JOURNAL OF THE

NEUROLOGICAL
SCIENCES
ELSEVIER Journal of the Neurological Sciences 140(I 996) I -11

Review article

Hematologic disorders associated with ischemic stroke

Turgut Tatlisumak a3b3
* , Marc Fisher aqc3d
’ Department cf Neurolog.~, The Medical Center of Central Massachusetts-Memorial. I19 Belmont Street, Worcester, MA, USA
h Department of Neurology. Helsinki Unicersir?; Central Hospital, Helsinki, Finland
’ Department of Neurology. University of Massachusetts Medical School, Worcester, MA, USA
’ Department of Radiology. UrGersi of Massachusetts Medical School, Worcester, MA, USA
Received 26 October 1995;revised 22 January 1996;accepted 17 February 1996

Abstract

Hematological disorders underlie a small proportion of all ischemic strokes. The association of these coagulation abnormalities with
ischemic stroke is not always clear. The etiology of stroke still remains uncertain in a large number of cases and proper screening for
coagulation abnormalities and the discovery of new coagulation disorders will probably increase the rate of strokes attributable to these
causes. Since large case-control studies with unselected and consecutive stroke patients from different ethnic origins have not yet been
performed to determine the role of coagulation abnormalities in ischemic stroke, our knowledge is dependent on case reports and small
series of mostly younger patients. Extensive hematologic evaluation of unselected stroke patients will likely yield little useful information
and be too expensive. Every stroke patient needs a careful evaluation, and in selected cases, this should include coagulation parameters.
Patients with unexplained strokes after a careful evaluation, previous thrombotic episodes, or a positive family history for thrombosis, are
good candidates for further coagulation studies. As long as the hypercoagulable state persists, both arterial and venous thromboembolic
recurrences can be expected. Many of these patients may benefit from anticoagulants. In patients with hereditary coagulation disorders,
studies should be extended to close relatives. Since some coagulation tests are fairly expensive, provide only equivocal data, and are not
widely available, we advise a step-by-stepapproach starting with the patient and family history.

Keywords: Ischemic stroke; Coagulation: Thrombosis; Anticoagulant; Hypercoagulable state; Heparin; Warfarin; Antiphospholipid

1. Introduction injury) (Virchow, 1856). Hemostusis is the arrest of hem-

In healthy individuals blood flow proceeds in vessels
without interruption to deliver essential nutrients to target
organs. The very delicate balance between the coagulant
and the anticoagulant systems assures the fluidity of circu-
lating blood. A healthy person may develop subclinical
microclots in response to different kinds of injuries. These
microclots are rapidly degradated by fibrinolytic activity,
thus not causing clinical syndromes. Several conditions,
however, may disturb this homeostasis and lead to patho-
logical thrombosis.
In 1845, Virchow described his famous triad including
the three major causes of thrombosis: (1) changes in blood
flow (e.g., stasis), (2) changes in the circulating blood
(e.g., excess of coagulants and/or deficiencies of antico-
agulants), and (3) changes in the vessel wall (e.g., vascular
’ Corresponding author. Fax: + I (508) 793-6695.
orrhage at sites of vascular injury by various means,
including clot formation and platelet deposition, with sub-
sequent restoration of perfusion by fibrinolysis (Nathwani
and Tuddenham, 1992). Blood should clot extremely
rapidly to prevent exsanguination and yet preserve liquid-
ity in the circulation. Excessive activity of the coagulation
system and/or insufficient activity of the fibrinolytic sys-
tem may cause abnormal coagulation in venous or arterial
circulations. Patients at increased risk for thrombosis have
been termed as having a hypercoagulable state (Bick and
Pegram, 1994). More precisely, hypercoagulubility is “a
state in which a clearly identified alteration or alterations
of the blood tend to shift the hemostatic balance to inap-
propriate or excessive platelet/fibrin deposition and lead
to arterial and/or venous thrombosis in response to vascu-
lar injury that would not trigger thrombus formation under
normal circumstances” (Joist, 1990). Prothrombotic state
is recognized as being associated with an increased inci-
dence of thrombosis, but the specific mechanisms leading

0022-510X/96/$15.00 Copyright 0 1996 Elsevier Science B.V. All rights reserved.

PII SOO22-510X(96)00051-2
to thrombosis remain unclear (Schafer. 1985). ‘Thrombo-
sis-prone’ is an individual having recurrent thrombotic
events, yet without recognizable predisposing factors
(Schafer, 1985). These conditions can be hereditary or
acquired, permanent or temporary.
Blood coagulation is triggered most commonly by a
vascular injury that is followed by excessive adhesion and
aggregation of platelets to the injury site and a local
vasospasm to reduce bleeding. The aggregation of platelets
results in a platelet plug providing immediate hemostasis,
though this plug is unstable. The coagulation system re-
sponds to the injury in a complex manner and after a long
cascade of reactions involving several factors, a more
stable plug, formed of fibrin filaments, will strengthen the
loose platelet thrombus. Thus, the final aim of the coagula-
tion system is to form a sufficiently large and durable
fibrin-platelet plug at the site of injury which gives time
for vascular endothelial repair. The natural anticoagulants
(antithrombin III, proteins C and S) will oppose uncon-
trolled fibrin formation. and limit the thrombus to the
injury site. Later, plasmin, cleaved from its zymogen,
plasminogen, by tissue plasminogen activator (t-PA), will
break the long fibrin molecules into water-soluble fibrin-
degradation products and demolish the plug. The vascular
lining helps to maintain the blood circulation by secreting
substances such as prostacyclin, von Willebrand factor,
nitric oxide and t-PA. Endothelial cells have a negative
surface charge that may serve to repel platelets, that are
also negatively charged.
Hematologic disorders account for the etiology of O-89
of all ischemic strokes and are somewhat more common in
younger stroke patients (Hart and Miller, 1983; Adams et
al.. 1986; Bogousslavsky et al.. 1988; Sandercock et al.,
1989; Lisovoski and Rousseaux, 1991). More than a dozen
primary hematologic disorders are associated with is-
chemic stroke (Hart and Kanter. 1990). Many ischemic
stroke patients with hematologic disorders may also have
other etiologic factors, making a cause-and-effect relation-
ship problematic.
In a considerable percentage of ischemic stroke patients
the etiology cannot be determined even after extensive
ancillary studies. Studies with younger stroke patients
demonstrate higher percentages of coagulation abnormali-
ties. possibly due to the lack of classic risk factors and
atherosclerosis in younger populations. Various authors
reported strikingly different numbers for stroke of undeter-
mined etiology depending on the selected patient popula-
tion (mostly age). diagnostic criteria. and the extensiveness
of studies. The rates vary from 4.2% (Bevan et al.. 1990)
to 458 (Grindal et al.. 1978). but typically represent about
20% of the total (Synder and Ramirez-Lassepas. 1980:
Lisovoski and Rousseaux. 199 I; Bogousslavsky, 1992). In
all these studies. patients were well-studied, thus all known
etiologic factors and risk factors were carefully excluded.
Patients with undetermined stroke etiology appear to be
good candidates for further hematologic studies and with
our expanding knowledge, probably new hematologic dis-
orders underlying stroke will be discovered.
2. Disorders of natural anticoagulants
Natural anticoagulants form a group of four distinct
molecules (heparin cofactor II, antithrombin III, protein C,
and protein S). Their role is to inhibit thrombosis. Defi-
ciencies of these natural anticoagulants may be hereditary
or acquired. Altogether these deficiencies are responsible
for approx. 20% of nontraumatic venous thromboem-
bolisms (Tuddenham, 19931, although their role in arterial
thrombosis remains unclear. Two studies, one retro-
spective, failed to document deficiencies in these natural
anticoagulant proteins in stroke patients (Mettinger et al.,
1979; Chancellor et al., 1989).
The natural anticoagulants can be assayed by both
functional and immunologic methods. Functional assays
can be performed using clotting or chromogenic methods,
and immunologic assays using either enzyme-linked im-
munosorbent assay (ELISA) or Laurel1 rocket assays. In
general, when screening for deficiencies of these natural
anticoagulant proteins, it is best to use a functional assay
first, so that both true deficiencies and dysproteinemias are
detected. Use of immunologic assays alone will fail to
detect many dysproteinemias (Kottke-Marchant, 1994).
Heparin c&ctor II has probably only a minor role in
venous thrombosis (Sic et al., 1985; Anderson et al., 1987;
Bertina et al., 1987). Furthermore, even though the defi-
ciency was first described in a stroke patient (Tran et al.,
l985), convincing data do not exist about its role in arterial
thrombosis.
Antithrombin III (AT III) is a plasma glycoprotein with
a molecular mass of about 58000 Da, synthesized in
hepatocytes and endothelial cells (Lane and Caso, 1989). It
is a primary physiologic inhibitor of thrombin and other
activated serine proteases including factors Xa, XIa, IXa,
and XIIa and kallikrein (Bick and Ucar, 1992; Bick and
Pegram, 1994). The gene for AT III is located on chromo-
some I (Bock et al.. 1985). AT III deficiency may be
congenital or acquired. Congenital AT III deficiency is
inherited as an autosomal dominant trait (Lane and Caso.
1989). In Type I deficiency. the plasma level is quantita-
tively low. on the contrary to Type II deficiency where the
plasma level is normal, but the molecule is dysfunctional.
Deficiency of AT III in the general population was esti-
mated as one in 2000 (Rosenberg, 1975) to 5000 (Odegaard
and Abildgaard, 1978). Thrombotic events have been re-
ported in patients with AT III levels as high as 70% of
normal (Bick, 1982). An acquired deficiency state can be
caused by severe hepatic failure, the nephrotic syndrome,
oral contraceptive use. heparin therapy. disseminated in-
travascular coagulation (DIG), surgery, aging. malnutri-
tion, diabetes and leukemia (Hathaway, 199 I ). Heparin
instantaneously increases AT III activity about 200 times
 T. Tutlisumnk, M. Fisher/Journul of the Neurologicd Sciences 140 (19961 I-l I

(Griffith, 1982). Heparin therapy will rapidly decrease AT

III plasma levels and the plasma level will normalize 2-3
days after cessation of heparin (Hart and Kanter, 1990).
Patients with AT III deficiency have a high risk of
developing venous thrombosis that increases with age.
More than 85% of patients will develop thrombosis by age
of 50; thrombosis is recurrent in 60% and clinical signs of
pulmonary embolism occur in 40% of patients (Menache,
199 I>. An initial thrombotic event at an early age (i.e.,
under 40 years old), family history of thromboembolism,
recurrent venous thrombosis, unusual sites like mesenteric
or cerebral veins, thrombosis during pregnancy and resis-
tance to heparin therapy should lead to suspicion of AT-III C&-binding protein
deficiency (Hirsh, 1989).
Several case reports indicated an association between
AT III deficiency and ischemic stroke (Vomberg et al.,
1987; Ben-Tal et al., 1989; Simioni et al., 1992; Martinez
et al., 1993; Barinagarrementeria et al., 1994). AT III
deficiency can also cause cerebral venous thrombosis,
venous infarctions and associated bleeding.
In the treatment of acute thrombotic disease with AT III
deficiency, heparin alone is not sufficient, because it needs
antithrombin to achieve its anticoagulant activity. Long- Fig. I. The protein C anticoagulant pathway. Thrombin converts factors
term treatment with warfarin is indicated following initial VIII and V to their activated forms. Thrombin-thrombomodulin complex
activates protein C. Activated protein C (APC) inactivates FVIIIa and
heparin therapy. It is not known yet if lifelong anti-
FVa. Protein S accelerates this reaction (copied with slight modification
coagulant therapy is indicated, but this approach should be from Bauer (1994) with prior written permission of the author and the
considered, depending on the severity of the condition, publisher).
recurrences, family history and the patient’s overall medi-
cal condition. Replacement therapy with the injection of
AT III concentrates has been encouraging (Menache, 1992) in individuals as a consequence of aging, the use of
and may become a routine therapy, especially when a contraceptives, pregnancy, and smoking (High, 1988).
deficient person is at high risk of thrombosis (e.g., preg- PC synthesis is encoded by a single gene located on
nancy, surgery, delivery, major trauma). chromosome 2 (Miletich, 1990). PC is converted to its
Protein C (PC) is a vitamin K-dependent zymogen of a activated form by thrombin (Stenflo, 1984). The natural
plasma serine protease that inactivates clotting factors Va anticoagulant function of PC is mediated by inactivation of
and VIIIa and enhances fibrinolysis (Clause and Comp, factors Va and VIIIa (Fig. I). PC has profibrinolytic
1983; Bick and Ucar, 1992). PC is synthesized in hepato- functions via antagonism of plasminogen activator in-
cytes and has a molecular weight of about 56000 daltons hibitor-l (PAI- protein (Coull and Clark, 1993). Throm-
(Bick and Ucar, 1992). Hereditary defects of PC are bolytic therapy is associated with generation of activated
inherited in an autosomal dominant fashion. Congenital PC PC (Gruber et al., 1993). Activity of PC is markedly
deficiency may account for up to 6- 10% of patients enhanced by protein S, another vitamin K-dependent natu-
presenting with venous thrombosis or pulmonary embolus. ral anticoagulant (Walker. 1984).
Congenitally deficient heterozygotes with 2S-50% of nor- There are numerous reports of stroke cases associated
mal antigenic levels were found in one of 200-300 unse- with PC deficiency (Israels and Seshia. 1987: Grewal and
lected blood donors (Miletich et al.. 19871. Symptomatic Goldberg, 1990; Haire and Newland. 1990; Kohler et al..
deficiency is far less common. perhaps as low as one in 1990: Camerlingo et al., 1991; Simioni et al., 1992: Dev-
36000 (Gladson et al., 1988). Deficiency of PC can be ilat et al., 1993; Martinez et al., 1993; Barinagarrementeria
recognized by a low concentration of the protein (e.g. et al., 1994). In the acute stage of stroke, low plasma
50%) or by low functional activity (Bertina, 1985). Arte- levels of PC probably reflect acute consumption, because
rial thrombosis has only rarely complicated hereditary PC in acute thrombotic disease both ongoing blood coagula-
deficiency (Coller et al.. 1987). Acquired PC deficiency tion and fibrinolysis cause changes in hemostatic variables.
occurs in patients with extensive thrombosis, severe liver There is not much experience on the management of
disease, the nephrotic syndrome, DIC syndrome, acute patients with PC deficiency and ischemic stroke. Long-term
respiratory distress, in the postoperative period. and in anticoagulant therapy with warfarin seems to be a reason-
patients receiving warfarin (Hart and Kanter, 1990; Bick able approach until more data are available. Alternatively,
and Ucar, 1992). A mild acquired deficiency is also seen long-term low-dose subcutaneous heparin may be used.
 Protein C concentrates have recently been developed for
the treatment of deficiency states.
Protein S (PS) is a vitamin K-dependent plasma glyco-
protein of about 70000 Da which serves as a cofactor for
activated PC. PS is synthesized primarily in liver and
encoded on chromosome 3. In plasma, about 60% of PS is
bound to a C4b binding protein (C4b-BP) and 40% is in
free form that is active. The free and bound forms of PS
are in equilibrium. The prevalence of PS deficiency is one
in 1.5000 to 20000 (Broekmans et al., 1986). The inheri-
tance is autosomal dominant. Hereditary PS deficiency is
recognized by a low (e.g., 50%) concentration or by low
functional activity on laboratory assays (Bertina, 1985).
Total PS is very low in the newborn, but free PS, although
lower than in adults, comprises most of the PS present,
because of very low levels of C4b-BP in the newborn
(Maim et al., 1986). Women have lower levels of PS than
men (Boerger et al., 1987). PS deficiency is responsible for
at least 5% of unexplained venous thrombotic episodes
(Gladson et al., 1988). Acquired PS deficiency occurs in
liver disease, DIC, during warfarin treatment, high dose
estrogen therapy, type I diabetes mellitus, pregnancy,
post-partum period, and in acute phase of thrombosis
(Nathwani and Tuddenham, 1992). Low PS levels with
war-farm treatment, pregnancy, and acute thrombotic events
should not be interpreted as true PS deficiency, but mea-
surements should be repeated later when the initiating
event is over.
Several case reports and small series found an associa-
tion between ischemic stroke and PS deficiency (Israels
and Seshia, 1987; Sie et al., 1989; Davous et al., 1990;
Green et al., 1992; Devilat et al., 1993; Martinez et al.,
1993; Barinagarrementeria et al., 1994). Sacco et al. (1989)
reported low free protein S levels in 20% of ischemic
stroke patients, but this probably only reflected an acute
phase response to thromboembolic disease. The authors
did not report follow-up or family studies. Their later
report (Mayer et al., 1993) showed a 20% incidence of low
free PS levels among hospitalized patients for reasons
other than stroke, thus the finding is not limited to stroke
patients. Treatment for ischemic stroke due to PS defi-
ciency is similar to PC.
Acticated protein C (APC) resistance is a recently
described hypercoagulable state (Dahlblck et al., 1993)
due to a single point mutation of the factor V gene on
chromosome I (Bertina et al., 1994). This mutation changes
the molecular configuration of factor V, so that APC
cannot inactivate it properly (Fig. 1). About 20% of all
venous thrombosis patients carry this mutation (Griffin et
al., 1993; Koster et al., 1993; Svensson and Dahlbick,
1994; Ridker et al., 1995), making this defect alone as
important as the sum of all anticoagulant protein deficien-
cies. In one study, APC resistance was found in 6 out of
30 young stroke patients (Halbmayer et al., 19941, but
another report with 15 patients did not support this finding
(Cushman et al., 1994). In a study from Helsinki, among
236 cerebral infarction and transient ischemic attack pa-
tients younger than 60, the mutation was found in 9 (3.8%)
and in only one (1.1%) of 87 controls (Kontula et al.,
1995). Ridker et al. (1995) found this mutation in 4.3% of
209 male stroke patients and 6% of healthy subjects. We
studied 99 consecutive non-cardiac ischemic stroke pa-
tients and observed similar results (Tatlisumak et al., 1995)
to Ridker et al. (1995). Furthermore, a recent report includ-
ing 161 elderly stroke patients ended with the same con-
clusion (Press et al., 1996). APC resistance is not likely to
be of major importance in the pathogenesis of ischemic
stroke; however, it may be the cause of stroke in rare
individuals (Simioni et al., 1995) or in young patients with
cryptogenic stroke (Halbmayer et al., 1994; Chimowitz et
al., 1996).
Wu$arin-induced skin necrosis is a rare, but serious
complication of oral anticoagulant therapy more common
among females and in patients with deficits of natural
anticoagulants. The pathogenesis is unclear and no therapy
has been proven to be beneficial. When indicated, starting
warfarin during heparin therapy and with small doses may
lower its incidence. The first symptom is usually localized
pain followed by a petechial rash and ecchymosis. The
final event is widespread full-thickness skin necrosis. If
any of these symptoms appear during warfarin therapy, the
drug should be immediately discontinued, vitamin K should
be injected parenterally, and heparin should be initiated or
continued (Eby, 1993).
3. Antiphospholipic antibodies
Antiphospholipid antibodies (aPL) are a heterogeneous
group of circulating serum polyclonal (IgG, IgM, IgA or
mixed) immunoglobulins that bind negatively charged or
neutral phospholipids. Lupus anticoagulant (LA) and anti-
cardiolipin antibodies (aCL) are the most important mem-
bers of this family leading to both venous and arterial
thrombosis. Arterial thrombosis tends to involve primarily
cerebral vasculature. aPL are present in both young and
elderly healthy people (El-Roeiy and Gleicher, 1988; Fields
et al., 1989). Population studies suggest a prevalence of
2-5% in healthy people (Coull et al., 1992). Systemic
lupus erythematosus is strongly associated with aPL (Love
and Santoro, 1990). In the absence of any autoimmmune
disease, the syndrome including the presence of aPL and
thrombotic events is called primary aPL syndrome.
aPL may lead to a hypercoagulable state by several
distinct mechanisms including antagonism of prostacyclin
production (Carreras and Veraylan, 1982), inhibition of
protein C anticoagulant pathway (Cariou et al., 19881,
complement activation (Davis and Brey, I99 1) and per-
haps fibrinolytic dysfunction (Tsakiris et al., 1989). aPL
antibodies were found in 1% (Montalban et al., 1994) to
46% (Brey et al., 1990) of stroke patients, depending on
the design and criteria of studies and the age distribution
 T. Tatlisumak, M. Fisher/Journal
of patients. About 10% is most likely, as indicated in the
APAS Study (APASS Group, 1993). The aCL syndrome
seems to be 5-6 times more common than LA syndrome
(Bick and Baker, 1994). Both small- and large-vessel
occlusive disease have been associated with aPL, but
vasculitis is rare (APASS Group, 1990). The stroke recur-
rence rate is high among these patients, and reports suggest
up to a 10% annual risk (Brey et al., 1990; APASS Group
1990). In young people, the risk for stroke recurrence was
&fold higher in patients with aPL than those without aPL
(Brey et al., 1990). Th e risk for thrombosis increases if
patient has both LA and systemic lupus erythematosus.
Bleeding complications are extremely rare among LA pa-
tients, about 1% (Bick and Pegram, 1994). aPL-positive
patients presenting with venous thrombosis tend to have
venous recurrences; while patients presenting with arterial
thrombosis are more likely to have arterial recurrences
(Rosove and Brewer, 1992; Khamashta et al., 1995). Re-
current stroke and vascular dementia at a relatively young
age are the most feared complications of aPL syndrome
(Asherson et al., 1987). There is an association between
multiple brain infarcts and higher aCL titers (Briley et al.,
1989).
In 1990, two groups independently demonstrated that
the true antigen for the antibodies in the ELISA system
was not cardiolipin alone, but a combination of cardiolipin
and a plasma protein, B,-glycoprotein I (B,.GPI), also
called apolipoprotein H (Galli et al., 1990; McNeil et al.,
1990). The discovery of a cofactor for the binding of aCL
in an ELISA system led to further research to identify a
cofactor for LA. For LA, two phospholipid binding cofac-
tors, B,-GPI and prothrombin were characterized (Bevers
et al., 1991; Oosting et al., 1992). Recently, protein C and
S were also identified as cofactors for the binding of aPL
to negatively charged phospholipids (Oosting et al., 1993).
These findings suggest that there are several subpopula-
tions of aPL having complex reactions with several distinct
plasma proteins and suggest a number of interesting specu-
lations. B,-GPI has a critical role in the recognition of
cardiolipin by aCL in patients with autoimmune disease,
but not in infected patients (Hughes, 1993). This indicates
that the interaction of autoimmune-type aCL with B,-GPI
is directly associated with thrombosis. Several findings
suggest that B,-GPI may be the key immunogen in the aPL
syndrome (Gharavi et al., 1992). Many patients with the
aPL syndrome develop a widespread arteriopathy. The
apolipoprotein H @I,-GPI) structurally resembles the LDL
molecule, and LDL is believed to have a central role in the
progression of atherosclerosis (Witzum and Steinberg,
199 1). The recently demonstrated cross-reaction between
aPL and oxidized LDL antibodies (Vaarala et al., 1993)
supports the hypothesis that aPL may play a role in the
pathogenesis of atherosclerosis.
aPL may occur during ingestion of various drugs, in-
cluding phenytoin, fansidar, quinidine, hydralazine, pro-
cainamide, phenothiazines, alpha-interferon and cocaine.
of the Neurological Sciences 140 (1996) 1-l 1 5
Also, aPL may appear during the course of some viral
infections. These aPL elevations are often transient, of low
titer, of the IgM isotype, and not cross-reactive with
negatively charged phospholipids. aPL with these charac-
teristics are usually considered nonpathogenic, although
this is still controversial. Low and transient titers of aPL
probably do not require aggressive therapy. One unit of
aPL is equal to 1 pg/ml and values less than 5 or 10 units
are considered to be negative, below 20 units low positive,
21-40 units moderately positive, and over 40 units high
positive (APASS Group, 1993).
Several coagulation assays can identify LA, but no
uniform opinion exists regarding the minimum criteria for
the diagnosis of LA. Activated partial thromboplastin time
(APTT) is no longer considered sensitive enough (APASS
Group, 1990; Bick and Pegram, 1994) and dilute Russell
viper venom time (dRVVT) is currently considered the
most sensitive test. (Bick and Pegram, 1994). In general,
tests with the least amount of phospholipid in the test
system are the most sensitive for detection of LA. These
include the kaolin clotting time, dRVVT, tissue thrombo-
plastin inhibition test and dilute APTT. Probably, using a
combination of these tests may be the most reliable ap-
proach. The enzyme-linked immunosorbent assay (ELISA)
has been studied and standardized to detect the aCL anti-
bodies of IgG, IgA and IgM type (Harris, 1992).
Several therapeutic approaches including corticos-
teroids, immunosuppressives, plasma exchange, an-
tiplatelets and anticoagulants have been tried with various
outcomes (Babikian and Levine, 1992). Two studies
demonstrated a clear benefit for high-intensity (intema-
tional normalized ratio 2 3) long-term warfarin therapy as
compared to low-intensity warfarin or aspirin among 147
patients with 947 patient-years of follow-up (Khamashta et
al., 199.5) and 70 patients with 361 patient-years of follow-
up (Rosove and Brewer, 1992).
4. Defects in the fibrinolytic system
A reduction of fibrinolytic activity may provoke throm-
botic events. Defective librinolysis has been associated
with stroke (Tengbom et al., 1981). Plasminogen defi-
ciency may cause recurrent venous thrombosis (Lottenberg
et al., 1985). Case reports of young stroke victims with
plasminogen deficiency exist (Furlan et al., 1985; Dolan et
al., 1988). Excessive plasma concentrations of plasmino-
gen activator inhibitor (PAI) was reported in venous
thrombosis (Jorgensen and Bonnevie-Nielsen, 1987) and in
myocardial infarction (Hamsten et al., 1985) patients.
Hereditary dysfibrinogenemia is characterized by aberrant
fibrinogen molecules that are resistant to cleavage by
plasmin. This extremely rare disorder was linked to throm-
bosis including stroke (Coull and Clark, 1993). PA1 levels
show a circadian rhythm being lowest in the early morning
when ischemic strokes are more prevalent. This finding
6 T. Tutlisumak, M. Fisher/
may suggest a temporal relation between the low fibri-
nolytic activity and high thrombosis risk. The fibrinolytic
system has not yet been fully studied in stroke patients.
5. Erythrocyte disorders
Polwythemiu vet-u (PV) is a primary myeloproliferative
disorder with an increased count of red blood cells and a
high hematocrit, causing hyperviscosity. Stroke is the most
serious neurologic manifestation and seen in 4-5% of PV
patients annually (Hart and Kanter, 1990). Common neuro-
logic symptoms such as headache, dizziness, visual blur-
ring and confusion among polycythemia vera patients may
be due to hyperviscosity-related diminished cerebral blood
flow. Phlebotomy and aspirin therapy may reduce the risk
of thrombotic events, but this approach may result in a
substantial risk of bleeding (Tartaglia et al., 1986). Sec-
ondary polycythemias have also been related to stroke
(Schwartz et al., 1993). Young adults with cyanotic con-
genital heart disease and compensatory polycythemia did
not have any stroke episodes during 204 patient-years of
follow-up (Rosove et al., 1986). In 100 patients with
secondary polycythemia, perioperative risk of thrombotic
and hemorrhagic complications did not differ from age-,
sex-, operation- and physical status-matched patients
(Lubarsky et al., 199 1). Patients with pseudopolycythemia
are usually hypertensive, obese and smoker, middle-aged
men having increased hematocrit values due to diminished
plasma volume, thus, the role of polycythemia on throm-
botic complications is uncertain (Doll and Greenberg,
1985).
Purqvsmal nocturnal hemoglnbinuria is a rare disorder
in which red cell membranes are sensitive to lysis by
complement. The clinical syndrome is a chronic hemolytic
anemia. Cortical and sagittal vein thrombosis are common
(Ware et al., 1991) while stroke is occasional (Coull and
Clark, 1993).
Sickle cell anemia patients have a high risk for ischemic
stroke (Powars et al., 1978; Wood, 1978). The exact
mechanisms of stroke are not clear. but sickle cell crisis
and a moyamoya-like vasculopathy play roles. Up to 17%
of these patients will have ischemic strokes (Ohene-Frem-
pong. I99 I) and the recurrence rate may be as high as 67%
(Powars et al., 1978). The actuarial or predictive risk of an
initial stroke during the first two decades is 0.761 episodes
per 100 person years, whereas after age 20, the risk is
0.524 episodes per 100 person years (Powars et al., 1978).
Sickle cell disease is an important cause of brain infarction
in black children, adolescents, and young adults (Hess et
al., 1991). The severity of sickle cell disease was not
different in patients with or without stroke (Powars et al..
1978), although this is controversial. In one study, 75% of
patients with cerebrovascular complications of sickle cell
disease were under 15 years of age (Wood, 1978). Cere-
bral ischemia occurs in 15% of patients homozygous for
Journal cfthr Neurologicul Sciences 140 (1996) I-11
HbSS and the mean age at onset is approx. 15 years (Hart
and Kanter, 1990). Before 15 years of age, 8% of all
children with sickle cell disease experience stroke (Bal-
karan et al., 1992). The prevalence of HbSA among
African-Americans is 8.5% and HbSS is 0.03 to 0.2%
(Coull and Clark, 1993). HbSA was found in 3.9% of a
large population-based study in the Mediterranean area of
Turkey and it was more prevalent (9.6%) among the
Arabic-speaking residents (Kocak et al., 1995). Up to 24%
of patients with HbSS may have silent infarcts (Glauser et
al., 1995); however, the best clinical response to the
discovery of silent brain infarction is unknown (Adams,
1995). Subarachnoidal and intracerebral hemorrhages in-
crease in adults with sickle cell disease due to aneurysm
formation and a moyamoya-like vasculopathy. Surgically
correctable single or multiple aneurysms are found fre-
quently (Powars et al., 1978).
Angiographic studies were not done commonly, be-
cause of evidence that radiographic dyes may enhance
intravascular sickling (Cheatham and Brackett, 1965;
Richards and Nulsen, 1971). However, Stockman et al.
(1972) demonstrated the occlusion of large cerebral vessels
in 6 of 7 patients with neurologic manifestations, using
cerebral angiography without notable adverse effects. All
these patients received aggressive transfusion therapy prior
to angiography, so that the hemoglobin S comprised less
than 20% of the total hemoglobin present. Strokes in sickle
cell disease are not only due to small vessel disease, but
consist of both small and large cerebral vessel occlusions
(Powars et al., 1978; Adams et al., 1988).
Patients with sickle cell disease should receive aggres-
sive transfusion therapy to keep the HbSS concentration at
30% or less (Russell et al., 1984; Pegelow et al., 1995).
There are no convincing data relating thalassemia to stroke.
Moreover, alpha thalassemia associated with sickle cell
disease may have a protective effect against stroke (Adams
et al., 1994).
6. Platelet disorders
Essential thrombocythrmia is a myeloproliferative dis-
order in which blood platelet counts over I000000/mm’
occur. Thrombocytes are usually large and dysfunctional.
Stroke is a well-recognized complication (Kessler et al..
1982; Schafer, 1984; Murphy et al.. 1986) of this hypervis-
cosity syndrome. Aspirin prolongs the bleeding time in
these patients and may prevent further thrombotic events,
but is associated with an increased bleeding tendency.
Hydroxyurea reduces the risk of thrombosis effectively in
these patients (Cortelazzo et al.. 1995). Secondary throm-
bocytosis is apparently not related to ischemic stroke.
Thrombotic thrombocytopenic put-put-n (TTP) is a
thrombotic disorder rather than a hemorrhagic one. It is
characterized by thrombocytopenia, microangiopathic
hemolytic anemia, renal failure, fever and neurological
 T. Tatlisumak, M. Fisher/Journal
symptoms. Almost all patients have neurological symp-
toms and neurological findings may be the primary mani-
festation in up to 60% of patients (Massey and Riggs,
1989). Stroke is common and brain infarcts are usually
small. A disorder similar to TTP is hemolytic-uremic
syzdmme (HUS) that occurs mainly in children younger
than 5 years old. It is a multisystemic disorder in which the
deposition of fibrin in the microvasculature leads to in-
travascular thrombosis. The clinical picture and pathology
resemble TTP and the differential diagnosis may be diffi-
cult. In HUS, brain involvement occurs in 20-52% of
patients (Rooney et al., 197 1; Bale et al., 1980; Sheth et
al., 1986; Hahn et al., 1989) and indicates a poor prognosis
(Kelles et al., 1994). lschemic and hemorrhagic stroke are
frequent (Sheth et al., 1986; Trevathan and Dooling, 1987;
Hahn et al., 1989).
Heparin-associated thromboqtopenia is a rare, im-
mune-mediated disorder that leads to thrombotic events
including stroke (Atkinson et al., 1988). About l-5% of
patients receiving heparin develop thrombocytopenia which
may cause a thrombotic complication after cessation of
heparin. Even though the platelet count may decrease to
20000/mm3, hemorrhagic complications are unusual. The
outcome of stroke from heparin-associated thrombocytope-
nia is poor (Becker and Miller, 1989).
7. Unusual hematological disorders
Disseminated intracuscular coagulation (DIG) is char-
acterized by fibrin thrombi in small vessels and hemor-
rhagic lesions. Cerebral injury alone may precipitate DIC,
as the brain contains potent thromboplastin (Massey and
Riggs, 1989). Stroke is not rare in DIG, especially if
cancer underlies the syndrome. Acute DIC is grave and
easily recognized, while chronic DIG is insidious and
frequently overlooked. Thrombocytopenia and stroke in
cancer patients should remind the physician of the possibil-
ity of DIG.
Malignancy may cause stroke by several mechanisms.
Marantic (nonbacterial) endocarditis is a common feature
in cancer patients and 30% of these patients develop stroke
(Hart and Kanter, 1990). In situ thrombosis due to
Table I
Degrees of association between hematologic disorders and ischemic stroke
Stroll& Moderate
Sickle cell anemia Lupus anticoagulant
Polycythemia vera Anticardiolipin antibodies
Essential thrombocythemia Heparin associated thrombocytopenia
DIC
Malignity
Thrombotic thrombocytopenic purpura
of the Neurological Sciences 140 (19961 1-l 1 7
Trousseau’s syndrome is also well-recognized in cancer
patients. Chemotherapy for malignity was suspected to
cause stroke in some patients (Feinberg and Swenson,
1988).
Leukemia and paraproteinemias (Massey and Riggs,
19891, increased levels of fibrinogen (Kannel et al., 1987),
high hematocrit, tissue trauma, bums, pregnancy, postoper-
ative period, major surgery, infections, puerperium, oral
contraceptive use and nephrotic syndrome all may cause a
hypercoagulable state, though the relationships are not
always clearly demonstrable.
Coagulation factors circulate in excessive amounts in
the blood and convert to active forms in response to
stimuli. Whether factor XII and prekallikrein deficiencies
and excesses of coagulation factors V and VIII are related
to thrombosis is controversial. Since the plasma concentra-
tions of the coagulation factors are normally present in
excess, increases in the concentration of nonactivated clot-
ting factors appear unlikely to contribute to a prethrom-
botic state (Coull and Goodnight, 1990).
8. Suggestions for hematologic evaluation of ischemic
stroke patients and relatives
Most stroke patients do not require an extensive evalua-
tion for an occult disorder of hemostasis. Which patients
should be examined for coagulation abnormalities is partly
a question of resources. A stepwise approach from the
cheapest to the most expensive, noninvasive to most inva-
sive, for the most common etiologic factors to the rarest is
a logical one. The evaluation should save money, cause the
least discomfort to patients and answer clinically relevant
questions.
The early phase of stroke is not a suitable time for
studying coagulation parameters, because both ongoing
coagulation and fibrinolysis will lead to false results. Anti-
coagulant therapy is another reason for false results. Coag-
ulation parameters should be measured at least several
weeks after stroke to obtain reliable results.
Every stroke patient should undergo a systematic evalu-
ation including a complete blood count, activated partial
thromboplastin time and protrombin time. A complete
Weak Questionable or negative
Antithrombin III Heparin cofactor II
Protein C Secondary polycythemias
Protein S Paroxysmal nocturnal hemoglobinuria
APC resistance
Pardproteinemias Thalassemia
High hematorit Excess of coagulation factors
Oral contraceptive use
Fibrinolytic disorders
8 T. Tutlisumak, M. Fisher/ Journal
blood count will screen for polycythemia Vera, thrombocy-
tosis and anemia (e.g., sickle cell anemia). A sponta-
neously long APTT may indicate the presence of LA,
although this test is not sensitive enough in high-risk
patients. Patients with a history of miscarriages, throm-
botic events, collagen disease and thrombocytopenia should
be carefully evaluated for aPL. A family history of throm-
bosis, especially in unusual sites, should suggest deficien-
cies of natural anticoagulants. In younger blacks and East-
em Mediterraneans, sickle cell anemia should be excluded
with hemoglobin electrophoresis in the presence of ane-
mia. If a systemic disease is suspected, fibrin degradation
products and serum protein electrophoresis should be done.
Platelet aggregation studies, coagulation factor assays and
tests for fibrinolysis are rarely indicated, as their role in
ischemic stroke is doubtful (Table 1).
If a hereditary abnormality of hemostasis is found, close
relatives should also be screened even if they have no
history of thrombosis. Individuals with deficiency states
should be properly informed. These probands are at high
risk of developing thrombosis, especially during preg-
nancy, delivery, postpartum and perioperative periods, and
during prolonged bed rest of any cause. Determining the
presence of a clotting disorder will allow the physician to
start a prophylactic anticoagulant regimen or a concentrate
of deficient factor. These asymptomatic relatives should be
counselled to reduce their risk for thrombosis.
Our approach is to examine all patients for a hypercoag-
ulable state who are younger than 50 years and without an
obvious etiology for ischemic stroke. Older patients un-
dergo coagulation studies only occasionally depending on
their medical history, presence or absence of an etiologic
factor for stroke and the results of routine blood tests.
Thus, in young patients, our indication for coagulation
studies is the absence of an obvious etiology, while in the
older population, they are performed only if there is a
substantial suspicion for a coagulation abnormality. Pa-
tients with prior thrombotic episodes, especially at unusual
sites, and with a family history of thrombosis should be
carefully studied. Our battery includes measurements of
AT-III, PC, PS, prothrombin time, LA, aCL and APC
resistance with the classic coagulation test as described by
Dahlback et al. (1993). Only if the patient is APC-re-
sistant, then we order a Factor V point mutation analysis,
since the mutation analysis is expensive and not yet avail-
able worldwide. Abnormalities on routine laboratory tests
may sometimes lead to more specific tests, and these
should be performed as indicated.
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