PBL Sessions: Reproductive Organ System

Page 10

Final Discussion of Case:

Figure 16: Gross appearance of the TIPS procedure

Key Issues

The patient is a 24-year-old woman who is pregnant for the third time. Her prior pregnancies ended in fetal loss by 20 weeks gestation. She recently had an episode of chest pain with dyspnea. A year later she presents with complaints of fatigue and abdominal discomfort. She has the signs, symptoms, and imaging data that lead to a diagnosis of Budd-Chiari syndrome. The primary cause for obstruction of the inferior vena cava is a clot formation in the vessel that leads to chronic portal hypertension, ascites and hepatomegaly. After the initial diagnosis, a transjugular intrahepatic portosystemic shunt (TIPS) was performed to reduce the portal blood pressure. She has returned to the physician with similar problems again that are most likely the result of occlusions of the inferior vena cava (IVC) superior to the liver. The case will focus on finding an underlying cause for these multisystem findings, which is antiphospholipid syndrome.

Pathologic / Radiologic / Anatomical Learning Issues

• Causes for venous thrombosis

• Laboratory testing for coagulopathies

• Vascular supply and drainage of the liver

• Portal-systemic anastomoses

• Cross-sectional anatomy of the abdomen

Clinical Learning Issues

• Pregnancy loss

• Acute dyspnea

• Hepatomegaly

• Caput medusa

• Abdominal imaging

• Medical liability

Discussion

Anti-phospholipid Syndrome

The antiphospholipid syndrome (APS) is an autoimmune condition characterized by certain clinical features and the presence of autoantibodies that bind to complexes of proteins and negatively charged phospholipids. As a group, these autoantibodies are called antiphospholipid antibodies (aPL). Three are well-characterized: lupus anticoagulant (LA), anticardiolipin antibody (aCL), and the autoantibody that results in the false-positive serological test for syphilis.

The three best-established clinical features of APS are thrombosis (venous or arterial, including stroke), fetal loss, and autoimmune thrombocytopenia. Others include neurological conditions (transient ischemic attacks, amaurosis fugax, migraine headaches, chorea), vascular conditions (arterial ischemia, gangrene, persistent cutaneous ulceration, myocardial infarction, Budd-Chiari syndrome, renal vein thrombosis), and obstetric conditions (fetal growth impairment, fetal distress, severe preeclampsia).

APS may occur in patients with no other autoimmune conditions (primary APS) or in association with another autoimmune disease (secondary APS). Up to 40% of patients with systemic lupus erythematosus (SLE) have detectable aPL, but far fewer have APS. Certain infections (e.g., HIV) and drugs (e.g., chlorpromazine, procainamide) have been associated with the emergence of aPL and the clinical features of APS.

Paradoxically, LA causes prolongation of in vitro phospholipid-dependent clotting times. The most widely used screening assay in the U.S. is the activated partial thromboplastin time (aPTT), but other screening clotting tests may be used. If the screening test is prolonged, the patient's plasma is mixed with an equal volume of normal plasma and the test is re-run. This mixing study excludes factor deficiencies as the cause of the initially prolonged clotting time. Since the primary site of activity of LA is the prothrombinase complex, a dilute Russell's viper venom time (dRVVT) is considered more specific in the detection of LA. The vast majority of patients with LA have normal prothrombin times. Heparin interferes with the detection of LA by causing false positive results; Coumadin may do the same. A patient most likely has LA who:

• Has a prolonged phospholipid-dependent clotting time with a positive mixing study,

• Has no history of a bleeding diathesis, and

• Is not on heparin or Coumadin.

Up to 5% of apparently normal people have detectable aPL, especially low-levels of aCL, but far fewer have LA or medium-or-high positive aCL. In contrast, most patients with APS have LA, medium-to-high positive IgG aCL, or both. A few patients with APS will be positive for LA and negative for aCL or visa versa. Thus, both LA and aCL should be ordered when considering the diagnosis of APS. Low-positive IgG aCL results and IgM aCL without the presence of LA or IgG aCL are of questionable significance. Physicians must exercise careful clinical judgment in the interpretation of low-positive IgG aCL or isolated IgM aCL results.

Recent recommended testing algorithms now include three different autoantibodies to properly diagnose APS or to assess the risk for thrombosis or recurrent fetal loss. These include anti-cardiolipin (aCL), anti-Beta 2 Glycoprotein I (ß2GPI), and more recently, anti-phosphatidylserine (aPS).

Anticardiolipin antibodies (aCL) are a heterogeneous group of antibodies that react with negatively charged phospholipids. One subgroup of autoantibodies directed against cardiolipin is frequently found in systemic lupus erythematosus (SLE) patients, as well as in patients with both venous and arterial thrombosis, thrombocytopenia, and recurrent fetal loss. Patients who present with these latter manifestations have what is termed the "antiphospholipid antibody syndrome" (APS). Another subgroup of anticardiolipin antibodies is found in patients with syphilis and other infectious diseases who have no evidence of coagulation disorders.

Studies in the early 1990s identified Beta 2 Glycoprotein I (ß2GPI) as a necessary cofactor for antiphospholipid antibody binding in immunoassays. More recent studies, however, have reported that anticardiolipin antibodies derived from autoimmune patients (SLE and APS) were directed only against the ß2GPI molecule when coated on polystyrene plates. There is a well known potential for traditional anticardiolipin tests to produce false positive results due to cross-reactivity of phospholipid antibodies present in certain infectious disease samples, most notably syphilis, and with certain other autoantibodies such as antibodies to double-stranded DNA. By eliminating phospholipid from the solid phase and using only ß2GPI, the test becomes more specific for detecting potential coagulation problems. Other important antibodies may be missed, however; thus, testing for aCL and aPS antibodies is still recommended.

The third and most recently recognized clinically significant antiphospholipid antibody, aPS, is directed against phosphatidylserine. Unlike cardiolipin, phosphatidylserine is a more physiologically relevant phospholipid due to its presence in cell membranes of endothelial cells and platelets and its role in the coagulation cascade. The detection of anti-phosphatidylserine antibodies has been recommended for the serological diagnosis of antiphospholipid syndrome. Patients with positive results to both cardiolipin and phosphatidylserine are more likely to have clinical complications than those who are positive for only one antibody.

These tests should be utilized in patients with unexplained arterial or venous thromboembolic disease or recurring pregnancy loss and in the workup of systemic lupus erythematosus. A lupus anticoagulant panel should probably be run prior to these individual antibody tests.

In pregnancy, APS leads to uteroplacental insufficiency with atherosis, arteriopathy, and massive intervillous fibrin deposition resembling maternal floor infarction. There is intrauterine growth retardation, increased fetal loss, and prematurity. Aspirin, corticosteroids, and heparin have been utilized in treatment with a reduction in the severity of the complications.

There are several diseases which are in the differential diagnosis of recurrent thrombosis in a young person:

A single point mutation in the factor V gene prevents a peptide bond in the coagulation molecule from being cleaved by activated protein C (APC). During normal homeostasis, APC limits clot formation by proteolytic inactivation of factor Va and VIIIa. Resistance to this activity increases the risk of deep-vein thrombosis. The allelic frequency of the mutation may approach 5% and is at least 10 times higher than all other known genetic risk factors for thrombosis (protein C, protein S, and antithrombin deficiency).

The factor V Leiden mutation accounts for > 90% of cases with APC resistance. Inherited thrombosis due to APC resistance is considered an autosomal dominant disease. Heterozygote carriers of the factor V Leiden polymorphism have an increased risk of thrombosis of 5- to 10-fold while homozygotes have an 50- to 100-fold increased risk. Estimated penetrance for homozygotes is close to 80%, with a reduced penetrance for heterozygotes (approximately 12-20%). Mutations in other genes or other mutations in the factor V gene that may cause APC resistance and venous thrombosis are not ruled out.

Moderately elevated plasma homocysteine (tHcy) is an independent predictor for atherosclerosis and thromboembolism. Patients with homocystinemia are also at risk for deep-vein thrombosis. tHcy is a graded risk factor and, consequently, the risk for vascular disease increases progressively with tHcy concentration. In addition, individuals with moderate hyperhomocysteinema and coagulating factor defects may have thrombosis at a very young age.

The factor II (prothrombin) mutation is the second most common genetic defect for inherited thrombosis, with factor V Leiden being the most common. The G20210A mutation is associated with increased prothrombin levels. A single copy of this variant (heterozygote) increases the risk of venous thrombosis to 3-11%. Two copies of the 20210A allele further increases this risk. In Caucasians, the prevalence of factor II G20210A heterozygotes is 1% to 6%, whereas in non-Caucasian populations it is very rare or absent. The 20210A allele is associated with an increased risk for thrombosis in both men and women and the allele increases the risk for all age groups.

The G20210A mutation causes elevated plasma prothrombin levels, which in turn increase the risk for a thrombotic event. The 20210A allele of the prothrombin gene may be coinherited with the factor V Leiden mutation. The combined heterozygosity for the two defects leads to an earlier onset and a more severe thrombotic episode than single-gene defects.

Protein C is a naturally occurring vitamin K-dependent plasma anticoagulant, whose anticoagulant effect is largely due to a rapid inactivation of factors Va and VIIIa. Protein C must be converted to an active serine protease, activated protein C (APC), to be physiologically functional. Protein S, protein C's cofactor, potentiates the binding of APC to the platelet or endothelial cell surface through a calcium ion bridge. Protein C deficiency is a minor cause of inherited thrombosis.

Protein S is a plasma vitamin K-dependent protein that has an essential anticoagulant function. It acts as a cofactor of activated protein C, to which it forms a stoichiometric complex. In the presence of calcium, this complex binds strongly to the phospholipid surface, regulating the coagulation process and inhibiting thrombin-activated factors V and VIII. Protein S also greatly enhances the anticoagulant function of activated protein C (APC), most likely by increasing protein C affinity for phospholipid membranes. Protein S deficiency is a minor cause of inherited thrombosis.

Antithrombin (AT) is a beta-globulin inhibitor of activated serine proteases. Approximately 75% of the plasma coagulation inhibitory activity is derived from AT. AT deficiency is a cause of inherited thrombosis.

Reference: Guide to Laboratory Testing, at http://www.aruplab.com

Are there medical liability issues with this case? There was a delay in diagnosis, or a failure to make the diagnosis before the patient had complications of the disease. It doesn't matter if this was your fault or someone else's. It is best to be honest. Furthermore, if legal fears are the problem, it is important to remember that doctors who don't admit their mistakes get sued more, while doctors who admit their mistakes and regret them--who seem human--get sued less. This same pattern is also true for doctors who do end up being sued and lose the case: those who admitted mistakes lose less money. Those who tried to cover it up, and vigorously fought the case against them, lose much more money--and punitive damages can be added!