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Dr. Stephan Moll
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Physician Viewpoint
The Q&A Forum:
Questions from Doctors & Healthcare Providers
 Patient: Can you tell me about post thrombotic disease, and clot risk while on therapy?
Complete Question & Dr. Moll's Response 
Patient: Are there alternative therapies for pregnant HD patients?
Complete Question & Dr. Moll's Response
Physician: What are the advantages of AT replacement vs. normal VTE prophylaxis?
Complete Question & Dr. Moll's Response
Patient: What are traditional treatment options for children & adults?
Dr. Moll's Response
Physician: What are the treatment options for post-thrombotic syndrome?
Dr. Moll's Response
Physician: Can a child have HD if both parents do not?
Dr. Moll's Response
Patient: Can you explain HD inheritance patterns?
Dr. Moll's Response
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I have been diagnosed with antithrombin deficiency. I am now 37 years old. When I was 25, I had a massive pulmonary embolism (PE), 7 weeks after having given birth. Six months ago I had numerous blood clots, and then 3 days later suffered a stroke. I have a strong family history of blood clots: (a) My mother, who is now 57, had 2 episodes of PE at age 52; (b) my grandfather had a stroke at 40 and died of a PE when he was 61; (c) my great-grandmother died of a PE at the age of 47. This family history led to testing and the discovery that both my mother and I have antithrombin deficiency.
I have 4 questions:
(1) “I have been left with a lot of pain in my right leg and right arm; heavy aching and barely able to move them some days, especially if I have been overdoing things.
What causes the pain and will it get better?
(2) Can I get blood clots even on warfarin? My target INR is 2-3, but my INR is usually 1.8-2.0. I am so scared that I could have another blood clot or, even worse, another stroke.
(3) Can PE cause long lasting damage to the lungs? After 6 months I still get out of breath and have chest pain. Is that normal?
(4) Is there any other blood thinner than warfarin that one can use long-term?
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“I have been left with a lot of pain in my right leg and right arm; heavy aching and barely able to move them some days, especially if I have been overdoing things. What causes the pain and will it get better?”
It is not clear what kind of “numerous clots” this patient had.
Were they in veins or in arteries? This is important to know to be able to discuss the causes of the pain, appropriate
treatment, and prognosis. (a) Vein clots: Patients who suffer a clot in a big vein, i.e. a DVT in a leg or arm, often
develop chronic extremity pain and swelling of various degrees. This is due to damage of the veins and impaired blood return
from the extremity to the heart. It is referred to as “postthrombotic syndrome” or “venous stress disorder”.
Its causes, symptoms and treatments are discussed in detail in a publication by the non-profit patient organization NATT
(National Alliance for Thrombosis and Thrombophilia) and can be found at
www.stoptheclot.org/Newsletters/Natt_Newsletter_Spring_2006.pdf.
The main treatment consists of well fitting compression stockings, weight normalization, and appropriate pain medication.
Occasionally, vascular surgery procedures (balloon widening and stenting of vein) can be beneficial.
Electrical muscle stimulation may also be beneficial - www.adremtechnology.com
(b) Arterial clots: Firstly, patients who suffer a clot in an artery in the leg or arm, may have chronic pain for two reasons.
It may be due to chronic nerve damage suffered at the time of the acute clot from lack of oxygen delivery to the nerves.
This is referred to as ischemic neuropathy or neuropathic pain. Appropriate pain medication management and the use of medications such as Gabapentin (Neurontin) are key in improving symptoms.
Secondly, if the arterial clot leads to chronically impaired blood flow to the extremity, patients may experience pain
with physical exercise, referred to as “claudication”, which eases within a few minutes of stopping exercise.
Balloon widening of the artery, stenting, or bypass surgery often improve these symptoms.
“Can I get blood clots even on warfarin?
My target INR is 2-3, but my INR is usually 1.8-2.0. I am so scared that I could have another
blood clot or, even worse, another stroke”.
The appropriate target INR for patients who have suffered a DVT is, indeed, 2.0-3.0.1
This is true for patients with and without antithrombin deficiency.2,3 However, studies have shown that INRs of
1.5-2.0 are also fairly effective in preventing DVTS, even though not quite as effective as INRs of 2.0-3.0.4, 5
Based on these data, I typically recommend a target INR of 2.0-3.0 and recommend an increase in warfarin if the INR is below 2.0, but do
not worry too much about INRs that are temporarily below 2.0.
As for the patient’s history of “stroke”: As with clots in the legs and arms, strokes can be due to clots in veins
(and are then called “sinus vein thrombosis” or “cerebral vein thrombosis”) or arteries (termed “ischemic stroke”).
And, thirdly, they may also be due to a bleed into the brain (called “hemorrhagic stroke”).
It is important to know the cause of the stroke, to be able to choose appropriate treatment and make predictions about risk of recurrence.
Sinus vein thrombosis is typically treated with warfarin, ischemic strokes with Aspirin, Aggrenox or Plavix.
Antithrombin deficiency is clearly a risk factor for sinus vein thrombosis.
It is not clear whether it is also a risk for stroke due to arterial clots - a recent publication showed that antithrombin deficiency does
not increase the risk for arterial strokes.6 However, this has to be further investigated in follow-up studies.
“Can PE cause long lasting damage to the lungs? After 6 months I still get out of breath and have chest pain. Is that normal?”
Our lung has an incredible ability to dissolve blood clots, and even large clots are often completely dissolved over time.
However, in some patients this mechanism does not work as well and these patients may develop chronic lung damage and have persistence of
shortness of breath. After an acute episode of PE the shortness of breath typically improves over a few weeks.
Some mild chronic shortness of breath may persist. Severe chronic shortness of breath is uncommon, occurring in less than 5%
of patients with PE.7 It is due to the lung damage, which is called “pulmonary hypertension”.
If a PE was large and a patient has chronic shortness of breath, appropriate work-up includes (a) pulse oximetry at rest and after exercise
(such as climbing a few flights of stairs). If this shows that the patient does not get enough oxygen into his/her blood, i.e.
has oxygen desaturation at rest or after exercise, several more detailed follow-up tests are needed: (a) heart echo to assess
right heart function and pulmonary artery pressure, (b) nuclear medicine VQ X-ray scan to look for chronic PE, and (c) consideration of
invasive pulmonary artery pressure measurement and pulmonary arteriogram. If a patient is found to have significant
pulmonary hypertension, surgical removal of the clots can be considered, termed “pulmonary endarterectomy”.
This is a major surgery performed only in a few specialized enters. Some medications are also available to treat
pulmonary hypertension.
“Is there any other blood thinner than warfarin that one can use long-term?”
Three groups of oral blood thinners are presently available:
• The so-called coumarin “vitamin K antagonists” (VKA), to which warfarin, phenprocoumon and acenocoumarol belong.
They all work through the same mechanism and have similar side effects.
• The so-called indandiones, to which Phenindione and Fluindione belong.
They work through the same mechanism as the coumarins, but are a different kind of chemical class.
These are only available in some parts of the world. They have no advantage over the coumarins.
• The new oral blood thinners Dabigatran and Rivaroxaban are presently (December 2009) only available for DVT prevention purposes, i.e. at low doses, and only in some parts of the world.
Other oral drugs are in clinical trials, such as Apixaban, Edoxaban, Betrixaban, and others.
Several injection blood thinners are available, which are called low molecular weight heparins and fondaparinux. They can be used long-term, but are typically not the first choice of treatment,
as they need to be injected into the skin (subcutaneously) once or twice daily, which makes them less attractive than drugs taken by mouth.
References
1. Kearon C, Kahn SR, Agnelli G, Goldhaber SZ, Raskob GE, Comerota AJ. Antitthrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133:454-545.
2. Kearon C, Julian JA, Kovacs MJ, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood 2008; 112:4432-4436.
3. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008; 14:1229-1239.
4. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism. N Engl J Med 2003; 348:1425-1434.
5. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of Low-Intensity Warfarin Therapy with Conventional-Intensity Warfarin Therapy for Long-Term Prevention of Recurrent Venous Thromboembolism. N Engl J Med 2003; 349:631-639.
6. Mahmoodi BK, Brouwer JLP, Veeger NJGM, Van der Meer J. Hereditary deficiency of protein C or protein S confer increased risk of arterial thromboembolic events at a young age. Results from a large family cohort study. Circulation 2008; 118:1659-1667.
7. Meyer G, Planquette B, Sanchez O. Long-term outcome of pulmonary embolism. Curr Opin Hematol 2008; 15:499-503.
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"Are there ever situations where a patient with a confirmed diagnosis of
antithrombin III deficiency can be treated effectively with medicines such as aspirin or the herb butcher's broom? Particularly, is it possible
during a period when they are at higher risk for clots such as during pregnancy?"
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The clear answer is: No. The details are as follows: Individuals with antithrombin deficiency are particularly at
increased risk for blood clots in their veins, such as clots in the legs (deep vein thrombosis; DVT) or the lung
(pulmonary embolism; PE). These clots are mostly made up of clotting proteins 1. Blood platelets do not play much
of a role in making these types of clots. That's why medications and herbal products that make platelets slick and
prevent them from sticking together (aspirin, garlic, ginkgo) are typically not effective in preventing clots in
veins. Reference 1 discusses this topic in detail 1. The drugs that are effective in preventing clots in veins are
those that act against the clotting proteins, i.e. heparin, low molecular weight heparin (Lovenox®, Fragmin®, Innohep®),
Fondaparinux (Arixtra®) or warfarin (coumadin®, Janotven®). Therefore, individuals who have antithrombin deficiency are
typically treated with one of these latter drugs at times of higher risk for blood clots, such as pregnancy.
Antithrombin deficiency may also slightly increase the risk for clots in arteries, such as heart attack and stroke.
However, this association has not been well studied. As clots in arteries are made up of platelets, aspirin and herbs
effecting platelet function can prevent such clots 1. Therefore, if a person with antithrombin deficiency is not on
warfarin or heparin, I recommend for her/him to be on long-term aspirin, because it may have a protective effect against
clots in arteries. However, as pregnancy and surgery mostly increase the risk for clots in veins, heparin and similar
drugs are the appropriate prevention treatment in the individual with antithrombin deficiency (or any other clotting
disorder [thrombophilia].
Butcher's broom (Rucus aculeatus) is a plant of the Lilly family native to the Mediterranean Europe and Africa 2. It
contains substances that decrease the permeability of blood vessels and may, therefore, be useful for people with leg
swelling (edema) of various causes. A nice scientific summary on the effects of Butcher's broom, including a number of
good references, has been published 3. There is no evidence or reason to believe that Butcher's broom would have any
effect on preventing blood clots from forming.
References
1. http://www.fvleiden.org/ask/103.html.
2. Ruscus aculeatus (butcher's broom). Monograph. Altern Med Rev 2001; 6:608-12.
3. Vanscheidt W, Jost V, Wolna P, et al. Efficacy and safety of a Butcher's
broom preparation (Ruscus aculeatus L. extract) compared to placebo in patients suffering from
chronic venous insufficiency. Arzneimittelforschung 2002; 52:243-50.
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"I have a patient with a distant history of venous thromboembolism on birth control pill, and recently diagnosed AT III deficiency (repeated AT III levels of 55%). Patient plans to have upcoming gastric bypass surgery. What are the advantages of using Antithrombin replacement vs. normal VTE prophylactic measures?"
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As usual, first of all I wonder what the etiology of this patient's low antithrombin levels is.
Are they due to laboratory error or acquired or inherited deficiency? Does this patient's morbid obesity explain her low antithrombin levels?
Normally, AT levels increase somewhat with increasing body weight 1. However, in the morbidly obese individual, published data are conflicting:
normal antithrombin levels have been reported compared to individuals of normal body weight 2, 3 , as well as decreased levels 4. Discrepant results
have also been published on the effect of surgical treatment of morbid obesity on plasma antithrombin levels: no change has been reported 2 , as well
as a normalization of levels after surgery 4.
Thus, I am not sure whether this patient's morbid obesity can explain her low levels. Does she have renal disease or proteinuria? Does she have liver
synthetic dysfunction? Does she have a family history of VTE and has her parents' blood been tested for antithrombin activity? Since acquired AT
deficiency has different thromboembolic risk (typically lower risk) and treatment consequences (typically no AT concentrate indicated) than inherited
AT deficiency, a solid diagnosis should be made.
What are the implications if she is found to have true inherited AT deficiency? There is no published evidence to suggest that individuals with true
inherited AT deficiency need to receive more intense or longer duration thromboprophylaxis than other patients in similar clinical circumstances.
However, empirically, I tend to recommend somewhat higher prophylactic heparin doses than for non-AT deficient patients, in view of the potential for
individuals with AT deficiency to have some degree of heparin resistance, rendering heparins less effective. It has been argued that Fondaparinux, even
though also AT-dependent in its anticoagulant action, might still be fully effective when given in standard doses to AT deficient patients 5 . Finally,
also empirically, I tend to recommend somewhat longer postoperative VTE prophylaxis in individuals with AT deficiency compared to non-deficient patients
undergoing similar surgical procedures, in view of the thrombogenicity of AT deficiency.
Clearly, the patient described here is at significantly increased risk for VTE, due to her risk factors: (a) previous VTE, (b) morbid obesity, (c)
upcoming abdominal surgery, (d) probable immobility after the surgery, (e) possible inherited antithrombin deficiency. She needs VERY good DVT
prophylaxis. That would, in my opinion, mean (a) intermittent compression devices during surgery and as long as she is bedridden, (b) some form of
q 12 hr s.c. low molecular weight heparin (at higher than usual prophylactic doses) or i.v. unfractionated heparin (such as keeping the aPTT in the
lower half of the therapeutic range, (c) consideration of AT concentrate immediately pre-operatively and for a few days postoperatively, (d) LMWH or
Fondaparinux for possibly 6 weeks after the surgery, (d) good patient education about the symptoms of DVT and PE.
Regarding the use of AT concentrates it is important to state that no randomized clinical trials have been performed assessing the need for and efficacy
of AT replacement therapy at times of surgery. Its use has been reported in case series and case reports only 6-8. No guidelines or consensus statements
exist as to when to use AT concentrates and when not, and, if given, what doses to use and how long to give it.
References
1. Bowles LK, Cooper JA, Howarth DJ, Miller GJ, MacCallum PK. Associations of
haemostatic variables with body mass index: a community-based study. Blood Coagul
Fibrinolysis 2003; 14:569-73.
2. Primrose JN, Davies JA, Prentice CR, Hughes R, Johnston D. Reduction in factor VII,
fibrinogen and plasminogen activator inhibitor-1 activity after surgical treatment of
morbid obesity. Thromb Haemost 1992; 68:396-9.
3. Gleysteen JJ, Hussey CV, Caya JG. Preoperative coagulation indices in patients with
morbid obesity. Int J Obes 1989; 13:195-201.
4. Batist G, Bothe A, Jr., Bern M, Bistrian BR, Blackburn GL. Low antithrombin III in
morbid obesity: return to normal with weight reduction. JPEN J Parenter Enteral Nutr 1983;
7:447-9.
5. Bauersachs R, Alban S. Perioperative bridging with fondaparinux in a woman with
antithrombin deficiency. Thromb Haemost 2007; 97:498-9.
6. Schwartz RS, Bauer KA, Rosenberg RD, Kavanaugh EJ, Davies DC, Bogdanoff DA. Clinical
experience with antithrombin III concentrate in treatment of congenital and acquired deficiency
of antithrombin. The Antithrombin III Study Group. Am J Med 1989; 87:53S-60S.
7. Konkle BA, Bauer KA, Weinstein R, Greist A, Holmes HE, Bonfiglio J. Use of recombinant
human antithrombin in patients with congenital antithrombin deficiency undergoing surgical
procedures. Transfusion 2003; 43:390-4.
8. Menache D, O'Malley JP, Schorr JB, et al. Evaluation of the safety, recovery, half-life,
and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III
deficiency. Cooperative Study Group. Blood 1990; 75:33-9.
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"I am a 34 year old male who was recently diagnosed with hereditary antithrombin deficiency
(antithrombin level was at 62%). I experienced a deep vein thrombosis (DVT) several months ago after a flight, and am receiving treatment
with Marcumar® [= phenprocoumon; a drug similar to warfarin; mostly used in Germany]. My mother was also diagnosed with AT deficiency
(after a pulmonary embolism) and is treated with Coumadin® [=Warfarin].
Both of my children (7 year old girl and 4 year old boy) have had their AT levels tested. The boy came back with a slightly low level,
78%, but my daughter was at 44%. My doctor has booked an appointment with a specialist at a University Hospital for further tests to decide
on the best treatment options for me and my children.
I would like to go armed with some expectations of tests they might consider performing, and an understanding of what the traditional treatment
options are for children and adults with AT deficiency. Also, if suggested treatments for either of my children involve prolonged use of
anticoagulants, how can I find out about potential side effects so I can also discuss potential concerns with their health care provider?"
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Making the Diagnosis
Before diagnosing somebody with "inherited antithrombin deficiency", one wants to make sure that the diagnosis is correct.
Whenever "low antithrombin levels" are found, there are a number of issues that a physician will want to see clarified:
· What is the normal range of the test in the laboratory that performed the test?
The typical normal range for antithrombin levels is in the order of 80 to 120 %, but differences exist between laboratories.
Newborns and infants have lower levels of antithrombin than adults, but at six months of age adult levels are typically reached.
Most individuals with inherited antithrombin deficiency have antithrombin activity levels in the range of 40 to 60%. Typically,
affected individuals in one family have similar antithrombin levels. Thus, regarding the patient above, I would want to know
(a) what was the normal range of the antithrombin tests for his and his children's results?
· Was the test done at the time of the acute clot, while on heparin therapy?
Since acute clots and heparin therapy can lead to a temporarily low antithrombin blood level, a low antithrombin level in such
situations does not necessarily indicate an inherited antithrombin deficiency. Repeat testing at a later time is important to
confirm a low level. Also, some disorders (certain liver and kidney diseases) cause an acquired antithrombin deficiency that
is not inherited. Such conditions need to be excluded, before ascribing a low antithrombin level to an inherited problem. Thus,
the patient asking the questions above should have a repeat test done and all reasons for an acquired antithrombin deficiency
should be ruled out, before assuming that he has inherited antithrombin deficiency.
· Was the test repeated on a new sample?
Since antithrombin levels can be transiently low, repeat testing on a separate sample is always recommended, before making a
diagnosis of antithrombin deficiency. Thus, the children of the patient above should have a repeat antithrombin test
(antithrombin activity test) done on a new sample. I am a little surprised that the daughter's level is significantly lower
than the level of the patient, as levels are typically similar between individuals with antithrombin deficiency in a given family;
repeat testing, preferably in the same laboratory, should clarify this discrepancy.
· What kind of test was done, an antithrombin activity or antigen test?
As the risk of future thrombosis varies depending on what subtype of antithrombin deficiency an individual has ( the sub
classification the type of antithrombin deficiency11), it is important to know what type of antithrombin test the laboratory
performed - an antithrombin activity test (= functional antithrombin test) or an antithrombin antigen test? Thus, my question
to the patient above would be: What type of antithrombin test was done in you and your children?
· What further tests should be done?
The risk of thrombosis varies depending on the type of antithrombin deficiency. Families with the so called type IIb deficiency
(also called "heparin binding site defect") have a lower risk for thrombosis than families with the other antithrombin deficiencies1.
Thus, once antithrombin deficiency has been established, further testing to clarify the subtype is helpful. Tests to be considered
in addition to the antithrombin activity are (a) antithrombin antigen, (b) "progressive antithrombin assay" in the absence of
heparin or with only low concentrations of heparin1, and (c) genetic testing (sequencing) of the antithrombin gene. In the family
above, once the diagnosis of inherited antithrombin deficiency has been established, I would want to know what subtype of antithrombin
deficiency the family has. I would order: (a) an antithrombin activity, (b) antithrombin antigen, (c) the "progressive antithrombin assay" or sequencing of the antithrombin gene for a heparin binding site defect, if the antithrombin activity and antigen assays suggest a type II
deficiency.
Management of individuals with AT Deficiency who have never had a clot
Asymptomatic individuals with AT deficiency who have never had a blood clot typically are not treated with long-term anticoagulants
(= drugs that prevent blood clots, such as warfarin, phenprocoumon and others), because their risk to develop a clot is relatively low.
In medical-statistical terms the means: the incidence for venous thromboembolism (i.e. blood clots in veins, such as deep vein thrombosis
and pulmonary embolism) is between 0.9-2.9 % per year, with a recent large prospective study showing an incidence of 1.7 % per year2.
With such a relatively low risk, long-term treatment with anticoagulants is often considered to be more risky than beneficial.
The "Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology" has, thus, made a statement that there
is no evidence to support the use of long-term anticoagulants in asymptomatic family members3.
Superb prophylaxis against blood clots in risk situations for DVT and PE, such as major surgery, immobility, wearing a cast, major
trauma is important. Women should be aware that estrogen preparations (birth control pill and patch, hormone replacement therapy) and
some progestin preparations (high dose progestins) increase the risk of blood clots and may, therefore, not be advisable in the person
with antithrombin deficiency. Also, women with AT deficiency may benefit from anticoagulant therapy during pregnancy. In addition,
antithrombin concentrates are sometimes given to individuals with antithrombin deficiency to prevent blood clots after major surgery,
trauma, and at the time of delivery. Finally, individuals and families with antithrombin deficiency should be very knowledgeable about
the symptoms of blood clots and should seek medical attention if such symptoms occur.
If a diagnosis of antithrombin deficiency is made in the children of the patient above, then it may be reassuring for the father to know
that blood clots only uncommonly occur in individuals with antithrombin deficiency before the age of 20. However, parents should know the
symptoms of blood clots and make sure that the children get medical attention if such symptoms occur. The parents should also make sure
that the children get good prophylaxis at times of surgery, major trauma, and prolonged immobility.
Side effects of Anticoagulants
Bleeding is the major side effect of anticoagulants.
Further information
A comprehensive brochure written for patients on antithrombin deficiency can be downloaded
here.
References
1. Rossi E, Chiusolo P, Za T, et al. Report of a novel kindred with
antithrombin heparin-
binding site variant (47 Arg to His): demand for an automated progressive
antithrombin
assay to detect molecular variants with low thrombotic risk. Thromb Haemost 2007;
98:695-697.
2. Vossen CY, Conard J, Fontcuberta J, et al. Risk of a first venous thrombotic event
in carriers
of a familial thrombophilic defect. The European Prospective Cohort on
Thrombophilia (EPCOT).
J Thromb Haemost 2005; 3:459-64.\
3. Walker ID, Greaves I, Preston PE. Guideline: Investigation and management of
heritable thrombophilia.
Br J Haematol 2001; 114:512-528.
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"My sister developed a clot in her leg 7 months ago due to AT deficiency.
I am a nurse and help her with her healthcare. The clot has affected her quality of life. She is 32 years old and finds
it difficult to go outside the home most days because of general lethargy, and a swollen, sore leg secondary to this clot.
I believe she could benefit from additional treatments, such as thrombolysis or AT therapy during or after the process.
Are there generally accepted interventions for such patients with "post clot" syndrome? Are there treatments that I might
encourage her to discuss with her health care provider? Can clots still exist after treatment, and if so, what do health care
providers typically do to treat them."
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The patient described above has postthrombotic syndrome. This is a condition that can occur after a person
has had a blood clot (deep vein thrombosis or DVT) in the leg or arm.
A detailed discussion of symptoms and treatment options can be found in the brochure, Postthrombotic Syndrome / Venous Stress Disorder.
You may download a copy of this brochure
here.
The treatment is independent of what caused the DVT, i.e. the treatment is no different for a patient with and without antithrombin
deficiency. Treatment options include:
• elevation of the extremity
• compression stocking
• compression pump at home
• radiological procedures that open up an occluded vein, such as angioplasty and stenting.
• whether wearing an electrical muscle stimulator (VeinoPlus® device)
might be beneficial in decreasing symptoms, has not been investigated.
While clot busters (=thrombolytics) may be considered in the acute treatment of DVT (i.e. in the first 1-4 weeks after a DVT), they are
not effective if the clot is old and the person has already developed postthrombotic syndrome.
Similarly, antithrombin concentrate may be considered in the treatment of acute DVT, but does not improve the symptoms of postthrombotic
syndrome. Therefore, there is no reason to administer antithrombin in this situation.
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"If both parents test normal on blood tests for antithrombin III, how is it that a child can have antithrombin III deficiency?"
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Antithrombin deficiency is either (a) inherited, (b) acquired, or (c) incorrectly diagnosed
based on a misinterpretation of lab tests.
a) If it is inherited then one would expect one of the two parents to also have low antithrombin levels.
b) Causes of acquired deficiency are listed in the table below.
c) Misinterpretation of the antithrombin lab tests can happen due to several reasons:
(1) if a temporarily low level, such as seen during heparin therapy or at the time of
an acute clot, is mistaken for an inherited deficiency. In my practice, several patients
referred with "Antithrombin Deficiency" have turned out not to have the deficiency -
they just had temporarily low AT levels and somebody erroneously gave them the
diagnosis of "Antithrombin Deficiency". I, therefore, always encourage patients to
question their diagnosis. A low antithrombin level should always be confirmed by a
second testing at a later date.
(2) Discrepant results between parents and children
can also be seen in type 2 antithrombin deficiency. These individuals have normal
antithrombin antigen test results and low antithrombin activity results. If the child was
tested with the activity assay (and this was found to be low), and the parents were
tested only with the antigen level (and this was found to be normal) discrepant results
occur, even though one of the parents would likely have low antigen levels, if the antigen
test was performed. Therefore, the optimal screening test is always the antithrombin
activity test. (3) Lastly, every so often, paternity needs to be questioned, if the inheritance
pattern does not fit.
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Causes of Acquired Antithrombin Deficiency
- Liver failure (such as liver cirrhosis)
- Nephrotic syndrome (a kidney disorder)
- Widespread (metastatic) tumors
- Acute blood clots
- Heparin therapy
- DIC (= disseminated intravascular coagulation)
- Severe trauma
- Severe burns
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"If I have antithrombin deficiency, will my children necessarily have it as well?"
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If a person has inherited (=congenital) antithrombin deficiency there is a 50 % chance that
the child will have it, too. However, if the person has an acquired deficiency, then the
antithrombin deficiency will not be passed on to the child.
Genetics work as follows: We all carry 2 genes for each trait. We received one of these
genes from our mother, the other one from our father. For example: we have 2 genes that
make antithrombin. If one gene is defective (mutated) the person is said to be heterozygous;
in our case: heterozygous for antithrombin deficiency. Almost all people who have inherited
antithrombin deficiency are heterozygous.
If both genes are mutated, the person is homozygous. Homozygous antithrombin deficiency
is almost never compatible with life - the fetus typically dies before birth and a miscarriage
results. However, a few surviving individuals with homozygous antithrombin deficiency have
been reported (ref 1-4).
The following graphics show how genes are passed on. There are always 4 possible gene
combinations in the children, depending on which of the 2 genes the children get from their
father and which of the 2 genes from their mother.
References
1. Picard V et al: Antithrombin Phe229Leu: a new homozygous variant leading to
spontaneous antithrombin polymerization in vivo associated with severe childhood
thrombosis. Blood 2003;102:919-25.
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Mutat. 7: 7-22.
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