The big point of this podcast, to me, is to consider getting a hematology consult for both provoked and unprovoked DVTs and PEs. There are so many subtleties to this subject.
Today, I review, link to and excerpt from COREIM‘s Hypercoagulability Workup: Five Pearls Segment.
All that follows is from the above resource.
Posted: March 19, 2025
By: Dr. Sam Kumarasena, Dr. Alice Kennedy, Dr. Kenneth Bauer, Dr. Rebecca Karp-Leaf, Dr. Jean Connors and Dr. Martin Fried
Graphic: Dr. Steven Parkin
Audio: Jerome C. Reyes
Peer Review: Dr. Jonathan BerryPodcast: Play in new window | Download
Time Stamps
- 02:06 PEARL 1: Rethinking “provoked” and “unprovoked” venous clots
- 09:11 PEARL 2: Virchow’s Triad 201
- 17:01 PEARL 3: Inherited thrombophilia testing, part 1: the three protein deficiencies
- 28:49 PEARL 4: Inherited thrombophilia testing, part 2: the two prothrombotic mutations
- 38:38 PEARL 5: Rewind and applications
Show Notes
PEARL 1: Rethinking “provoked” and “unprovoked” venous clots
- The traditional teaching is that there are two major buckets for clots: “provoked” and “unprovoked”.
- Provoked clots are clearly associated with a risk factor, eg. a patient who has a knee arthroplasty who then develops a calf DVT.
- Unprovoked clots are not clearly associated with a risk factor.
- The main question surrounding anticoagulation after DVT/PE is often “how long do we keep anticoagulating?”
- The provoked/unprovoked dichotomy is classically used to drive duration. Unprovoked clots have far higher recurrence rates than provoked clots [citation], with stark differences depending on the provoking factor.
- Provoked clots are treated for 3-6 months of short-term therapeutic AC.
- No difference has been found between 3 or 6 months. [citation]
- Unprovoked clots are treated long-term, typically indefinitely. The rationale is that unprovoked clots have some occult risk factor that persists with time.
- What is challenging is that some provoked clots can also have high risks of recurrence, if that provoking factor sticks around long-term.
- A long-term provoking factor would imply a persistent risk of future clot, which doesn’t disappear after 3-6mo.
- When thinking about provoked clots, always think about “reversibility” of the provoking factor, since that’s the driver of management.
- Our suggested “buckets” for thinking about AC duration:
- (1) Provoked-reversible clots: the classic short-term risk factors (surgical, trauma, air travel). Treat for the short-term, 3-6mo.
- (2) Provoked-irreversible clots: more nuanced risk factors which may persist (obesity, inflammatory disorders, cancer). Consider treating long-term, for as long as that risk factor sticks around.
- (3) Unprovoked clots: Treat indefinitely.
PEARL 2: Virchow’s Triad 201
- The elements of Virchow’s triad are:
- (1) Stasis: Slow or turbulent flow in a vessel, with sluggish flow promoting clot formation
- (2) Endothelial injury: disruption or injury to the vessel lining, exposing prothrombotic factors
- (3) Hypercoagulable state: Overactivation of the coagulation cascade, resulting in more platelet activation and fibrin clot formation
- Use Virchow’s triad to broaden your differential for potential risk factors for clot. Don’t be too hasty to call a clot “unprovoked”!
- Instead, carefully consider all potential contributors – and which ones are “reversible” and “irreversible” in your patient.
- Some underappreciated risk factors, by Virchow’s:
- Stasis:
- Immobility: post-stroke, air travel (but only if >5-6 hours, and this is a relatively weak risk factor)
- Sluggish flow: HFrEF
- Vascular obstruction: Tumor, pregnancy, anatomic abnormalities (eg May-Thurner syndrome)
- Hyperviscosity: polycythemia, leukemia, Waldenstrom’s
- Endothelial injury:
- Spontaneous: bacteremia, skin and soft tissue infections, scarring from prior clot
- Iatrogenic: Indwelling catheters/lines, radiation therapy
- Hypercoagulable state:
- Primary hematologic causes: inherited thrombophilias, APLAS
- Secondary:
- Increase in prothrombotic factors: pregnancy, OCP use, or other high-estrogen state
- Loss of natural anticoagulants: cirrhosis, nephrotic syndrome
- There are some other hematologic conditions in this bucket: paroxysmal nocturnal hemoglobinuria (PNH), myeloproliferative neoplasms (MPNs), and certainly leukemias/lymphomas
- Remember the strength and reversibility of all these risk factors can be a gray area. Don’t hesitate to talk to a hematologist to sort things out.
PEARL 3: Inherited thrombophilia testing, part 1: the three protein deficiencies
- There are two types of primary thrombophilias (aka hypercoagulable disorders):
- Inherited thrombophilias: what we usually refer to when we’re talking about testing for hypercoagulable states when someone has an unprovoked clot
- Acquired thrombophilias: The big do-not-miss in this category is APLAS [Anti-phospholipid antibody syndrome], the subject of a future pearl. We are talking about inherited thrombophilias only for the next 2 pearls.
- The common “inherited thrombophilia” testing includes 5 disorders:
- Inherited protein deficiencies: Antithrombin III deficiency, Protein C deficiency, Protein S deficiency – these three are the focus of Pearl 3.
- Inherited prothrombotic mutations: Factor V Leiden, prothrombin G20210A – these two are the focus of Pearl 4.
- Antithrombin III (ATIII) deficiency:
- ATIII is one of our natural anticoagulants. It works to reduce the activity of the clotting cascade.
- To help you remember: heparin works through ATIII, by increasing its activity.
- ATIII deficiency is one item on your differential for heparin resistance – heparin resistance itself is a whole topic in itself for another day.
- Pitfalls with ATIII testing
- Things that can falsely imitate an inherited ATIII deficiency: anticoagulation with heparins or warfarin, large clot burden, high-estrogen state, nephrotic syndrome, or acute inflammation
- Things that can obscure a real inherited ATIII deficiency: testing while on a DOAC
- Protein C and Protein S deficiencies:
- These two are lumped together because they carry similar pathophysiology
- They prevent clots by inhibiting factors V and VIII in the coagulation cascade.
- Their synthesis is vitamin K-dependent.
- Pathophysiology connection: warfarin is a vitamin K antagonist, which temporarily creates a protein C- and S-deficiency in the first few days of initiation.
- This temporary deficiency of proteins C/S is the reason why warfarin temporarily creates a prothrombotic state when first started – it is one reason why a “bridge” is needed.
- Warfarin skin necrosis is also caused by the longer-term deficiency of proteins C/S associated with chronic warfarin use, which results in formation of microthrombi in the skin.
- Pitfalls with Protein C/S testing
- Things that can falsely imitate inherited protein C or S deficiencies: anticoagulation with warfarin or DOAC, large clot burden, high-estrogen state, nephrotic syndrome, acute inflammation, cirrhosis, or another vitamin K-deficient state
- Protein testing is VERY tricky to interpret with all the caveats above. If tests have already been sent, your differential for an apparent “deficiency” of ATIII/protein C/protein S is as follows:
- (1) A true, inherited deficiency
- (2) A secondary, temporarily-deficient state: related to clot burden, high-estrogen, inflammation, or underlying disease (nephrotic syndrome, cirrhosis)
- (3) A fake-deficiency: due to testing while on anticoagulation, since the anticoagulant can cause artifact in the test tube.
- With all the difficulties in interpretation, we recommend avoiding testing in the acute setting. Remember that with this testing, a “low” result can be a label that follows your patient for life.
- Lots of gray areas here – if you’re wondering whether testing might be beneficial, ask a hematologist for help!
PEARL 4: Inherited thrombophilia testing, part 2: the two prothrombotic mutations
- These tests look for germline genetic mutations, so they’re not affected by your patient’s current health status, clot burden, or anticoagulation.
- However, they are subject to the general pitfalls of hypercoagulability testing:
- Factor V Leiden heterozygosity is quite common, but it has variable penetrance.
- Remember the majority of patients with FVL heterozygosity do not develop clots.
- Even FVL homozygosity does not mean your patient is guaranteed to clot.
- Finding your patient is FVL heterozygous does not mean it’s the reason they had their clot – it may very well be a bystander.
- There are many other common and underappreciated risk factors, such as obesity and age itself.
- Age >60 is itself considered a risk factor (though an irreversible one). A first clot at age 60 or greater would not be a reason to pursue hypercoag testing.
- How clots manifest in the patient and their family is just as important (if not more so) than the results of testing.
- A patient with little to no personal/family history of clot with positive testing, renders you less likely to believe that their mutation would be the cause of a hypothetical new clot – especially if they are older.
- Conversely, for a patient with a really strong family history and negative testing, that negative testing is not necessarily reassuring – they are all having clots for a reason.
- The results of testing do not change your choice of anticoagulant – all available anticoagulants are effective in any of these inherited thrombophilias.
- Testing can rarely impact the duration of therapy, but even among hematologists there are some significant differences in opinion.
- When might you consider testing, knowing all these caveats?
- (1) In a young patient with an unexplained clot and a strong family history in family members <60
- (2) In a patient with a clot and some question of inherited disorder, with a child planning pregnancy, OCP use, or other high-estrogen state – testing might help guide their child’s care.
- (3) If you and your patient both feel they would benefit from testing to help them understand the nature of their condition. Just be prepared for how you might counsel them in the event their testing is positive (or negative).
- Don’t hesitate to ask a hematologist if you’re thinking about testing for any of the above reasons! This is a challenging space with a lot of nuance.
PEARL 5: Rewind and applications
- Case 1: a 48 year old male with an ankle sprain followed by 2 days of immobility, found 1 week later with a DVT and subsegmental PE. Family history of unprovoked PE in his mother at age 50, and his sister with a provoked clot in the postpartum setting. He’s admitted, already on a heparin drip.
- Type of clot: provoked-reversible
- His family history is moderately concerning, with an unprovoked clot in a relative under 60
- Tests you can send now: Factor V Leiden, prothrombin G20210A.
- You should not send the protein-deficiency tests (ATIII, protein C, protein S) while on anticoagulation.
- Management: start anticoagulation (to be continued for minimum 3 months) until he can see Hematology as an outpatient, to consider further inherited thrombophilia testing. Make sure he sees his PCP for age-appropriate cancer screenings.
- A reminder when you think about testing: think about whether you should send APLAS testing. In this case, with a reasonable provoking factor, a family history, and a lower-morbidity venous clot, we’d defer testing for APLAS.
- Case 2: A 40 year old female with DVT/PE after an ankle sprain, with a DVT in a 70 year old aunt. She has completed 3 months of DOAC. She has a 16 year old daughter who’s considering an OCP.
- Type of clot: provoked-reversible
- Her family history is not very compelling: a first clot in a family member aged >60 is not a red-flag for an inherited disorder.
- It might be reasonable to test to inform her daughter’s choice of OCP.
- Tests you can send now: any of them, since she’s off AC! Factor V Leiden, prothrombin G20210A, ATIII, protein C, protein S.
- Management: Consider testing for all of the above to inform her daughter’s care. In the meantime, 3 months of AC is probably sufficient, since our overall suspicion for an inherited disorder is low. If a test were to be positive, refer to Hematology for more risk-benefit discussion.
