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Thrombophilia: Grading the risk

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Michael Makris at The University of Sheffield
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Abstract

In this issue of Blood, Lijfering and colleagues provide data on the absolute risk for both initial and recurrent venous thromboses in persons with thrombophilia. Based on these data, they subgroup thrombophilic defects into high- and low-risk disorders. They also conclude that some defects are not independent risk factors.
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doi:10.1182/blood-2009-02-203281
2009 113: 5038-5039
Michael Makris
Thrombophilia: grading the risk
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clearance. It also remains to be seen whether
Vav3 mediates inside to outside signaling to-
ward other integrins that tether apoptotic
cells. Interestingly, the Vav3⫺/⫺KO macro-
phages also showed decreased binding to ␣v␤3
integrin, this latter integrin having been
clearly shown to recognize MFG-E8 on the
surface of apoptotic cells and promote phago-
cytic clearance.5Recent studies suggest that
␣v integrins also stimulate TGF-␤production
during physiological clearance.6
Finally, these studies raise the provocative
possibility that Vav3 may be a selective target
to alter macrophage responses in pathologic
conditions. Although in the current study the
authors showed the importance of phagocyte-
derived TGF-␤for controlling the wound
healing microenvironment, TGF-␤produced
in the microenvironment of tumors, possible
via the same clearance mechanisms described
within, promotes tumor progression and ex-
travasation of tumor cells from blood vessels,
an essential stage for metastasis.7In broader
terms, strategies to target Vav3 may open up
an important avenue of therapeutic medicine
that harnesses phagocytic responsivity to apo-
ptotic cells.
Conflict-of-interest disclosure: The authors
declare no competing financial interests. ■
REFERENCES
1. Savill JS, Wyllie AH, Henson JE, et al. Macrophage
phagocytosis of aging neutrophils in inflammation. Pro-
grammed cell death in the neutrophil leads to its recognition
by macrophages. J Clin Invest. 1989;83:865-875.
2. Sindrilaru A, Peters T, Schymeinsky J, et al. Wound
healing defect of Vav3⫺/⫺mice due to impaired ␤2-integrin–
dependent macrophage phagocytosis of apoptotic neutro-
phils. Blood. 2009;113:5266-5276.
3. Peters T, Sindrilaru A, Hinz B, Hinrichs R, et al.
Wound-healing defect of CD18(⫺/⫺) mice due to a decrease
in TGF-beta1 and myofibroblast differentiation. EMBO J.
2005;24:3400-3410.
4. Gumienny TL, Brugnera E, Tosello-Trampont AC, et
al. CED-12/ELMO, a novel member of the CrkII/
Dock180/Rac pathway, is required for phagocytosis and
cell migration. Cell. 2001;107:27-41.
5. Hanayama R, Tanaka M, Miwa K, et al. Identification of
a factor that links apoptotic cells to phagocytes. Nature.
2002;417:182-187.
6. Lacy-Hulbert A, Smith AM, Tissire H, et al. Ulcerative
colitis and autoimmunity induced by loss of myeloid alphav
integrins. Proc Natl Acad Sci U S A. 2007;104:15823-15828.
7. Padua D, Zhang XH, Wang Q, et al. TGFbeta primes
breast tumors for lung metastasis seeding through
angiopoietin-like 4. Cell. 2008;133:66-77.
●●●THROMBOSIS & HEMOSTASIS
Comment on Lijfering et al, page 5314
Thrombophilia: grading the risk
----------------------------------------------------------------------------------------------------------------
Michael Makris UNIVERSITY OF SHEFFIELD
In this issue of Blood, Lijfering and colleagues provide data on the absolute risk for
both initial and recurrent venous thromboses in persons with thrombophilia. Based
on these data, they subgroup thrombophilic defects into high- and low-risk disor-
ders. They also conclude that some defects are not independent risk factors.
Ever since the first description of antithrom-
bin deficiency as a cause of familial throm-
bophilia by Egeberg in 1965,1the number of
reported inherited risk factors for venous throm-
bosis has been increasing, especially in the past
15 years.2Most previous studies have reported
on relative rather than absolute risks and dealt
with single defects. It is clear that thrombophilia
is multi-factorial due to gene-gene and gene-
environment interactions. While relative risk is
useful in terms of learning about the pathophysi-
ology of the disease, the clinician requires abso-
lute risk information to help make decisions
about patient management.
In this study involving 3 Dutch hospitals,
Lijfering et al investigate 2479 relatives of
877 probands with thrombosis.3To avoid bias,
probands were excluded from the analysis. The
risk for a first deep vein thrombosis (DVT) was
1.52% to 1.90% per year for those with deficien-
cies of antithrombin, protein C or protein S, and
0.34% to 0.49% per year for those with factor V
Leiden, the prothrombin mutation or elevated
FVIII. Within these 2 groups, the thrombotic
risk was similar for each of the individual defects,
and in the paper, the 2 groups were classified as
high- and low-risk thrombophilias, respectively.
The risk of recurrence was 55% at 10 years for
defects in the first group, 25% for the second (see
table). Although elevated levels of FIX, XI,
TAFI, and homocysteine appeared to be associ-
ated with an increased thrombotic risk, all were
closely linked to concomitant elevated FVIII and
were not risk factors in isolation.
In analyzing the risk of venous thrombosis,
the authors assume that the risk in persons with
antithrombin, protein C, or protein S deficiency
is the same, irrespective of the severity of the
deficiency or mutation causing the defect. How-
ever, as they have recently shown in protein S
deficiency,4this may not be the case, and one
would logically expect an inverse relationship
between deficiency and risk.
Whether or not to test for thrombophilia is
controversial because the clinical utility of doing
so has not yet been proven.5For FIX, XI, TAFI,
and homocysteine, this study suggests the an-
swer is a definitive no, since elevated levels are
not associated with increased thrombotic risk
independent of elevated levels of FVIII. In the
case of heterozygosity for factor V Leiden, or the
prothrombin mutation, or for elevated FVIII,
the answer is also probably no because the risk of
a first DVT at under 0.5% per year is not high
enough to warrant primary warfarin prophylaxis
and the recurrence risk is no different from that
reported for patients with first DVT who have
not been tested for thrombophilia.6
More difficult is the issue of the higher risk
thrombophilias represented by the deficiencies
of the natural anticoagulants antithrombin, pro-
tein C, and protein S. The authors suggest that
these are conditions with a much higher risk of
first and recurrent thrombosis and should be
managed differently from the commoner throm-
bophilias. Although based on these data alone
Based on the annual risk of first venous thrombosis and recurrence risk, thrombophilic defects can be
subdivided into 3 groups.
5038 21 MAY 2009 IVOLUME 113, NUMBER 21 blood
For personal use only. by guest on December 31, 2011. bloodjournal.hematologylibrary.orgFrom
there would be reluctance to advocate long-term
primary prophylaxis, this should certainly be
offered at times of additional high risk, such as
after surgery, immobility, or pregnancy.
Clinically, the issue of thrombophilia testing
and management is more relevant in the setting
of patients who have experienced an event al-
ready. If testing has been performed and high-
risk thrombophilia has been identified, this
should certainly be taken into account when de-
ciding on extended anticoagulation, especially
for spontaneous events. The issue of whether all
patients with a DVT should be screened for
high-risk thrombophilia is unresolved7but, for
those with a spontaneous event at a young age
and a positive family history, this should be con-
sidered. Definition of a positive family history is
difficult, but the suggestion offered in this paper
of more than 20% of relatives affected is not
evidence-based and would be dependent on
relatives being available for study.8
Any decision on whether to offer long-term
anticoagulation will depend on the risk of bleed-
ing while on anticoagulants as well as the throm-
botic risk. This study reports a very low annual
bleeding risk at 0.29% but with wide confidence
intervals, because it is based on only 2 events.
The authors speculate that this may be because
the thrombophilic defect reduces the bleeding
risk, and this observation certainly requires con-
firmation. Alternative explanations are the young
age of the cohort, the fact that the patients are
cared for by expert centers, and the small num-
ber of events.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Egeberg O. Inherited antithrombin deficiency caus-
ing thrombophilia. Thromb Diath Haemorrh. 1965;13:
516-530.
2. Raffini L. Thrombophilia in children: Who to test, how,
when and why? Hematology Am Soc Hematology Educ
Program. 2008;2008:228-235.
3. Lijfering WM, Brouwer J-LP, Veeger NJGM, et al.
Selective testing for thrombophilia in patients with first
venous thrombosis: results from a retrospective family
cohort study on absolute thrombotic risk for currently
known thrombophilic defects in 2479 relatives. Blood.
2009;113:5314-5322.
4. Lijfering WM, Mudler R, ten Kate MK, et al. Clinical
relevance of decreased protein S levels: results from a retro-
spective family cohort involving 1143 relatives. Blood.
2009;113:1225-1230.
5. Simpson EL, Stevenson MD, Rawdin A, et al. Throm-
bophilia testing in people with venous thromboembolism:
systematic review and cost effectiveness analysis. Health
Technology Assessment. 2009;13:1-91.
6. Prandoni P, Lensing AWA, Cogo A, et al. The long
term clinical course of acute deep vein thrombosis. Ann
Intern Med. 1996;125:1-7.
7. Cohn D, Vansenne F, de Borgie C, et al. Thrombophilia
testing for prevention of recurrent venous thromboembolism.
Cochrane Database of Systematic Reviews. 2009;1. Art.
No.: CD007069. DOI: 10.1002/14651858.CD007069.
pub2
8. Cosmi B, Legnani C, Bernardi F, et al. Role of family
history in identifying women with thrombophilia
and higher risk of venous thromboembolism during
oral contraception. Arch Intern Med. 2003;163:
1105-1109.
●●● THROMBOSIS & HEMOSTASIS
Comment on Banno et al, page 5323
ADAMTS13’s tail tale
----------------------------------------------------------------------------------------------------------------
Karen Vanhoorelbeke, Hendrik B. Feys, and Simon F. De Meyer KATHOLIEKE UNIVERSITEIT LEUVEN,
CAMPUS KORTRIJK
In mice, a long form and a short form of the VWF-cleaving protease ADAMTS13
have been identified, the latter lacking the 4 distal carboxyl-terminal domains.
While these are not strictly required for regulating normal size distribution of
VWF multimers, in this issue of Blood, Banno and colleagues reveal the role of
these domains in down-regulating thrombogenesis in vivo.
Since the discovery of ADAMTS13 as a
metalloprotease with a multi-domain
structure, numerous studies have attempted to
shed light on the specific roles of each of the
ADAMTS13 domains in digesting large
von Willebrand factor (VWF) multimers into
smaller, less reactive ones. ADAMTS13 is com-
posed of a signal peptide, propeptide, metallo-
protease domain, central TSR (thrombospondin
type 1 repeat), Cys-rich region, spacer domain,
7 additional TSRs, and 2 CUB domains. The
active site of this enzyme is situated in the metal-
loprotease domain while the spacer domain plays
a crucial role in substrate binding by interacting
with a VWF exosite located at the C-terminus of
the A2 domain. The exact physiologic signifi-
cance of the carboxyl-terminal TSRs and the
2 CUB domains still remains unclear, in particu-
lar due to the use of different types of in vitro
tests, often performed under nonphysiological
conditions.
To unravel the in vivo role of the carboxyl-
terminal domains of ADAMTS13, Banno and
coworkers elegantly take advantage of the pres-
ence of 2 kinds of Adamts13 genes in laboratory
mouse strains.1The 129/Sv strain has the
Adamts13 gene encoding full-length ADAMTS13
while several other strains, including C57BL/6,
harbor an Adamts13 gene that expresses a trun-
cated form of the enzyme, lacking the 2 C-
terminal TSRs and CUB domains due to the
insertion of an intracisternal A-particle retro-
transposon. By introgressing the C57BL/6-
Adamts13 gene onto the 129/Sv genetic back-
ground, the authors generate congenic mice
that had the distal C-terminally truncated
ADAMTS13 on a 129/Sv genetic background
(Adamts13S/S) and use wild-type mice that have
full-length ADAMTS13 (Adamts13L/L) and
ADAMTS13⫺/⫺mice on the same 129/Sv ge-
netic background for comparison.
The most obvious role of ADAMTS13 is to
regulate VWF multimer size. Indeed,
ADAMTS13 digests unusually large VWF mul-
timers into smaller less thrombogenic forms,2
hence preventing the spontaneous intravascular
platelet aggregation seen in patients with
ADAMTS13 deficiency. Interestingly, Banno et
al showed that both Adamts13L/L and
Adamts13S/S mice do not have ultra large VWF
multimers in their plasma, implying that the
C-terminal domains are not strictly needed for
maintaining normal VWF size. Consequently,
the 2 C-terminal TSRS and CUB domains are
not essential for the removal of ultralarge VWF
multimers from the plasma.
Following VWF size regulation, a fascinating
role of ADAMTS13 in attenuating thrombus
growth has been described, possibly by cleaving
VWF multimers that are peripheral to or incor-
porated in platelet rich thrombi.3In this study,
Banno et al used the congenic mice to demon-
strate that the 2 C-terminal TSRs and CUB do-
mains play a role in the down-regulation of
thrombogenesis under high shear conditions.
Both in vitro flow chamber experiments at high
shear rates and in vivo thrombosis models show
that blood from Adamts13S/S mice is more
thrombogenic. This is evidenced by accelerated
thrombus formation and decreased time to oc-
clusion respectively when compared with blood
from Adamts13L/L mice. Whether this would
blood 21 MAY 2009 IVOLUME 113, NUMBER 21 5039
For personal use only. by guest on December 31, 2011. bloodjournal.hematologylibrary.orgFrom
... 133 A distinction is made between low-risk or 'mild' and high-risk or 'severe' thrombophilias based on the annual risks for the first DVT and risk of recurrent VTE. 134 Heterozygous mutations in Factor V Leiden (FVL) and prothrombin-G20210A (PTG) are classified as 'mild' thrombophilias whilst severe thrombophilias include double heterozygosity or homozygosity of FVL and PTG, deficiency of antithrombin (AT), protein C (PC), protein S (PS) or persistently high titres of lupus anticoagulant (LAC). ...
... 136,137 Antiphospholipid syndrome (APS) is the most common acquired thrombophilia imposing a high-risk for both venous and arterial thrombosis, stroke and heart attacks. 134 Antiphospholipid antibodies are present in 1-5% of the general population 138 and in 30-40% of patients with SLE. 139 APS may also be associated to a lesser extent with other autoimmune conditions, infections, drugs and malignancies. ...
... and risk for recurrent VTE is 40% at 5 years and 55% at 10 years. 134 Two or more different types of thrombophilias may be concurrently present in 30% of patients such as FVL mutation combined with antiphospholipid antibodies. 140 VTE risk with multiple thrombophilias is exponentially higher than that for individual abnormalities. ...
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... 133 A distinction is made between low-risk or 'mild' and high-risk or 'severe' thrombophilias based on the annual risks for the first DVT and risk of recurrent VTE. 134 Heterozygous mutations in Factor V Leiden (FVL) and prothrombin-G20210A (PTG) are classified as 'mild' thrombophilias whilst severe thrombophilias include double heterozygosity or homozygosity of FVL and PTG, deficiency of antithrombin (AT), protein C (PC), protein S (PS) or persistently high titres of lupus anticoagulant (LAC). ...
... 136,137 Antiphospholipid syndrome (APS) is the most common acquired thrombophilia imposing a high-risk for both venous and arterial thrombosis, stroke and heart attacks. 134 Antiphospholipid antibodies are present in 1-5% of the general population 138 and in 30-40% of patients with SLE. 139 APS may also be associated to a lesser extent with other autoimmune conditions, infections, drugs and malignancies. ...
... and risk for recurrent VTE is 40% at 5 years and 55% at 10 years. 134 Two or more different types of thrombophilias may be concurrently present in 30% of patients such as FVL mutation combined with antiphospholipid antibodies. 140 VTE risk with multiple thrombophilias is exponentially higher than that for individual abnormalities. ...
Sclerotherapy of lower limb veins: Indications, contraindications and treatment strategies to prevent complications - A consensus document of the International Union of Phlebology-2023
Article
Full-text available
  • Mar 2023
  • Phlebology
Background: Sclerotherapy is a non-invasive procedure commonly used to treat superficial venous disease, vascular malformations and other ectatic vascular lesions. While extremely rare, sclerotherapy may be complicated by serious adverse events. Objectives: To categorise contraindications to sclerotherapy based on the available scientific evidence. Methods: An international, multi-disciplinary panel of phlebologists reviewed the available scientific evidence and developed consensus where evidence was lacking or limited. Results: Absolute Contraindications to sclerotherapy where the risk of harm would outweigh any benefits include known hypersensitivity to sclerosing agents; acute venous thromboembolism (VTE); severe neurological or cardiac adverse events complicating a previous sclerotherapy treatment; severe acute systemic illness or infection; and critical limb ischaemia. Relative Contraindications to sclerotherapy where the potential benefits of the proposed treatment would outweigh the risk of harm or the risks may be mitigated by other measures include pregnancy, postpartum and breastfeeding; hypercoagulable states with risk of VTE; risk of neurological adverse events; risk of cardiac adverse events and poorly controlled chronic systemic illness. Conditions and circumstances where Warnings and Precautions should be considered before proceeding with sclerotherapy include risk of cutaneous necrosis or cosmetic complications such as pigmentation and telangiectatic matting; intake of medications such as the oral contraceptive and other exogenous oestrogens, disulfiram and minocycline; and psychosocial factors and psychiatric comorbidities that may increase the risk of adverse events or compromise optimal treatment outcomes. Conclusions: Sclerotherapy can achieve safe clinical outcomes provided that (1) patient-related risk factors and in particular all material risks are (1a) adequately identified and the risk benefit ratio is clearly and openly discussed with treatment candidates within a reasonable timeframe prior to the actual procedure; (1b) when an individual is not a suitable candidate for the proposed intervention, conservative treatment options including the option of 'no intervention as a treatment option' are discussed; (1c) complex cases are referred for treatment in controlled and standardised settings and by practitioners with more expertise in the field; (1d) only suitable individuals with no absolute contraindications or those with relative contraindications where the benefits outweigh the risks are offered intervention; (1e) if proceeding with intervention, appropriate prophylactic measures and other risk-mitigating strategies are adopted and appropriate follow-up is organised; and (2) procedure-related risk factors are minimised by ensuring the treating physicians (2a) have adequate training in general phlebology with additional training in duplex ultrasound, procedural phlebology and in particular sclerotherapy; (2b) maintain their knowledge and competency over time and (2c) review and optimise their treatment strategies and techniques on a regular basis to keep up with the ongoing progress in medical technology and contemporary scientific evidence.
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... However, in both studies, the demonstrated sensitivity and specificity at this level suggest that the serum Apelin-13 level can serve as a novel diagnostic biomarker for individuals with pulmonary thromboembolism. Makris et al. reported that the most specific test to confirm the definitive diagnosis of pulmonary thromboembolism is selective pulmonary angiography, which can also detect emboli as small as 1-2 mm, but this method is invasive and causes possible complications in the patient [32]. Also, although CT angiography has recently been proposed as a diagnostic gold standard in studies [33], for people who have a low susceptibility based on the existing criteria and scores for diagnosis, performing this method is not justified. ...
Evaluation of elevated serum apelin-13 and D-dimer concentrations in individuals diagnosed with pulmonary embolism
Article
Full-text available
  • Apr 2024
Background Given the limited specificity of D-dimer, there is a perceived need to discover a more precise marker for diagnosing individuals who are suspected of having pulmonary embolism (PE). In this study, by evaluating the increase in the serum level of Apelin-13 and D-dimer, we found valuable findings about Apelin-13, which can be suggested as an auxiliary and non-invasive diagnostic biomarker in individuals with suspected PE, based on the obtained results. Methods In this case-control study, 52 Iranian individuals were included, all of whom were suspected to have PE. These individuals were then divided into two groups based on the results of CT angiography, which is considered the gold standard imaging method for diagnosing PE. The two groups were patients with PE and patients without PE. Finally, the levels of certain markers in the serum were compared between the two groups. Results The mean serum D-dimer levels in patients with PE were significantly elevated (p < 0.001) in comparison to those without PE (1102.47 to 456.2 ng/ml). Furthermore, the mean level of Apelin-13 was significantly higher in patients with PE (49.8 to 73.11 ng/L) (p < 0.001). The cutoff point of Apelin-13 has been calculated at 58.50 ng/ml, with 90.9% sensitivity and 90% specificity. The D-dimer cutoff point was 500 ng/ml, with 95.5% sensitivity and 43.3% specificity. Conclusions Based on the results of this study, the serum level of Apelin-13 can be used as a novel diagnostic and screening biomarker in patients with pulmonary thromboembolism.
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... Makris et al reprted that the most speci c test to con rm the de nitive diagnosis of pulmonary thromboembolism is selective pulmonary angiography, which can also detect emboli as small as 1-2 mm, but this method is invasive and causes possible complications in the patient (45). ...
Evaluation of Elevated Serum Apelin-13 and D-dimer Concentrations in Individuals Diagnosed with Pulmonary Embolism
Preprint
Full-text available
  • Dec 2023
Background: Given the limited specificity of D-dimer, there is a perceived need to discover a more precise marker for diagnosing individuals who are suspected of having pulmonary embolism (PE). In this study, by Evaluating the increase in the serum level of Apelin-13 and D-dimer, we found valuable findings about Apelin-13, which can be suggested as an auxiliary and non-invasive diagnostic biomarker in individuals with suspected PE, based on the obtained results. Methods: In this case-control study, 52 Iranian individuals with a suspicion of pulmonary embolism, were included and then were separated into two groups based on CT angiography results serving as the gold standard imaging method for diagnosing PE: patients with and without PE. Finally, the serum levels of these markers were compared in these two groups. Results: The mean serum D-dimer levels in patients with PE were significantly elevated (p<0.001) in comparison to those without PE (1102.47 to 456.2 ng/ml). Furthermore, the mean level of Apelin-13 was significantly higher in patients with PE (49.8 to 73.11 ng/L) (p <0.001). The cutoff point of Apelin-13 has been calculated 58.50 ng/ml, with 90.9% sensitivity and 90% specificity. The D-dimer cutoff point was 500 ng/ml, with 95.5% sensitivity and 43.3% specificity. Conclusions: Based on the results of this study, the serum level of Apelin-13 can be used as novel diagnostic and screening biomarker in patients with pulmonary thromboembolism Keywords: Pulmonary embolism, Thromboembolism, Apelin-13, D-dimer.
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... Varrias et al factor V Leiden, prothrombin gene mutations, factor VIII deficiency, and low-risk thrombophilias encompass factor XI, factor IX, and hyperhomocysteinemia. 40 Furthermore, additional criteria such as the zygosity of the mutation and prior personal or family history significantly influence the risk for VTE in pregnancy. 35 As more of those criteria are met, the risk of thrombosis increases. ...
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Enfermedad Tromboembolica Primaria, Revisión de la Literatura Hacia una Aproximación Terapéutica Basado en la Evidencia Científica
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La hipercoagulabilidad o trombofilia es el aumento de la tendencia de la sangre a la trombosis. Una respuesta normal y saludable al sangrado para mantener la hemostasia involucra la formación de un coágulo estable, y el proceso se llama coagulación. La hipercoagulabilidad describe el estado patológico de coagulación exagerada o coagulación en ausencia de sangrado. La trombosis arterial, como en el infarto de miocardio y el accidente cerebrovascular, es diferente de las trombosis venosas, como la trombosis venosa profunda (TVP) y la embolia pulmonar (EP). Esta actividad repasa la causa y presentación de la hipercoagulabilidad y destaca el papel del equipo interprofesional en su manejo
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Approach to Thrombophilia in Pregnancy—A Narrative Review
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Thrombophilia is a genetic predisposition to hypercoagulable states caused by acquired haemostasis conditions; pregnancy causes the haemostatic system to become hypercoagulable, which grows throughout the pregnancy and peaks around delivery. Genetic testing for thrombophilic gene mutations is evaluated using different methodologies of real-time polymerase chain reaction and DNA microarrays of specific genes. Adapting the general care of the pregnant woman to the particularities caused by thrombophilia is an important component, so screening is preferred to assess the degree of genetic damage that manifests itself as a risk of thrombosis. The major goal of this narrative review was to quantitatively evaluate the literature data on the specific care of pregnant women with thrombophilia that are at risk of developing unplanned miscarriages.
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Full-text available
  • May 2009
To assess the effectiveness and cost-effectiveness of breaks in care in improving the well-being of informal carers of frail and disabled older people living in the community and to identify carer needs and barriers to uptake of respite services. Major electronic databases were searched from the earliest possible date to April 2008. Selected studies were assessed and subjected to extraction of numerical data for meta-analysis of quantitative studies and extraction of text for thematic analysis of qualitative studies. Quality of the studies was assessed using checklists specifically designed for the current review. In total, 104 papers were identified for inclusion in the quantitative synthesis, 16 of which were appropriate for meta-analysis. Carer burden was reduced at 2-6 months' follow-up in single-sample studies but not in randomised controlled trials (RCTs) and quasi-experimental studies. Depression was reduced in RCTs in the short term and for home care but not for day care. These effects, however, were not significant in random-effects models. There was a trend for longer interventions to have more positive effects than shorter interventions. There was no effect of respite on anxiety, but it had positive effects on morale and anger and hostility. Single-group studies suggested that quality of life was worse after respite use. There were increased rates of institutionalisation after respite use; however, this does not establish a causal relationship as it may be a result of respite being provided late in the caregiving career. A total of 70 papers were identified for inclusion in the qualitative synthesis. Uptake of respite care was influenced by: carer attitudes to caring and respite provision; the caregiving relationship; knowledge of, and availability of, services; the acceptability to, and impact of respite care on, care recipients; hassles resulting from the use of respite care; quality of respite care; and the appropriateness and flexibility of service provision. Carers expressed needs for active information provision about services, support offered early in the caregiving career, access to a variety of services with flexible provision, reliable transport services, continuity of care, good-quality care, appropriate environments, care that provides benefits for care recipients (socialisation and stimulation), and appropriate activities for care recipients' levels of abilities and interests. There was some evidence to support respite having a positive effect on carers but the evidence was limited and weak. It is difficult, therefore, to make recommendations as to the most appropriate form of delivery of respite, apart from the suggestion that a range of services is probably most appropriate, to provide flexibility of respite provision and responsiveness to carer and care recipient characteristics and needs and also changes in those needs over time. There is a need for further high-quality larger trials that include economic evaluations.
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Selective testing for thrombophilia in patients with first venous thrombosis: Results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives
Article
Full-text available
  • May 2009
  • BLOOD
Thrombophilia screening is controversial. In a retrospective family cohort, where probands had thrombosis and a thrombophilic defect, 2479 relatives were tested for thrombophilia. In antithrombin-, protein C-, and protein S-deficient relatives, annual incidences of venous thrombosis were 1.77% (95% CI, 1.14-2.60), 1.52% (95% CI, 1.06-2.11), and 1.90% (95% CI, 1.32-2.64), respectively, at a median age of 29 years and a positive family history of more than 20% symptomatic relatives. In relatives with factor V (FV) Leiden, prothrombin 20210G>A, or high FVIII levels, these were 0.49% (95% CI, 0.39-0.60), 0.34% (95% CI, 0.22-0.49), and 0.49% (95% CI, 0.41-0.51), respectively. High FIX, FXI, and TAFI, and hyperhomocysteinemia were not independent risk factors. Annual incidence of major bleeding in antithrombin-, protein C-, or protein S-deficient relatives on anticoagulants was 0.29% (95% CI, 0.03-1.04). Cumulative recurrence rates in relatives with antithrombin, protein C, or protein S deficiency were 19% at 2 years, 40% at 5 years, and 55% at 10 years. In relatives with FV Leiden, prothrombin 20210G>A, or high levels FVIII, these were 7%, 11%, and 25%, respectively. Considering its clinical implications, thrombophilia testing should address hereditary deficiencies of antithrombin, protein C, and protein S in patients with first venous thrombosis at young age and/or a strong family history of venous thrombosis.
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Thrombophilia testing in people with venous thromboembolism: Systematic review and cost-effectiveness analysis
Article
Full-text available
  • Feb 2009
To assess whether thrombophilia testing following a venous thrombotic event is clinically effective and cost-effective in the management of thrombosis compared with no testing for thrombophilia. Major electronic databases were searched from September to November 2006. A systematic review of the clinical effectiveness and cost-effectiveness literature was undertaken according to standard methods. A discrete event simulation model was constructed to assess the cost-effectiveness of changing the standard 3-month duration of warfarin treatment to 10 years, 20 years or lifelong. No clinical studies were identified that met the inclusion criteria for the systematic review. Further literature searches and clinical opinion were therefore used to inform the cost-effectiveness analysis. Thrombophilia testing in patients with pulmonary embolism (PE) had an estimated mean cost per quality-adjusted life-year (QALY) of below 20,000 pounds regardless of sex or age. In patients with a previous deep vein thrombosis (DVT), thrombophilia testing had an estimated mean cost per QALY of below 20,000 pounds in men aged 69 years or less and in women aged 49 years or less. The estimated duration of warfarin treatment (lifelong, 20 years, 10 years or no extended treatment) that was most cost-effective is presented for each age, sex, initial venous thromboembolism (VTE) event and type of thrombophilia. In terms of determining the duration of anticoagulation management, scenarios were found in which the cost per QALY of thrombophilia testing was below 20,000 pounds. However, these results are subject to great uncertainty, largely because of lack of knowledge about the increased risk of recurrence with each type of thrombophilia. Results are influenced by the fact that men have a greater risk of recurrence than women and by the fact that the frequency of adverse events associated with warfarin treatment increases with age. Further research, for example on the likely sensitivity and specificity of the tests for specific types of thrombophilia, is needed to reduce the uncertainty associated with these results. Studies comparing patients with VTE tested for thrombophilia with those whose risk assessment was based on personal and family history of thrombosis would also be beneficial.
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Clinical relevance of decreased free protein S levels: Results from a retrospective family cohort study involving 1143 relatives
Article
Full-text available
  • Oct 2008
  • BLOOD
Conflicting data have been reported on the risk for venous thrombosis in subjects with low free protein S levels. We performed a post-hoc analysis in a single-center retrospective thrombophilic family cohort, to define the optimal free protein S level that can identify subjects at risk for venous thrombosis. Relatives (1143) were analyzed. Relatives with venous thrombosis (mean age 39 years) had lower free protein S levels than relatives without venous thrombosis (P < .001), which was most pronounced in the lowest quartile. Only relatives with free protein S levels less than the 5th percentile (< 41 IU/dL) or less than the 2.5th percentile (< 33 IU/dL) were at higher risk of first venous thrombosis compared with the upper quartile (> 91 IU/dL); annual incidence 1.20% (95% confidence interval [CI], 0.72-1.87) and 1.81% (95% CI, 1.01-2.99), respectively; adjusted hazard ratios 5.6, (95% CI, 2.7-11.5) and 11.3 (95% CI, 5.4-23.6). Recurrence rates were 12.12% (95 CI, 5.23-23.88) and 12.73% (95% CI, 5.12-26.22) per year; adjusted hazard ratios were 3.0 (95% CI, 1.03-8.5) and 3.4 (95% CI, 1.1-10.3). In conclusion, free protein S level can identify young subjects at risk for venous thrombosis in thrombophilic families, although the cutoff level lies far below the normal range in healthy volunteers.
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The long term clinical course of acute deep vein thrombosis
Article
Full-text available
  • Aug 1996
In patients who have symptomatic deep venous thrombosis, the long-term risk for recurrent venous thromboembolism and the incidence and severity of post-thrombotic sequelae have not been well documented. To determine the clinical course of patients during the 8 years after their first episode of symptomatic deep venous thrombosis. Prospective cohort study. University outpatient thrombosis clinic. 355 consecutive patients with a first episode of symptomatic deep venous thrombosis. Recurrent venous thromboembolism, the post-thrombotic syndrome, and death. Potential risk factors for these outcomes were also evaluated. The cumulative incidence of recurrent venous thromboembolism was 17.5% after 2 years of follow-up (95% CI, 13.6% to 22.2%), 24.6% after 5 years (CI, 19.6% to 29.7%), and 30.3% after 8 years (CI, 23.6% to 37.0%). The presence of cancer and of impaired coagulation inhibition increased the risk for recurrent venous thromboembolism (hazard ratios, 1.72 [CI, 1.31 to 2.25] and 1.44 [CI, 1.02 to 2.01], respectively). In contrast, surgery and recent trauma or fracture were associated with a decreased risk for recurrent venous thromboembolism (hazard ratios, 0.36 [CI, 0.21 to 0.62] and 0.51 [CI, 0.32 to 0.87], respectively). The cumulative incidence of the post-thrombotic syndrome was 22.8% after 2 years (CI, 18.0% to 27.5%), 28.0% after 5 years (CI, 22.7% to 33.3%), and 29.1% after 8 years (CI, 23.4% to 34.7%). The development of ipsilateral recurrent deep venous thrombosis was strongly associated with the risk for the post-thrombotic syndrome (hazard ratio, 6.4; CI, 3.1 to 13.3). Survival after 8 years was 70.2% (CI, 64.7% to 75.6%). The presence of cancer increased the risk for death (hazard ratio, 8.1; CI, 3.6 to 18.1). Patients with symptomatic deep venous thrombosis, especially those without transient risk factors for deep venous thrombosis, have a high risk for recurrent venous thromboembolism that persists for many years. The post-thrombotic syndrome occurs in almost one third of these patients and is strongly related to ipsilateral recurrent deep venous thrombosis. These findings challenge the widely adopted use of short-course anticoagulation therapy in patients with symptomatic deep venous thrombosis.
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Inherited Antithrombin Deficiency Causing Thrombophilia
Article
  • Jan 1965
Blood coagulation systems were studied in members of a family with remarkably high incidence of thrombo - embolic diseases. Thrombotic episodes most often occurred as deep venous thrombosis in the legs, with the first attack at the age of 10-25 years. Pro coagulant factor activities were found within normal variation ranges. Plasma antithrombin III (progressive antithrombin) activity was abnormally low in members with history of thrombosis and in some of their children, with an average level of about 50 per cent of normal. Heparin resistance measured with plasma heparin thrombin time was increased in members with low antithrombin III, and plasma heparin cofactor activity was decreased. The results strongly support the explanation that antithrombin III and heparin cofactor are one and the same plasma substance, and that deficiency of this antithrombin can cause a severe tendency to thrombosis. The antithrombin deficiency seems to be inherited as an autosomal dominant trait.
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The Long-Term Clinical Course of Acute Deep Venous Thrombosis
Article
  • Jul 1996
Background : In patients who have symptomatic deep venous thrombosis, the long-term risk for recurrent venous thromboembolism and the incidence and severity of post-thrombotic sequelae have not been well documented. Objective : To determine the clinical course of patients during the 8 years after their first episode of symptomatic deep venous thrombosis. Design : Prospective cohort study. Setting : University outpatient thrombosis clinic. Patients : 355 consecutive patients with a first episode of symptomatic deep venous thrombosis. Measurements : Recurrent venous thromboembolism, the post-thrombotic syndrome, and death. Potential risk factors for these outcomes were also evaluated. Results : The cumulative incidence of recurrent venous thromboembolism was 17.5% after 2 years of follow-up (95% Cl, 13.6% to 22.2%), 24.6% after 5 years (Cl, 19.6% to 29.7%), and 30.3% after 8 years (Cl, 23.6% to 37.0%). The presence of cancer and of impaired coagulation inhibition increased the risk for recurrent venous thromboembolism (hazard ratios, 1.72 [Cl, 1.31 to 2.25] and 1.44 [Cl, 1.02 to 2.01], respectively). In contrast, surgery and recent trauma or fracture were associated with a decreased risk for recurrent venous thromboembolism (hazard ratios, 0.36 [Cl, 0.21 to 0.62] and 0.51 [Cl, 0.32 to 0.87], respectively). The cumulative incidence of the post-thrombotic syndrome was 22.8% after 2 years (Cl, 18.0% to 27.5%), 28.0% after 5 years (Cl, 22.7% to 33.3%), and 29.1% after 8 years (Cl, 23.4% to 34.7%). The development of ipsilateral recurrent deep venous thrombosis was strongly associated with the risk for the post-thrombotic syndrome (hazard ratio, 6.4 ; Cl, 3.1 to 13.3). Survival after 8 years was 70.2% (Cl, 64.7% to 75.6%). The presence of cancer increased the risk for death (hazard ratio, 8.1 ; Cl, 3.6 to 18.1). Conclusion : Patients with symptomatic deep venous thrombosis, especially those without transient risk factors for deep venous thrombosis, have a high risk for recurrent venous thromboembolism that persists for many years. The post-thrombotic syndrome occurs in almost one third of these patients and is strongly related to ipsilateral recurrent deep venous thrombosis. These findings challenge the widely adopted use of short-course anticoagulation therapy in patients with symptomatic deep venous thrombosis.
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Thrombophilia testing for prevention of recurrent venous thromboembolism
Article
  • Feb 2009
Tests for thrombophilia are being performed on a large scale in people after venous thromboembolism (VTE) even though the benefits of testing are still subject to debate. The most important benefit would be a reduction in the risk of recurrent VTE due to the use of additional prophylactic measures. The objective of this review was to assess the benefit of testing for thrombophilia after VTE in terms of risk reduction of recurrent VTE. The Cochrane Peripheral Vascular Diseases (PVD) Group searched their Trials Register (last searched 15 October 2008) and CENTRAL (last searched The Cochrane Library 2008, Issue 4). We searched MEDLINE, EMBASE, and reference lists. Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that compared the rate of recurrent VTE in participants with VTE who were tested for thrombophilia with the rate in participants with VTE who were not tested were eligible. We planned to extract data from identified studies using data extraction forms. No studies were included because no RCTs or CCTs could be identified. There are currently no randomized controlled trials or controlled clinical trials that have assessed the benefit(s) of testing for thrombophilia on the risk of recurrent VTE.
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Thrombophilia in Children: Who to Test, How, When, and Why?
Article
  • Feb 2008
Thrombosis and thrombotic risk factors in children are receiving increased attention, and pediatric hematologists frequently are asked to evaluate children with symptomatic thrombosis, or asymptomatic children who have relatives affected with either thrombosis or thrombophilia. The clinical utility of thrombophilia testing has become increasingly debated, both in adults and children. Children with thrombosis are a heterogeneous group, and it is unlikely that a single approach to testing or treatment is optimal or desirable. A causative role of inherited prothrombotic defects in many pediatric thrombotic events, particularly catheter-related thrombosis, has not been established. Pediatric patients most likely to benefit from thrombophilia testing include adolescents with spontaneous thrombosis and teenage females with a known positive family history who are making choices about contraception. Recent data suggest that some inherited thrombophilic defects are associated with a higher risk of recurrent venous thromboembolism in children, though optimal management of these patients has yet to be determined. The decision to perform thrombophilia testing in asymptomatic patients with a family history should be made on an individual basis after discussion with the family. Given that the field of pediatric thrombosis continues to evolve, and the settings in which many of these events occur are unique to childhood, prospective longitudinal analyses of such patients to determine outcome and response to treatment as well as the impact of known thrombophilic states on these outcomes are clearly needed.
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Role of Family History in Identifying Women With Thrombophilia and Higher Risk of Venous Thromboembolism During Oral Contraception
Article
  • Jun 2003
  • ARCH INTERN MED
Unrecognized thrombophilic defects increase the risk of venous thromboembolism (VTE) in women during oral contraception (OC). We evaluated the sensitivity and specificity of a family history of VTE to identify thrombophilia in women before OC and after venous thrombotic complications during OC. Thrombophilia screening was performed after obtaining a family history by means of a standardized questionnaire in (1) thrombosis-free women before OC and (2) women after an episode of VTE during OC. We evaluated 479 thrombosis-free women before OC (age range, 15-49 years); family history was positive in 49 (10.2%). Thrombophilic defects were identified in 36 participants (7.5%; 95% confidence interval [CI], 5%-10%), 3 of whom had a positive family history (8.3%). The sensitivity and positive predictive value of family history of thrombophilic defects were 8.3% (95% CI, 2%-22%) and 6.1% (95% CI, 1%-17%), respectively. We also evaluated 189 women after VTE complications during OC (age range, 15-49 years); family history was positive in 48 (25.4%; 95% CI, 19%-32%), 22 of whom had a thrombophilic defect (45.8%; 95% CI, 31%-61%). Thrombophilic defects were identified in 81 women (42.8%; 95% CI, 36%-50%). The sensitivity and positive predictive value of family history of thrombophilic defects were 27.2% (95% CI, 18%-38%) and 45.8% (95% CI, 31%-61%), respectively. Family history of VTE has low sensitivity and positive predictive value for identifying women with thrombophilia who are more susceptible to VTE complications during OC.
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