Setting: ED
CC: “My leg is swollen.”
VS: R: 14 breaths/minute; BP: 126/86 mm Hg; P: 84 beats/minute; T: 100.8°F
HPI: A 34-year-old woman comes to your hospital ED by taxicab after getting off a plane from Gujarat, India. She developed pain in her leg that she noticed when disembarking from the plane. Her leg feels tight and “swollen.” She denies dyspnea, chest pain, or light-headedness.
PMHX: tobacco smoker
Medications: oral contraceptives
PE:
Cardiovascular: normal
Chest: normal
Extremities: swelling of left leg, warm to touch
Homans sign (pain in calf on dorsiflexion) has limited accuracy.
A pain in the leg after a long flight and immobility is a clear risk for DVT. But even a long plane ride should not be enough to make a normal person clot. Plane rides unmask underlying thrombophilia (hypercoagulable state). This history, however, is enough to warrant therapy without waiting for results of duplex ultrasound.
Initial Orders:
Lower extremity duplex ultrasound
Enoxaparin (low molecular weight heparin [LMWH])
Chest x-ray
Oximeter
CBC, INR, PT, aPTT
Clots, such as DVT or pulmonary embolus, give fever.
Results:
The duplex ultrasound shows a large clot in the femoral vein.
The chest x-ray, CBC, and oximeter results are all normal.
Even though the patient denies dyspnea, on CCS you can order “extra” tests that are reasonably related to the chief complaint. You will not lose points for getting an x-ray or oximeter for someone at risk of pulmonary embolus (PE). You will not lose points for getting a baseline CBC in someone you are potentially going to anticoagulate.
Orders:
Enoxaparin to continue subcutaneously
Warfarin with target INR 2 to 3
You do not have to order a thrombophilia evaluation for the first clot.
Warfarin inhibits factors II, VII, IX, and X.
The patient should not be admitted to the hospital just for a DVT. The patient can inject her own LMWH and be discharged with follow-up by her own doctor or an ambulatory care clinic. It takes at least 2 to 3 days for the INR to change in response to warfarin. Warfarin only stops production of new clotting factors, it does not alter the effect of clotting factors already present.
Make sure you advise the patient to stop smoking!
Warfarin causes skin necrosis with protein C deficiency because protein C is an anticoagulant.
Protein C:
• It has the shortest half-life of any factor.
• It is vitamin K dependent.
• Warfarin removes the anticoagulant.
The patient is moved to the “Home” location. Move the clock 3 days forward for a visit in the office location. Perform “Interval History” to check symptoms. You will need to check the INR every 1 to 2 days until the patient reaches a “steady state” on her warfarin dose.
Which form of thrombophilia should be tested for this patient?
a. None
b. Protein C
c. Protein S
d. Antithrombin III
e. Antiphospholipid (APL) syndrome
f. Factor V Leiden mutation
g. Homocysteine
Answer a. None
It is an attractive choice to want to test for a form of thrombophilia in this patient. It just does not matter on the first clot. The intensity of warfarin to an INR of 2 to 3 is the same whether there is a thrombophilia or not. The duration of anticoagulation is the same at 6 months. None of these thrombophilias is proven to need lifelong anticoagulation with a single clot. In this patient’s case, the main management is to tell her to stop smoking and stop using oral contraceptives.
Orders:
CBC
INR
The patient’s CBC is normal. After 3 days on warfarin, the patient’s INR is 1.5. You advise the patient strongly to stop smoking and stop using oral contraceptives as a form of contraception. She needs to continue enoxaparin (LMWH) for several more days until her INR is <2.
Protein S is a vitamin K-dependent anticoagulant just like protein C.
You have a daily check of the INR with the patient coming to the office each day. Three days later (after 6 days of warfarin), her INR is 2.1 and you stop enoxaparin. Advise the patient that she will need 6 months of therapy and that she should come in every 2 to 3 days for INR monitoring until you know the level is stable.
Factor V Leiden mutation is the most common genetic cause of thrombophilia.
Mechanism of Factor V Mutation
• Factor V does not respond to protein C.
• Protein C usually inhibits factor V.
• When mutated, factor V is resistant to protein C.
• The mechanism is the same as that in protein C deficiency.
Over the next 6 months, the patient’s INR stays in the range of 2 to 3 and she is asymptomatic. Warfarin is stopped. A year later she develops shortness of breath over a few hours.
Which form of thrombophilia is most likely to have a recurrent clot?
a. All are equal
b. Protein C
c. Protein S
d. Antithrombin III
e. APL syndrome
f. Factor V Leiden mutation
g. Homocysteine
Answer e. APL syndrome
APL is most likely to recur and it is the only form of thrombophilia in which you may consider lifelong therapy with warfarin from the first clot. Because this patient does not have lupus or any other sign of autoimmune disease, there was no point in testing her. The most likely cause of this person’s clot was smoking in a person on oral contraception.
The patient in the ED is markedly hypoxic and tachycardic. A CT angiogram shows a clot. Her blood pressure is normal and thrombolytics are not used. She is given a bolus of IV unfractionated heparin. The follow-up aPTT shows little elevation. A second IV bolus of heparin is given with only a slight rise in aPTT.
What is the reason for lack of response to IV heparin?
a. All are equal
b. Protein C
c. Protein S
d. Antithrombin III
e. APL syndrome
f. Factor V Leiden mutation
g. Homocysteine
Answer d. Antithrombin III
When a patient is resistant to the effects of IV heparin, it is most likely from antithrombin deficiency. Heparin works through potentiating the effects of antithrombin. Antithrombin is a misnomer in that it inhibits the effect of not only thrombin, but also the effect of all the clotting factors in the whole cascade. You recognize it when you bolus with IV heparin and there is no response.
APL Syndromes
• Lupus anticoagulant
• Anticardiolipin antibodies
• May raise aPTT, but cause clotting
The Russell viper venom test is the most accurate test for lupus anticoagulant.
The patient becomes stable by the end of the first hospital day. Heparin is continued. Warfarin is started. On the third hospital day, the platelet count begins to drop from 170,000/μL to 120,000/μL to 100,000/μL.
After stopping heparin, what is most appropriate course of action?
a. Give antiplatelet factor IV antibodies
b. Order serotonin release assay
c. Start argatroban
d. Start enoxaparin
Answer c. Start argatroban
Argatroban is a direct-acting thrombin inhibitor. There is no cross-reaction with heparin. Enoxaparin is a type of heparin. You must stop all forms of heparin when faced with heparin-induced thrombocytopenia (HIT).
It is not appropriate to wait for confirmatory laboratory testing for HIT. Although antiplatelet factor IV antibodies and serotonin release assay are the most accurate tests, it is more important to switch therapy.
HIT presents with thrombosis, not bleeding. Platelets “clump out.”