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CHAPTER
10
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Evaluation of hypercoagulable
states and molecular markers
of acute venous thrombosis
Iva Minga, Alfonso J. Tafur, and Joseph A. Caprini
10.1 INTRODUCTION
Vessel injury, venous stasis, and accelerated coagulability
disrupt the necessary hemostasis needed for the balance
between clot formation and clot dissolution. These three
factors, described in 1856 as Virchow’s triad, disrupt the
normal hemostatic processes [1]. Pulmonary embolism
(PE) and deep vein thrombosis (DVT) are categorized as
venous thromboembolism (VTE). VTE is one of the three
most common causes of cardiovascular disease and a major
cause of mortality and morbidity worldwide [2]. The risk
of VTE can be predicted by the presence of these predisposing risk factors and create epidemiological expectations
across different demographics [3, 4]. (See Chapter4 for a
more detailed discussion on the epidemiology and risk factors for VTE.)
High awareness of VTE history and VTE risk factors
is necessary to provide the individual patient with appropriate thrombosis prophylaxis, including anticoagulation.
VTE incidence within 90 days in a prospective postoperative cohort of patients chronically anticoagulated due
to high VTE risk was 1.8%, including major hemorrhage
(1.8%) representing perioperative morbidity and mortality of 1.7% [5]. The risk of complications continues to
increase when patients are followed for 6 months (95% CI,
3.1%–6.6%) [6].
In this chapter, we will examine several congenital and
acquired coagulation disorders governing the probability
of perioperative VTE.
10.2 HOW TO APPROACH
THROMBOPHILIA
Thrombophilias are associated with an increased tendency
for VTE due to altered blood coagulation [2]. From the
clinical perspective, although we gravitate to think about
venous thrombosis rst, the patient can present with
venous, arterial, or sometimes thrombosis on both vascular beds (Figure10.1). In patients with arterial thrombosis, the evaluation should rst focus on a review of images,
looking for vessel disease such as the extent of atherosclerosis, dissection, aneurysmal dilatation, bromuscular
dysplasia, etc. Thrombophilia presenting as arterial events
is not common, and the assessments should include a distinction between embolic or focal thrombosis. Few diseases
present with simultaneous arterial and venous thrombosis.
When this occurs, we advocate investigation of underlying
malignancy, vasculitis, vasculopathy (i.e., thromboangiitis
obliterans), heparin-induced thrombocytopenia, antiphospholipid syndrome, or COVID coagulopathy. The next segment expands on the signicance of these diseases.
The prevalence of hereditary venous thrombophilia is
variable depending on the population [7], with important variations by ethnicity [7]. The connection between
VTE and thrombophilia in the past has led to the widespread practice or testing for thrombophilic defects in this
population [2], yet this practice is argued against, as the
long-term prognosis of these patients and anticoagulation
strategy are often unaltered by nding a genetic thrombophilia. In a cohort of patients with VTE who underwent
wide screening including acquired and hereditary thrombophilia, the probability of a thrombophilia decreased from
49% among patients younger than 20years old to one in
ve patients in those over 70years of age. Apositive nding was also more likely in those with unprovoked VTE
[8]. Patients with thrombophilia can be identied based on
their personal and family history of VTE [9]. Other factors
associated with the presence of inherited thrombophilia
include a strong family history of VTE, VTE in conjunction
with weak provoking factors at a young age, recurrent VTE
events, VTE in a usual site such as central nervous system
or splanchnic veins, resistance to heparin, warfarin-induced
skin necrosis, or purpura fulminans [9]. Although usually
not listed as a thrombophilia, sickle cell mutation is also a
risk factor for VTE [10].
Less characterized hemostasis disorders may be clustered as an increase of activity or decrease in activity. Among
uncommon disorders with increased activity, there is a
growing body of evidence suggesting an association with
thrombosis for lipoprotein a, clotting factor IX, clotting
factor XI, clotting factor XIII Val34Leu, brinogen, homocysteine, PAI-1 4G/5G polymorphism, and TAFI [11, 12].
DOI: 10.1201/9781003328971-12
9595
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10.1 Assessment of the patient with suspected thrombophilia based on clinical presentation.
For disorders characterized by decreased activity, MTHFR
mutation was previously considered a possible factor. Yet,
the data are not consistent, and the current position of
the International Society of Thrombosis and Haemostasis
(ISTH) is against testing for this mutation [13]. In contrast,
for protein Z, TFPI, and EPCR mutations, the association
with clinically relevant thrombosis is increasing [11].
10.3 CONGENITAL THROMBOPHILIA
10.3.1 Protein C deficiency
Protein C deciency is a severe congenital thrombophilia
classied into two types: type I implies a reduction in
both functional and antigenic levels, and type II implies a
reduced functional level but a normal antigenic level. More
than 160 mutations result in protein C deciency, which
makes genetic testing impractical [14]. Protein C deciency
is present in approximately 0.17%–0.40% of the general
population, with the majority being type Ideciency. Heterozygous deciency is present in 1.5%–11.5% (mean:
4%) of patients with VTE [14].
Protein C deciency should be diagnosed with a functional protein C level. Warfarin and other vitamin K antagonists are the most common reasons for low protein C
functional or antigenic levels; thus, waiting to test until 4
weeks after warfarin is discontinued is prudent [15]. By
40years of age, about 50% of patients with heterozygous
protein C deciency will have had an episode of VTE.
Relative to controls, the risk of rst VTE with protein C
deciency is very high (odds ratio [OR]: 7.51, 95%CI:3.21–
17.52; P <0.00001). Similarly, the rate of VTE recurrence
in patients with protein C deciency is about three times
higher than in patients without protein C deciency (OR:
2.94; 95%CI:1.43–6.04) [16].
10.3.2 Protein S deficiency
Like protein C, protein S is a vitamin K–dependent endogenous anticoagulant that is primarily produced in the liver
[15, 17]. Approximately 0.03%–0.2% of the general population have protein S deciency, but the true prevalence
is unknown due to the difculty in making an accurate
diagnosis. Protein S is a cofactor for activated protein C’s
(APC’s) inactivation of factors Va and VIIIa. Protein S
deciency differs from the other two deciencies of natural anticoagulants in that 60%–70% of the total protein
S is bound to the transport protein C4b-binding protein
and is not available as a cofactor for APC. More than 131
mutations are associated with protein S deciency [17].
Protein S deciency is classied into three types based on
free, total, and functional tests. Type Ideciency denotes
low levels of both free and total antigen, type II denotes
low activity but normal free and total levels, and type III
denotes low free but normal total levels. Type III deciency usually results from abnormal binding of protein S
to C4b-binding protein [17].
Diagnosing protein S deciency is challenging due to
multiple factors affecting the free protein S level. Total
protein S level is not a clear predictor of VTE risk [18].
The available tests for the diagnosis of protein S deciency
are free antigen level, total antigen level, and functional
(APC cofactor activity) level. The functional test is inuenced by factors other than protein S activity and should
be interpreted with caution. Thus, factor V Leiden may also
interfere with protein S activity results [19]. In addition,
uctuations in protein S levels have been noted over time;
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thus, the diagnosis should be conrmed with a second test.
The recommended sequence of testing is rst to rule out
other conditions, then test for free protein S and, if low, then
test for activity and conrm low levels 4–6 weeks later [20].
The rates of VTE being associated with protein S deciency range from zero to 11.5-fold [15]. In a meta-analysis,
patients with protein S deciency had ve times the odds of
thrombosis relative to those with no deciency (OR 5.37;
95%CI:2.70–10.67). Yet, the odds of recurrence were not
signicantly higher (OR: 2.52; 95%CI:0.89–7.16) [16].
Afamilial study showed that 50% of patients with protein
S deciency develop VTE by 45years of age [17].
10.3.3 Antithrombin deficiency
Antithrombin (formerly termed “antithrombin III”) is a
natural anticoagulant that binds and inactivates factors IIa
(thrombin), IXa, Xa, XIa, and XIIa to reduce clot formation
[14]. More than 100 mutations may result in antithrombin
deciency, which is inherited as an autosomal dominant
trait. Antithrombin deciency is classied into two types:
type Iindicates reduced levels of both functional (activity)
and antigenic antithrombin, while type II indicates reduced
functional but preserved antigenic levels [14].
Congenital antithrombin deciency is rare, present in
0.07%–0.2% of the general population and 0.5%–8% of
patients presenting with VTE. Moreover, antithrombin
levels can be decreased during an acute thrombotic event,
so laboratory diagnosis should occur at least 3 months
after the event. Diagnosis should also be deferred until at
least 5 days after the cessation of heparin therapy, as antithrombin levels may be low during therapy. Most (>50%)
patients with heterozygous mutations will develop VTE
by 30 years of age [15]. It is an aggressive thrombophilia; compared to controls without antithrombin deciency, their odds of VTE are 16 times higher (OR: 16.26,
95%CI:9.90–26.70). The odds of VTE recurrence in
patients with antithrombin deciency are also signicantly
elevated (OR: 3.61; 95%CI:1.46–8.95) [16]. Apreoperative conrmation of the antithrombin level is necessary
to calculate supplementation [(120% * patient level%)
* Weight in Kg/1.4)]. Replacement ideally is with recombinant antithrombin, yet plasma can supplement in case
antithrombin is unavailable. Monitoring of the perioperative levels and added supplementation are also recommended, with the measurement at 20 minutes of peak and
again at 12hours followed by maintenance every 24hours
as needed.
10.3.4 Factor V Leiden mutation
APC resistance refers to the delay of factor V to cleavage by
APC by about 10-fold and thus increasing thrombin production [14, 15]. Factor V Leiden (FVL) is the most common inherited thrombophilia, affecting approximately 5%
of Caucasians, 1.2% of African Americans, 2.2% of Hispanic Americans, 1.2% of Native Americans, and 0.45%
of Asian Americans. The lifetime probability of symptomatic VTE in patients with a heterozygous FVL mutation
is approximately 10%; thus, the vast majority of patients
will not develop complications due to this mutation [21].
Adjusted HRs of 2.2 (95% CI: 2.0–2.5) have been reported
for people with heterozygous mutations and 7.0 (95% CI:
4.8–10) for those with homozygous mutations [22]. The
risk of recurrent VTE is higher in people with heterozygous
FVL compared to those without (OR: 2.4, 95% CI: 1.6–
3.6, P < 0.01) [23]. However, a heterozygous FVL does not
dictate a need for extended anticoagulation. Conversely,
the odds of recurrence among patients with homozygous
FVL is much higher compared to controls (OR 13.9 [95
% CI 9.9–19.7]) [24]. Therefore, extended anticoagulation
after the rst event is generally accepted.
10.3.5 Prothrombin gene 20210A mutation
The prothrombin G20210A (P20210) mutation is a G to
Apoint mutation on the factor II gene at position 20210,
which results in higher circulating levels of functionally
normal prothrombin [14, 15, 25]. P20210 is the second
most common inherited thrombophilia. The prevalence in
the United States is 1%–2%. About 5%–10% of patients
with VTE have P20210 [25].
Since P20210 is a mutation, it can be diagnosed with a
genetic test and can be tested regardless of the patient’s current conditions [15]. The adjusted risk for VTE in people
with homozygous prothrombin P20210 is higher (HR: 11,
95% CI: 2.8–44) than for those with a heterozygous mutation (HR: 1.5, 95% CI: 1.2–1.9) [22]. The risk of recurrent VTE is less signicant, with an OR of 1.72 (95% CI:
1.27–2.31) for recurrence after a rst event in patients who
are heterozygous for P20210, which is lower than the risk
for rst VTE, but higher than the risk for noncarriers [26].
10.3.6 Fibrinogen disorders
Fibrinogen is a large hexameric glycoprotein produced by the
liver that has primary and secondary hemostasis effects [27].
It mediates platelet aggregation via the binding of glycoprotein IIb–IIIa and is converted to brin with thrombin cleavage
in secondary hemostasis. Fibrin is stabilized and strengthened
with factor XIII–mediated crosslinks. Fibrinogen is encoded
by three genes (FGA, FGB, FGG), and multiple rare congenital brinogen disorders are associated with its expression
[28]. It is structured as a dimer of trimers, where each half has
three polypeptide chains: Aα, Bβ, and ϒ [27]. Leading from a
diverse mechanism of action, congenital brinogen disorders,
classied as abrinogenemia, hypobrinogenemia, dysbrinogenemias, and hypodysbrinogenemia, clinically have a variable presentation including bleeding and venous or arterial
thrombosis. The thrombotic phenotype is more commonly
seen in dysbrinogenemia.
Although brinolysis assays are increasingly being used,
many limitations remain and challenge the diagnosis. Testing assays include PT, PTT, thrombin time, reptilase time,
brinogen measurement, and rotational thromboelastometry (ROTEM) [27].
10.3.7 Lipoprotein a
Lipoprotein a [Lp(a)] is a lipoprotein particle to which
apolipoprotein B100 is covalently linked to apolipoprotein(a) [29]. Patients with elevated plasma levels of Lp(a)
have an increased cardiovascular risk in several clinical
studies due to accelerated atherothrombosis. An increased
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risk of venous events is also seen. In a meta-analysis of
more than 14,000, a high Lp(a) was related to a mildly
increased risk of VTE (OR: 1.56, 95% CI: 1.36, 1.79) [30].
Although thrombosis in children is uncommon, elevated
Lp(a) levels are associated with an increased VTE risk in
this population. In a case-control study, the risk for thromboembolic events in children withhigh Lp(a) was 7.2 (95%
CI, 3.7–14.5) [31].
The mechanism by which Lp(a) and thrombosis promote VTE is not well dened. Due to conformation similarities with apo(a) and plasminogen, the speculated
mechanism of action is one that strongly suggests an antibrinolytic role [29]. Aspirin may avert major adverse cardiac events in older individuals with elevated lipoprotein(a)
genotypes in primary prevention [32]. There is a growing
interest to develop novel therapeutics for this target, and
one such therapy, olpasiran, a small interfering RNA, has
been effective in decreasing Lp(a) levels. However, the clinical impact on arterial or venous events still requires further
evaluation [33].
10.3.8 Factor VIII
Elevated plasma levels of factor VIII (FVIII), one of ve
cofactors that control the generation of thrombin, have
been associated with an increased risk of recurrent VTE
[34]. This risk was initially identied in patients who had
an FVIII level in about the 90th percentile [35]. Cosmi
etal. found an adjusted multivariate hazard ratio (HR)
of 4.5 (95% CI: 1.7–12.2) in patients with a FVIII level
above the 75th percentile compared with a normal D-dimer [36]. When compared with an abnormal D-dimer, the
HR of an elevated FVIII (>75th percentile) was 7.1 (95%
CI: 2.8–17.6) [36]. However, since FVIII is activated
during an acute phase, these results demand careful interpretation. In a follow-up study of people who presented
with an initial VTE and FVIII levels >230 IU/dL, the probability of recurrent thrombosis at 2 years after discontinuing anticoagulation was 30% (95% CI: 13%–46%)
[37]. Adose-response relationship between higher levels
of FVIII and recurrence risk is now repeatedly demonstrated [38, 39].
New genetic studies can provide more insight into the
association between FVIII and VTE. Simoni etal. investigated the molecular bases of high FVIII levels in two Italian
families with severe thrombophilia [40]. Genetic analysis
revealed a 23.4kb tandem duplication of the proximal portion of the F8 gene (promoter, exon1, and large part of
intraon1) in a family with FVIII levels >400%. This mutation correlated with high FVIII levels and was absent in
the healthy controls. In another family with FVIII levels
>250%, the same F8 arrangement was identied. Carriers
of the duplication from both families showed a twofold
or greater upregulation of F8 messenger RNA (mRNA)
[40]. As personalized medicine continues to develop and
the genetic footprints of thrombophilia are identied, early
genetic screening can identify high-risk patients, and early
treatment and monitoring can prevent future VTE events.
Despite discoveries of genetic predisposition for an elevated FVIII, they can also reect acquired inammatory
conditions. Thus, a transition to thrombosis risk factors is
typically acquired.
10.4 ACQUIRED PREDISPOSING
CONDITIONS
10.4.1 Hyperhomocysteinemia
Hyperhomocysteinemia (HHC) refers to an elevation of the
plasma homocysteine levels, a metabolic substrate derived
from the amino acid methionine [14, 41]. HHC may occur
in certain medical conditions, such as renal insufciency,
hypothyroidism, or deciencies in folate, vitamin B
min B
lism of homocysteine. Warfarin use has also been suggested
to contribute to HHC, since patients often avoid green
vegetables that supply these necessary vitamins [42]. HHC
may also be suggestive of a mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. Indeed, inherited HHC can result from mutations in the genes coding
enzymes involved in homocysteine metabolism: MTHFR,
cystathionine b synthase (CBS), or methionine synthase [14,
41]. The prevalence of the heterozygous MTHFR C677T
mutation is 34%–50%, and the prevalence of the homozygous mutation is 12%–15%, depending on the population.
The MTHFR A1298C mutation is less common [14, 41].
But mutations do not always lead to HHC [15]. Moreover,
they are not directly associated with thrombosis; therefore,
screening is discouraged [13].
people with HHC [43]. HHC is associated with both arterial and venous thrombosis. Fasting homocysteine levels
have been positively associated with myocardial infarction
risk in women (relative risk [RR]: 3.4, 95% CI: 1.3–8.7,
P=0.01) even after controlling for additional risk factors
[44]. HCC increased the risk of PE (OR: 5.1; 95%CI: 1.9–
13.6;P=0.001). Similarly, in a study by Lu etal. [45]total
plasma homocysteine levels were signicantly higher in
patients with PEthan in healthy control subjects (16.6 ±
1.8μmol/L vs 12.5 ± 1.5μmol/L;P< 0.01), and HHC was
an independent risk factor for PE in the Chinese population.
fully elucidated but may involve effects on the endothelium, factor V, thrombomodulin, and tissue factor [14]. The
value of evaluation remains arguable, as there is no denite
therapeutic action [46–49].
, since these vitamins are important in the metabo-
12
A 4.8-fold increased risk of VTE has been found in
The mechanism of HHC-associated thrombosis is not
10.4.2 Antiphospholipid antibody
syndrome
Antiphospholipid syndrome (APLS) is a systemic, antibody-mediated hypercoagulable state, dened as clinically
manifested with arterial, venous, or small vessel thrombosis and/or recurrent early pregnancy loss, fetal loss, or
pregnancy morbidity [50]. The diagnostic criteria require
persistently positive antiphospholipid antibodies, including
lupus anticoagulant, anticardiolipin, or anti-B2glycoprotein
antibodies. The antiphospholipid antibodies can exist in the
absence of clinical criteria or temporarily after treatment
with certain medications and also during periods of infection, yet the clinical signicance in these scenarios is unclear
[51]. This stresses the persistence of the antibodies as part
of the diagnostic criteria. Antiphospholipid antibodies are
found after COVID infection as well. While the presence of
, or vita-
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APL antibodies appears to be associated with disease severity, there is no clear association with mortality [52, 53].
Although laboratory evidence of APLS is considered
an indication for indenite anticoagulant therapy, the data
on recurrence risk are heterogeneous. Yet, in a meta-analysis comparing patients with APLS, the unadjusted RR
for recurrent VTE after stopping anticoagulant therapy in
patients with an anticardiolipin antibody was 1.5 (95% CI,
0.8–3.1) and higher for patients with a lupus anticoagulant:
2.8 (95% CI, 0.8–9.6) [54]. The only oral agent recommended for chronic anticoagulation of APLS remains warfarin, at a moderate intensity of 2–3 INR [55]. Although
there is active research on alternative options, research on
direct oral anticoagulants has repeatedly failed in proving
efcacy; thus, the risk of recurrent thrombosis with direct
oral anticoagulants compared to warfarin is higher (RR
2.6, 95% CI 1.4–4.7) and more so for arterial events [56].
Patients with triple-positive disease appear to be at even
higher risk of anticoagulation failure when treated with
direct oral anticoagulants (RR 4.5, 95% CI 1.9–10.6) [56].
There are other manifestations of this syndrome [50].
Patients may have skin manifestations including livedo
reticularis or cutaneous ulcerations. Hematologic ndings
can include thrombocytopenia or hemolytic anemia. Other
systemic complications are valvular heart disease, nephropathy, and psychiatric complications such as psychosis,
delirium, depression, anxiety, and aggressive behavior [57].
The most severe form of APLS is catastrophic antiphospholipid syndrome, in which patients develop multiorgan
involvement including small vessel ischemia [58]. Given
the severity of the often-fatal nature of the disease, the persistence of antibodies is not mandatory for the diagnosis.
10.4.3 Cancer
VTE is a major cause of morbidity and mortality among
patients with cancer. The frequency of new and recurrent
VTE is much higher in patients with cancer than in patients
without cancer.
In addition, early VTE is an independent predictor of
mortality [59]. Leukocytosis, immobility, metastatic disease, and PE at presentation are predictors of early mortality [60]. Low-molecular-weight heparin or, among
patients without a high risk of gastrointestinal or genitourinary bleeding, direct oral anticoagulants are the preferred choices for anticoagulation [61, 62]. Despite therapy
advances, the rate of anticoagulation failure remains a concern; in clinical trials, the 6-month incidence of VTE recurrence on anticoagulation occurs in 1:10 to 1:20 patients
with cancer-associated thrombosis [63–65].
Primary prevention of cancer-associated thrombosis is increasingly considered in surgical and nonsurgical
patients. Patient selection is the cornerstone of balancing
thrombotic risk versus bleeding likelihood. The most validated risk tool for extended VTE prophylaxis in a patient
with cancer is the Khorana score. The Khorana score is
anchored on cancer type, BMI, white count, hemoglobin,
and platelet count [66, 67]. Although there are concerns
about the generalizability of this score, there are now prospective data demonstrating a lower risk of cancer-associated thrombosis among selected patients given 6 months of
prophylaxis [66–68].
10.4.4 Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is a severe
pathological adverse effect of heparin that involves an
immunoglobulin-mediated response to the heparin molecule, leading to platelet activation and thrombin generation. Although heparin-induced antibody formation occurs
in <1%–20% of heparin-treated patients, most of these
patients never develop thrombosis. Without treatment, the
rate of thrombosis is approximately 6% per day, adding
to 20%–60% of the cases. Thus, early suspicion is imperative. HIT can cause VTE as well as arterial thrombosis.
Bleeding complications are also a concern during the treatment of the disease. Thrombocytopenia is frequently seen
in hospitalized patients, which creates a diagnostic challenge. Akey aspect of HIT pathophysiology is thrombocytopenia which usually occurs between 5 and 10 days after
exposure [69]. Not surprisingly, timing is a component of
the 4T score. The percentage drop in the platelets (thrombocytopenia), new thrombosis, other potential causes, and
timing of the platelet falling are also components of the 4T
score. Ascore of <3 has a high negative predictive value of
0.99 [70]. Patients with intermediate and high probability
scores require further evaluation. Laboratory assays can
detect the presence of anti-PF4/heparin antibodies using
functional (platelet activation assays) or immunoassay
testing. While immunoassays are ubiquitous due to their
technical simplicity and high sensitivity (>99%), the specicity is low (30%–70%) [71]. Functional assays (i.e., functional ow cytometric assay [72], C-serotonin release assay
[73], heparin-induced platelet aggregation [74], platelet
aggregation test [75]) have a superior specicity of over
95% [76]. Thus, when assessing a patient with suspected
HIT, heparin products should be interrupted in any patient
with intermediate or high risk while an immunoassay is
ordered. If the immunoassay is positive, functional conrmation is needed. Patients with low clinical probability do
not need laboratory workup [77].
The treatment of choice may vary depending on renal
and liver function as well as the bleeding risk. Direct
thrombin inhibitors such as argatroban or bivalirudin are
convenient due to a shorter half-life, while fondaparinux
and direct oral anticoagulants are alternative options for
patients who do not need procedures. Similarly, if a patient
has a remote history of HIT, these are preferred options for
prophylaxis instead of heparin products [77].
10.4.5 Myeloproliferative disorders
Chronic myeloproliferative neoplasms (MPNs) are characterized by clonal proliferation of hematopoietic cells
and are associated with thrombo-hemorrhagic complications and a propensity to transform into myelobrosis or
acute leukemia. Patients may present with polycythemia
vera (PV), essential thrombocythemia (ET), and primary
myelobrosis (PMF). The molecular abnormality V617F
mutation in theJAK2exon 14 is prevalent and aids in the
diagnosis of these patients [78]. The rate of arterial and
venous thrombosis is higher in patients with MPN, with a
cumulative rate of 3.8 events per 100 person-years [79]. In
ET, the incidence of arterial events is twice as high as that
of venous events [80]. While rare in other thrombophilia,
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splanchnic vein thrombosis, including Budd–Chiari syndrome, can be a complication of MPN. The hypercoagulable state is mediated not only by cell burden but also by an
excess of circulating microparticles and prevalent activated
protein C resistance, which is mediated by the secretion
of inammatory cytokines and the expression of adhesion
molecules [81].
Twice-daily low-dose aspirin is recommended to prevent arterial thrombotic recurrence in MPN [81]. Oncedaily dosing appears inadequate given the faster renewal
of platelet cyclooxygenase-1 [80]. Some patients may also
need phlebotomy, hydroxyurea, and interferon-α according to their presentation. Long-term anticoagulation is also
recommended after a VTE.
10.4.6 COVID
COVID-19 is a very serious infection involving virus-induced inammation that is associated with several pathophysiologic reactions, including tissue factor release,
thrombin generation, and activation of brinolysis, all of
which may produce clinical bleeding and/or thrombosis.
This illness attacks vascular endothelium anywhere in the
body, but there is a predilection for this endotheliitis to
occur in the alveolar area [82]. The virus enters the endothelial cells as a spike glycoprotein facilitated by ACE 2
receptors. The clinical manifestations of this process include
thrombosis, brinolysis, increased vascular permeability,
vasodilatation, bradycardia, angioedema, histamine release,
and hypotension. We now realize that the administration of
adequate anticoagulation very early in the disease is important to minimize the incidence of VTE and death.
Clinical trials have shown the value of early anticoagulation therapy, although the use of prophylactic or therapeutic dosing has been debated. The clinical trials to date
have produced a somewhat surprising conclusion that full
anticoagulation early in the disease to hospitalized patients
not in intensive care reduces the incidence of thrombosis
by 50% with a low bleeding rate. Conversely, seriously ill
patients in the ICU, including those requiring mechanical
ventilation, did not benet from full anticoagulation compared to prophylactic levels. Using therapeutic anticoagulation in these seriously ill patients tripled the incidence of
bleeding [83–86].
One possible explanation is therapeutic anticoagulation
administered early in the disease blocked plasma coagulation factor XII, limiting the synergistic effects of activation of factor XII and the virus on thrombosis, brinolytic,
immunologic, and inammatory pathways. The value of
vaccination, including booster updates, has been demonstrated to signicantly reduce the incidence, morbidity, and
mortality associated with this disease. Adverse reactions
following vaccination are extremely rare, although they
can be quite serious [87].
Individual risk assessment has been done in one small
trial using either the IMPROVEDD score or Caprini Risk
Score (CRS) in COVID-19 patients. Those patients with a
low IMPROVEDD score had a 15% incidence of mortality
compared to those with a high-risk score, where the mortality was 66%–68%. Those patients with a CRS of 0–2
had a death rate of 0%, whereas it rose to 80% in those
with a score of 9+ [88]. Individual risk assessment has also
been proposed to provide extended prophylaxis to those
patients who are high risk. Patients with an IMPROVEDD
VTE score of ≥4 or 2–3 with a D-dimer >500 ng/mL were
randomly assigned (1:1) to receive rivaroxaban 10 mg/day
or no anticoagulation for 35 days at hospital discharge. The
primary efcacy outcome occurred in 5 (3%) of 159 patients
assigned to rivaroxaban and 15 (9%) of 159 patients
assigned to no anticoagulation (p=0.03). No major bleeding occurred in either study group. The authors concluded
that in patients at high risk discharged after hospitalization
due to COVID-19, thromboprophylaxis with rivaroxaban
10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis [89].
10.5 BEST PRACTICES
10.5.1 Testing
The combination of a genetic thrombophilic defect and
one or more acquired risk factors, such as surgery or oral
contraceptive use, leads to a higher risk of VTE than the
separate effects of these single factors. Universal testing
for inherited thrombophilia is inappropriate and not recommended. Anegative test only rules out the presence of
the thrombophilic defects for which the patient has been
tested and is not necessarily proof that an unidentiable
defect does not exist. Thus, in each case, evaluating and
documenting a detailed initial clinical history is crucial.
Afamily history of thrombosis is an important indicator of
increased risk in the surgical patient who has no personal
prior history of thrombosis.
Currently, there are no consistent guidelines in the literature by which patients should be considered for thrombophilia workup and which specic tests should be included
if patients are tested. Many of the function and antigen
assays for thrombophilias can be affected by a variety of
external factors, such as medications, acute thrombosis,
and other acquired conditions. Thus, these assays should
be repeated after ruling out any external factors and before
a nal diagnosis of inherited thrombophilia is made [90].
10.5.2 Risk assessment using scoring
systems
There are several scoring systems for evaluating VTE risk in
surgical patients. The most widely validated surgical score
is the CRS [91]. This construct consists of several common
risk factors, each of which is assigned a numerical weight.
This weight reects the likelihood of that factor resulting
in a thrombotic event. For example, a 42-year-old female
taking birth control pills with a BMI of 30 has a CRS of
3, since each of these three risk factors has a value of 1.
The VTE risk in this patient is low. Compare that patient
to a 76-year-old patient with a previous PE and a history
of cancer. Although the patient also has three risk factors,
his CRS is 8 (3 points each for age and PE history and 2
points for cancer). The risk of VTE is high in this patient
10.5 Best practices 101
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even though he has only three risk factors. Although both
patients have three risk factors, calculating the weight of
these risk factors more accurately predicts VTE incidence
and helps decide who would benet from anticoagulant
prophylaxis.
In studies conducted to date, the total score has been
compared to the actual development of a thrombotic
event within 30–60 days postoperatively. This system has
been tested in over 5million patients worldwide in more
than 300 publications, including both medical and surgical patients. The risk of a clinical VTE event increases as
the CRS total rises. Initially, the 2012 CHEST guidelines
reported that patients with a score of ≥5 had a 6% chance
of developing VTE [92]. Researchers worldwide have now
found that the CRS thresholds are more complicated.
Recently, an analysis of 4,207,895 patients found that the
CRS indicating high risk for VTE varied by specialty or
type of illness. CRS values in these patients varied from
2.2% to 47.1% in those with a score of ≥5 [93]. The success of the CRS in centers around the world has recently
been documented [94]. The authors state that VTE risk for
individual patients increases dramatically at a threshold
CRS of 7–11. The clinically relevant VTE rate increases
parallel to rising scores. The concept seems to hold regardless of the specialty tested. Scores of 9 or more increase the
VTE risk to nearly 40% after some type of operation in
the previous meta-analysis. It is critical to update the score
during hospitalization due to complications and before discharge. Achange in risk level may require ongoing prophylaxis following hospital discharge.
Fatal PE are the leading preventable cause of death
following surgery or hospitalization. Landmark research
organized by Professor Kakkar in 1975, followed by hundreds of additional investigations around the world using
this protocol, demonstrated how to prevent these events
[95, 96]. Alarge study by Lord Kakkar and associates in
2005 reported that 99% of these fatalities can be prevented using appropriate anticoagulant prophylaxis [97].
PE events have not decreased, which is thought to be a
result of the failure to uniformly provide prophylaxis.
As a result, researchers in the United Kingdom used individual risk assessment coupled with an evidence-based
pathway providing prophylaxis based on risk. Linking
implementation to reimbursement prevented over 900
deaths from PE in 2years. Continuing this program in
the United Kingdom and encouraging other countries to
adopt it could result in lowering the incidence of fatal PE
worldwide [98].
Another example of mandatory implementation of an
evidence-based algorithm resulting in a sustained low VTE
risk in surgical patients is seen in the Boston University
program. Boston University has shown outstanding results
using the CRS tied to a mandatory prophylaxis schema
[99]. Patients with a score of 4 or less can receive prophylaxis at the discretion of the treating physician (low to moderate risk) during hospitalization. Many of these low-risk
patients are not given anticoagulant prophylaxis since the
risk of a clinical bleeding event is greater than the chance
of a clinically evident thrombosis. On the other hand, those
with a score of 5–8 are considered high-risk and need to
BOX 10.1 Patients who may be considered for thrombophilia
workup
• Unexplained or “idiopathic” thromboembolism (rst event)
• Secondary, non-cancer-related rst event and age
<50 years (includes thrombosis on oral contraceptives
and hormone replacement therapy)
• Recurrent “idiopathic” or secondary non-cancer-related
events
• Thrombosis at unusual sites (portal vein, sinus veins, etc.)
• Extensive thrombosis
• Strong family history of venous thromboembolism
be protected for the time shown in clinical trials to prevent postoperative thrombosis. They are given prophylaxis
for 7–10 days regardless of their length of hospital stay.
Finally, patients with a score of 9 or more (highest risk) are
given prophylaxis for 30 days since the incidence of real
thrombotic events is 6%–18% in this group. These rules
are mandatory, but physicians can opt out if the bleeding
risk is high. Physician compliance in high-risk patients
was 89%, and it was 77% in the highest-risk group. The
VTE rate in general surgery was 0.2%, and the PE rate
approached zero during this time. This system at Boston
University has recorded the lowest VTE event rates ever
seen in the National Surgical Quality Improvement Project
(NSQIP) database [99]. Boston University has maintained
a very low VTE incidence for about 12years to date since
the program began. Over the years compliance continues
to improve, as all the physicians wish to share the good
results of the program with their patients. One key feature
of the program is LMWH prophylaxis was supplied to all
patients regardless of their ability to pay for the drug. This
was achieved with the cooperation of the manufacturer
and insurance programs.
10.5.3 The importance of scoring in
patients with thrombophilia
Patients with a history of thrombosis receive a score of 3
points, with an additional 3 points for those with a thrombophilic defect. Family history of thrombosis increases the
score to 9. This means that in some patients who are contemplating elective quality-of-life procedures, a high score
may cause them to rethink the advisability of going ahead
with the planned surgery. The risk of major or fatal complications in this small subset of patients may be as high
as 5%.
10.5.4 General recommendations
Informed consent should be obtained from patients, and
especially asymptomatic family members, before thrombophilia testing is performed. Counseling should be
provided to patients who test positive for one or more
thrombophilia regarding their risk of thrombosis, the
signs and symptoms of VTE, and the benets of antithrombotic prophylaxis in high-risk situations such as
elective surgery or pregnancy.
10
102 Chapter 10 Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis
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Consensus Statements 10.0 of the American Venous Forum on evaluation of hypercoagulable states and molecular
markers of acute venous thrombosis
No. Consensus Statements
10.1 Universal testing for inherited thrombophilia is inappropriate and should not be performed.
10.2 Patients with the following conditions may be considered for thrombophilia workup:
1. Unexplained or “idiopathic” thromboembolism (rst event)
2. Secondary, non-cancer-related rst event and age <50years (includes thrombosis on oral contraceptives and hormone
replacement therapy)
3. Recurrent “idiopathic” or secondary non-cancer-related events
4. Thrombosis at unusual sites (portal vein, sinus veins, etc.)
5. Extensive thrombosis
6. Strong family history of venous thromboembolism
10.3 The most widely validated surgical score for VTE risk assessment is the Caprini Risk Score (CRS). ACRS of ≥5 has a 6% chance
of developing VTE, and the risk increases signicantly at a CRS of 7–11. VTE prophylaxis in these patients has been effective.
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