Progress in Pediatric Cardiology 56 (2020) 101193

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Progress in Pediatric Cardiology

journal homepage: www.elsevier.com/locate/ppedcard

Review

Hematologic changes in cyanotic congenital heart disease: a review T

⁎
J.D. Griesman, D.S. Karahalios, C.J. Prendergast
Upstate Golisano Children's Hospital

A R T I C LE I N FO A B S T R A C T

Keywords: Several hematologic changes occur in children and adults with chronic cyanosis – some adaptive, some mala-
Hematology daptive. Changes in blood viscosity, iron metabolism, coagulation profile change, and thromboembolic risk all
Congenital heart disease occur with secondary erythrocytosis. It is important that medical professionals understand these changes and
Cyanosis their clinical significance as chronic cyanosis has multi systemic consequences. This article will focus on a review
Hyperviscosity, iron deficiency
of pathophysiology and clinical practice guidelines as they pertain to hyperviscosity, iron deficiency, hyperur-
Thrombosis
icemia, bleeding tendencies, thromboembolism, and central nervous system complications.

1. Introduction theoretical management of hyperviscosity is to lower the RBC mass,

Patients with cyanotic congenital heart disease (CCHD) must adapt
to low oxygen tension and low oxy-hemoglobin saturations [1–5].
Secondary erythrocytosis describes the physiologic response of in-
creasing red blood cell (RBC) mass to improve oxygen delivery. Main-
tenance of a steady state of hemoglobin and RBC function for a given
oxygen saturation is sought so as to optimize tissue delivery of oxygen.
This steady state is called compensated erythrocytosis. Patients with
ongoing laboratory signs of erythrocytosis, for example elevated re-
ticulocyte count, elevated erythropoietin (EPO), and a right-shifted
oxyhemoglobin dissociation curve, are said to be in decompensated
erythrocytosis [5].
Secondary erythrocytosis can have unintended consequences.
Hyperviscosity can develop secondary to increased RBC mass [1–5].
Iron deficiency is very common, may be symptomatic, and can con-
tribute to decompensation of erythrocytosis in a dangerous feedback
loop [1–9]. Increased cell turnover and cyanotic nephropathy may lead
to hyperuricemia [4,10]. Coagulopathy can develop causing both
bleeding and thrombosis [5].
This article will focus on pathophysiology and management of these
consequences and will focus on new studies that have been published
over the last ten years.
2. Hyperviscosity
Secondary erythrocytosis leads to an increase in red blood cell mass.
This has been historically suggested to increase whole blood viscosity
and cause symptoms of hyperviscosity [2,3,5,11]. These symptoms can
include headache, visual changes, muscle aches and fatigue. The
either by phlebotomy to remove red blood cells, or by oral or parenteral
fluid administration to dilute the hematocrit.
Routine or prophylactic phlebotomy is discouraged by multiple
sources. In a 2013 position statement, the American Heart Association
stated that phlebotomy is a reasonable approach to preventing throm-
boembolic events in two situations based on class IIa evidence: in adult
patients with hyperviscosity symptoms with hemoglobin greater than
20 mg/dL and hematocrit greater than 65% who do not have evidence
of dehydration or iron deficiency, and in adult patients undergoing non-
cardiac surgery when the hematocrit is greater than 65% [12]. Sub-
sequent studies have further suggested evidence to discourage such
practice [11,13–15].
Hyperviscosity was previously thought to be a primary risk factor
for thromboembolic events in patients with CCHD. A cross-sectional
study in 2015 studied 98 stable patients with CCHD examined the in-
cidence of pulmonary and cerebral thrombotic events using imaging
and questionnaires [13]. This study showed a higher incidence of
thromboembolism than previously thought: 47% of patients had
radiographic evidence of cerebral infarction and 31% had evidence of
pulmonary thromboembolism. Contrary to popular belief, secondary
erythrocytosis was not found to be associated with thromboembolism in
these patients. Iron deficiency, however, was found to be an in-
dependent risk factor for thromboembolic events. Microcytic cells are
less deformable and have reduced oxygen carrying capacity, and this is
speculated to explain why iron deficiency is an independent risk factor
for ischemic stroke in patients with CCHD.
Salimipour et al. describe a case of a patient who developed chronic
transient symptoms similar to transient ischemic attack after under-
going phlebotomy for fatigue and dizziness [11]. The authors

⁎
Corresponding author.
E-mail address: prenderc@pcacny.com (C.J. Prendergast).

https://doi.org/10.1016/j.ppedcard.2020.101193
Received 1 October 2019; Received in revised form 8 January 2020; Accepted 10 January 2020
Available online 11 January 2020
1058-9813/ © 2020 Elsevier B.V. All rights reserved.
J.D. Griesman, et al.
hypothesized that these attacks were related to an acute change in
oxygen delivery. Another case report described a patient with head-
aches and elevated hematocrit who was found to have papilledema
[14]. Treatment with a carbonic anhydrase inhibitor successfully
ameliorated his symptoms, and therefore highlighted the importance of
funduscopic examination in identifying alternative causes for hy-
perviscosity symptoms.
Hydroxyurea was used in four patients with hyperviscosity symp-
toms in a small case series [15]. The authors showed encouraging re-
sults in relieving hyperviscosity symptoms by myelosuppression and
corresponding decrease in hematocrit and red blood cell count without
sacrificing iron stores. It also increased the Mean Cell Volume (MCV),
and by extension the authors postulated that this might allow the cells
to be more deformable and less likely to cause occlusive complications.
The current best practice suggestion for management of hy-
perviscosity symptoms is to first identify other sources of symptoma-
tology, such as dehydration and iron-deficiency anemia [1,3,4]. In re-
fractory cases, phlebotomy may be attempted, provided the lost volume
is replaced with plasma or albumin [5].
3. Iron deficiency
The secondary erythrocytosis in CCHD causes a high marrow de-
mand for iron [1–5]. Iron can be further depleted by phlebotomy and
other sources of bleeding (e.g. epistaxis, menorrhagia) which will be
explored in the section below. A relative state of iron deficiency in the
setting of secondary erythrocytosis has also been seen in patients who
are status post palliation with the Fontan operation [16].
Broberg et al. sought to define the relationship between hemoglobin
and oxygen saturation [8]. They found that in patients without la-
boratory evidence of ongoing decompensated erythrocytosis, the he-
moglobin was related to the oxygen saturation with the formula:
Predicted Hemoglobin = 61–(oxygen saturation/2)
They further found that patients with hemoglobin below that cal-
culated prediction had worse VO2 after six-minute walk test. Therefore,
it was not the hemoglobin itself that affected exercise capacity, but the
deviation from this patient-specific ideal hemoglobin.
Some providers have been hesitant to provide iron supplementation
from fear that the resultant erythrocytosis would worsen hyperviscosity
and risk for stroke. Terlemez et al. supplemented 39 patients with iron
deficiency and directly measured blood viscosity using a Viscoelastic
Profiler [17]. Hemoglobin and hematocrit increased after treatment,
but viscosity did not. Patients reported a statistically improvement in
symptoms such as blurry vision and headache, which are symptoms
that commonly overlap with hyperviscosity. Tay et al. treated 25 pa-
tients with CCHD with ferrous fumarate for three months [18]. This
improved their six-minute walk distance without inducing hy-
perviscosity symptoms. As mentioned above, iron deficiency is an in-
dependent risk factor for stroke in these patients; hematocrit is not.
Blanche et al. were able to improve their patient's iron deficiency with
intravenous iron, and none of the 163 patients treated developed hy-
perviscosity symptoms [7].
It should be noted that red cell indices (Mean Corpuscular Volume,
Mean Corpuscular Hemoglobin Concentration) may not accurately re-
flect iron deficiency in hypoxemic patients [5]. This is partly because
cyanosis induces macrocytosis. Ferritin can be useful for trending, but it
can be falsely elevated as it is an acute phase reactant. Broberg et al.
recommend using transferrin saturation less than 20% as an indication
for iron replacement [1]. Increased Red Cell Distribution Width (RDW)
has also been shown to be an early indicator of iron deficiency as a
reflection of anisocytosis. Interestingly, elevated RDW has been shown
to be significantly related to adverse cardiovascular events in adult
patients with congenital heart disease, independent of NT-pro-BNP [6].
2
Progress in Pediatric Cardiology 56 (2020) 101193
4. Hyperuricemia
Hyperuricemia is common in patients with CCHD [10]. These pa-
tients have increased production of uric acid due to increased cell
turnover, and decreased secretion, thought to be due to cyanotic ne-
phropathy and diuretic use. Rodriguez-Hernandez et al. identified BMI,
renal insufficiency, cyanosis, and the use of diuretics as risk factors for
hyperuricemia in congenital heart disease [19]. The incidence of gout is
low relative to what one would expect given the prevalence and extent
of hyperuricemia. Clinical gout can be hard to diagnose, as patients
suffer from pain related to hypertrophic osteoarthropathy and perios-
titis. It is recommended that uric acid levels are checked yearly as part
of health screening in patients with CCHD [3]. The degree of hyper-
uricemia is correlated to poorer outcomes in these patients. For patients
with gouty flares, colchicine is recommended. For those with recurrent
flares, prophylactic treatment with a xanthine oxidase inhibitor, such as
Allopurinol, is recommended. Allopurinol is not indicated for asymp-
tomatic hyperuricemia [19].
5. Bleeding diathesis
Bleeding is the most common postoperative problem in patients
with newly corrected CCHD. The most common types of bleeding are
intracranial, endotracheal, and pulmonary bleeding. In female patients,
menorrhagia is also common [20,21]. Polycythemia causes a predis-
position to bleeding through multiple different mechanisms.
One such mechanism is the inhibition of megakaryocyte differ-
entiation caused by chronic hypoxia. Mukai et al. found that this me-
chanism is driven by altered expression of erythrocyte microRNA,
which protectively causes erythrocytosis while simultaneously causing
inhibition of megakaryocyte differentiation and thrombocytopenia
[22].
The anatomical right to left shunting of children with CCHD further
compounds thrombocytopenia. Right to left shunting allows blood to
bypass the pulmonary bed, which is a key location for megakaryocyte
fragmentation into platelets. Interestingly, studies of people with
normal cardiac anatomy living in high altitude regions have shown that
they have normal platelet counts, despite being exposed to chronic
hypoxia. This confirms the key role that the lungs play in platelet
production [23,24].
Patients with CCHD have also been reported to have altered levels
of coagulation factors compared to healthy controls. Cyanotic patients
have decreased levels of fibrinogen and factors II, V, VII, VIII, IX, and X,
predisposing them to bleeding [12,21]. Stenotic valvular, muscular,
and mechanical cardiac lesions also place shear forces on high mole-
cular weight von Willebrand factor multimers, fragmenting them and
mimicking von Willebrand disease type [25,26]. In fact, an inverse
relationship between the degree of stenosis and the level of von Will-
ebrand factor multimers has been reported. This relationship is sup-
ported by a rapid increase in the amount and activity of von Willebrand
factor multimers following surgical correction of stenotic cardiac le-
sions [25].
Another proposed mechanism for the development of acquired von
Willebrand syndrome is consumption of the protease responsible for
cleaving von Willebrand factor, ADAMTS-13. In a small study, Soares
et al. demonstrated that consumption of ADAMTS-13 seen in cyanotic
patients is a predictor of postoperative bleeding [21]. Interestingly,
levels of factor VIII, a key target of von Willebrand factor, have been
described as elevated after Fontan palliation, possibly supporting the
findings by Soares et al. [12].
One of the complications of polycythemia and its resultant hy-
perviscosity is vascular stasis. Vascular stasis causes platelet deposition
and activation of coagulation factors. Chronically, this can lead to an-
other cause of platelet and coagulation factor consumption, similar to a
subacute state of disseminated intravascular coagulation. Studies have
also shown decreased platelet function in addition to quantitiave
J.D. Griesman, et al.
deficiency of platelets, which is proportional to the degree of poly-
cythemia [12].
Patients with CCHD are also predisposed to bleeding through vas-
cular remodeling. Chronic hypoxia causes increased release of nitric
oxide, predisposing vessels to dilation and aneurysm. These patients are
also polycythemic, which increases shear forces placed on blood vessel
walls and further increases the propensity towards dilation and an-
eurysm. These shear forces are greater in arterial vessels than in venous
vessels [12,20].
Patients with CCHD who are not anticipated to undergo correction
of their heart defect for a long time may benefit from folic acid sup-
plementation to aid cell division and increase platelet counts [27]. If
splenic sequestration is contributing, then splenectomy has also been
performed [23].
While phlebotomy is a controversial therapy for treating poly-
cythemia, it has been shown to increase platelet count. Lill et al. have
suggested that preoperative phlebotomy may be a way to decrease the
risk of postoperative bleeding [24]. However, this may have negative
consequences on oxygen carrying capacity and increase the need for
intraoperative blood transfusions. Further studies are needed to eluci-
date whether this is a viable therapy.
6. Thrombosis
While patients with CCHD have a predisposition to bleeding, they
also carry a simultaneous predisposition to thrombosis. Interestingly,
the risk for thrombosis due to polycythemia in cyanotic patients is
lower than the risk for thrombosis due to polycythemia vera [28]. This
fact highlights the influence of hypoxia and the complex nature of he-
mostasis in patients with CCHD. Generally, the risk factors that con-
tribute to thrombosis in these patients are no different from the general
population; however, hypoxia-induced polycythemia presents unique
considerations for the pathogenesis and treatment of thromboembolism
[12].
The most common reported thromboembolic events in patients with
CCHD are stroke, deep vein thrombosis, and pulmonary thrombosis,
though the exact prevalence of each is unclear. Jensen et al. reviewed
the clinical history and imaging of 98 adults with CCHD and found a
stroke prevalence of 47% [13]. However, older studies have reported
prevalence of stroke as low as 14% and even 5% [20]. While the exact
prevalence of stroke in patients with CCHD unclear, identified risk
factors for stroke in these patients include age, degree of hypoxia, and
longer time to corrective surgery [13,29]. Risk factors that have not
been found to be associated with stroke include degree of erythrocytosis
and hemostatic abnormalities, such as hematocrit, platelet count, iron
status, and thromboelastography [13].
Jensen et al. also studied the prevalence of pulmonary thrombosis in
patients with CCHD and discovered a prevalence of 31% [13]. Pul-
monary artery embolism occurs in up to one third of patients with Ei-
senmenger syndrome [20,21]. Other thromboembolic events include
embolism of vascular stents or catheters [12]. Risk factors identified for
pulmonary embolism include degree of hypoxia, female gender, older
age, and factors related to slower pulmonary blood flow and stasis [21].
As is the case with bleeding, there are many factors that contribute
to the pathogenesis of hypercoagulability in patients with CCHD. Many
coagulation proteins are altered both before and after correction of
their heart lesions and may lead to hypercoagulability. Giglia et al. have
demonstrated that children with CCHD have a decrease in protein C,
antithrombin III, and plasminogen before Fontan surgery and continue
to have decreased protein C after Fontan surgery [12]. Conversely,
Factor VIII has been described as elevated following Fontan surgery. An
etiology for this increase remains unclear, but Odegard et al. report a
positive correlation between Factor VIII levels and central venous
pressure. They hypothesize that elevated central venous pressure sti-
mulates the liver sinusoidal endothelium to produce Factor VIII [30].
Multiple genetic polymorphisms associated with hypercoagulability
3
Progress in Pediatric Cardiology 56 (2020) 101193
have been associated with cyanotic congenital heart disease, including
factor V Leiden and prothrombin gene 20,210 [12]. On the other hand,
polymorphisms in the methylene tetrahydrofolate reductase gene
(MTHFR) were initially thought to predispose patients to coagulopathy
by causing hyperhomocysteinemia, but this notion has since been dis-
credited. Patients with MTHFR polymorphisms have questionably ele-
vated homocysteine and many environmental and physiologic factors
contribute to hyperhomocysteinemia independently of MTHFR geno-
type [31].
As described above, decompensated erythrocytosis leads to hy-
perviscosity and relative iron deficiency anemia. Iron deficiency has
implications on red blood cell deformability. Rather than being a bi-
concave disk, erythrocytes take on a spherical shape about 8 μm in
diameter. In addition to being smaller, the iron-deficient erythrocyte is
also more rigid and less amenable to passing through the micro-
circulation, where the diameter of blood vessels lies between 4 and
6 μm [12]. This ultimately causes hyperviscosity and stasis, a risk factor
for thrombosis in Virchow's triad.
It is important to note that chronic hypoxia also has effects on blood
vessels as well as erythrocytes. Oxygen is a vasodilator; therefore,
chronic hypoxia worsens the size discrepancy between erythrocytes and
blood vessels in the microcirculation. This phenomenon not only causes
hyperviscosity and stasis, but it also causes endothelial damage, an-
other one of the risk factors for thrombosis in Virchow's triad [12,21].
On the other hand, examination of retinal vessels in patients with
chronic cyanosis reveals that they are dilated and tortuous, which has
been associated with retinal vein occlusion [12,32,33]. These changes
seen in the retina may also occur in other areas of the microcirculation
and contribute to blood turbulence, stasis, and ultimately, hypercoa-
gulability.
Chronic hypoxia also leads to polycythemia via increased ery-
thropoietin released from the kidneys [9,21,22]. Mukai et al. describe
that similar feedback appears to occur at the level of the bone marrow
via altered expression of blast cell microRNA. It was found that in pa-
tients with CCHD; Mir-486-3p expression was elevated compared to
controls, diverting hematopoietic stem cell differentiation from the
megakaryocyte lineage to the erythroid lineage. Similarly, there was
also increased expression of mir-486-5p, which upregulates hemato-
poietic stem cell replication, thus increasing the amount of stem cells
available to differentiate into erythrocytes [22]. While this study was
observational, it is significant in that it highlights the multitude of
factors that contribute to erythrocytosis leading to hypercoagulability
as well as thrombocytopenia leading to risk of hemorrhage.
Despite the increased risk of thromboembolism, patients with CCHD
are not given routine anticoagulation because of their simultaneous risk
of bleeding. When thromboembolism occurs, they are treated with
standard anticoagulation similarly to a patient without congenital heart
disease. Standard anticoagulation is reserved for patients who have
recurrent thromboembolic events or who have atrial arrhythmias [21].
As discussed above, phlebotomy is generally avoided until patients have
moderate to severe symptoms and at a higher target hematocrit level of
greater than or equal to 65%, compared with 40 to 45% in other pa-
tients [28]. In general, correction or palliation of the underlying con-
genital heart lesion increases the risk of thromboembolism immediately
after surgery, but the risk of thromboembolism over the long term is
reduced.
7. Conclusion
Secondary erythrocytosis is a life-sustaining response to chronic
hypoxia and is necessary in patients with cyanotic congenital heart
disease. The increase in red blood cell mass has historically been as-
sociated with symptoms of hyperviscosity such as headaches, blurry
vision, and fatigue. Phlebotomy continues to be discouraged by mul-
tiple sources, including the American Heart Association, except in se-
vere circumstances. Alternative explanations for symptoms, such as
J.D. Griesman, et al.
dehydration and iron deficiency, should be sought. Hydroxyurea may
be a viable method of reducing red blood cell mass without causing iron
deficiency, but more research is needed to recommend its use in
common practice. Iron deficiency is very common in patients with
CCHD and iron supplementation is recommended to optimize ery-
throcytosis. Multiple studies have shown that correcting iron deficiency
improves exercise capacity and symptoms that may mimic hy-
perviscosity. Iron supplementation does not lead to increased blood
viscosity. Furthermore, iron deficiency has been found to be an in-
dependent risk factor for stroke in these patients. Iron deficiency is
further exacerbated by repeated blood draws, and an increased
bleeding tendency. Several mechanisms are proposed for increased
bleeding and there are no consensus guidelines for preventing in-
traoperative bleeding. Though thromboembolism is common in these
patients, prophylactic anticoagulation is not recommended.
Declaration of competing interest
None.
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