Subject

Review Polycythem ia
and the Heart
A Review
Paolo Venegoni, MD Thrombosis of the coronary arteries, heart chambers, and great vessels is a complica-
Gerald Cyprus, MD 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
Key words: Heart; coronary Boughton and coworkers6 found in vivo thrombosis to be accompanied by in
thrombosis; myocardial vitro impairment of platelet aggregation, adhesion, and function. Platelet derange-
infarction; polycythemia ments in patients with PV may be profound, although they have not been com-
vera; treatment
pletely elucidated. In these patients, there exists a subgroup of abnormally large
platelets showing evidence of partial activation. This activation could be caused
From: The Department of by collisions among these large platelets, which form microaggregates in the cir-
Internal Medicine, Division
of Cardiology, The University culation. This phenomenon, known as disseminated intravascular platelet aggre-
of Texas at Houston (Dr. gation,6'7 is at least partially responsible for in situ thrombosis in areas of low flow
Venegoni) and the Depart- (for example, in coronary arteries with atherosclerosis).7 In addition, continuous
ment of Internal Medicine,
Division of Hematology, aggregation and disaggregation of platelet microemboli in the circulation impairs
Baylor College of Medicine the release reactions of the platelets.6
(Dr. Cyprus), Houston, Texas In patients with PV, Mehta and colleagues7 found that platelet aggregation was
77030
markedly decreased in the presence of epinephrine. In contrast, the level of
thromboxane A2 in platelets and whole blood was markedly increased. Those
Address for reprints: researchers speculated that endogenous thrombin promotes the generation of
Paolo Venegoni, MD,
6431 Fannin, Room 1.246 thromboxane A2 and prostanoids. Other abnormalities include shortening of fi-
Houston, TX 77030 brinogen half-life, decreased platelet aggregation with adenosine diphosphate and

198 Polycythemia and the Heart 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 Fig. 1 Right anterior oblique view of the left anterior
underlying coronary artery disease.8-'0 Whether the descending coronary artery in a patient with polycythemia
incidence of coronary atherosclerosis is higher in vera and acute-onset chest pain.
such patients is uncertain; the prevalence of hyper- (From: Venegoni FP Schroth G,'7 with permission.)
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 tients with PV,16 perhaps because of the abnormali-
Several potent drugs are now used routinely to ties in platelet adhesion and aggregation. In vitro,
treat acute coronary disease. Heparin and thrombo- aspirin has been shown to be ineffective in inhib-
lytic agents are in common use, and in the near iting the propagation of platelet aggregates.6 No
future newer antithrombin and antiplatelet agents reports of systemic thrombolytic therapy, oral ticlop-
such as hirudin, hirulog, and 7E3 will also be used. idine, or low-molecular-weight heparin in the setting
One of the factors to consider in choosing a therapy of PV and coronary thrombosis have appeared in the
for myocardial infarction in patients with PV is the literature. We, however, have reported a case of in-
increased risk of bleeding associated with the use of tracoronary administration of urokinase without sub-
thrombolytic therapy. sequent bleeding.'7 No studies have been done to
Massive thrombi often develop in patients with PV determine the effectiveness of heparin, thrombolytic
who do not have severe underlying coronary athero- agents, or antithrombin agents in preventing propa-
sclerosis (Fig. 1). Reisner and co-authors'3 have gation of thrombosis. We found several reports of
suggested that embolization to proximal coronary emergency coronary bypass grafting in the literature,
arteries may play a role. This hypothesis has not most of which were successful.18"19
been confirmed by clinical data, partly because of Heart catheterization can cause potentially cata-
the difficulty of evaluating such events. strophic complications in patients with PV. Zinn and
The accepted treatment for acute myocardial in- coworkers'5 reported the case of a patient in whom
farction in a patient with PV is based on exchange acute aortic obstruction occurred after right heart
phlebotomy and platelet pheresis. These therapies catheterization but before the femoral artery was
acutely lower the red blood cell count, the platelet punctured. This case suggests that, if catheterization
count, or both. In some rare cases, however, phle- is to be used, aggressive anticoagulation is neces-
botomy can cause potentially life-threatening com- sary. It is unclear how to prevent further clotting,
plications. Kiraly and colleagues'4 have reported the since aspirin and Persantine appear to be ineffective
occurrence of myocardial infarction and cardiovas- and heparin has not been systematically evaluated.
cular collapse after routine phlebotomy with inad- Therefore, elective catheterization should be de-
equate fluid and electrolyte replacement. ferred until after 4 to 6 months of myelosuppressive
To date, there have been no controlled studies in therapy. 16
patients with PV to assess how other therapies com- In the future, more specific antithrombotic and
pare with exchange phlebotomy and platelet phe- antiplatelet agents may prove useful in treating pa-
resis or phlebotomy alone. Experience has shown, tients with thromboses, particularly those with PV or
however, that agents such as heparin are clinically other blood dyscrasias that cause profound altera-
ineffective.15 Curiously, aspirin, an antiplatelet agent, tions in platelets, such as essential thrombocytosis
does not appear to improve clinical outcome for pa- or the myelodysplastic syndromes.

Texas Heart Instituteiournal Polycythemia and the Heart 199

 Combining acute intervention with exchange benefit from immediate catheterization, thrombolytic
phlebotomy may be an appropriate comproimiise be- therapy, or both. The availability of catheterization
tween the increased risk of bleeding and the neces- laboratories and highly trained physicians and staff
sity of dealing with acute coronary thrombosis (Figs. offers the best chance for successful treatment of
2 and 3). The appropriateness of intravenous throm- these gravely ill patients.
bolytic agents depends on the location of ischemic
injury and the area at risk. For example, regardless Intracardiac Involvement
of the increased risk of bleeding, reperfusion should Thrombus formation in the cardiac chambers is ex-
be attempted and anticoagulants sshould be given to tremely rare, except in the presence of predisposing
patients with acute anterior myocardial infarction. factors such as myocardial muscular impairment,
We think that patients with acute myocardial infarc- atrial fibrillation, or chamber dilatation.
tion and hematological abnormalities who are pre- Ali and associates2' reported the case of a PV pa-
disposed to both bleeding and thrombosis might tient with intractable cardiac failure in whom an
endothelialized thrombus occupying 75% of the left

F. 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
Fig. 2 Right anterior oblique view of the left anterior Reisner and colleagues'" performed transthoracic
descending coronary artery after intracoronary administration
of thrombolytic agents. 2-dimensional and Doppler echocardiography in 30
patients with myeloproliferative disorders, 19 (63%)
(From: Venegoni FP Schroth G, II with permission.)
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-
Fig. 3 Right anterior oblique view of the left anterior raphy would probably provide clarification.
descending coronary artery after emergency percutaneous
transluminal coronary angioplasty Aortic Involvement
(From: Venegoni fP Schroth G, 17 with permission.) Although PV affects primarily small- and medium-
sized vessels, acute thrombosis of a major arterial

200 Polycythemia and the Heart Vblume 21, Number3, 1994

conduit can occur. Acute aortic obstruction in a pa- 10. Barr I, Cohen P, Berken A, Lown B. Thrombocythemia and
tient with PV, although rare, can be life-threatening. myocardial ischemia with normal coronary angiogram. Arch
Acute abdominal aortic obstruction has been ob- Intern Med 1974;134:528-33.
11. Benjamin D, Yeshurun D, CharnilasJ. Pinkhasj. Hyperlipild-
served during catheterization in patients with PV.'523 emia and myocardial infarction among 118 patients with
Josephson and co-authors24 reported the case of 1 polycythemia vera. Am j Med Sci 1978;276:23-6.
such patient in whom a free-floating thrombus in the 12. Cheitlin MD, McAllister HA, de Castro CM. Myocardial
descending thoracic aorta caused extensive embo- infarction without atherosclerosis. JAMA 1975;231:951-9.
lization to the femoral and superior mesenteric ar- 13. Reisner SA, Rinkevich D, Markiewicz W, Tatarsky I, Brenner
teries. In this case the patient underwent successful B. Cardiac involvement in patients with myeloproliferative
disorders. Am J Med 1992;93:498-504.
emergency intraabdominal surgery with thrombec- 14. KiralyJF III, FeldmannJE, Whehy MS. Hazards of phlebotomy
tomy. It is difficult to determine whether systemic or in polycythemic patients with cardiovascular disease. JAMA
local thrombolysis might have been a useful alterna- 1976;236:2080-1.
tive. 15. Zinn P, Applegate RJ, Walsh RA. AcuLte total aortic occlusion
during cardiac catheterization associated with polycythemia
vera. Cathet Cardiovasc Diagn 1988;14: 108-10.
Pulmonary Artery Involvement 16. Tartaglia AP, GoldbergJD, Silverstein MN, Dresch C, Tatarsky
Pulmonary artery hypertension is a common find- I, Pisciotta AV, et al. Aspirin and Persantine do not prevent
ing in PV, occurring in up to 13% of patients,'3 and thrombotic complications in patients with polycythemia vera
is probably related to thrombotic pulmonary venous treated with phlebotomy. Blood 1981;58(Suppl I):240a.
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mia vera: how should we treat it? Cathet Cardiovasc L)iagn
routine studies, the presence of pulmonary venous 1994;32:259-61. Copyright 1994; Wiley-Liss, Inc., a subsid-
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for coronary thrombosis complicating polycythaemia rUbra
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22. Libman E, Sacks B. A hitherto undescribed form of valvUlar
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