Hemostasis = love.
Everyone talks about, but no one understands it.
Hemostasis is complex. The process of hemostasis has several outcomes, including physiologically
arresting blood loss at sites of vascular injury. In simple terms, this is achieved
by formation of a “plug that seals the hole.” This “plug” comprises a framework of
blood components that act together to create a stable mass that stops further blood
leakage.
Hemostasis involves the complex interaction of many integrated processes.[1 ] Central to hemostasis is the blood milieu, containing platelets, which in part act
like “bricks,” and many adhesive plasma proteins, which in part act like “mortar,”
working together to develop a framework that we sometimes call the “platelet plug.”
However, neither the platelets nor the plasma proteins are passive agents in this
process. When hemostasis works, everything is in physiological balance, and we are
not even cognizant of this activity taking place in our own bodies. When hemostasis
gets out of balance, however, disease or pathological processes can occur.
Plasma is complex, but platelets are even more complicated.[2 ]
[3 ] This journal has published several papers on platelet physiology, and the ongoing
popularity of these papers attests to the complexity of platelet physiology and their
interest in our readership.[4 ]
[5 ] Each individual platelet expresses a huge number of proteins on their surface that
we call platelet receptors, and these interact with many plasma components including
other proteins. There are around 100 million platelets in each mL of our blood.
Hemostasis can be conveniently separated into primary and secondary hemostasis, with
primary hemostasis reflecting predominantly vessel wall and platelet activity (including
adhesion), and secondary hemostasis mainly reflecting the plasma coagulation system
(including clot formation).[1 ] Although this provides a convenient separation to help teach hemostasis to junior
scientists, and to study this process in vitro, it needs to be recognized that, in
vivo at least, these systems do not work in isolation. Primary and secondary hemostasis
work in concert to form the platelet plug. Injury to a blood vessel causes a cascade
of events. The injury releases cellular components including “tissue factor,” as well
as exposing subendothelial surfaces that are normally not exposed to this blood. This
causes activation of “secondary hemostasis” by several mechanisms. Sometimes we use
terms such as the “coagulation cascade,” but the important elements here are generation
of thrombin and conversion of soluble plasma protein fibrinogen to “insoluble” fibrin.
The vessel injury also leads to platelet activation and platelet adhesion to the damaged
site. Integral to the process of platelet adhesion are the platelet receptors and
many plasma proteins, including von Willebrand factor (VWF), which act as a kind of
sticky string to “glue” the platelets together and fasten them to the damaged subendothelial
surface.[6 ] Platelets aggregate to form the scaffolding of the platelet plug, and the entire
structure is further stabilized by the fibrin being formed, as robustly integrated
into the platelet plug.
Indeed, much hemostasis activity goes into creating the platelet plug. In normal physiology,
this platelet plug seals the hole, and thus permits wound healing to subsequently
occur. However, if the process of hemostasis is dysfunctional, pathological situations
can ensue. On one side of this unbalanced hemostasis is where hemostasis may be “under-active”
and patients can bleed (e.g., if the plasma components or platelets do not work as
well as they should, the formation of the platelet plug may be delayed, or else it
may not be formed properly). If hemostasis is “over-active,” patients may be at increased
risk of thrombosis. In such situations, the platelet plug may grow too large and block
off a blood vessel. If this occurs in a venous vessel in the leg, it may cause a deep
vein thrombosis (DVT), which (should some of the thrombosis break off and travel to
the lung to block off some of its blood vessels) can then lead to the development
of pulmonary embolism. If the thrombosis-related blockage occurs in the heart, it
may lead to a heart attack, and if it occurs in the brain, it may cause an ischemic
cerebral infarction (i.e., stroke). If the thrombosis occurs in a placenta, it can
cause pregnancy morbidity.
There is a general belief that platelets, along with the plasma protein VWF, represent
more important hemostasis components in the arterial blood system, due to the importance
of shear stress in VWF/platelet function. This concept is supported by evidence that
arterial thrombi are more “enriched” in platelets, because the risk of arterial vascular
events can theoretically be prevented by use of antiplatelet agents such as aspirin.[7 ] Conversely, there is a general belief that the plasma coagulation components (i.e.,
secondary hemostasis) are more important in the venous blood system. This concept
is supported by evidence that venous thrombi are more “enriched” in fibrin, because
the risk of venous vascular events can theoretically be prevented by use of anticoagulation
agents such as heparins, vitamin K antagonist drugs (e.g., warfarin), or direct oral
anticoagulants. Additional evidence includes that coagulation factor (F) deficiencies
(e.g., FVIII or FIX, leading to hemophilia) primarily cause bleeding in venous vessels
(e.g., hematomas), and that deficiencies in natural anticoagulants (e.g., protein
S, protein S, antithrombin) more frequently cause thrombosis in venous vessels (e.g.,
DVT).
However, these concepts oversimplify hemostasis. Although primary and secondary hemostasis
can be evaluated separately in vitro, simply by separating out the components, the process is intertwined in vivo, with
clear overlaps or “shades of gray.” For example, more detailed investigation of venous
thrombi will uncover the presence of platelets, and more detailed investigation of
arterial thrombi will uncover the presence of fibrin.[7 ] Similarly, sometimes antiplatelet agents are prescribed to prevent thrombotic complications
that occur outside the arterial bed.
Workers in hemostasis in general accept the concept that deficiencies of coagulation
proteins can lead to bleeding, that deficiencies of natural anticoagulants can cause
venous thrombosis, and that venous thrombosis can be prevented by anticoagulant therapy.
Workers in hemostasis also accept the concept that deficiencies of platelets, or that
the existence of platelet dysfunction, can lead to bleeding. Workers in hemostasis
even accept that these events may have a congenital or acquired basis.
Workers in hemostasis have also started to accept additional concepts, for example,
that excesses in some coagulation proteins can increase the risk of thrombosis—this
is now accepted for FVIII, and starting to be accepted for VWF. However, workers in
hemostasis seem to have mixed feelings about the involvement of overactive platelets
in thrombosis and any arising pathophysiology. On the one hand, most will accept that
treatment of patients at risk of arterial thrombosis with antiplatelet agent will
help to lower such risk. On the other hand, some workers in the field seem to be less
prone to accept the presence of “hyperactive” platelets, or at least that congenital
forms of “hyperactive” platelets may lead to thrombosis.
This journal has published several recent articles on the condition popularly called
“sticky platelet syndrome (SPS).”[8 ]
[9 ]
[10 ] This is believed, by those who deem the condition to exist, to represent platelet
hyperactivity having a familial tendency (i.e., congenital or inherited) in at least
some cases. The commonly proposed pathophysiological outcome includes thrombosis,
namely venous thrombosis events, and pregnancy morbidity. Indeed, the current issue
of this journal includes one such paper, another update review on SPS.[11 ] We hope that users of Seminars in Thrombosis and Hemostasis (STH) read this paper with an open mind.
In this commentary, we ask the question “Does SPS exist?,” because we know that many
of our hemostasis colleagues have doubts about its existence. We know they have such
doubts because they tell us so, and sometimes reflect surprise that STH seems to publish
periodically on SPS, when other major hemostasis journals do not, and when many in
the hemostasis field do not even believe SPS to exist.
Just as primary and secondary hemostasis is intertwined, so too is the history of
SPS and STH. Indeed, the founding Editor-in-Chief of STH, Eberhard F. Mammen, was
a strong advocate for SPS, and his early works (including the first article ever published
using the moniker of “sticky platelet syndrome” according to a PubMed search of this
term)[12 ]
[13 ] have formed the foundation of current research in the field.[9 ]
[10 ]
[11 ] Does STH really publish a lot of papers on SPS? A recent PubMed search of the term
“sticky platelet syndrome” identified a total of 63 papers, 8 of which were published
in STH. Another journal publishing in the area of thrombosis and hemostasis has published
more of these papers, at a count of 13. But there were no papers in the highest impact
factor hematology journals.
In any case, SPS seems to be building up some sort of belief base, if we accept that
the increasing publication rate identified by our PubMed search ([Fig. 1 ]) represents increasing acceptance of SPS as a prothrombotic tendency among peers.
Fig. 1 Results of a recent PubMed search of the search term “sticky platelet syndrome.”
A total of 63 papers were identified, with numbers seeming to be on the increase (Note:
@ 14th October, 2018—so, 2018 data are incomplete).
Why is SPS plausible, and why is SPS alternatively plausibly deniable? Unless a worker
in the field of research has actively investigated a condition, that worker may have
a healthy skepticism about whether a particular condition exists. We explored this
in an earlier commentary on hematidrosis.[14 ] Accordingly, unless a worker in the field of thrombosis research has actively investigated
SPS as a prothrombotic condition, that worker may have a healthy skepticism about
whether SPS really exists as an autonomous clinical entity. Investigating SPS, and
indeed platelet-related research, is problematic. Unlike plasma-based hemostasis research
work, the study of SPS and platelets requires fresh patient material and highly meticulous
sample collection and handling. In other words, the patient under investigation requires
blood collection at the time of investigation, and then platelet function testing
needs to be performed immediately afterwards by experienced personnel.
Neither of the authors to this commentary currently undertake extensive platelet research.
This is not because we are not capable of performing this research, but platelet research
is very challenging and we perhaps undertook “other/easier/more-productive/less debated”
paths. Accordingly, neither of us has ever systematically investigated SPS as an entity
within our routine laboratory activity. Indeed, most workers in hemostasis research
have never systematically investigated SPS. Nonetheless, we tend to believe that hyperactive
platelets can cause prothrombotic events and induce pregnancy morbidity. We also believe
that there is at least some element of genetics or inheritability in such platelet
hyperactivity, at least on occasion. So, call it hyperactive platelets or “sticky
platelet syndrome,” we do not doubt the plausibility of hyperactive primary hemostasis
leading to adverse pathophysiology.[15 ] There are many examples of “acquired” conditions leading to activated platelets
and subsequent thrombosis—including heparin-induced thrombocytopenia.[16 ]
[17 ] Of course, SPS may not be a single discrete condition—just as hemophilia is not
just a single discrete pathological bleeding condition reflective of secondary hemostasis.
We are also reminded that there are several precedents for inherited bleeding conditions
caused by genetic changes in platelet receptors, for example, the glycoprotein Ib
receptor, which acts as the primary VWF binding receptor on platelets. That condition
is called “platelet-type von Willebrand disease” (PT-VWD), and in essence creates
“hyperactive” platelets that lead to loss of high molecular weight forms of VWF, and
usually also (mild) thrombocytopenia.[18 ] No one in the hemostasis field doubts in the existence of PT-VWD, although perhaps
counter-intuitively, PT-VWD presents as a bleeding disorder. PT-VWD is also a “cousin”
(or nonidentical “twin”) to type 2B VWD, which represents a hyperactive form of VWF.[19 ]
[20 ]
[21 ]
[22 ] Also, no one doubts the genetic basis of either PT-VWD or 2B VWD.
The update review in the current issue of this journal[11 ] provides other insights into why some workers in hemostasis may not believe in SPS.
The purpose of this particular commentary is to encourage further dialogue, not only
in regard to SPS but also as related to other potential controversies in thrombosis
and/or hemostasis, as the situation may present in the future. It is acceptable to
have healthy scientism. It is also acceptable to have an open mind.
