Thrombocytopathies: Not Just Aggregation Defects—The Clinical Relevance of Procoagulant Platelets
Abstract
:1. Introduction
2. Platelet Activation End-Points and Related Defects
2.1. Adhesion
2.1.1. Bernard-Soulier Syndrome
2.1.2. Platelet Type von Willebrand’s Disease
2.2. Secretion
2.2.1. α-Storage Pool Disease or Gray Platelet Syndrome
2.2.2. δ-Storage Pool Disease
2.3. Aggregation
Glanzmann Thrombasthenia
- -
- ߓType I, the most severe form of GT: the expression of GPIIb/IIIa is absent (<5% of normal); platelet fibrinogen and clot retraction are also absent;
- -
- ߓType II, a moderate form of the disease: surface GPIIb/IIIa is reduced with a level of expression varying between 10–20% of normal; reduced fibrinogen content and clot retraction;
- -
- ߓType III, a variant form: the expression of GPIIb/IIIa is near normal or normal (between 50–100%), but the receptor is dysfunctional; variable platelet fibrinogen content and clot retraction.
2.4. Procoagulant Activity
3. Expression of Negatively Charged Phospholipids and Their Role in Coagulation
4. Procoagulant Platelets
4.1. Clinical Features of Procoagulant Platelets
4.1.1. Low Level of Procoagulant Platelets Is Associated with Impaired Platelet Function and Bleeding Diathesis
4.1.2. High Level of Procoagulant Platelets Worsens Thrombotic Events
4.1.3. Procoagulant Platelets in Non-Haemostatic Pathologies
4.2. Pharmacological Modulation of Procoagulant Platelets
4.2.1. Antiplatelet Drugs
4.2.2. Off-Target Procoagulant Platelet Modulation
4.3. Laboratory Work-Up for Investigating Procoagulant Platelets
4.3.1. Quantification and Characterization of Procoagulant Platelets
4.3.2. Assessment of the Overall Coagulation Potential and Procoagulant Activity of Platelets
4.3.3. In-Vivo Investigations of Procoagulant Platelets
5. Thrombocytopathy Associated to COVID-19
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Endpoint | Description | Common Markers | Phenotype in Procoagulant Platelets | Phenotype in Non-Procoagulant Platelets |
---|---|---|---|---|
Necrotic-like | ||||
Phosphatidylserine | Negatively charged amino-phospholipids of platelet membrane bilayer, contribute to the procoagulant activity | Annexin V, lactadherin | Positive | Negative |
Mitochondrial membrane depolarization | Mitochondrial events (depolarization) are implicated in platelet procoagulant activity process | Rhodamine (such as TMRM) | Low TMRM staining | High TMRM staining |
JC-1 | Lower JC-1 fluorescence ratio (red/green) | Higher JC-1 fluorescence ratio (red/green) | ||
Fibrinogen receptor GPIIb/IIIa (integrin αIIbβ3) | Platelet membrane glycoprotein; in its activated conformation binds to fibrinogen and mediates platelet aggregation | Anti-CD41/CD61 IgM antibody recognizing the activated conformation (PAC-1) | Negative | Positive |
Platelet surface coating by α-granule proteins | Proteins present in α-granule secreted upon platelet activation and retained on the platelet surface by a serotonin- and transglutaminase mechanism | Specific antibodies against α-granule proteins, such as FV/Va, fibrinogen, VWF, fibronectin, thrombospondin, and α2-antiplasmin | Positive | Negative |
Type of Sample | Assay What Does It Measure? | Assay Name and Principle | Advantages | Disadvantages | References |
---|---|---|---|---|---|
WB | Coagulation potential (subsampling TG measurement) | TGA chromogenic | Presence of all blood cells and coagulation factors | Tedious subsampling at interval points; Time consuming; Only a snapshot picture of TG is available | [228] |
Coagulation potential (continuous TG measurement) | TGA Paper based WB-TG assay Fluorogenic (rhodamine 110-based thrombin substrate) | Close to physiological haemostasis; Presence of all blood cells and coagulation factors | Potential of procoagulant platelets is not specifically targeted; Calibration is difficult because of haemolysis and/or haematocrit might vary in WB sample; Interference of contact activation; Needs experienced operator | [229,230] | |
TGA Novel WB-TG assay Fluorogenic (rhodamine 110-based thrombin substrate) | Close to physiological haemostasis; Presence of all blood cells and coagulation factors; Stable light transmission achieved by continuous mixing of the assay plate | Potential of procoagulant platelets is not specifically targeted; | [231] | ||
PRP | Coagulation potential (continuous TG measurement) | TGA e.g., Thrombinoscope (Stago), Techno-thrombin (Techno-clone) Fluorogenic | Mimics in vivo condition; Consider the interaction of platelets and coagulation factors | Potential of procoagulant platelets is not specifically targeted; Standardization is difficult; Reactivity of platelets: easy to provoke unwanted activation | [232] |
PPP | Coagulation potential (continuous TG measurement) | TGA e.g., Thrombinoscope (Stago), ST Genesia (Stago) Fluorogenic | Defined concentration of tissue factor and artificial phospholipids; Standardization possible in automated version; Possible to store frozen samples | Potential of procoagulant platelets is not specifically targeted; Do not consider the interaction of platelets with coagulation factors; Loss of sensitivity for the intrinsic pathway if high amount of TF is used | [222,233] |
TM-TGA ST Genesia (Stago), Fluorogenic | To study the role of protein C system by comparison of TM− and TM+ samples | TGA automated version: exact tissue factor concentration is not communicated | [223,234] | ||
Spatio-temporal dynamics of coagulation (real time TG and fibrin clot formation) | Thrombodynamics Video microscopy system based on measurements of light scattering images intensity | Pre-analytics is standardized; TG and fibrin formation measured at the same time; Allows to investigate separately TF-dependent and TF-independent coagulation; PRP can be added to the mix | Problematic with lipemic samples; Available only in specialized laboratory | [235,236] | |
Gel filtered or washed platelets | Coagulation potential (continuous TG) | Modified TGA assay fluorogenic | Targets specific procoagulant populations | Preparation is laborious; Requires experienced operator | [126,201] |
Quantifies the number of procoagulant platelets | Flow cytometry fluorescence | Targets procoagulant platelet formation and associated markers | [131] | ||
Measures the rate of clot growth | Experimental video microscopy Based on intensity of light scattering images | Specifically assess the contribution of activated platelets to clot growth | Requires experienced operator | [126] | |
PMPs | Quantifies procoagulant potential of PMPs expressing PS. | Zymuphen MP Activity assay (Hyphen BioMed) ELISA, chromogenic | Easy to perform; High speed of sample analysis | Size of the PMPs can affect binding to Annexin V, thus lower detection of PS; No information on count, size or origin | [220,221,237,238] |
Procoagulant potential of PMPs expressing PS added to phospholipid free plasma | Procoag PPL (Stago) Clotting time Number of PMPs is inversely proportional to clotting time | Can be used also on WB, PRP, PPP; Easy to perform | No information on count, size or origin | [239,240,241] | |
Quantifies PMPs derived from gel filtered/washed platelets | Flow cytometry fluorescence Identification of PMPs by size (FSC) and fluorescence (e.g., bodily-label) | Target PMPs derived specifically from procoagulant platelets; Gel filtration/washing remove plasmatic components | PMPs are close to electronic noise and debris, part of the population might be below the threshold Require expertise and sensitive cytometer | [125,242] | |
Coagulation potential (continuous TG) | Modified TGA Fluorogenic Isolation of PMPs by centrifugation | Specifically assess contribution of PMPs derived from procoagulant platelets to TG | Preparation is laborious | [126] | |
Measures the rate of clot growth | Experimental video microscopy systemBased on intensity of light scattering images | Specifically assess the contribution of PMPs isolated from activated platelets to clot growth | Require experienced operator | [126] |
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Aliotta, A.; Bertaggia Calderara, D.; Zermatten, M.G.; Marchetti, M.; Alberio, L. Thrombocytopathies: Not Just Aggregation Defects—The Clinical Relevance of Procoagulant Platelets. J. Clin. Med. 2021, 10, 894. https://doi.org/10.3390/jcm10050894
Aliotta A, Bertaggia Calderara D, Zermatten MG, Marchetti M, Alberio L. Thrombocytopathies: Not Just Aggregation Defects—The Clinical Relevance of Procoagulant Platelets. Journal of Clinical Medicine. 2021; 10(5):894. https://doi.org/10.3390/jcm10050894
Chicago/Turabian StyleAliotta, Alessandro, Debora Bertaggia Calderara, Maxime G. Zermatten, Matteo Marchetti, and Lorenzo Alberio. 2021. "Thrombocytopathies: Not Just Aggregation Defects—The Clinical Relevance of Procoagulant Platelets" Journal of Clinical Medicine 10, no. 5: 894. https://doi.org/10.3390/jcm10050894