small intestine, and had partial resection of the affected small intestine. Histologically, irregular dilatation and proliferation of the blood vessels were demonstrated in the submucosa in bleeding spots from a resected small intestine, and these findings were consistent with the features of acquired angiodysplasia. The development of gastrointestinal angiodysplasia may not only be associated with a dysfunction of von willebrand factor but also with that of platelets. ( info) |
210/223. Studies of a second family with the quebec platelet disorder: evidence that the degradation of the alpha-granule membrane and its soluble contents are not secondary to a defect in targeting proteins to alpha-granules. We recently described a quebec family with an autosomal dominant bleeding disorder characterized by mildly reduced-low normal platelet counts, an epinephrine aggregation defect, multimerin deficiency, and proteolytic degradation of several, soluble alpha-granular proteins. Similar clinical features led us to investigate a second family with an unexplained, autosomal dominant bleeding disorder. The affected individuals had reduced to normal platelet counts, absent platelet aggregation with epinephrine, and multimerin deficiency. Their platelet alpha-granular proteins factor v, thrombospondin, von Willebrand factor, fibrinogen, fibronectin, osteonectin, and p-selectin were proteolyzed and comigrated with the degradation products found in patients from the other family. However, their platelet albumin, IgG, external membrane glycoproteins, CD63 (a lysosomal and dense granular protein), calpain, and plasma von willebrand factor were normal, indicating restriction in the proteins proteolyzed. Electron microscopy studies indicated preserved alpha-granular ultrastructure, despite degradation of soluble and membrane alpha-granular proteins. Immunoelectron microscopy studies of the patients' platelets indicated that fibrinogen, von willebrand factor, p-selectin, multimerin, and factor v were within alpha-granules, with normal to reduced labeling for these proteins. Pathologic proteolysis of alpha-granular contents, rather than a defect in targeting proteins to alpha-granules, may be the cause of the protein degradation in the quebec platelet disorder. ( info) |