Thomas S. Kickler

A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis

BACKGROUND Platelet glycoprotein IIb/IIIa is a membrane receptor for fibrinogen and von Willebrand factor, and it has an important role in platelet aggregation. It is known to be involved in the pathogenesis of acute coronary syndromes. Previously, we found a high frequency of a particular polymorphism, PlA2, of the gene encoding glycoprotein IIIa in kindreds with a high prevalence of premature myocardial infarction. METHODS To investigate the relation between the PlA2 polymorphism and acute coronary syndromes, we conducted a case-control study of 71 case patients with myocardial infarction or unstable angina and 68 inpatient controls without known heart disease. The groups were matched for age, race, and sex. We used two methods to determine the PlA genotype: reverse dot blot hybridization and allele-specific restriction digestion. RESULTS The prevalence of PlA2 was 2.1 times higher among the case patients than among the controls (39.4 percent vs. 19.1 percent, P=0.01). In a subgroup of patients whose disease began before the age of 60 years, the prevalence of PlA2 was 50 percent, a value that was 3.6 times that among control subjects under 60 years of age (13.9 percent, P=0.002). Among subjects with the PlA2 polymorphism, the odds ratio for having a coronary event was 2.8 (95 percent confidence interval, 1.2 to 6.4). In the patients less than 60 years of age at the onset of disease, the odds ratio was 6.2 (95 percent confidence interval, 1.8 to 22.4). CONCLUSIONS We observed a strong association between the PlA2 polymorphism of the glycoprotein IIIa gene and acute coronary thrombosis, and this association was strongest in patients who had had coronary events before the age of 60 years.

Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients.

BACKGROUND AND METHODS Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, central nervous system abnormalities, and renal dysfunction. In early reports the mortality approached 100 percent. A treatment protocol was introduced in 1979 for patients admitted to Johns Hopkins Hospital with the diagnosis of TTP-HUS. Treatment regimens included 200 mg of prednisone a day, for patients with minimal symptoms and no central nervous system symptoms, and prednisone plus plasma exchange, for patients with rapid clinical deterioration who did not improve after 48 hours of prednisone alone and for patients presenting with central nervous system symptoms and rapidly declining hematocrit values and platelet counts. RESULTS A total of 108 patients were treated, and 91 percent survived. Prednisone alone was judged to be effective in 30 patients with mild TTP-HUS (two relapses and two deaths). Plasma exchange plus prednisone was given to 78 patients with complicated TTP-HUS, resulting in 67 relapses and 8 deaths. Relapses occurred in 22 of 36 patients given maintenance plasma infusions. Neither splenectomy nor treatment with aspirin and dipyridamole was effective in those with a poor response to plasma exchange. None of the 71 patients tested had positive cultures for O157:H7 Escherichia coli. Nine percent of the patients were pregnant, and none gave birth to infants with TTP-HUS. CONCLUSIONS Effective treatment with 91 percent survival is available for patients with TTP-HUS.

Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists

BACKGROUND Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl(A2) polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity. METHODS AND RESULTS In this study, we characterized functional parameters in platelets from healthy donors with the Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) to Pro (Pl(A2)) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(A1,A2), and 16 Pl(A2,A2)). Compared with Pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl(A2,A2) platelets after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 versus Pl(A1,A2)). Pl(A1,A2) platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab. CONCLUSIONS Pl(A2)-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl(A) alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.

Single-donor platelets reduce the risk of septic platelet transfusion reactions

BACKGROUND: Septic platelet transfusion reactions (SPTRs) are the most common, serious risk of transfusion. Because SPTRs result from donor skin flora or asymptomatic bacteremia, the use of single‐donor platelets (SDPs) has been proposed to reduce the risk of SPTRs from the risks with pools of platelet concentrates (PCs).

Bacterial sepsis secondary to platelet transfusion: An adverse effect of extended storage at room temperature

ABSTRACT: In a 3‐month period four episodes of bacterial sepsis related to contaminated random donor platelet concentrates were observed. Evaluation incriminated extended (5 or more days) platelet storage. To determine if platelets stored for longer periods were likely to have greater bacterial contamination, platelet concentrates were innoculated with bacteria and daily quantitative bacteriology was performed. In vitro studies using polyolefin bags indicated contamination could occur with a single organism of Staphylococcus epidermidis. By 72 hours, platelet concentrates contained from 103 to 108 organisms per 0.1 ml depending on the inoculum size. By 6 days all inoculated units contained 107 to 109 organisms per 0.1 ml.

In utero cerebral hemorrhage in alloimmune thrombocytopenia

Central nervous system hemorrhage is a well-recognized complication of neonatal alloimmune thrombocytopenia attributed to perinatal trauma from passage through the birth canal. That central nervous system (CNS) hemorrhage can occur in utero is not as well recognized, and congenital CNS lesions have only circumstantially been linked to thrombocytopenia. We report two cases of intrauterine CNS hemorrhage shown to have occurred prenatally, resulting in porencephaly. The second case is unique in that the necropsy finding of a porencephalic cyst arising from an old hemorrhagic site pathologically confirms that the etiology of congenital CNS lesions in alloimmune thrombocytopenia is due to hemorrhage. This second case received close prenatal monitoring and yet died as a result of hemorrhage that was not detected until emergency operative delivery. A review of the literature revealed 10 cases, including two other pairs of siblings, who had CNS damage attributable to intrauterine hemorrhage. These findings indicate that congenital CNS lesions in alloimmune thrombocytopenia are due to intrauterine hemorrhage that careful obstetric and prenatal care may not identify or prevent. This fact should be included when genetic counseling is offered to alloimmunized mothers.

Limitations of D-dimer testing in unselected inpatients with suspected venous thromboembolism.

PURPOSE To determine the utility and limitations of D-dimer testing for the evaluation of venous thromboembolism in hospitalized patients. METHODS We performed D-dimer testing by four different methods in unselected inpatients undergoing radiologic evaluation for possible venous thromboembolism. We included patients with a history of malignancy, recent surgery, thrombosis, and anticoagulation treatment. C-reactive protein levels were assayed as a measure of inflammation. RESULTS Of 45 patients with radiographically proven proximal deep venous thrombosis or pulmonary embolism, 43 had elevated D-dimer levels by enzyme-linked immunosorbent assay (ELISA) (sensitivity, 96%); the specificity of the test was 23% (36/157). The qualitative non-ELISA tests had higher specificities, but their sensitivities were <70%. Nineteen patients (42%) with thrombosis had false-negative D-dimer tests by at least one assay. The specificity of the tests decreased with increasing duration of hospitalization, increasing age, and increasing C-reactive protein levels. D-dimer testing had little or no utility in distinguishing patients with thrombosis from those without in patients who had been hospitalized for more than 3 days, were older than 60 years, or had C-reactive protein levels in the highest quartile. CONCLUSION In unselected inpatients, D-dimer testing has limited clinical utility because of its poor specificity. This is particularly true for older patients, those who have undergone prolonged hospitalization, and those with markedly elevated C-reactive protein levels. In some patient subsets, a negative non-ELISA D-dimer test cannot discriminate between inpatients with and without thrombosis.

Gene frequencies of the five major human platelet antigens in African American, white, and Korean populations

BACKGROUND: The study of the immunogenetics of the human platelet antigens is important to the improvement of diagnosis and genetic counseling and to the development of screening programs for women at risk of having babies with neonatal alloimmune thrombocytopenia. Description of the immunogenetics of the human platelet antigens in some racial groups has been incomplete.

Immature Granulocyte Measurement Using the Sysmex XE-2100 Relationship to Infection and Sepsis

We determined the usefulness of immature granulocyte measurement as a predictor of infection or positive blood culture and compared the results with total WBC count and absolute neutrophil count (ANC). Blood samples from 102 infected and 69 noninfected patients were analyzed using the Sysmex XE-2100 automated blood cell counter (Sysmex, Kobe, Japan). The percentage of immature granulocytes was significantly higher in infected than in noninfected patients and in patients with positive than patients with negative blood cultures. Receiver operating characteristic curves showed that the percentage of immature granulocytes was a better predictor of infection than the WBC count and comparable to the ANC. Automated immature granulocyte measurements reflect a biologically and clinically relevant phenomenon but are not sensitive enough to be used as screening assays for prediction of infection or bacteremia. However, although infrequently encountered, a percentage of immature granulocytes of more than 3 was a very specific predictor of sepsis and might help expedite microbiologic laboratory evaluation of a subset of patients.

Immature Granulocyte Measurement Using the Sysmex XE-2100

We determined the usefulness of immature granulocyte measurement as a predictor of infection or positive blood culture and compared the results with total WBC count and absolute neutrophil count (ANC). Blood samples from 102 infected and 69 noninfected patients were analyzed using the Sysmex XE-2100 automated blood cell counter (Sysmex, Kobe, Japan). The percentage of immature granulocytes was significantly higher in infected than in noninfected patients and in patients with positive than patients with negative blood cultures. Receiver operating characteristic curves showed that the percentage of immature granulocytes was a better predictor of infection than the WBC count and comparable to the ANC. Automated immature granulocyte measurements reflect a biologically and clinically relevant phenomenon but are not sensitive enough to be used as screening assays for prediction of infection or bacteremia. However, although infrequently encountered, a percentage of immature granulocytes of more than 3 was a very specific predictor of sepsis and might help expedite microbiologic laboratory evaluation of a subset of patients.