The hemostatic system is responsible for limiting blood loss upon vascular injury
and is designed to rapidly react to breaches in the endothelial cell lining. Components
of this system are subject to powerful regulatory mechanisms including various antihemostatic
actions of the endothelium, antihemostatic actions from proteins in plasma, and blood
flow that removes activated hemostatic proteins from the growing thrombus. A well-orchestrated
balance between pro- and antihemostatic forces ensures hemostatic balance and avoids
spontaneous bleeding or thrombotic episodes. It is evident that hemostatic balance
is crucial to avoid these complications, as evidenced by the pathology associated
with a deficiency of pro- or anticoagulant proteins (e.g., severe and spontaneous
bleeding in hemophilia and substantially elevated thrombotic risk in patients with
deficiencies in some of the natural anticoagulants). While congenital or acquired
disorders may alter multiple components of the hemostatic system simultaneously, such
complex changes in the hemostatic system may not necessarily lead to severe pathology.
For example, the complex hemostatic changes in patients with liver disease lead to
a hemostatic rebalance without a clinical phenotype in many patients, which demonstrates
the resilience of the hemostatic system.[1] Likewise, hemostatic challenges resulting from surgery or trauma are not necessarily
related to a dismal hemostatic outcome.[2]
[3] In this issue of Seminars of Thrombosis and Hemostasis, we explored consequences of remarkable physiological or pathological conditions
on the hemostatic system. As we will see, some “extreme” conditions may be without
clinical consequences, whereas others are related to a substantial risk of bleeding
or thrombosis. Moreover, there is a remarkable set of challenges to the hemostatic
system, that is, hemostatic activators or inhibitors in a variety of venoms, which
are potentially useful as therapeutic agents.
We will start this issue by discussing effects of physiological extremes. First, Kenet
et al[4] discuss the hemostatic system in the very young. It is well known that the hemostatic
system in newborns and very young children has a remarkably different composition
than that in adults, with decreased plasma levels of most of the activators and inhibitors.
Despite these differences, most children fortunately do well and are in excellent
hemostatic balance. The paper by Kenet et al discusses those rare cases in which young
children suffer from bleeding or thrombotic complications in the context of the concept
of developmental hemostasis. Next, Tzoran et al[5] discuss the hemostatic changes that occur as a consequence of aging. As in the very
young, the hemostatic system in the oldest old is substantially different from younger
adults. However, in this population, the risk of thrombotic disease increases tremendously,
and interactions with chronic illnesses are associated with important thrombotic issues.
The subsequent “extreme condition” is discussed by Hunt,[6] who addresses hemostatic changes in extremes of body weight. Very low body weight
is associated with incompletely characterized hemostatic changes, which include decreased
blood cell counts and platelet hyperaggregability. Among the many clinical consequences
of severe obesity is a hypercoagulable state that is related to an increased risk
of venous and arterial thrombosis. The author also discusses mechanisms and clinical
consequences of the hemostatic changes associated with (severe) obesity. The next
paper by Kicken et al[7] deals with extreme exertion. The authors propose that a hypercoagulable state induced
by strenuous exercise is balanced by a concomitant development of a hyperfibrinolytic
state. However, this compensatory mechanism largely disappears during recovery, which
may be important in the context of an increased risk of cardiovascular events in athletes.
The next section in this issue discusses hemostatic challenges caused by disease.
Levi[8] discusses effects of abnormal body temperature on the hemostatic system. Heatstroke
is used to provide an example of hemostatic changes that may occur as a result of
hyperthermia. Heatstroke may lead to disseminated intravascular coagulation, which
may contribute to a dismal outcome. Hypothermia may occur in conditions such as trauma
or imposed intentionally to protect the brain in patients who have had a cardiac arrest
or acute liver failure. Although hemostatic changes do occur, the clinical consequences
may be limited. Hoirisch-Clapauch[9] then discusses the risks of bleeding and thrombosis related to anxiety. The author
puts forward the thought-provoking hypothesis that anxiety combined with hypofibrinolytic
states (defined as severe depression or a high-carbohydrate, low-protein, low-fiber
diet and a sedentary lifestyle) has a role in the pathogenesis of thrombotic events
and that part of these events, currently classified as unprovoked, are in reality
provoked by high anxiety states. The next paper by Bentur et al[10] deals with the effects of stress on the hemostatic system and concludes that the
hypercoagulable state induced by stress could be related to a combination of neurotransmitters
and hormones, and the effects of stress on hemodynamics. Vadasz and Toubi[11] then discuss the hemostatic changes in allergy, specifically in asthma and chronic
spontaneous urticaria. The authors show complex hemostatic changes in both disorders
and demonstrate that these changes are, at least partly, related to the effects of
the immune system on hemostasis. Subsequently, Elbers et al[12] discuss the interplay between thyroid hormones and hemostasis, showing that hypothyroidism
is associated with hypocoagulability and risk of bleeding, and hyperthyroidism is
associated with hypercoagulability and risk of venous thrombosis. In addition, the
paper describes effects of malignant thyroid disease on developing venous thrombosis,
which relates to local stasis of the blood due to compression effects of the expanding
tumor. The next paper by Putri et al[13] discusses thrombocytopenia and platelet function defects that are frequent complications
of tropical diseases such as malaria and Dengue fever. Interestingly, in some tropical
diseases in which patients commonly develop thrombocytopenia bleeding is rare (e.g.,
in malaria), whereas in other diseases, bleeding is an important complication of the
disease, which may be related to preservation of platelet function in malaria. The
paper therefore discusses mechanisms and clinical consequences of thrombocytopenia
and platelet function defects in tropical diseases and highlights the difficulties
in studying platelet properties in resource-poor countries where these such diseases
are frequent. A final contribution by Koh et al[14] gives an extensive overview of proteins and peptides isolated from different types
of venoms that interfere with a variety of hemostatic processes. The paper also gives
an overview of discovery and development of venom-derived antiplatelet, anticoagulant,
and thrombolytic agents. Venom-derived compounds are not only used in diagnostic assays
of hemostasis (e.g., ristocetin-induced platelet agglutination or the Russell Viper
Venom time) but have clear potential as pharmacological agents (e.g., hirudin).
Taken together, the papers in this issue of the journal highlight subtle or pronounced
hemostatic effects of a wide variety of physiological or pathological extremes. The
clinical consequences associated with hemostatic alterations by these extremes may
teach us valuable lessons about the requirements for hemostatic balance in health
and disease. In addition, these reviews accentuate the variety of triggers that may
alter the hemostatic system, and stress links between physiological or pathological
conditions and hemostasis that may not be immediately apparent. We sincerely hope
you enjoy reading the wide range of papers assembled in this issue.
