Peter A. Kouides MD
Bloodline Co-Editor
Assistant Professor of Medicine, University of Rochester School of Medicine
Medical Director, Mary M. Gooley Hemophilia Treatment Center
Rochester, New York

This 18-year-old white male was in his usual state of good health working this summer as a house painter.

10 days PTA (prior to admission) he noted epistaxis that was more brisk than usual.

5 days PTA, he awoke with bilateral foot pain with swelling localized to the right ankle with purplish discoloration.

2 days PTA, a CBC showed a WBC of 8.7, Hct 42%, platelet count 58K.

Since then, he has had increasing right lower extremity edema now extending from the ankle to the calf with purplish-red discoloration. He has also noted moderate bleeding after shaving each morning for the past 3 days. He notes no recent URI symptoms, constitutional symptoms or arthralgias. No medication use or toxin exposure save paint. No history of IVDA. No history of trauma to the calf.

PE - Afebrile, BP 110/70. He is a pale, ill-appearing white male complaining of right lower extremity pain. HEENT showed palatal petechiae and hemorrhagic crusting at sites of shaving face. Neck is notable for several .5 x 1 cm posterior nodes. Cardiopulmonary WNL. No hepatosplenomegaly. Extremities with petechiae bilaterally, violaceous discoloration of the right ankle with increased circumference greater than left by 4 cm with extension to right mid-calf 2 cm. greater than left. Equal lower extremity arterial pulses.

Laboratory data:
WBC 4.5, PMNs 78, Eos 9, Lymphs 7, Monos 6, Hct 48, MCV 89
Platelet count 38K.
PT 10.8, PTT 36.3 (upper range of control range=31.4)

What would you do next?

Answer(s):

There is no right answer here, probably multiple tasks to do:

(a) examine peripheral blood smear to assess thrombocytopenia
(b) work-up slightly prolonged PTT
(c) image lower extremity to confirm that this is a bleed and determine the extent of the bleed.

1. Rule out clumping (pseudothrombocytopenia)
   
2. Look for abnormal WBCs and/or RBCs. If WBC and/or red cell count are abnormal then also strongly consider bone marrow.
   
3. Look for giant platelets (defined as at least half the diameter of the adjacent RBC). If present on smear, then peripheral immune-mediated destruction or consumption by hypersplenism, DIC, or TTP/HUS is most likely.

(b) work-up slightly prolonged PTT

DIC screen:
Fibrinogen 194 (normal 200-400)
FSP greater than 40 less than 80
Re-review of smear - no fragmentation of RBCs

Interpretation of DIC screen: a definite maybe!
Asymmetric calf swelling was seemingly out of proportion to coagulopathy and thrombocytopenia

Doppler ultrasound: consistent with DVT, not bleed!!!!

In retrospect, the DIC screen probably just represented on-going endogenous fibrinolysis from the clot formed.

Thrombosis in a young adult. Hypercoaguable work-up led to discovery of a lupus anti-coagulant (recall that his PTT was 5 seconds above the upper limit of normal).

Teaching point: The Significance of a Prolonged PTT

In one study of 100 consecutive patients with a prolonged PTT, in 50% of these cases, the PTT did not signify risk for bleeding:

14 had normal PTT upon repeating it (ie. poor venepuncture techniques or heparin contamination); 33 had the lupus anti-coagulant; 3 had Factor XII deficiency or dysfibrinogenemia- both which correlate with thrombosis. The remaining 50% had some risk to bleed due out to Vitamin K deficiency, liver disease, DIC, inhibitor, or mild hemophilia.

Clinical Pearls

Make sure that the patient is bleeding in the first place. In this case the platelet count was never low enough in the absence of trauma to account for a calf bleed. Lupus anticoagulant is not associated with bleeding despite the fact that we term it an anticoagulant. In vitro it is an anti-coagulant as it interferes with the PTT because of its avidity for phospholipid (a better term is anti-phospholipid). In vivo it is a procoagulant because of avidity so involves the endothelium.

Teaching points on the Anti-Phospholipid Antibody Syndrome

Variation in nomenclature: You will come across various terms describing this condition in the literature. Historically, the term used has been lupus anti-coagulant, but this is a misnomer since the majority of patients do not have lupus. Though it is an anti-coagulant in vitro, in vivo it is a procoagulant as that same avidity it has for the phospholipid in the coagulation test is also towards the phospholipid-laden endothelial membrane which can possibly lead to vessel wall damage. As such, it makes better sense to use the term anti-phospholipid antibody than lupus anti-coagulant.

Variability in laboratory diagnosis: Patients with the Anti-phospholipid Antibody Syndrome roughly follow the rule of thirds:

- 1/3rd will have a positive lupus anticoagulant screen and positive anti-cardiolipin antibody

- 1/3rd will have a positive lupus anticoagulant screen but negative anti-cardiolipin antibody

- 1/3rd will have a negative lupus anticoagulant screen but positive anti-cardiolipin antibody

More on the variability of APAS

Patients with the antibody fall into the following categories:
Autoimmune Diseases: though the majority of patients do not have lupus and fall into one of the other categories, patients with lupus do have a high incidence of the antibody (anywhere from 10-50% depending on the type of coagulation test done) and patients with other autoimmune disesases such as Rheumatoid Arthritis can have the antibody.

Arterial or venous thrombosis that is unexplained: (ie. no history of stasis, vessel wall injury or other causes of hypercoaguability.

Drug-induced: phenothiazines, hydralazine, quinidine, procainamide.

Viral-related: childhood viral infection (antibody will be transient) or AIDS.

Incidental: detection on the basis of a prolonged PTT from a routine blood test. This probably constitutes the largest category as 1/3rd of patients with a prolonged PTT will have the antibody. Virtually all these patients will be asymptomatic (ie. no clots) so they do not have to be anti-coagulated.

Variability in Clinical Outcome: not all patients who have the antibody will ultimately develop thrombosis. In particular, those with viral infections including HIV will not and those with drug-induced antibody probably will not develop thrombosis. As such, we do not anti-coagulate a patient just for a positive test that is as controversial as is whether they should be anti-coagulated life-long after one thrombotic event. The patient should probably be anti-coagulated if the event was arterial or if the venous event was major (PE or large DVT), though this case is a toss-up whether he should be on life-long anti-coagulation or not. Probably he should be unless he has significant bleeding events and APA tests become detectable.

More on APAS

Variability in clinical presentation:

Regardless of the category the patient is in, they can present with one or two or the triad of:

Recurrent events occur usually on the same side (ie. if first clot is arterial, recurrent one is usually arterial) in this case, the patient was thrombocytopenic which is seen in 25-40% of cases.

Bonus Question

What should be this patient's target INR?

- "usual" 2.0-3.0 ?

- or 3.0-4.0 ?

Answer: again there is no right answer:

Based on 2 retrospective studies, one by Rosove et al at UCLA as well as one from the father of this field, Graham Hughes of St. Guy's in London, it has been advised to anti-coagulate these patients intensely to an INR of 3.0-4.0. However, there is a recent study by Moll and Oertel who have shown, I believe convincingly, that the anti-phospholipid antibody also can interfere with the INR. A plausible explanation why patients fare the best in terms of the least clotting with an INR of 3.0-4.0 in the above studies may be because of the interference of the antibody when the patients with INRs at 2.0-3.0 probably were truly at 1.2-2.2. On the other hand, European data does not seem to support this. As a compromise, we aim for a INR exactly at 3.0, but periodically measure a chromogenic Factor X assay and raise the Coumadin dose to an INR closer to 4.0 than 3.0 if the Factor X assay is subtherapeutic.

References

1. Kitchens CS. Prolonged activated partial thromboplastin time of unknown etiology: a prospective study of 100 consecutive cases referred for consultation. American Journal of Hematology. 27(1):38-45, 1988 Jan.

2. Chong BH. Brighton TC. Chesterman CN. Antiphospholipid antibodies and platelets. Seminars in Thrombosis & Hemostasis. 21(1):76-84, 1995.

3. Galli M. Finazzi G. Barbui T. Thrombocytopenia in the antiphospholipid syndrome. British Journal of Haematology. 93(1):1-5, 1996 Apr.

4. Macchi L. Rispal P. Clofent-Sanchez G. Pellegrin JL. Nurden P. Leng B. Nurden AT. Anti-platelet antibodies in patients with systemic lupus erythematosus and the primary antiphospholipid antibody syndrome: their relationship with the observed thrombocytopenia. British Journal of Haematology. 98(2):336-41, 1997 Aug.

5. Godeau B. Piette JC. Fromont P. Intrator L. Schaeffer A. Bierling P. Specific antiplatelet glycoprotein autoantibodies are associated with the thrombocytopenia of primary antiphospholipid syndrome. British Journal of Haematology. 98(4):873-9, 1997 Sep.

6. Cuadrado MJ. Mujic F. Munoz E. Khamashta MA. Hughes GR. Thrombocytopenia in the antiphospholipid syndrome. Annals of the Rheumatic Diseases. 56(3):194-6, 1997 Mar.

7. Rosove MH. Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Annals of Internal Medicine. 117(4):303-8, 1992 Aug 15.

8. Khamashta MA. Cuadrado MJ. Mujic F. Taub NA. Hunt BJ. Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. New England Journal of Medicine. 332(15):993-7, 1995 Apr 13.

9. Moll S. Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Annals of Internal Medicine. 127(3):177-85, 1997 Aug 1.

10. Tripodi A. Mannucci PM. Monitoring warfarin therapy in patients with lupus anticoagulants. (LA) Thrombosis & Haemostasis. 80(2):349-350, 1998 Aug.