Review And Insights Into The Bleeding Mechanism Incited By Antithrombotic Therapy: Mechanistic Nuances Of Dual Pro-Hemorrhagic Substrate Incorporating Drug-Induced Microvascular Leakage
Petras Stirbys MD, PhD
The Department of Cardiology, Hospital of Lithuanian University of Health Sciences , Kaunas Clinic, Kaunas, Lithuania.
In patients with atrial fibrillation antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. Cerebrovascular risk-benefit ratio for oral anticoagulation therapies continues to be debated. Macro and/or microhematomas as well as visible or cryptic ones may appear unexpectedly in any anatomic region.
The diagnostic and prognostic value of subcutaneous hematomas (petechia, ecchymosis, bruise) potentially predisposing intracerebral micro- or macrobleeding might be reconsidered. Hypothetically, subcutaneous hemorrhagic events are “transparent” signs and reflect the coexistence of remote vulnerable sites that are potential bleeding sources. Obviously vigilance is needed for early signs of drug-related petechiae evaluation to determine whether it is a local/superficial subtlety or a systemic problem. Any bleeding complication, regardless of its scale and anatomical location, might be treated as a worrisome clinical symptom requiring subtle correction of antithrombotic regimen. The focus of this article is to review the current knowledge of drug-related hemorrhage with special emphasis on underlying mechanisms and links between the visible bleeding (predominantly subcutaneous) and remote (such as cerebral) hemorrhagic sources. To mitigate inappropriate therapy, we should consider new conceptual insights and more individualized approaches to achieve an optimal balance of efficacy and safety. We hypothesize that bleeding complications occur as a result of two factors – impact of antithrombotic drugs and related detrimental effect on microvascular network. Most likely the microvasculature undergoes pro-hemorrhagic medication stress leading to unfavorable vascular wall “fenestration” with ensuing consequences. If so, it suggests the presence of dual substrate responsible for hemorrhagic events.
Corresponding Address : Petras Stirbys MD, PhD,A. Ramanausko-Vanago str. 4-7,49306 Kaunas,Lithuaniany
Atrial fibrillation (AF) is the most common rhythm disturbance worldwide. As a non-life threatening arrhythmia it carries a great risk of ischemic stroke along with severe hemorrhagic events, especially when oral antithrombotic drugs (OAD) are instituted. Untreated, AF increases the risk of ischemic stroke fivefold making stroke the leading complication of AF.1 Eighty percent of strokes are caused by arterial occlusion of cerebral arteries, whereas the remaining twenty percent are caused by intracerebral hemorrhages.2 However, although clinically intriguing, antithrombotic therapy can act like a double edged sword with both beneficial and adverse effects.
Meanwhile oral antithrombotic therapy (OAT) remains the best treatment option to prevent cardioembolism in AF.3 Drug-related hematomas as a concomitant “metastatic ectopy” may simultaneously occur subcutaneously, in the brain or in any other topographic location of the human body. Cutaneous or subcutaneous hemorrhagic areas may cover lower extremities, neck, buttocks and may also affect large areas. Such therapeutic endpoints should not be interpreted as “innocent” symptoms. Spontaneous bruising is important but the bruise should be over 3 cm in size to be significant.4
We would like to focus on conspicuous subcutaneous hematomas appearing as a result of antithrombotic treatment. These hematomas as precursors may herald more severe bleeding in other locations, predominantly in the brain. Thus, such correlation likely raises the risk of bleeding expansion. For this reason intracerebral microbleeding and subcutaneous hemorrhage may represent a peculiar clinical relationship. Regarding the mechanism of hemorrhage the OADs presumably affect both blood coagulation parameters and microvascular/angiogenic factors. Thus, better understanding is needed to avoid excessive out-of-control bleeding.
This review is part of the ongoing efforts to improve clinical results in patients undergoing antithrombotic therapy.
Background And Reflections
The prevention and containment of bleeding is a major therapeutic goal in patients suffering from AF. Recently Fischer et
al.5 have offered a new term – mixed cerebrovascular disease which
incorporates clinical and subclinical syndromes including ischemic
stroke, intracerebral hemorrhage and cerebral microbleeds. The
balance between the risk of bleeding and the risk of stroke needs to be
estimated for each patient based on patient’s values and preferences,
as well as awareness of the prognostic implications of bleeding.3
Hematomas range from small and relatively benign to severe,
including life-threatening ones. Numerous reports have amply
demonstrated clinical emergency due to acute or subacute
intracranial, intracerebral, retropharyngeal or intramuscular
hemorrhagic outbreaks resulting in serious brain damage, lifethreatening
suffocation, anemia and/or death.6-14 The findings of
Risch and colleagues.15 confirm that intracranial, muscular and softtissue
hemorrhagic events exclusively occur in patients who receive
Underlying mechanisms of coagulation-bleeding physiology
implicate very complex biological interactions between blood
and tissue factors.16 even without interference of OADs. Sporadic
reports suggest that microhemorrhages are preferential focuses of
intracerebral hemorrhage (ICH) in patients receiving OAD, most
likely because the drug unmasks ICH that would otherwise remain
asymptomatic.17 Extensive anticoagulant effect is well-established as
a powerful risk factor for ICH.8 Fortunately the menace of AFrelated
stroke and hemorrhage in most cases is amenable to medical
control at least when conventional OAD medication is applied.
Ubiquity of multiple hemorrhagic foci actually alerts clinicians and
their patients as well. However, it is still unclear where the bleeding
starts first – subcutaneously (superficially), intracerebrally, selectively
anywhere or uniformly in the whole body. In general, unnoticed or
ignored subcuticular hemorrhage may negatively influence the clinical
course of AF therapy. Moreover, there is a concern that patients as
well as their physicians may become reconciled to the trivial petechiae,
eventually paying no attention to alarming abnormality. Aspirational
target of medical community is zero hazard ratio – an ideal bleedingfree
as well as stroke-free clinical course of AF.
With regard to bleeding substrate one can hypothesize that we
deal with the integral bleeding circuit with individual components of
favorable/prohemorrhagic conditions. Responsible mechanisms are
not clear and may relate to individual effects of local vasculopathy
subtlets - bleeding per diapedesis in proportion to medication,
microvascular disintegration, capillary fragility, etc. Recently Altman
.19 has emphasized that bleeding is an eventuality that occurs in places
of “locus minoris resistentiae”. This might serve as a starting point
for some clinical revelations, specifically to verify the etiology of the
hemorrhage. It seems, at least hypothetically, that OADs activate
microvascular “weakest links” residing in the soft tissues.
Under physiological circumstances the concerted action of platelets,
active biological blood components, and tissue factors influence the
coagulation cascade and maintains hemostasis.3 Interfered by specific
drugs the coagulation system is affected significantly; that is why
antithrombotic therapy faces many challenges.
Any bleeding events are categorized as major and minor by
anatomical site.20 Major bleeding is defined as an intracranial
hemorrhage, a decrease in blood hemoglobin level of more than 5.0 g/
dL, the need for a transfusion of two or more units of blood, the need for corrective surgery, or any combination of these events ;21 minor
bleeding is defined as a subcutaneous ecchymosis or hematoma,
gastrointestinal bleeding, or bloody sputum.
The study of Guo and colleagues.21 demonstrated that there were
no thromboembolic events in elderly patients taking OAD, but
33% of them had bleeding complications. According to Goldstein
and Greenberg12 while bleeding is the major risk, not all bleeding
events are equally damaging. Recently Jacobs and colleagues22
have suggested that anticoagulation with inherent period of
supratherapeutic and subtherapeutic effects provoke both chronic
microemboli and microbleeds; patients with prior ischemic cerebral
injury may be more likely to experience repetitive or worsened injury
with longer anticoagulation use.
There are disparities in efficacy between pharmacologic groups of
OADs. Regarding the intracerebral bleeding there is a perception
that aspirin is effective and is safer than warfarin.23 The incidence
of major hemorrhage with aspirin monotherapy is approximately
1.5% per year.24 In general, antiplatelet treatment is likely safer, as
antiplatelet agents carry a substantially lower risk of bleeding.25,
26 Conversely, vitamin K’s antagonist warfarin therapy has been
shown to be more effective than aspirin for the prevention of stroke
in patients with AF.27 Unfortunately, there is no absolutely “safe”
INR (international normalized ratio) even with the conventionally
therapeutic range.8 New anticoagulant dabigatran is associated with a
surprisingly enhanced risk for both thrombo-embolism and bleeding
disorders clearly indicating the importance of accurate follow-up
of AF patients.28 However, the only reversal option for dabigatran
is emergency dialysis which can be a challenge when it comes to
patients with a threatening ICH.29 This procedure takes time which
is why the therapeutic efficacy may be overtaken by intense bleeding.
Several OADs, i.e. dual or triple therapy and their interactions have
been shown to increase the risk of serious bleeding.6, 30 Warfarin
interaction with at least one drug was considered in a retrospective
study as the main contributor to bleeding in almost half of the cases.31
Controversies Of Intracerebral Microbleeding
The increasing use of antithrombotic drugs in an aging population
is associated with a dramatic increase in the incidence of intracerebral
hemorrhage.15, 32 A group of clinicians33 have stated that the count of
microbleeds or macrobleeds predicts an increased risk of hemorrhagic
stroke in survivors of ICH. With anticoagulation, however, the benefit
has to be balanced against an increased risk of ICH, which is the
most feared complication of anticoagulation, causing death or severe
disability in up to 75% of patients.13 Increasing use of warfarin to
prevent cardioembolic stroke due to AF has led to a fivefold increase
in the incidence of anticoagulant-related ICH, which now accounts
for approximately 15% of all ICH.34 It is a paradox that many of
these patients at the highest risk of cardioembolic stroke are also at
the highest risk of ICH.35 Recent work in the field.29 has recognized
that OAT related intracerebral hemorrhage rises up more questions
Cerebral microbleeds (CMB) are small chronic brain hemorrhages
which are likely caused by structural abnormalities of the small vessels
of the brain.31 Yates et al.36 declared that microscopic hemorrhages
occur in the setting of impaired small vessel integrity, commonly due
to either hypertensive vasculopathy or cerebral amyloid angiopathy.
Recently Shoamanesh and colleagues.37 have demonstrated that
microbleeds on magnetic resonance imaging were associated with evidence in prior bleeding in 81% (e.g. hemosiderin-laden
macrophages or old hematoma).
Vascular release of blood components in the absence of trauma
in orally anticoagulated patients defines the clinical entity being of
great interest. In literature, the risk/benefit ratio of anti-thrombotic
drugs in individuals with CMBs is controversial.31 Microbleeds
which have long been perceived as harmless and irrelevant in disease
development, were found in 23 percent of patients with Alzheimer’s
disease in the review of five studies;38 a previous study showed that
6.5% of healthy 45-to 50-year olds have microbleeds, whereas 35.7%
of people 80 and older have them. Some investigators have concluded
that CMBs are not just an incidental finding revealed by new
neuroimaging technology.39 From a pathophysiological standpoint,
CMBs appear to be the expression of a hemorrhage-prone state of
the brain, which might carry greater risk of ICH.31
There are some controversies related to whether the intracerebral
microbleeding is harmful or not. The presence of cognitive decline
symptoms in anticoagulated patients is also debated. Most cerebral
microhemorrhages identified by gradient-echo imaging are
clinically silent.39, 40 Some investigators, however, have shown that
microvascular damage plays a key role in cognitive impairment,
especially in older patients.31 Because CMBs reflect small areas of
hemorrhage, and are common in both ischaemic and intracerebral
hemorrhage,41 they have caused concern regarding the risk of future
intracerebral hemorrhage.39 Kakar and colleagues39 have postulated
that CMBs develop over time and are common in populations
likely to be exposed to antithrombotic drugs. Anti-platelet agents,
traditionally safer than anticoagulants, are associated with an
increased risk of ICH, especially in subjects with high number of
CMBs.42, 43 Apparently every anticoagulated individuum possesses its
own hemorrhagic scenario. The ability to concentrate or disseminate
the hemorrhagic foci in specific anatomic regions represents the
phenomenon to yet be elucidated.
The rate of intracerebral hemorrhage in patients given OADs
has been hypothesized to be the inherent risk multiplied by a factor
determined by intensity of anticoagulation.44 It looks like weak
points are or provoked with the anticoagulation as a parent material
which activates a bleeding cascade. Specifically, increase in dose often
leads to exacerbation of hemorrhage or to proliferation of “weakest
points”. When collated, multilateral interrelationship of “high
anticoagulation - high vulnerability - high risk” might be traced.
Clinical Importance Of Subcutaneous Bleeding
In individuals under antithrombotic treatment clinicians often
observe multiple hemorrhages scattered across the patient’s body.
Anatomical distribution of bleeding sites varies within wide
range allowing the hemorrhagic foci to overlap several territories.
Hemorrhagic events sometimes are represented by simultaneous
appearance of subcutaneous and intraorganic/intraparenchymal
hematomas, both overt and/or cryptic. It is still unclear whether
subcutaneous hemorrhage is strongly associated with systemic
bleeding. Again, it is worth to discuss whether the subcutaneous
bleeding is a clinically remarkable symptom or not. Also the recurrence
of subcutaneous bleeding is to be estimated mostly in terms of its
diagnostic and prognostic value. No doubt, we deal with the plural,
i.e. loci minores resistentiae which, according to the manifestation
pattern might be defined as sporadic, multiple, migrans, cryptic and/
or visible. In theory, the patient without visible hematomas is not free from supposed hemorrhage. If so, petechia likely coexists with
other bleeding sources, e.g. intracerebral microhematomas. Literature
sources available do not provide a distinct relationship in this regard.
Some investigators31, 35, 39 have declared that CMBs are potential
predictors of future intracerebral hemorrhage. In turn, by
extrapolation, clinical significance of CMBs likely is comparable
to subcutaneous hemorrhage as far as their etiological similarity. In
other words, subcutaneous bleeding foci are important not per se,
but may reflect the presence of intracerebral hemorrhage and vice
versa. Thus, any bleeding events wherever they are most often reflect
the common anticoagulation status and increased bleeding risk in
any possible anatomical site. If so, the entire body of the patient
comprises the feasibility of hemorrhagic outbreaks at any time and
in any topographic area, especially under excessive anticoagulation.
There are no recommendations related to clinical strategy and
how to care for the noticed subcutaneous bleeding, particularly
when it is extensive. Physical removal of OADs even provisionally
might be a risky maneuver unless worsening signs do appear.
Reduced anticoagulation particularly in repeat bleeding events and
subsequent monitoring of blood markers is beneficial. Some clinical
reports suggest that optimal antithrombotic therapy selection for
patients with AF must be mainly accomplished based on individual
and accurate risk stratification for both thromboembolism and
hemorrhage during therapy, not based only on the risks before
treatment.21 The cautious approach to OAT in patients with bleeding
risk is suggested by many clinicians.31, 44
Co-Participation Of Anticoagulation And Vascular
Disintegrity: New Insights
The precise mechanism by which anticoagulation increases
the incidence of intracerebral bleeding is unclear.7 Immediate
precipitants could be as trivial as an interval of relatively higher
blood pressure or minor mechanical stress such as the shear forces
of vigorous head shaking;8 one idea is that the anticoagulation may
cause subclinical brain hematomas to grow to clinical importance.
Classical bleeding supportive causes might be taken into account, e.g.
per diapedesis or per microvascular rupture resulting in extravasation
of blood components. Bleeding likely evolves from both the intensity
of medication and individual characteristics of small vascular
peculiarities. Herein we do not analyze the subclinical or clinical
injuries originating from physical impact.
Meanwhile the hypothesis of “locus minoris resistentiae” provides
the best explanation of the behavior of bleeding-prone locations.
However, this approach fails to disclose the cause and the mechanism
of hemorrhagic foci migration across the anticoagulated human
body. We can observe sporadic, multiple or single hemorrhagic
spots (bruises) which may appear or reappear in the same site or
in alternating regions. Likely the local architectonic and structural
tissue specificities along with “anticoagulant-induced vasculopathy”
reflect the clinical threats which might be construed and incorporated
into the discussion. Seemingly, unique tissue/vascular conditions
may determine different bleeding intensity in specific vulnerable/
susceptible anatomic sites.
Under physiological conditions the breakage of the endothelial
barrier leads to exposure of extravascular tissue factor which provides
additional hemostatic protection.16 Consequently, drug-induced
vascular disintegration conjoined and reinforced by the loss of blood’s
clotting capability eventually cause blood spillage into surrounding tissues most often in a form of imbibition. So, it is reasonable to
suspect that dual substrate, i.e. both the antithrombotic agent and
microvascular abnormality most likely are responsible for the bleeding
event. Conceptually AODs open the bleeding sources which were
tightly closed before the therapy. These gates likely resist until the
crucial shift in concentration of AOD’s is reached; then bleeding of
non-traumatic origin is launched. In other words the extravasation
of clotting-free blood is impossible without vasogenic component.
Findings of Charidimou and Werring35 have shown that OADs
provide direct evidence of blood leakage from pathologically fragile
small vessels. The contributing role of local vascular disease, such
as cerebral amyloid angiopathy, is favored by observation of a high
frequency of this angiopathy in individuals with warfarin-related
ICH.29 Negative influence of OADs on capillary or pre-capillary
endothelial cells, including their disintegration, might be conceivable.
However, individual characteristics of small vascular peculiarities
as an indispensable cofactor presumably influence the bleeding
intensity from patient to patient under the same antithrombotic
regimen. Taken together it could be suspected that AODs, especially
in high-doses, may have direct impact on microvascular damage, at
least enhanced capillary or precapillary permeability.
Despite percolation of blood’s “corpuscles” and plasma through
the capillary the cardiovascular system represents a unique, securely
sealed and well-organized entity. From a purely mechanical point
of view functional harmony of the closed circulatory system might
be characterized by an axiom: no vascular leakage, no sanguination
regardless of the presence of blood thinners.
As stressed by Yates et al.36 microscopic hemorrhages occur due to
impaired small vessel integrity. It supports our conceptual viewpoint.
It could be suspected that anticoagulant milieu do facilitate capillary
fragility and potentiate microvascular damage, most likely its
auto-rupture. Deductively, the microvasculature undergoes prohemorrhagic
medication stress. The exposure to critical dose of OADs,
in the absence of physical impact, might explain the mechanism of
sanguination. Eventually, the higher the serum drug concentration is
the greater risk of blood eruption. Figuratively speaking the vascular
“fenestration” (of iatrogenic origin), abundantly adverse, is a critical
condition, otherwise the bleeding will not be evoked by any blood
thinner even when using maximum dosage.
In a metaphorical sense, loss of coagulability as such covers just
a half or two thirds of the “distance” until bleeding is initiated.
The remaining “distance” – up to the bleeding manifestation - is
surmounted and finalized by drug-dependent microvascular changes.
Clinical observations demonstrate the potential presence of
multiple hemorrhagic sources in different anatomic regions. In reality
these focal points are dormant unless OADs are introduced. More
surprising is the fact that bleeding foci may change their topographic
areas, as if migrating occasionally with a period of clinical latency
eventually related to anticoagulation regimen.
Despite the fact that almost all subcutaneous hematomas
resolve spontaneously without clinical consequences their presence
and reappearance should not be underestimated or ignored.
Therapeutic vigilance is needed to eliminate two risks – bleeding
and cardioembolism. Hence, OAD’s dose re-adjusting strategy in
response to anticoagulation fluctuations should be the best solution
of clinical problem. An ideal approach – treatment lege artis with painstaking control of both bleeding and cardioembolism is the goal
of clinical practice. In summary, the following methods should be
1) Enhanced surveillance for visible bleeding sites in patients
during their routine visits should be taken into account.
2) To maintain adequate anti-coagulated status the risk/benefit
ratio should be considered and care should be individualized,
especially in those patients with visible subcutaneous hemorrhage.
3) Dose re-adjusting strategy to reach ne plus ultra therapeutic
condition is highly recommended.
4) Under the thromboprophylaxis the bleeding likely stems from
dual substrate – impact of antithrombotic drug which, in turn, evokes
detrimental effect on microvascular network.
5) Further studies are needed to improve the understanding of the
mechanism of drug-related hemorrhage.