The current review describes inherited platelet disorders, illustrates their clinical phenotype and molecular genetic defects. Platelets are the key molecules mediating haemostasis via adhesion, ...activation and clot formation at the site of injury. The inherited platelet disorders can be classified according to their platelet defects: receptor/cytoskeleton defects, secretion disorder, and signal transduction defect. Patients with inherited thrombocytopathia present with mucous membrane bleedings (epistaxis, gingival bleeding) and may present with serious life threatening bleedings following surgery or trauma. Therefore, biochemical and molecular genetic characterization of inherited platelet disorders is important to understand these disorders and to support an efficient therapy.
Blockade of the platelet glycoprotein IIb/IIIa receptor by abciximab (c7E3 Fab) during coronary intervention reduces the incidence of ischemic complications, but has been associated with a doubling ...of the risk for bleeding complications. The present pilot study investigated whether modification of heparin dosing and/or early sheath removal would reduce the hemorrhagic complications associated with abciximab. One hundred three patients undergoing coronary intervention received abciximab (0.25 mg/kg bolus, 10 μg/min infusion for 12 hours) and aspirin and were randomized by a 2 × 2 factorial design to 1 of 2 weight-adjusted heparin doses and to 1 of 2 strategies for heparin discontinuation and vascular sheath removal. In the “standard-dose heparin” group, an initial bolus of 100 U/kg was administered to achieve a procedural activated clotting time (ACT) ≥300 seconds; in the “low-dose heparin” group, an initial bolus of 70 U/kg was administered without adjustment for ACT. In the “late sheath removal” arm, heparin infusion was continued for the 12-hour duration of abciximab infusion, followed by sheath removal; in the “early sheath removal” group, heparin was stopped after the interventional procedure and sheaths were removed during the abciximab infusion. There were no apparent differences between patients randomized to the different treatment groups with regard to the occurrence of ischemic end points. Rates of bleeding and blood transfusion were reduced by low-dose heparin and early sheath removal and were lowest when both strategies were combined. Reduction and weight adjustment of heparin dose and early sheath removal in the setting of platelet inhibition with abciximab during coronary intervention may be useful in diminishing the incidence of hemorrhagic complications without loss of clinical efficacy.
Patients undergoing coronary intervention received abciximab and were randomized to 1 of 2 weight-adjusted heparin doses and to 1 of 2 strategies for heparin discontinuation and vascular sheath removal. Reduction and weight adjustment of heparin dose and early sheath removal in the setting of platelet inhibition with abciximab during coronary intervention appeared to diminish the incidence of hemorrhagic complications without loss of clinical efficacy.
Coronary artery thrombosis plays an important pathophysiological role in unstable angina and non-Q-wave myocardial infarction. To date, heparin and thrombolytic therapy has not provided complete or ...consistent benefit. We hypothesized that recombinant hirudin, a direct thrombin inhibitor, would prevent accumulation of coronary artery thrombus in a manner superior to heparin.
Patients with rest ischemic pain, abnormal ECG, and baseline angiogram indicating a > or = 60% stenosis of a culprit coronary artery or saphenous vein graft with visual appearance of thrombus were randomized to one of two different doses of heparin (either a target activated partial thromboplastin time aPTT of 65 to 90 or 90 to 110 seconds) or one of four doses of hirudin (0.05, 0.10, 0.20, or 0.30 mg.kg-1.h-1 infusion) in a dose-escalating protocol. After 72 to 120 hours of study drug, a repeat coronary angiogram was obtained, and the paired studies underwent quantitative analysis. The primary end point was change in the average cross-sectional area of the culprit lesion. Other efficacy end points also involved changes in culprit lesion dimensions and TIMI flow grade. Recombinant hirudin led to a dose-dependent elevation of aPTT that appeared to plateau at the 0.2-mg/kg dose. A higher proportion of hirudin-treated patients had their aPTT within a 40-second range (16% heparin versus 71% hirudin, P < .001). Overall, the 116 patients treated with hirudin tended to show more improvement than the 50 patients receiving heparin relative to the primary efficacy variable--the average cross-sectional area (P = .08)--as well as minimal cross-sectional area (P = .028), minimal luminal diameter (P = .029), and percent diameter stenosis (P = .07).
Recombinant hirudin appears to be a promising antithrombotic intervention compared with heparin for inhibition of coronary artery thrombus. Large-scale comparative trials are warranted.
We and others have found that platelets play an important role in the recruitment of endothelial progenitor cells to sights of vascular injury. However, it is not clear whether the EPCs mature and ...differentiate to endothelial cells following recruitment to the vascular injury sites. In addition, there is limited in vivo data to support the role of EPCs in re-endothlialization following vascular injury. We conducted in vitro experiments to investigate the maturation of EPCs on platelet based-media and in vivo experiments to evaluate the recruitment of EPCs following vascular injury. In in vitro experiments human EPCs were isolated from donated buffy coats by magnetic microbeads and flow cytometry cell sorting using CD133 and VEGFR-2, respectively, as cell markers. Isolated viable EPCs (CD133+, VEGFR-2+ cells) were plated on human fibronectin or a monolayer of washed human platelets. Cell colonies were counted 7 days after plating and stained for the endothelial cell markers CD31 (PECAM-1) and CD144 (VE-cadherin). The mean number of colony-forming cells was 35±2.6 colonies/106 cells on platelets, which was significantly higher than 18±4.2 colonies/106 cells on fibronectin (n = 4, P<0.01). Apart from the difference in colony numbers, the EPC colonies grew faster on the platelet substrate, were larger, and had more spindle-shaped cells (Figure 1 - staining of EPC colonies for CD31 and CD144). In the in vivo experiments a model of transluminal injury to mouse femoral arteries was used. Femoral artery denudation was performed by 0.25-mm-diameter angioplasty guidewire. Injured femoral arteries were compared to the contra-lateral controls (uninjured), and were harvested 1.5 hours following the injury and immunostaining performed with an anti-VEGFR-2 antibody. Four experiments showed a markedly higher number of VEGFR-2+ cells in the artery that has undergone denudation. These experiments indicate that a media composed of platelets promotes the maturation and differentiation of EPCs. Furthermore, in vivo, EPCs are recruited early following vascular injury. Thus, homing, maturation, and differentiation of EPCs are mediated by platelets.
Endothelial progenitor cells (EPCs) are bone marrow-derived undifferentiated cells that are rapidly mobilized in response to tissue ischemia and incorporated into sites of neovascularization. EPCs ...co-express surface CD34, CD133 and vascular endothelial growth factor receptor-2 (VEGFR-2) antigens and develop an endothelial phenotype in culture. In animal models of tissue ischemia EPCs were shown to participate in angiogenesis and vasculogenesis. We sought to determine whether circulating EPCs level correlate with collateral formation following a non-ST segment elevation myocardial infarction (NSTEMI). In addition, we sought to evaluate the effect of percutaneous coronary intervention (PCI) on the levels of circulating EPCs. Twenty patients who underwent PCI within a week of NSTEMI were divided into two groups: patients without collaterals coll(−), n=10 and patients with Rentrop grade 3–4 collaterals coll(+), n=10. Two blood samples were drawn from all patients: before PCI and 24±2 hours after PCI. Using flow cytometry the percentage of cells co-expressing VEGFR-2 and CD133 was determined. In addition, EPC colonies were grown from peripheral blood mononuclear cells, characterized, and counted after 7 days of culture. The clinical characteristics of the two groups were similar. The coll(+) group had a higher degree of culprit vessel stenosis and lower initial TIMI flow grade. The relative number of EPCs (co-expressing VEGFR-2 and CD133) before PCI was significantly higher in the coll(+) group than in the coll(−) group (1.49±0.9% vs. 0.77±0.4%, P=0.045). There were no significant inter-group differences in the number of EPC colony-forming cells. The number of EPC colonies increased significantly in the coll(−) group following PCI (from 9.5±4.8 to 14.0±5.9 per 106 cultured cells, P=0.01). This study supports an association between circulating EPC levels and collateral formation in patients with a NSTEMI. Furthermore, these findings suggest that vascular injury during PCI triggers mobilization of EPCs to the peripheral blood, especially in patients without coronary collaterals. Our data suggest that patients with high levels of circulating EPCs are more likely to form coronary artery collaterals and that vascular injury induces EPC recruitment.
Mechanisms of death among patients who died within 18 h of enrollment in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) study were analyzed. Of 3,339 patients enrolled, 32 died within ...the 1st 4 h and 31 died within the subsequent 14 h. Thirteen of the 63 patients had shock at enrollment; 22 had advanced hemodynamic compromise without shock and 28 initially had minimal to no compromise.
Prior infarction was present in 16 patients (25%). Pump failure was responsible for 39 early deaths (62%), ventricular rupture for 10 (16%), arrhythmia for 8 (13%) and complications of therapy for 6 (10%). Nine of 720 patients randomized to immediate intravenous beta-adrenergic blocking agent therapy had an early death compared with 6 of 714 assigned to deferred beta-blocker therapy.
Thus, mortality is highest in the early hours after myocardial infarction, even in patients treated with thrombolytic therapy and is most frequently due to pump failure. These results imply that efforts to reduce mortality during this critical time period should be directed at prevention, limitation or palliation of early pump failure.
There is wide variability in the responses of individual patients to aspirin and clopidogrel. Polymorphisms of several platelet receptors have been related to increased platelet aggregation. We ...therefore aimed to evaluate whether these polymorphisms are related to altered response to aspirin or clopidogrel.
Patients (
n
=
120) undergoing percutaneous coronary intervention who received aspirin for ≥
1
week but not clopidogrel were included. Blood samples were drawn at baseline and 20–24
h after a 300-mg clopidogrel dose. Aspirin insensitivity was defined as 5
μM ADP-induced aggregation ≥
70% and 0.5
mg/mL arachidonic acid-induced aggregation ≥
20%. Clopidogrel insensitivity was defined as baseline minus post-treatment aggregation ≤
10% in response to 5 and 20
μM ADP. PlA polymorphism of glycoprotein IIIa, T744C polymorphism of the P2Y
12 gene and the 1622A
>
G polymorphism of the P2Y
1 gene were genotyped by polymerase chain reaction.
There were no differences in polymorphism frequencies between drug-insensitive vs. drug-sensitive patients. There were also no significant differences in response to aspirin (assessed by arachidonic acid-induced aggregation) or to clopidogrel (assessed by ADP-induced aggregation or activation markers) when patients were grouped according to genotype. The only trend observed was lower reduction in PAC-1 binding following clopidogrel in PlA
2 carriers (
P
=
0.065).
We did not find an association between polymorphisms in the platelet receptors GP IIIa, P2Y
12 or P2Y
1 and response to aspirin or clopidogrel in cardiac patients. These findings suggest that the variability in response to anti-platelet drugs is multi-factorial and is not caused only by single gene mutations.
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