Thrombosis/Embolism, Hypercoaguable States & Antiphospholipid Syndrome

I. APPROACH TO ARTERIAL THROMBOSIS/EMBOLISM
The workup starts with having a basic differential diagnosis. Atherosclerosis and Embolism are by far the most common causes, and must be excluded before pursuing the rarer causes of hypercoagulability.
1) Atherosclerosis – causing plaque rupture/thrombosis. This is the typical pathophysiology behind MI, thrombotic CVA’s, etc. Also, plaque rupture and thrombosis can then break off and embolize downstream – as seen in carotid stenosis causing TIA/CVA, also aortic atherosclerotic plaques can rupture and cause thrombosis which then embolize to the brain causing strokes.
2) Embolism

Atrial fibrillation – leading to LA thrombus that flicks off and causes arterial embolism
Atrial Myxoma – Benign tumors, ~80% occur in the left atrium, commonly have constitutional symptoms (fever, weight loss) and embolic phenomenon.
LV thrombus – most commonly after MI’s, leading to LV dysfunction and aneurysm that predisposes to thrombus formation.
Endocarditis – both infectious and noninfectious.
Paradoxical Embolism – when venous thromboemboli pass from the right side of the heart to the left (through PFO, ASD, VSD), leading to arterial emboli, especially stroke.
Cholesterol Emboli – caused mainly by aortic atheroscloeric plaques – small pieces of atheromatous material break off and cause small artery occlusions à strokes, acute renal failure, “blue toe syndrome,” ulcers/gangrene, purpura/petechiae, livdeo reciularis, etc. ** 50% of cholesterol emboli occur spontaneously; the other 50% are iatrogenic, mainly due to cardiac cath (~85).

3) Vasculitis – Polyarteritis Nodosa, others
4) Decompression Sickness (“The Bends”) – occurs in people who rapidly return from compressed underwater environments to atmospheric pressure à gas bubbles form in the vasculature leading to emboli and infarcts in multiple tissues. Hopefully, this entity should be suspected based on history.
5) Certain hypercoagulable states: **Inherited thrombophilias (i.e. Factor V Leiden, Prothrombin Mutation, Protein C/S Deficiency, Antithrombin III Deficiency) are primarily associated with venous thrombosis, NOT arterial thrombosis. If you suspect hypercoagulable state causing arterial thrombosis, this carries a much narrower differential diagnosis (see below) **

Initial workup should definitely include a transthoracic and transesophageal echocardiogram to r/o endocarditis, atrial or ventricular thrombus, R-L shunts (for paradoxical emboli, using “bubble study” on echo), atrial myxomas, and also to look for aortic atherosclerotic plaques that can hint at cholesterol emboli. CTA or MRA of the brain (and carotid ultrasound) can be useful to evaluate the vasculature to look for signs of significant atherosclerosis. Autoimmune workup to look for vasculitis is reasonable if this workup is negative. Hypercoagulable workup should be really limited to the ones that cause arterial thrombosis – see below.

II. HYPERCOAGULABLE STATES ASSOCIATED WITH BOTH ARTERIAL AND VENOUS THROMBOSIS
As a general rule, these states all cause venous thrombosis more commonly than arterial.
1) Antiphospholipid Syndrome – main clinical manifestations are 1) Venous and arterial thromboses, 2) Pregnancy complications, and 3) Thrombocytopenia.
2) Heparin-Induced Thrombocytopenia – causes an extremely thrombogenic state! Suspect in patients with heparin exposure, non-severe thrombocytopenia, etc.
3) Hyperviscosity States

Waldenstrom’s Macroglobulinemia
Leukostasis in the setting of leukemia
Sickle Cell Disease

4) Myeloproliferative Disorders – again, much more commonly cause venous thrombosis, but arterial events are not unheard of.

Polycythemia vera
Essential Thrombocythemia
CML

5) Paroxysmal Nocturnal Hemoglobinuria- acquired defect in the RBC membrane that leads to increased complement binding to the RBCs. Clinically, presents as hemolytic anemia, bone marrow dysfunction (progression to MDS, leukemia), and an extremely hypercoagulable state.
6) TTP/HUS, DIC – all of these can cause both venous and arterial microthrombi. In DIC, more commonly get thrombosis in chronic DIC, whereas in acute DIC bleeding tends to be more the problem.
7) Dysfibrinogenemia – various defects in fibrinogen that can lead to both bleeding and thrombophilia. Most common reason is acquired as in liver disease.

Cryofibrinogenemia is a state where patients get cold-insoluble proteins composed of fibrinogen, fibrin, and fibronectin, that leads to cold sensitivity, Raynaud’s purpura, urticaria, skin ulcerations, and arterial and venous thrombosis. This is seen in association with autoimmune diseases, malignancy, and infection.

8) Hyperhomocysteinemia ? - associated with CV events, and strokes. However, not a huge risk factor, as smoking, diabetes, HTN, HLD tend to increase your risk for these events more than elevated homocysteine levels. Of note, trials looking at decreasing VTE risk with folic acid supplementation have largely been negative.
As you can see, many of these disorders are fairly rare and zebra-ish, so think outside the box if you see a patient with multiple arterial thromboses and if you’ve excluded the conditions in part I (atherosclerosis, emboli, etc).

III. OVERVIEW OF ANTIPHOSPHOLIPID SYNDROME
Etiologies:
1) Primary (Idiopathic)
2) Secondary – associated with Autoimmune Disorders (especially SLE), Malignancy (both solid and heme tumors), Infections (bacterial, virla, and parasites), and Drug Reactions
Diagnostic Criteria:
Needs both clinical AND laboratory evidence to make the diagnosis of APS.
A. Clinical: 1 or more episodes of venous or arterial thrombosis, and/or pregnancy complications (unexplained fetal loss after 10 weeks, 3 or more unexplained fetal losses prior to 10 weeks, or 1 or more premature birth prior to 34 weeks)
B. Laboratory: Antiphospholipid Abs on 2 or more occasions, at least 12 weeks apart.

Lupus Anticoagulant – suspect if you have prolonged PTT (that does NOT correct with mixing studies). However, only ~50% of patients with LA have prolonged PTT, so normal PTT does not rule this out! Dilute Russell Viper Venom Time (dRVVT) is a more sensitive assay for LA.
Anticardiolipin Antibodies – IgG is more specific than IgM. Usually moderate-high titer.
Abs vs Beta-2 Glycoprotein I

** Importance of confirming these Abs on repeat 6-12 weeks later – Transient ACL Abs positivity is seen in ~10% of healthy patients, usually low-titer, but persist in only ~1-2%. Must repeat labs and correlate clinically **
Other clinical manifestations and pearls:

Classic setting to suspect APS is a stroke in a young person without obvious risk factors.
Thrombosis is more commonly venous vs arterial, but recurrence tends to follow the same pattern (i.e. after initial arterial emboli, recurrence tends to be arterial rather than venous).
Venous thrombosis often occurs in unusual locations – e.g. cerebral sinuses, renal vein, hepatic or portal veins, retinal veins, etc).
Thrombocytopenia is another classic manifestation of APS. Can also get microangiopathic hemolytic anemias like TTP/HUS, HELLP, and in Catastrophic APS (see below)
Skin manifestations are common and include splinter hemorrhages, livedo reticularis, skin necrosis/infarction and digital gangrene.
In terms of cardiac manifestations, can also get valvular thickening and vegetations that can be infectious or non-infectious.

Management: Mainly centers around anticoagulation.
1. Secondary prevention – after initial DVT or arterial event, management is initially the same as for other DVTs – anticoagulation with heparin (or LMWH), bridged to Coumadin.

The importance of making the diagnosis of APS is in the duration of anticoagulation: untreated, the recurrence rate is enormously high at 20-30%/year, and so these patients should receive lifelong anticoagulation!!
The goal INR has been controversial, and in the past a goal INR of 3-4 was often recommended.
However, the current recommendation is for a goal INR of 2-3 after an initial VTE event.
If patients have recurrent VTE, you can either add ASA 81 mg to Coumadin, or increase the goal INR to 3-4. Generally, the first option is preferred.
For initial arterial thrombosis, some would recommend a goal INR of 3-4.

2. Primary prevention – this has been long debated and controversial, but basically there does not appear to be much benefit for prophylactic anticoagulation if patients with (+) Antiphospholipid Abs have never had a thrombotic event, UNLESS these patients have SLE in which case they are at high risk à recommendation is to treat with ASA +/- Plaquenil (shown to decrease platelet activation in APS).

IV. CATASTROPHIC APS
Refers to widespread thrombotic disease with multiorgan failure. Fortunately, this is fairly rare and in one study occurred in <1% of 1000 patients with APS followed over 7 years (and majority was found at the time of diagnosis).
Preliminary Proposed Criteria:

3 or more organs or systems involved
Occurring simultaneously or within 1 week or each other
Lab evidence of LA or Anticardiolipin Abs
Confirmed by histopathology of small vessel occlusion in at least one organ or tissue.

All 4 criteria = Definite Catastrophic APS, whereas certain combinations give you Probable Catastrophic APS.
Treatment:

Acute anticoagulation with IV heparin
High dose steroids (Solumedrol 1 g IV x 3 days, followed by a taper)
Plasmapheresis +/- IVIG if signs of microangiopathy.

Mortality is high at ~50%, even with treatment.

(Chanu Rhee MD, 3/15/11)