The Role Of Platelets In The Prognosis Of Renal Disease
Over the years, our understanding of the role of platelets in the prognosis of renal disease has increased. They been found to be a critical player in many physiological processes.
Author:Suleman ShahReviewer:Han JuAug 08, 202445.7K Shares618.5K Views
Here, we explore the role of platelets in the prognosis of renal diseaseand examine their significance in outcomes.
Identified as “little globules” or “granular masses,” platelets, which are small non-nucleated cells, were first discovered in 1842.
Far from the first somewhat tentative identification of platelets as distinct morphologic elements in the blood in the 19th century, we have now amassed much information about their structure and function.
They are non-nucleated fragments of megakaryocytes.
As each megakaryocyte develops in the bone marrow under the control of thrombopoietin, it fragments yielding in excess of 1,000 platelets.
In the absence of endothelial activation, platelets circulate in the blood for approximately 10 days before being cleared primarily by the spleen.
Despite being simple cytoplasmic fragments, platelets have:
- a remarkable structure, with various surface proteins involved in aggregation and adhesion
- secretory granules releasing proteins involved in hemostasis
- the ability to alter their shape and size upon activation
Platelets are, of course, key players in the process of hemostasis and have long been credited as being fundamental to the formation of stable blood clots upon activation of the coagulation cascade and via their interaction with exposed subendothelial von Willebrand factor (vWF) in the microcirculation.
Increasingly, however, they are recognized to have many additional functions. In particular, platelets are acknowledged as contributors to:
- vascular inflammation
- the development of atherosclerotic disease
They also:
a. secrete mediators of inflammation, such as:
- cytokines
- chemokines
- growth factors
- adhesion molecules
- coagulation factors
b. interact with other cells to promote their activation and recruitment to sites of inflammation, such as:
- dendritic cells
- leukocytes
- progenitor cells
The aim of this review is to discuss the role of platelets in the prognosis of renal disease.
Inflammation And Cardiovascular Disease
Before examining the role of platelets in inflammation, it is important to remember that it has been long known that inflammation is involved in the development of atherosclerosis in the general population.
Atherosclerosis is now very much recognized as being a chronic inflammatory condition of the vessel wall, with the development of atherosclerotic lesions being shaped by immune responses and regulations and the hemostatic system acting as a moderator.
Elevated levels of high-sensitivity C-reactive protein (hs-CRP) and plasma proinflammatory cytokines particularly the Interleukin-1 (IL-1) and Interleukin 6 (IL-6) pathways have been repeatedly implicated in atherogenesis.
Equally, patients with chronic kidney disease (CKD) are well recognized to be in a proinflammatory state, with evidence that C-reactive protein (CRP), IL-1, IL-6, and tumor necrosis factor alpha (TNF-α) are elevated alongside intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) and act as predictors of cardiovascular death.
Platelets In Inflammation
Platelets have been identified as being effector cells that enhance inflammatory responses, with the ability to “cross-talk” with endothelial cells and leukocytes.
When activated, they release over 300 proteins and molecules:
a. some preformed and stored in dense bodies or alpha-granules, including:
- chemokines
- angiogenic factors
- adenosine diphosphate (ADP)/adenosine triphosphate (ATP)
- coagulation factors
- thromboxane
- reactive oxygen species
- IL-1b
In addition to secreting these various biologically active factors, activated platelets have also been shown to shed membrane microparticles (MPs).
MPs are phospholipid-rich and protein-rich submicron particles 0.1 to 2 mm in size.
They shed from the membranes of several cell types when they are injured, activated, or undergoing apoptosis in response to:
- cytokines
- thrombin
- endotoxin
- hypoxia
- shear stress
Cells known to shed MPs include platelets and endothelial cells.
The most abundant MPs in the circulation are those from activated platelets, and they are thought to generate and deposit various complement components.
Membrane microparticles are believed to be involved in atherogenesis, being found in higher levels in those with severe hypertension and those with increased coronary heart disease risk.
They have been implicated as a prognostic marker for atherosclerotic vascular disease. In addition, endothelial MPs are involved in inflammation and vascular function.
Another key factor linking platelets with inflammation may take the form of microRNAs.
MicroRNAs are small non-coding RNA molecules that function in transcriptional and post-transcriptional regulation of gene expression.
Those that regulate immune cell differentiation would thus be expected to be important during plaque formation.
It has been shown that microRNAs:
- contribute to megakaryocytopoiesis
- are expressed in platelets
- re involved in defining platelet function
An additional point of interest is one of the proinflammatory mediators released from platelets, myeloid-related protein 8/14.
This has been investigated as a biomarker for adverse cardiovascular events.
Interestingly, myeloid-related proteins 8 and 14 (MRP8/MRP14) can also activate innate immunity via interaction with toll-like receptor 4 (TLR-4) as well as promoting endothelial cell apoptosis, further serving to illustrate the link between inflammation and thrombosis.
Interest has also been given to platelet size, which has been found to be linked with platelet activity.
The mean platelet volume has been found to be associated with cardiovascular risk and, due to the relative ease of measuring it (available with routine blood counts), has been proposed as a potential tool for identifying high-risk patients.
As well as platelet size, the ratio of platelets to other circulating cells has been used as a tool for identifying inflamed and subsequently high-risk patients.
Neutrophil-to-lymphocyte ratio has previously been suggested as a potential marker to determine inflammation in CKD patients.
Recently, platelet-lymphocyte ratio has also been investigated.
It is known that platelet-lymphocyte ratio is positively correlated with inflammatory markers, such as TNF-α and IL-6 in cardiac patients.
In the CKD population, this has now also been shown to predict:
- inflammation
- potential cardiovascular risk
Effect Of Uremia On Platelets
Since the advent of dialysis, it has been clear that uremia has an effect on platelet function, as evidenced by the key clinical problem of excessive bleeding.
It has been identified that there are several contributing factors to platelet dysfunction in uremia:
- various platelet abnormalities
- abnormal platelet-vessel wall interaction
- altered interaction with other circulating cells included
Given the excess of cardiovascular morbidity and mortality in patients with CKD, the evidence that atherosclerosis is an inflammatory condition and the fact that dialysis patients are known to be chronically inflamed, it would seem plausible that the abnormalities in platelets seen in this population would also play a role in their excessive cardiovascular risk.
Platelet Function In Uremia
The most common abnormality is prolongation of bleeding time, with multiple platelet abnormalities contributing to defective aggregation and a delay in time to formation of the primary hemostatic plug
Among the platelet abnormalities seen in uremia are:
- abnormal granule content and release
- abnormal arachidonic metabolism
- abnormal cyclo-oxygenase activity
- abnormal handling of cyclic adenosine monophosphate (cAMP)
- intracellular calcium
- serotonin
- abnormal binding of glycoprotein (GP) IIb/IIIa
Furthermore, uremic platelets have attenuated response to thrombin, with reduced secretion of ATP and other granule contents, and have diminished ATP release to arachidonic acid, producing an aspirin-like effect as evidenced by platelet aggregation studies.
Also interestingly, the abnormalities seen in intracellular calcium may be linked with ambient parathyroid hormone concentration, and thus hyperparathyroidism may further affect platelet reactivity.
It has also been shown that, in addition to these baseline abnormalities, platelet reactivity and aggregation are altered throughout the course of a dialysis session, with similar increases in reactivity as seen in patients with coronary artery disease.
Interaction With Vessel Wall
The fact that platelets do not adhere to normal endothelial cells has been ascribed to inhibition by nitric oxide, prostacyclin, and adenosine, which are known to be generated by healthy vascular endothelium.
Interestingly, it has been shown that uremic platelets placed in normal plasma retain normal function, thus suggesting a putative uremic toxin or toxins.
The role of nitric oxide forms an interesting link.
Nitric oxide limits both platelet-platelet interaction and platelet adhesion to endothelium by modulating vascular tone.
In normal subjects, it prolongs the bleeding time.
We have shown that platelets from hemodialysis patients generate more nitric oxide than healthy subjects.
Furthermore, guanidinosuccinic acid (GSA) has also been shown to significantly lengthen bleeding time, and this effect is attenuated by a specific nitric oxide inhibitor, with evidence suggesting that nitric oxide formation by uremic vessels is GSA-dependent.
GSA accumulates in uremia as part of an alternative pathway for ammonia detoxification.
Furthermore, platelet interaction with the endothelium may be disrupted by abnormal interaction with von Willebrand factor (vWF).
It has been demonstrated that glycoprotein expression is lower on resting platelets in patients with chronic kidney disease, and that this reduction correlates with the severity of renal impairment.
The same investigators also found that glycoprotein Ib (GP Ib) expression on stimulated platelets increases in hemodialysis patients.
GP1b is involved in platelet adhesion to the endothelium and is the vWF receptor.
There is also an interesting association with anemia.
Bleeding time is further prolonged in uremia patients who are also anemic, proportionately to the degree to anemia.
This is ameliorated when the hematocrit is increased to at least 30%.
The correction occurs as more erythrocytes in the circulation push more platelets and leukocytes to the periphery, allowing improved contact with the endothelium and improved stability of the primary hemostatic plug.
Interaction With Other Circulating Cells
As part of their role in inflammation, platelets aggregate with leukocytes via their P-selectin receptor interacting with its natural ligand P-selectin glycoprotein ligand-1 on monocytes and neutrophils.
P-selectin is translocated to the surface of activated platelets, where it contributes to platelet-assisted enhancement of thrombosis at sites of endothelial injury.
These aggregates form an anchoring source for inflammatory cells on activated platelets and contribute to ongoing injury at the sites of atheromatous plaques.
Levels of platelet-monocyte aggregates have been found to be significantly higher in dialysis patients.
In patients with normal renal function, platelet-monocyte aggregates have been associated with cardiovascular disease.
Data from our unit would suggest that this also applies in uremic patients, with a significant increase in cardiovascular morbidity and mortality seen in those patients with higher levels of circulating platelet-monocyte aggregates.
Effect Of Platelets In Uremic Patients
In light of the various platelet aberrancies discussed above in uremic patients, it would follow that platelets are crucial players in the prognosis of patients with chronic kidney disease.
Both thrombocytosis and thrombocytopenia are commonly seen in patients with end-stage renal disease, and the role of antiplatelet agents in these patients is, at best, controversial.
Thrombocytosis
Relative thrombocytosis has been linked with severity of cardiovascular disease in the chronic kidney disease population.
In peritoneal dialysis patients, it has been demonstrated that relative thrombocytosis (platelet count >300) correlates significantly with both coronary and peripheral artery disease.
In long-term hemodialysis patients, it has also been shown that a platelet count of >300 is associated with an increased death rate.
The investigators here linked this relative thrombocytosis with a reduction in iron stores, which may also be a key player.
Their study, with Elani Streja as lead author, was published in 2008 by the American Journal of Kidney Diseases.
In a study published in 2011 by The American Journal of Clinical Nutrition, the authors, with Miklos Z. Molnaras lead author, suggested that relative thrombocytosis in chronic kidney disease patients was associated with higher all-cause and cardiovascular death, by means of its association with malnutrition inflammation cachexia syndrome (MICS).
They found that patients with a platelet count >300 had poorer cardiovascular outcomes, with mortality rates higher the greater the platelet count.
Interestingly, when they adjusted for MICS, these associations were negated, suggesting that relative thrombocytosis is a marker of a worse MICS profile.
Thus, accounting for their increased morbidity and mortality.
Thrombocytopenia
Conversely, patients with thrombocytopenia and chronic kidney disease are also commonly seen.
A reduction in platelet count during the course of a dialysis session is recognized, alongside platelet activation and degranulation, which is attributed to:
- exposure to the dialysis membrane and the roller pump
- results in platelet-lymphocyte aggregates
Thrombocytopenia may also be seen as part of the syndrome of heparin-induced thrombocytopenia in dialysis patients, whereby the generation of the platelet-factor 4/heparin (PF4) complex triggers antibody formation.
The complex then binds to the antibodies, cross-reacts with platelet surface receptor activation and aggregation, further PF4 release, and formation of procoagulant factors and thrombin.
It has been suggested that the presence of these antibodies is an independent predictor of cardiovascular morbidity and mortality.
Rejection
Humoral rejection can be seen as an extension of platelet-endothelial dysfunction.
Indeed, it has been shown that, after primary injury to endothelium, platelet aggregation is seen as the earliest morphological change and may precipitate release of platelet granules stimulating the endothelial activation and vascular damage that is seen in rejection.
Over two decades ago, the use of indium-111 platelet scintigraphy was examined in the detection of renal transplant rejection when it was suggested that platelet deposition was a potential tool for early detection of acute graft rejection.
Experimentally, it has been suggested that platelet aggregation is seen within a few minutes of reperfusion of a newly transplanted organ and that these activated platelets may contribute to the extent of the injury seen in the graft.
It has also been demonstrated that activated platelets can cause inflammation and ischemia of previously normal endothelium.
It is reasonable to suppose, therefore, that activated platelets at the time of transplantation may go on to cause endothelial injury.
HUS And TTP
This is about hemolytic uremic syndrome (HUS) and thrombotic thromocytopenic purpura (HUS-TTP).
The link with platelets and endothelial injury in renal patients is also seen clearly in the thrombotic microangiopathies, whereby abnormal platelet aggregation and thrombotic occlusion of the microvasculature is responsible for the clinical syndromes seen.
The role of von Willebrand factor (vWF) and the ability of ultra-large vWF to enhance platelet aggregation and adhesion to the subendothelium has been extensively examined in these conditions.
These interactions are widely reported and beyond the remit of this review, but adds just another example of the importance of platelets in renal disease.
The Use Of Antiplatelet Agents In Uremia
Given the plethora of platelet abnormalities and bleeding complications seen in uremic patients, it would seem obvious that antiplatelet agents should be avoided at all costs.
But the fact remains that end-stage renal disease patients have a significantly elevated cardiovascular disease burden; thus, suggesting that they may play a role in primary prevention.
A comprehensive review of the literature is out of the scope of this article, but suffice to say that there is an increasing body of research regarding the use of antiplatelet and oral anticoagulants in the chronic kidney disease population.
A recent meta-analysis suggested that antiplatelet agents do reduce myocardial infarction in such patients but with significant increases in major bleeding, which may outweigh any potential benefits.
Data published on major bleeding events in dialysis patients gives a frequency of events of 2.5% per person-year, increasing to 4.4% with the use of aspirin alone and 6.6% with its concomitant use with warfarin.
These data certainly add weight to the fact that any prescription of anti-platelet agents in chronic kidney disease patients should be considered on individual risk and benefit ratios.
Conclusion
It is clear that, far from being mere “particles in the blood,” platelets are remarkable and exciting cells that have highly evolved and have intricate functions spanning far beyond just hemostasis, encompassing many other physiological processes.
Their link with chronic kidney disease and its associated complications is beginning to be unraveled.
Platelets are a worthy topic of further study as we try to resolve the conundrum of inflammation and its deleterious, cardiovascular, and other effects in such patients.
Therefore, more studies should be conducted about the role of platelets in the prognosis of renal disease.
Jump to
Inflammation And Cardiovascular Disease
Platelets In Inflammation
Effect Of Uremia On Platelets
Platelet Function In Uremia
Interaction With Vessel Wall
Interaction With Other Circulating Cells
Effect Of Platelets In Uremic Patients
Thrombocytosis
Thrombocytopenia
Rejection
HUS And TTP
The Use Of Antiplatelet Agents In Uremia
Conclusion
Suleman Shah
Author
Suleman Shah is a researcher and freelance writer. As a researcher, he has worked with MNS University of Agriculture, Multan (Pakistan) and Texas A & M University (USA). He regularly writes science articles and blogs for science news website immersse.com and open access publishers OA Publishing London and Scientific Times. He loves to keep himself updated on scientific developments and convert these developments into everyday language to update the readers about the developments in the scientific era. His primary research focus is Plant sciences, and he contributed to this field by publishing his research in scientific journals and presenting his work at many Conferences.
Shah graduated from the University of Agriculture Faisalabad (Pakistan) and started his professional carrier with Jaffer Agro Services and later with the Agriculture Department of the Government of Pakistan. His research interest compelled and attracted him to proceed with his carrier in Plant sciences research. So, he started his Ph.D. in Soil Science at MNS University of Agriculture Multan (Pakistan). Later, he started working as a visiting scholar with Texas A&M University (USA).
Shah’s experience with big Open Excess publishers like Springers, Frontiers, MDPI, etc., testified to his belief in Open Access as a barrier-removing mechanism between researchers and the readers of their research. Shah believes that Open Access is revolutionizing the publication process and benefitting research in all fields.
Han Ju
Reviewer
Hello! I'm Han Ju, the heart behind World Wide Journals. My life is a unique tapestry woven from the threads of news, spirituality, and science, enriched by melodies from my guitar. Raised amidst tales of the ancient and the arcane, I developed a keen eye for the stories that truly matter. Through my work, I seek to bridge the seen with the unseen, marrying the rigor of science with the depth of spirituality.
Each article at World Wide Journals is a piece of this ongoing quest, blending analysis with personal reflection. Whether exploring quantum frontiers or strumming chords under the stars, my aim is to inspire and provoke thought, inviting you into a world where every discovery is a note in the grand symphony of existence.
Welcome aboard this journey of insight and exploration, where curiosity leads and music guides.
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