Subject
Review
Paolo Venegoni, MD
Gerald Cyprus, MD
Key words: Heart; coronary
thrombosis; myocardial
infarction; polycythemia
vera; treatment
From: The Department of
Internal Medicine, Division
of Cardiology, The University
of Texas at Houston (Dr.
Venegoni) and the Depart-
ment of Internal Medicine,
Division of Hematology,
Baylor College of Medicine
(Dr. Cyprus), Houston, Texas
77030
Address for reprints:
Paolo Venegoni, MD,
6431 Fannin, Room 1.246
Houston, TX 77030
198 Polycythemia and the Heart
Polycythem ia
and the Heart
A Review
Thrombosis of the coronary arteries, heart chambers, and great vessels is a complica-
tion of polycythemia. Previously, the treatment of coronary thrombosis in the presence
of this disease was based on exchange phlebotomy. However, the development of effi-
cient thrombolytic agents, emergency catheterization techniques, and coronary artery
bypass surgery may make phlebotomy obsolete. (Texas Heart Institute Journal 1994;
21:198-201)
In 1903, Oslerl was the first to describe the myeloproliferative disorder, poly-
cythemia vera (PV). Although the prevalence of PV is low (4 to 16 per mil-
lion)2 patients with PV often require cardiologic treatment. Thrombosis is the
most serious complication of PV; but treatment can prove difficult, particularly
in the presence of bleeding, which is another complication of this disease. Most
often, thrombosis occurs in the cerebral circulation, but it can appear anywhere
in the arterial tree, including the heart.3 Exchange phlebotomy has been the main
treatment of coronary thrombosis in the presence of PV. Still, PV often causes
death.
Thrombolytic agents and interventional techniques have revolutionized rou-
tine treatment of acute coronary thrombosis, but such therapy must be ap-
proached judiciously in patients with PV because of the coexistence of thrombosis
and bleeding. This article describes the types of complications in PV that affect
the heart and reviews potential treatments.
Bleeding and Thrombosis
Polycythemia vera differs from other forms of polycythemia, such as that caused
by smoking.4 In addition to altering the platelet and red blood cell counts, PV can
cause both bleeding and thrombosis in the same patient.5 Thrombocytosis is
present in about 50% of patients with PV. Quantitative platelet derangements may
play a major role in the development of thrombosis and ischemia and thus pre-
cipitate a stroke, peripheral arterial or venous thrombosis, or myocardial infarc-
tion. Platelet abnormalities may also predispose the patient to bleeding at virtually
any site. Studies have shown that these patients may have a bleeding diathesis.2'5
Boughton and coworkers6 found in vivo thrombosis to be accompanied by in
vitro impairment of platelet aggregation, adhesion, and function. Platelet derange-
ments in patients with PV may be profound, although they have not been com-
pletely elucidated. In these patients, there exists a subgroup of abnormally large
platelets showing evidence of partial activation. This activation could be caused
by collisions among these large platelets, which form microaggregates in the cir-
culation. This phenomenon, known as disseminated intravascular platelet aggre-
gation,6'7 is at least partially responsible for in situ thrombosis in areas of low flow
(for example, in coronary arteries with atherosclerosis).7 In addition, continuous
aggregation and disaggregation of platelet microemboli in the circulation impairs
the release reactions of the platelets.6
In patients with PV, Mehta and colleagues7 found that platelet aggregation was
markedly decreased in the presence of epinephrine. In contrast, the level of
thromboxane A2 in platelets and whole blood was markedly increased. Those
researchers speculated that endogenous thrombin promotes the generation of
thromboxane A2 and prostanoids. Other abnormalities include shortening of fi-
brinogen half-life, decreased platelet aggregation with adenosine diphosphate and
Volume 21, Number 3, 1994
collagen, and elevated levels of plasma and platelet
f-thromboglobulin.2 Unfortunately, these indices of
platelet function correlate poorly with clinical mani-
festations of disease, including bleeding and throm-
bosis. The tests currently available to the clinician
are not helpful in patients with PV: prothrombin
time, partial thromboplastin time, activated clotting
time, and bleeding time are all normal, even in the
presence of hemorrhagic manifestations, and re-
spond predictably to medications known to alter
such parameters (for example, heparin, warfarin,
and aspirin).7
Coronary Involvement
Myocardial infarction and sudden death are compli-
cations of newly diagnosed or untreated PV; they
occur most often in elderly people (.65 years) with
underlying coronary artery disease.8-'0 Whether the
incidence of coronary atherosclerosis is higher in
such patients is uncertain; the prevalence of hyper-
lipidemia, however, is higher and it is related to re-
peated phlebotomies." Younger patients with PV
who are free from coronary artery disease can also
be affected, and sometimes the outcome is death.8"12
Several potent drugs are now used routinely to
treat acute coronary disease. Heparin and thrombo-
lytic agents are in common use, and in the near
future newer antithrombin and antiplatelet agents
such as hirudin, hirulog, and 7E3 will also be used.
One of the factors to consider in choosing a therapy
for myocardial infarction in patients with PV is the
increased risk of bleeding associated with the use of
thrombolytic therapy.
Massive thrombi often develop in patients with PV
who do not have severe underlying coronary athero-
sclerosis (Fig. 1). Reisner and co-authors'3 have
suggested that embolization to proximal coronary
arteries may play a role. This hypothesis has not
been confirmed by clinical data, partly because of
the difficulty of evaluating such events.
The accepted treatment for acute myocardial in-
farction in a patient with PV is based on exchange
phlebotomy and platelet pheresis. These therapies
acutely lower the red blood cell count, the platelet
count, or both. In some rare cases, however, phle-
botomy can cause potentially life-threatening com-
plications. Kiraly and colleagues'4 have reported the
occurrence of myocardial infarction and cardiovas-
cular collapse after routine phlebotomy with inad-
equate fluid and electrolyte replacement.
To date, there have been no controlled studies in
patients with PV to assess how other therapies com-
pare with exchange phlebotomy and platelet phe-
resis or phlebotomy alone. Experience has shown,
however, that agents such as heparin are clinically
ineffective.15 Curiously, aspirin, an antiplatelet agent,
does not appear to improve clinical outcome for pa-
Texas Heart Instituteiournal
Fig. 1 Right anterior oblique view of the left anterior
descending coronary artery in a patient with polycythemia
vera and acute-onset chest pain.
(From: Venegoni FP Schroth G,'7 with permission.)
tients with PV,16 perhaps because of the abnormali-
ties in platelet adhesion and aggregation. In vitro,
aspirin has been shown to be ineffective in inhib-
iting the propagation of platelet aggregates.6 No
reports of systemic thrombolytic therapy, oral ticlop-
idine, or low-molecular-weight heparin in the setting
of PV and coronary thrombosis have appeared in the
literature. We, however, have reported a case of in-
tracoronary administration of urokinase without sub-
sequent bleeding.'7 No studies have been done to
determine the effectiveness of heparin, thrombolytic
agents, or antithrombin agents in preventing propa-
gation of thrombosis. We found several reports of
emergency coronary bypass grafting in the literature,
most of which were successful.18"19
Heart catheterization can cause potentially cata-
strophic complications in patients with PV. Zinn and
coworkers'5 reported the case of a patient in whom
acute aortic obstruction occurred after right heart
catheterization but before the femoral artery was
punctured. This case suggests that, if catheterization
is to be used, aggressive anticoagulation is neces-
sary. It is unclear how to prevent further clotting,
since aspirin and Persantine appear to be ineffective
and heparin has not been systematically evaluated.
Therefore, elective catheterization should be de-
ferred until after 4 to 6 months of myelosuppressive
therapy. 16
In the future, more specific antithrombotic and
antiplatelet agents may prove useful in treating pa-
tients with thromboses, particularly those with PV or
other blood dyscrasias that cause profound altera-
tions in platelets, such as essential thrombocytosis
or the myelodysplastic syndromes.
Polycythemia and the Heart 199
 Combining acute intervention with exchange
phlebotomy may be an appropriate comproimiise be-
tween the increased risk of bleeding and the neces-
sity of dealing with acute coronary thrombosis (Figs.
2 and 3). The appropriateness of intravenous throm-
bolytic agents depends on the location of ischemic
injury and the area at risk. For example, regardless
of the increased risk of bleeding, reperfusion should
be attempted and anticoagulants sshould be given to
patients with acute anterior myocardial infarction.
We think that patients with acute myocardial infarc-
tion and hematological abnormalities who are pre-
disposed to both bleeding and thrombosis might
F.
Fig. 2 Right anterior oblique view of the left anterior
descending coronary artery after intracoronary administration
of thrombolytic agents.
(From: Venegoni FP Schroth G, II with permission.)
Fig. 3 Right anterior oblique view of the left anterior
descending coronary artery after emergency percutaneous
transluminal coronary angioplasty
(From: Venegoni fP Schroth G, 17 with permission.)
200 Polycythemia and the Heart
benefit from immediate catheterization, thrombolytic
therapy, or both. The availability of catheterization
laboratories and highly trained physicians and staff
offers the best chance for successful treatment of
these gravely ill patients.
Intracardiac Involvement
Thrombus formation in the cardiac chambers is ex-
tremely rare, except in the presence of predisposing
factors such as myocardial muscular impairment,
atrial fibrillation, or chamber dilatation.
Ali and associates2' reported the case of a PV pa-
tient with intractable cardiac failure in whom an
endothelialized thrombus occupying 75% of the left
ventricular chamber was found. Hendler and col-
leagues2' reported a massive right atrial thrombosis
in a patient with PV in whom a permanent pace-
maker had been implanted 2 years earlier. Those
authors speculated that several cases of congestive
heart failure and eventual death in patients with PV
have actually been caused by clot formation in a car-
diac chamber. Diagnostic procedures such as echo-
cardiography, however, were not performed in these
patients, and their deaths were attributed to other
causes. Therefore, caution is recommended when
inserting pacemakers or vascular indwelling cath-
eters in patients with PV. Although it substantially
increases the risk of bleeding, anticoagulation is
probably necessary in these patients.
Valvular Involvement
Reisner and colleagues'" performed transthoracic
2-dimensional and Doppler echocardiography in 30
patients with myeloproliferative disorders, 19 (63%)
of whom had cardiac valvular abnormalities. Of the
patients with PV, 7800 (14/18) had valvular lesions.
Overall, in 40% (12/30) of the patients, echocardi-
ography showed a thickening of the valve leaflets,
particularly in the mitral and aortic valves. Interest-
ingly, vegetations resembling those encountered in
Libman-Sacks endocarditis22 were also present in
17% (5/30) of cases. At least 1 episode of systemic
thromboembolism was documented in 63% (12/19)
of the patients with valvular abnormalities, whereas
only 18% (2/11) without valvular abnormalities had
clinical evidence of embolization. In a control group
of patients with idiopathic systemic thromboembo-
lism but no PV, only 4.5% (1/22) of the patients had
valvular abnormalities. Because of the small number
of patients studied, it is difficult to determine the
prevalence and etiology of cardiac valvular abnor-
malities in patients with PV. Routine echocardiog-
raphy would probably provide clarification.
Aortic Involvement
Although PV affects primarily small- and medium-
sized vessels, acute thrombosis of a major arterial
Vblume 21, Number3, 1994
conduit can occur. Acute aortic obstruction in a pa-
tient with PV, although rare, can be life-threatening.
Acute abdominal aortic obstruction has been ob-
served during catheterization in patients with PV.'523
Josephson and co-authors24 reported the case of 1
such patient in whom a free-floating thrombus in the
descending thoracic aorta caused extensive embo-
lization to the femoral and superior mesenteric ar-
teries. In this case the patient underwent successful
emergency intraabdominal surgery with thrombec-
tomy. It is difficult to determine whether systemic or
local thrombolysis might have been a useful alterna-
tive.
Pulmonary Artery Involvement
Pulmonary artery hypertension is a common find-
ing in PV, occurring in up to 13% of patients,'3 and
is probably related to thrombotic pulmonary venous
occlusion. Although often difficult to ascertain by
routine studies, the presence of pulmonary venous
occlusion should be considered in a patient with PV
who has unexplained right heart failure.
Conclusion
Cardiac involvement is a common complication of
PV. The treatment of this often life-threatening con-
dition is difficult. Modern treatment of acute throm-
bosis is evolving rapidly. Whether new modalities
are appropriate for patients with PV is yet to be
established.
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Polycythemia and the Heart 201