Diabetes mellitus: a prothrombotic state Implications for outcomes after coronary revascularization

Figures & data

Figure 1 Angiographic images of stent thrombosis on RCA (A) and LAD (B).

Figure 2 Panel A: successful passage of the wire, while the balloon is inserted over another wire at the place where it stopped. Panel B and C: Final angiographic result on RCA (B) and LAD (C).

Table 1 Factors implicated in pathophysiology of in-stent thrombosis

Procedure-related factors
Stent malapposition and/or underexpansion
Stent length, multiple stent
Persistent coronary blood flow
Positive remodelling
Dissections
Residual stenosis
Late stent malapposition due to thrombus
Patient-related factors
Low-ejection fraction
Diabetes mellitus
Advanced age
Renal failure
Variability to wound healing
Antiplatelet therapy discontinuation
Lesion-related factors
Acute coronary syndromes
Bifurcations
In-stent restenosis lesions
Antiplatelet therapy
Discontinuation of antiplatelet therapy
Hyporesponsiveness
Stent factors
Design of stent (open-cell vs closed-cell)
Strut thickness
Polymer type
Drug of drug-eluting stents (lipophility)
Impaired re-endothelialization

Adapted from Luscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation. 2007;115:1051–1058.

Table 2 Insulin resistance and hyperglycemia effects on brinolysis, coagulation, and platelet function

Fibrinolysis	Coagulation	Platelets
Insulin resistance
↑ PAI-1	↑ FVII, vWF, FVIII	↓ Insulin-induced regulation
Hyperglycemia/AGE
↑ PAI-1, altered balance PAI-1/tPA	↑ TF, altered expressions FVII, FXII	Hyperreactivity, ↑ TX sensitivity/production

Figure 3 Pathways of platelet activation and mechanism of action of antiplatelet agents.

Abbreviations: ASA, acetylsalycilic acid; NSAIDs, nonsteroidal anti-inflameates inhibitors; PAF, platelet-activating factor; TXA₂, thromboaxane-A₂.

Table 3 Tests used to evaluate antiplatelet effect of ASA

Test	Method	Comment
TXB2concentration in serumor urine	Measurement of serum TXB2 or urinary d-TXB2 levels by radioimmunoassay or ELISA	TXA2 has a short half-life in serum and is rapidly converted into a stable matebolite, TXB2
Bleeding time	For study of the natural hemostasis; usually performed with a disposable template device; the test is based on the time necessary for bleeding to stop following incisions in the skin of the forearm	Nonspecific and insensitive, poorly reproducible and invasive; influenced by depth, location, direction of incisions, skin thickness, and skills of the technician performing the test; rarely used to assess platelet function
Flow cytometry	Using antibodies, measurement of common platelet activation markers such as: – Granule membrane markers (p-selectin, CD63, CD40L, etc) – Activation-dependent changes in GP IIb/IIIa complex conformation (PAC-1, etc)	Very powerful technique; uses whole blood, but requires expensive equipment/reagent and manipulation by experienced technician
Thromboelastography	Analysis of the clot’s physical property (strength) form formation to lysis, as an agonist is added (classically arachidonic acid or adenosine diphosphate)	Uses whole blood; easy and rapid to use; controversy as to correlation with classic aggregometry
Aggregometry	Analysis of light transmission as an agonist (classically arachidonic acid or adenosine diphosphate) is added to platelet rich plasma to provoke platelet aggregation	Assay well estabilished in the literature; time and labor consuming, requiring manipulation of sample by an experienced technician; removal of other blood elements forbids study of their influence on platelet aggregation
1) Classic platelet aggregometry (optical aggregation, light transmission analysis, classical turbidimetric aggregometry)
2) Whole blood aggregometry	Analysis of electrical impedance between two electodes immersed in whole blood in the presence of a platelet aggregation agonist (classically arachidonic acid or adenosine diphosphate)	Used to study the influence of whole blood constituents on platelet aggregation; time consuming, requiring manipulation by experienced technicians
Platelet function analyzers	Assessment of platelet aggregation under high shear: whole blood is aspirated through a small aperture cut in a membrane coated with type 1 collagen and either epinephrine or adenosine diphosphate; the time necessary for the formation of a hemostatic plug to occlude the aperture is recorded	Intend to imitate plug formation after injury to a small vessel wall under normal flow conditions; easy and rapid to use; controversy as to correlation with classic aggregometry; very expensive
1) Platelet function analyzer (PFA-100^®)
2) Rapid platelet function assay-ASA (RPFA-ASA, Verify Now Aspirin^®)
	The test cartridge contains a preparation of human brinogen-coated beads and a platelet agonist; as blood is inserted into cartridge, platelet agglutinate and form aggregated, which increases light transmittance	Specically developed for the detection of platelet dysfunction in whole blood due to ASA ingestion; easy and rapid to use; controversy as to correlation with classic aggregometry; very expensive

Table 4 Studies performed in diabetic patients treated with DES

Study	Design and results
Diabetes^Citation117	160 DM patients: 80 BMS 80 SES.
	Primary end point: LLL at 9 month
	In-segment LLLwas reduced from 0.470.5 mm for BMS to 0.060.4 mm for SES(P 0.001).
	TLR and MACE: 31.3% and 36% in BMS versus 7.3% and 11.3% in SES; both P 0.001). 9-month follow-up
	ST occurred in 2 BMS patients
	No ST in SES group
ISAR-DIABETES^Citation118	250 DM patients: 150 SES 150 PES
	Noninferiority of the PES vs SES:
	Primary end point: difference in LLL of no more than 0.16 mm, at 6–8 months follow-up.
	SES associated with a decrease in the extent of LLL in insulin-treated (p = 0.02) and noninsulin-treated (p = 0.03) patients.
Tomai and colleagues^Citation119	60 DM patients, 120 lesions: 60 SES, 60 PES, SES associated with a decrease in the extent of in-stent LLL at 8 months, suggesting a reduced risk of restenosis.
SCORPIUS^Citation120	200 DM patients : 98 SES 102 BMS
	Primary end point: in segment LLL. Secondary: MACE rate at 30 days and 8 and 12 months. LLL in SES was 0.18 mm; 0.74 mm in BMS. In-segment restenosis: 8.8% SES and 42.1% BMS (p < 0.0001). TLR: 5.3% in SES and in 21.1% in BMS (p = 0.002) MACE rate 14.7% in SES versus 35.8% in BMS.
DESSERT^Citation121	150 DM patients: 75(109 lesions) SES 75 (109 lesions) BMS.
	Primary end point: LLL Secondary: MACE and TVR at 30 days, 9 and 12 months. LLL decreased from 0.96 +/− 0.61 mm for BMS to 0.14 +/− 0.33 for SES (p <0.001), and in-segment binary restenosis was 38.8% versus 3.6%, respectively (p <0.001). 12 months MACEs 22.1% versus 40% (p = 0.023), TLR 5.9% versus 30% (p <0.001), and TVF 14.7% versus 34.3% (p = 0.008).

Table 5 Academic research consortium de nitions of stent thrombosis

Category	Definition
Definite	Angiographic conrmation based on Thrombolysis in Myocardial Infarction (TIMI) flow and 1 of the following within 48 hours: New acute onset of ischemic symptoms at rest New ischemic electrocardiographic changes suggestive of acute ischemia Typical increase and decrease in cardiac biomarkers as evidence of an acute myocardial infarction (MI) Pathologic conrmation of recent ST at autopsy or by tissue examination after thrombectomy
Probable	Any unexplained death within the first 30 days MI related to acute ischemia in the territory of the implanted stent without angiographic conrmation of ST and in the absence of any other obvious cause at any time after index procedure
Possible	Any unexplained death after intracoronary stenting from 30 days after index percutaneous coronary intervention until the end of trial follow-up

Table 6 ST classification according to time of presentation

Acute	<24 hr
Subacute	>24 hr <30 days
Late	>30 days <12 months
Very late	>12 months

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