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Chapter 10
https://t.me/medicina_free
Hypercoagulable States
SimonJ.McRae
Key Learning Points
Routine thrombophilia testing in unselected patients with venous or arterial
•
thrombosis is not recommended.
• Patients with provoked venous thrombosis should not undergo thrombophilia
testing.
• Thrombophilia testing, particularly for type 1 thrombophilic conditions (anti-
thrombin, protein C or protein S deciency), may be considered in patients with
unprovoked venous thrombosis in whom cessation of anticoagulation is being
considered or who have a rst degree female relative of child-bearing age.
•
Unprovoked venous thrombosis at young age, a family history of venous throm-
bosis in rst degree relatives, or recurrent thrombosis may indicate a greater
likelihood of an underlying venous thrombosis.
• Testing for antiphospholipid antibody syndrome is recommended in patients
with unprovoked venous thrombosis or unusual site arterial thrombosis. Patients
with a conrmed diagnosis should receive anticoagulation with warfarin rather
than a direct oral anticoagulant.
Testing for an underlying myeloproliferative disorder and paroxysmal nocturnal
•
haemoglobinuria should be performed in patients with unusual site thrombosis,
particularly unprovoked abdominal vein thrombosis.
S. J. McRae (*)
Department of Haematology, Launceston General Hospital, Launceston, Australia
e-mail: Simon.McRae@ths.tas.gov.au
R. Fitridge (ed.), Mechanisms of Vascular Disease,
https://doi.org/10.1007/978-3-030-43683-4_10
215© Springer Nature Switzerland AG 2020
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S. J. McRae
10.1 Introduction
Abnormal thrombus formation is central to the acute pathophysiology of both arterial and venous disease. Formation of thrombus superimposed upon the surface of
ruptured atherosclerotic plaque, producing vessel occlusion and resulting tissue
ischemia, is a common mechanism leading to acute symptoms and presentation in
patients with arterial disease. Deep vein thrombosis and its complication pulmonary
embolism, are also important causes of morbidity and mortality and result from
abnormal thrombus formation in the venous circulation. An understanding of conditions that may predispose to abnormal thrombus formation, including how the presence of these conditions may or may not impact on patient management, is therefore
important for all clinicians involved in the management of vascular disease.
First used in 1937 [1] and then also in the rst description of inherited antithrombin
deciency, the term “thrombophilia” can be dened as an increased tendency to
develop thrombosis, which may be either acquired or inherited [3]. Thrombophilic
conditions vary both in prevalence and in the magnitude of the associated increase in
risk of thrombosis. The discovery during the 1990’s of the high prevalence factor V
Leiden and prothrombin gene point mutations that predispose to thrombosis [4, 5],
meant that an underlying thrombophilic condition could be found in approximately
50% of unselected patients with venous thrombosis [6]. The belief that the presence
of such a condition may inuence prognosis and therefore help to guide patient management, led to a signicant increase in laboratory testing for inherited thrombophilia
[7]. It however has been demonstrated that testing for thrombophilia, particularly the
more common inherited conditions, is unlikely to inuence the management of the
majority of patients in whom it is performed [8] and guidelines as a result have recommended against widespread testing in unselected patients [9–11].
The chapter describes individual inherited and acquired conditions that predispose to an increased risk of thrombosis. The potential clinical rationale for testing
will be outlined, and current evidence and recommendations regarding the clinical
utility of laboratory testing in specic clinical scenarios will be discussed.
10.2 Classication ofThrombophilia
Thrombophilic conditions can be broadly classied as being either inherited or
acquired and will be described in these two broad categories.
10.2.1 Inherited Thrombophilia
In 2003 Crowther and colleagues proposed a classication of inherited thrombophilia into either type 1 conditions that involve a deciency of one of the naturally
occurring inhibitors of coagulation, and type 2 conditions that result in a gain of
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function or an increase in the level of one of the procoagulant proteins [12]. The
distinction is of clinical relevance as the majority of patients with a type 1 condition
will develop a symptomatic episode of venous thrombosis during their lifetime,
whereas the majority of individuals with a type 2 condition will not. Similarly the
presence of a type 1 thrombophilia clearly increases the risk of recurrent venous
thrombosis and therefore may inuence decision making regarding the duration of
anticoagulation [13], whereas type 2 conditions in isolation do not strongly inuence recurrence risk and their absence or presence should not be used in isolation to
determine duration of treatment [14].
10.2.1.1 Type 1 Conditions
Antithrombin Deciency
Antithrombin (AT) is a single chain plasma glycoprotein belonging to the Serine
Protease Inhibitor superfamily (serpins) [3]. It is a physiological inhibitor of thrombin and other activated coagulation factors (factors Xa, IXa, XIa). Heparin exerts its
anticoagulant effect by binding to AT, resulting in a conformational change that
increases the afnity of AT for thrombin more than 1000-fold. Familial AT deciency, described in 1965, was the rst identied inherited thrombophilia [2, 3].
Individuals with AT deciency typically have AT levels ranging between 40 and
80% of normal, and estimates of the prevalence of the condition range from 0.02 to
0.15% of the general population [15]. Approximately 0.5–2% of unselected individuals with venous thromboembolism (VTE) will have AT deciency [16]
Estimates of the increase in risk of VTE associated with AT deciency vary from 5
to 20-fold that of the general population, with pooled analysis suggesting an annual
risk of venous thrombosis of approximately 1% in previously asymptomatic individuals with the deciency state [17].
Protein C andProtein S Deciency
Protein C (PC) and protein S (PS) are both vitamin K-dependent plasma glycoproteins synthesized in the liver [18]. When activated by thrombin, a process potentiated by the binding of thrombin to thrombomodulin on the intact endothelium, PC
is converted to the active serine protease, activated protein C (APC). In combination
with its cofactor, PS, APC inactivates both factor Va and VIIIa, and plays a central
role in controlling the propagation phase of coagulation. In plasma, PS circulates
both free (40%) and bound to the C4b-binding protein (60%). It is the free form of
PS that has cofactor activity.
Inherited PC deciency was rst described as a cause of venous thrombosis in
1981 [19], whereas PS deciency was initially described as a cause of venous
thrombosis in 1984 [20]. PC and PS deciency both have type I (quantitative deciency) and type II (qualitative deciency) subgroups, and in addition a type III PS
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S. J. McRae
deciency state with normal total circulating but reduced free levels can occur. The
estimated prevalence of heterozygous PC deciency in the general population is
between 0.2 and 0.4% [21], and many of these individuals have no history of thrombosis. The community prevalence of PS deciency is estimated at approximately
0.2% [22]. PC deciency is found in 1–3%, and PS deciency in 1–7% of unselected
patients diagnosed with VTE.Estimates from case-control and family cohort studies of the increase in risk of VTE associated with PC deciency range from 5.0 to
10-fold, and 8.5 to 30-fold for PS deciency [9].
Homozygous PC deciency is a rare condition that may present as neonatal purpura fulminans, which is an acute thrombotic disorder that manifests as extensive
skin and soft tissue necrosis that can be fatal if not treated aggressively [23]. A
protein C concentrate, Ceprotinin®, is available, and should be given in combination
with anticoagulant therapy in such cases.
Care is needed when initiating warfarin in patients with conrmed protein C and
S deciency. This is due to the fact that both protein C and S are vitamin-K dependant proteins, and levels may reduce at warfarin initiation more quickly than procoagulant levels due to a shorter half-life. This may precipitate a pro-thrombotic
state that can result in warfarin related skin necrosis [24]. Bridging therapy with an
alternative anticoagulant, most commonly low-molecular-weight heparin, should be
administered while warfarin is being initiated in this patient group.
10.2.1.2 Type 2 Conditions
Factor V Leiden
In 1993, Dahlback and colleagues noted that plasma taken from a family with a
strong history of venous thrombosis was resistant to the anticoagulant effect of
APC [25]. This phenotype became known as APC Resistance. A point mutation in
506
the factor V gene (G1691A), resulting in an amino acid change (Arg
to Gly) at
the cleavage site involved in the inactivation of factor Va by activated protein C
was identied as the cause in more than 90% of individuals, and became known
as factor V Leiden (FVL) [4, 26]. The FVL mutation has a high community preva-
lence with 3–7% of Caucasians being heterozygous for the mutation, although a
lower incidence is found in other ethnic groups [27]. It is the most commonly
identied cause of inherited thrombophilia, being present in 12–20% of unselected
patients with VTE [28]. The heterozygous state is a relatively low risk thrombophilia being associated with a 3 to 7-fold increase in risk of VTE [9] with one
study nding greater than 90% of individuals remaining event free by the age of
65. Unlike individuals homozygous for natural anticoagulant deciency states,
homozygosity for FVL does not result in a catastrophic thrombotic state early in
life, and it is estimated that 0.1% of the population are FVL homozygotes [9]. The
risk of VTE, however, in homozygotes for FVL is greater than that in heterozygotes, with estimates of the magnitude of risk ranging from 25 to 80-fold that of
the healthy controls [29].
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The Prothrombin (G20210A) Gene Mutation
In 1996, Poort and colleagues described a common mutation (G20210) of the prothrombin gene, which has become known as the prothrombin gene mutation (PGM)
[5]. Located in the 3′ untranslated region of the gene, the mutation is associated
with increased mean plasma prothrombin levels due to increased efciency of 3′
end processing of the gene, resulting in accumulation of the encoded mRNA [30].
The prevalence of the mutation in Caucasian populations is approximately 2%, and
it is rare in Asian and African populations [31]. In unselected patients with venous
thrombosis the mutation has been found in between 4.0 and 7.1% of individuals [9]
and 18% of individuals with a strong family history of VTE.The PGM is a relatively weak risk factor for VTE, being associated with a 2 to 5-fold increase in
risk [9].
FVL/PGM Compound Heterozygotes
Given the high community prevalence of both the FVL and PGM mutations it is not
uncommon for individuals to be heterozygous for both conditions, with an expected
prevalence of 1/1000in Caucasian populations [32]. In a pooled analysis of case
control studies, double heterozygotes were estimated to have a 20-fold increase in
risk of VTE in comparison to healthy controls [32].
Other Inherited Conditions
Homozygosity for the C667T mutation in the methylenetetrahydrofolate reductase
(MTHFR) gene, producing a thermolabile gene product with reduced function, is
the commonest inherited cause of raised plasma homocysteine levels [33]. In prospective studies a 5μmol/L (micromolar) increase in total plasma homocysteine
levels has been shown to be associated with an approximate 1.3-fold increase in the
risk of venous thrombosis [34] and patients with peripheral vascular disease have
been shown to have a slight elevation of homocysteine levels in comparison to controls [35]. Conversely homozygosity for the C667T MTHFR mutation has been
shown to have no association with venous thrombosis in folate-replete societies [34]
and to have only a weak association with arterial disease (OR 1.2, 95% CI 1.0–1.4)
[
36]. A recent systematic review demonstrated that, in comparison to placebo,
homocysteine-lowering interventions did not prevent heart attack or reduce death
rates in participants at risk of, or living with, cardiovascular disease [37]. Performing
testing for this mutation is therefore not recommended as part of routine clinical
practice.
Elevated levels of the coagulation factors VIII, IX, XI and prothrombin (factor II)
have all been shown to be associated with increased VTE risk. In the case of factor
VIII, familial clustering of individuals with elevation of this factor has been demonstrated suggesting an underlying inherited cause, although a specic genetic defect
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is yet to be identied [8]. Other common mutations within coagulation proteins that
have been documented to increase the risk of venous thrombosis include the
Plasminogen activator inhibitor 4G/5G mutation (OR 1.62) and the alpha- brinogen
Thr312Ala point mutation (OR 1.4). However, there is no clear evidence that the
presence of these mutations should alter patient management at present [38].
S. J. McRae
10.2.2 Acquired Thrombophilia
There are a number of important acquired conditions that predispose to venous or
arterial thrombosis that can be dened by laboratory testing. External or environmental acquired risk factors such as recent surgery, hospitalization or cancer, while
often playing a central role in the causation of venous thrombosis, will not be discussed further.
10.2.2.1 Antiphospholipid Antibodies
The term antiphospholipid antibody syndrome (APLAS) was rst used in the
1980’s to describe a non-inammatory autoimmune condition characterized by
the presence of antibodies directed against a variety of phospholipid membrane
associated proteins, and a history of either arterial or venous thrombosis or adverse
pregnancy outcomes [39]. Laboratory conrmation of the presence of antiphospholipid antibodies requires the demonstration of the presence of a lupus anticoagulant, characterized by prolongation of phospholipid dependant coagulation
assays such as the APTT, or a positive immunoassay for anti-cardiolipin or
anti-beta2-glycoprotein1 antibodies. False positive or negative test results for the
presence of a lupus anticoagulant can be seen in the presence of a direct oral anticoagulant, and therefore ideally testing should be performed prior to such agents
being commenced [40]. To classify a patient as having APLAS, antibody testing
should be positive on at least two occasions 12weeks apart [41]. The risk of an
initial thrombotic event in patients with a positive test for antiphospholipid antibodies varies from no increase in blood donors in whom the often transient antibodies are an incidental nding, to an annual risk of thrombosis of 2–4% in
patients with SLE who are antibody positive [39]. Thrombotic risk is highest in
patients with a positive test result by all three separate assays (lupus anticoagulant, anti-cardiolipin or anti-beta2-glycoprotein1 antibodies all positive), with
such patients classied as being “triple positive” [42].
Importantly, a recent randomised trial demonstrated warfarin to be superior
to rivaroxaban in patients with triple positive APLAS (the TRAPS trial) [43]. A
clear excess of recurrent thrombosis, predominantly stroke, was seen in patients
receiving rivaroxaban. In addition patients with APLAS, particularly those with
a positive test for a lupus anticoagulant, are at increased risk of recurrent thrombosis and therefore they will usually receive long-term anticoagulation after an
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initial event [44]. Therefore conrmation of the presence of antiphospholipid
antibodies is likely to inuence clinical management.
10.2.2.2 Heparin Induced Thrombocytopenia
Heparin induced thrombocytopenia (HIT) is an immune-mediated adverse drug
reaction to heparin. It results from the formation of antibodies, in the majority of
patients directed against a complex of heparin and the positively charged molecule
platelet factor 4 (PF4) [45]. These antibodies then bind to the heparin-PF4 complex
bound to the platelet surface, leading to platelet activation most likely due to signaling via the platelet Fc receptors. Platelet and probable concurrent endothelial activation result in activation of the coagulation cascade and increased thrombin
generation, manifesting clinically as increased risk of venous and arterial thrombosis. Without institution of alternative anticoagulation, patients with conrmed HIT
have a daily incidence of new thrombotic complications of up to 6%, with the historical risk of death or amputation due to venous gangrene approaching 50% [46].
Early recognition of HIT is therefore important and monitoring of platelet counts
between day 2 and 14 of exposure should be performed in all patients receiving
heparin. A fall in platelet count to less than 150×109/L or all fall in total platelet
count by greater than 50% should prompt laboratory investigation for HIT
antibodies.
Heparin should be immediately ceased in patients suspected of having a diagnosis of HIT.Patients with a conrmed diagnosis of HIT antibodies should be started
on a non-heparin alternative anticoagulant [47]. Due to a high rate of cross- reactivity
with HIT antibodies, low-molecular-weight heparin should be avoided. Alternative
anticoagulants include argatroban, bivalirudin, danaparoid, fondaparinux, or a
direct oral anticoagulant (DOAC) [47]. Choice of drug will be determined by patient
factors such as renal and hepatic function, and individual clinician familiarity with
the alternative agents.
10.2.2.3 Myeloproliferative Disorders
The primary bone marrow disorders polycythaemia rubra vera (PRV), myelobrosis
and essential thrombocytosis (ET) make up the bcr-abl negative myeloproliferative
disorders. In almost all patients with PRV, and a signicant proportion with ET, a
somatic acquired mutation known as the JAK2 V617F mutation will be detected
[37]. Patients with PRV and ET in particular have been shown to be at an increased
risk of both venous and arterial thrombosis. The pooled prevalence of all thrombosis
among patients with myeloproliferative neoplasms (MPN) at initial diagnosis was
20.0%, with the prevalence of arterial thrombosis 16.2% and that of venous thrombosis of 6.2% [48].
Full blood examination is therefore recommended in all patients with arterial or
venous thrombosis. Patients with acute thrombosis in the setting of an MPN may
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also require cytoreductive therapy, including venesection to reduce the haematocrit
to <0.45, as well as therapeutic anticoagulant therapy [49]. While the evidence is
still limited, it appears that DOACs are efcacious and safe when used as anticoagulants in this setting [50]. Due to a high risk of recurrent thrombosis long-term anticoagulation is recommended in patients with MPN and clinically signicant venous
thrombosis [49].
It has been observed that a signicant proportion of patients with unprovoked
portal and mesenteric vein thrombosis will be found to have the JAK2 V617F mutation present, often without clear evidence of a myeloproliferative disease on the
peripheral blood examination. The CALR mutation is present in a smaller proportion of patients [49, 51]. Testing for these mutations should therefore be performed
in patients presenting with splanchnic vein thrombosis in the absence of an obvious
alternative cause. As patients with a proven MPN and prior abdominal vein thrombosis have a high risk of recurrent events, long-term anticoagulation, is recommended in the absence of contra-indications [49].
10.2.2.4 Paroxysmal Nocturnal Haemoglobinuria
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare clonal bone marrow
disorder, associated with a loss of glycosylphosphatidylinositol (GPI) anchor
proteins on hematopoietic cells, that results in an increased susceptibility to
complement- mediated haemolysis [52]. This results in an increase in the risk of
thrombosis, and approximately 10% of patients with PNH will have thrombosis
at presentation. Unusual site venous thrombosis particularly hepatic vein or
cerebral venous sinus thrombosis is common. Recurrent venous thrombosis may
occur in patients with PNH receiving standard anticoagulation, with the risk of
recurrence appearing to be reduced by use of the complement (C5) inhibitor
eculizumab [52]. Identication of this uncommon condition in patients presenting with unexplained unusual site venous thrombosis therefore has potential
therapeutic implications.
S. J. McRae
10.3 Potential Reasons forPerforming
Thrombophilia Testing
Clinical utility is an important concept when considering laboratory investigations
for any condition. The clinical utility of any investigation can be dened as the
degree to which the clinical outcome of an individual patient is improved by the
performance of that test. It is important that any clinician ordering thrombophilia
testing is able to articulate clearly what implications the results of the test will have
on the management of that individual patient. If the answer is no impact, then the
test should not be performed. The evidence for potential indications for testing for
an underlying thrombophilic condition are discussed below.
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10.3.1 Patients withVenous Thrombosis andTheir Relatives
10.3.1.1 Providing anUnderstanding oftheAetiology
ofaThrombotic Event
As discussed above, a number of inherited conditions have been shown to be clearly
associated with an increased risk of a rst episode of venous thrombosis (Table10.1)
[8, 9]. It is understandable that patients with venous thrombosis may want to
improve their understanding as to why an event occurred, and thrombophilia testing
may help provide some explanation in individual cases. It however should be
emphasized that venous thrombosis is a multifactorial disease with often many risk
factors present at the time of an event, and therefore care should be taken in attributing an event entirely to an underlying thrombophilic condition. Guidelines have
attempted to identify particular patient groups in which an underlying inherited
thrombophilia is likely to be identied, and have suggested that younger patients
(<50years of age) with unprovoked venous thrombosis, or individuals with unusual
site or recurrent venous thrombosis could be selected for testing [10]. As outlined
below the impact on management of these test results remains unclear.
The cost-effectiveness of performing thrombophilia testing solely to understand
the aetiology is questionable. As discussed below, it is also important that both the
patient and clinician understand that testing for the common genetic mutations, the
FVL and PGM mutations, is unlikely to change management, and that the results of
a positive test for these conditions are not over-interpreted. Finally the potentially
negative impact of testing including implications for insurance, and the risk of overinterpretation of results, should be taken into account before testing is performed.
As a result it is not recommended that thrombophilia testing is routinely performed
to understand the aetiology of an event.
10.3.1.2 Determining theChoice ofAntithrombotic Agent forInitial
Treatment ofThrombosis
The presence or absence of an inherited thrombophilia does not impact on
choice of initial anticoagulant therapy. Testing for these conditions therefore
should not be performed at the time of acute presentation, a recommendation
Table 10.1 Increase in risk of initial and recurrent venous thrombosis with inherited thrombophilia
AT
deciency
Increase in risk of
rst episode VTE
Increase in risk of
recurrent VTE
AT antithrombin syndrome, FVL Factor V Leiden, PGM prothrombin gene mutation, VTE venous
thromboembolism
a
Refers to heterozygote state
5 to 20-fold
2.0-fold (pooled data) 1.2 to 1.6
Protein C
deciency
5 to 10-fold 5 to 30-fold
Protein S
deciency
FVL
mutation
3 to 7-fold 2 to 3-fold
fold
a
PGM
mutation
1.4 fold
a
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S. J. McRae
reinforced by the fact that adequate counselling regarding genetic testing is
unlikely to occur in the emergency setting.
Acquired conditions that may alter the choice of initial anticoagulant choice
include HIT (non-heparin anticoagulant required), APLAS (warfarin preferred over
DOAC), the presence of a MPN (cytoreductive therapy also required), and PNH
(addition of eculizumab may be considered). Testing for these conditions in acute
presentations suggestive of their presence (e.g. signicant unprovoked venous
thrombosis for APLAS, unusual site thrombosis or recurrent thrombosis on anticoagulation for MPN and PNH) should be considered.
10.3.1.3 Determining theRisk ofRecurrence andTherefore Optimal
Duration ofAnticoagulation
Patients with venous thrombosis are at risk of recurrent events, with approximately
30% of affected individuals subsequently experiencing a recurrent event within
5years of ceasing anticoagulation [53]. A potential role for thrombophilia testing is
therefore to identify those patients at greatest risk of recurrent thrombosis, in whom
exposure to the increased risk of haemorrhage with long-term anticoagulation may
be justied.
Patients with provoked venous thrombosis associated with transient major risk
factors (surgery, limb fracture or other trauma, signicant immobilisation) are at
low risk of recurrent venous thrombosis, with an estimated rate of recurrence of
0.7% over a 2year period after ceasing anticoagulation [54]. As the presence of a
denable thrombophilia is unlikely to alter the risk/benet of ceasing anticoagulation, thrombophilia testing is not recommended in this patient group [9–11].
Patients with unprovoked venous thrombosis have a substantially increased risk
of recurrent thrombosis in comparison to patients in whom the event was associated
with a denite provoking risk factor. A meta-analysis of this patient group conrmed a risk of recurrent thrombosis of approximately 10% in the rst year after
ceasing anticoagulation, with an incidence of 36% at 10years [55]. These ndings,
combined with the lower incidence of major bleeding when patients receive anticoagulation with a DOAC, have led to guidelines recommending continued anticoagulation in patients with unprovoked venous thrombosis in the absence of
contra-indications. As outlined below, this decision is unlikely to be modied by the
absence of an underlying thrombophilia. Therefore, patients in whom a decision has
been made on clinical grounds to continue anticoagulation should not have thrombophilia testing performed.
The question of thrombophilia testing therefore becomes focused on patients
with unprovoked venous thrombosis in whom cessation of anticoagulation is being
proposed, and whether estimates of recurrence risk will be sufciently modied in
this patient group by the results to lead to a change in decision making.
The high-incidence inherited thrombophilic conditions, the FVL and PGM mutations, do not signicantly increase the risk of recurrent thrombosis. A recent metaanalysis found that patients heterozygous for the FVL mutation compared to patients
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