Reader Responses: What could provoke venous thromboembolisms in two teenaged siblings?

Here’s how readers responded to a You Make the Call question about large venous thromoembolisms in two teenaged siblings.

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I would recommend lifelong anticoagulation with a factor Xa inhibitor. Would also have a long talk with these two about the severity of the problem and that usually there are other precipitating factors associated with these clots. The latter I would do after they have been on anticoagulation for a while.

I cannot imagine the chance that other tests would simultaneously be positive in two separate cases.

Robert Fenning, MD
Medical University of South Carolina
Charleston, SC

I would also check antithrombin III levels and anticardiolipin antibody.

Mary Klix, MD
Anchorage, AK

I wonder about elevated homocysteine secondary to vitamin B12 deficiency from nitrous oxide abuse.

John Strouse, MD, PhD
Duke Adult Comprehensive Sickle Cell Center
Durham, NC

I would administer anticoagulants for six to 12 months and aspirin for six to 12 months for both siblings.

Arun Bhandari, MD
Chesapeake Oncology Hematology
Annapolis, MD

I would consider May-Thurner [iliac vein compression] syndrome.

Deborah Wienski, MD
Missouri Baptist Medical Center
Saint Louis, MO

I would check homocysteine level.

Robert Lerner, MD
New York Medical College
Valhalla, NY

I would administer extended anticoagulation for both. That is, anticoagulation so long as it is well tolerated, and they are not at high risk for bleeding.

David Baer, MD
Kaiser Permanente
Oakland, CA

I would request a methylenetetrahydrofolate reductase measure, plasminogen activator inhibitor type 1 polymerase chain reaction test, and a study of anticardiolipin and beta-2 glycoprotein antibodies and serum homocysteine.

Alejandro Flores, MD
Boston Children’s Hospital
Boston, MA

It seems rather obvious that the patients have another inherited thrombophilic condition that should be identified to decide the treatment.

Guillermo Ruiz Arguelles, MD, MACP
Centro de Hematologia y Medicina Interna de Puebla
Puebla, Mexico

I would make strong inquiries about lifestyle and any personal activities that may predispose to deep vein thrombosis (DVT) such as prolonged gaming, internet use, massive dehydration, drug use, or unusual postures while doing activities. Are they both very obese? You don’t mention the side of the DVT, but I would consider May-Thurner syndrome if left-sided in both; I bet a predisposition to this is inherited. I agree this would be a case reportable, long-shot.

It may be too late now, but I would have strongly considered catheter-directed thrombolysis for such young patients with such extensive DVTs.

No further tests are likely to be helpful for management.

I would aggressively treat with one month of full-dose, twice-daily low-molecular-weight heparin followed by a direct oral anticoagulant (DOAC) in therapeutic doses.

Unless a major reversible risk factor emerges, I would recommend indefinite treatment. If everything improves, I would consider dropping the dose to a long-term prophylactic dose in 6-12 months (which provides good protection at no risk).  Other issues to discuss with them include:

  1. need for optimal compliance with anticoagulant therapy
  2. return to normal activities as soon as possible
  3. sports safety
  4. contraception (and pregnancy) in the young lady
  5. management of possible menorrhagia
  6. don’t repeat the imaging without a very good reason

William Geerts, MD
Sunnybrook Health Sciences Centre
Toronto, ON

Is it contraceptives in the female and anabolic steroids in the man? (Although surprising at the age of 15!)

A genetic malformation such as vena cava atresia could play a role for which a CT venography could be done.

Duration, if provoked by contraceptives, could be limited to three months if contraceptives are stopped.

Menno Huisman, MD, PhD
Leiden University Medical Center
Leiden, Netherlands

Thrombophilia does not cause thromboembolism without intravascular injury. But it enhances thrombosis once vascular injury is initiated and intravascular thrombosis has started. Therefore, you have to ask whether the patients had any vascular access prior to thrombosis (extensive blood tests at doctor’s offices or in hospital, body trauma, surgery, or whether they are on any vascular accesses such as intravenous ports, portacath, catheter fistula for dialysis, or inferior vena cava filter, etc.). Please see PMID 30063477 and PMID 30234545.

Jae Chang, MD
University of California, Irvine
Irvine, CA

Presentation of these cases suggests that both siblings have been exposed to something; however, genetic predisposition with coincidental VTE has to be considered as well. There are many possibilities including a flimsy theory that both patients have developed hyperhomocysteinemia, since they live in the same household and are on the same (perhaps group B vitamin–deficient) diet. At this point, the most beneficial test for the patients would probably be a full set of thromboelastometry to determine whether these patients are still in a hypercoagulable state or not. If they are, thromboelastometry might also give some insight into what aspect of hemostasis is responsible for their thrombophilic state.

Andaleb Kholmukhamedov, MD
Versiti Blood Research Institute
Milwaukee, WI

I would recommend long term anticoagulation.

Mohammad Alkayem, MD
UPMC Altoona
Altoona, PA

Lifetime anticoagulation with factor Xa inhibitor.

Glenn Shamdas, MD
Fargo VA Health Care System
Fargo, ND

Test for paroxysmal nocturnal hemoglobinuria (PNH) and JAK2 V617F mutation.

Mixalis Mixail, MD
Nicosia General Hospital
Nicosia, Cyprus

I would consider a few more tests, such as antithrombin activity, peripheral blood immunophenotyping for PNH, and molecular tests for identification of myeloproliferative neoplasms (JAK2 V617F, CALR and MPL mutations). Both of these patients have a positive personal and family history of VTE by definition, and if these VTEs indeed happened without a provoking factor, I would also consider lifelong secondary prophylaxis with DOACs at the lowest dosage, as indicated by AMPLIFY-EXT and EINSTEIN CHOICE studies.

Stamatis Karakatsanis, MD
General Hospital of Athens
Athens, Greece

Some thoughts:

  • Full anti-polymer antibody assay, including all elements
  • ATT assay
  • JAK2
  • Complete blood count
  • serum protein electrophoresis
  • Lipoprotein 2a
  • Full exposure history

Anticipate lifelong anticoagulation.

Stephen Chandler, MD
Kaiser Permanente
Longview, WA

  • Ask about binge computer use, binge TV watching
  • Current practice is lifelong anticoagulation as long as it’s tolerated and safe.

I would use an anticoagulant for life if I cannot prove a provoking incident. Which, in this case, would be extraordinary.

James Puckett, MD
Charles George Veterans Affairs Medical Center
Asheville, NC

  1. Family history is not included but is necessary.
  2. Very extensive proximal thrombosis. High risk for postphlebitic syndrome. I would have given systemic tissue plasminogen activator, but that’s not in fashion now. The extent of thrombosis suggests a serious hypercoagulable state and teen years lead to changes that may then precipitate thrombosis in a high-risk person. My own experiences have led me to believe that the long-term outcomes are much better for patients who were thrombolysed (I used serum immunoelectrophoresis to monitor many decades ago) and gradually increasing resolution of clots is seen consistently even if only partial clot lysis is obtained initially. Patients must be on adequate anticoagulation, and encouraged to exercise (such as bicycling or lap swimming).
  3. I favor long-term anticoagulation with serial monitoring of D dimers.
  4. Other workup after stopping anticoagulants.
  5. Germ-line mutation testing if feasible.

Rajalaxmi McKenna, MD
Hinsdale, IL

It was interesting to read the case report. We often come across such instances.

Long-term anticoagulation is indicated in certain situations, including thrombosis of extensive nature, at unusual sites, that has recurred, and so on. Even if all possible investigations show normal results, a patient may still need  to be anticoagulated for a long time. The duration in such situations is determined by clinical factors like ongoing thrombosis, as shown by D dimer levels or Compression Doppler study, rather than by presence or absence of a likely factor.

So, in my opinion, leaving aside purely research situations, it is unfair to perform an extensive search to identify an underlying factor, even in recurrent, extensive, or unusual thrombosis, because of the following reasons:

  1. Even if one factor has been identified, there may be additional factors.
  2. Knowing that the patient has any such cause will not be helpful, since in any case you are going to anticoagulate for a longer period than usual and will stop anticoagulants only when there is no evidence of ongoing thrombosis.
  3. You will, of course, advise thromboprophylaxis in such situations, irrespective of presence or absence of detectable underlying cause.
  4. There are no data or practice guidelines to administer lifelong anticoagulation, perhaps except in conditions such as antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, sickle cell trait, and antithrombin deficiency.

I suggest we should have a minimum of such screening tests to rule these conditions, which will need to be treated if detected to be present, rather than doing routine screening of Pr C, S and Prothtombin, factor V mutations, which actually do not contribute towards patient care.

Ajay Sharma, MD
Sir Ganga Ram Hospital

New Delhi, India