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New Treatments for  Coagulation Disorders in Pregnancy

Disorders of coagulation can lead to both bleeding diatheses and alternatively, to thromboembolism. Pregnancy can exacerbate these conditions and thromboembolism is the leading cause of maternal mortality in Western countries. At the conclusion of the presentation, we will have reviewed the physiology of coagulation and the changes that are seen in pregnancy; we will go over some of the major inherited and acquired bleeding disorders; inherited and acquired thrombophilias, or propensities to clotting; and then discuss the risk factors, diagnosis and treatment of thromboembolism in pregnancy.

First, we'll talk about the physiology of coagulation. This was the course that we all hated in medical school, with all the factors. Hemostasis is designed to control bleeding at the site of injury. It involves complex interactions between the vascular endothelium, platelets and coagulation factors. So it begins with disruption of the vascular endothelium, exposure of tissue factor and collagen.

We will first talk about inherited bleeding disorders, starting with von Willebrand's disease. Generally, that is inherited as an autosomal dominant condition, although there are recessive variants. It occurs in 1:10,000 individuals. In women, menorrhagia and delayed post partum hemorrhage are common presentations. Levels of von Willebrand factor can be normal in pregnancy because of the increased production in the liver, but they return to pre-pregnancy values by three days post partum and that is why it is actually delayed post partum hemorrhage that is more of an issue. Other clinical manifestations include bleeding, epistaxis, gingival bleeding.

The next inherited bleeding disorder is hemophilia A; this is an X-linked recessive disorder in one in ten thousand white males. However, for our purposes, females can be affected if they have an affected father and a carrier mother; if they have an X-chromosome abnormality, such as Turner's syndrome or mosaic for Turner's syndrome; or due to extreme lyonization. If you remember, lyonization is when one X chromosome gets inactivated. If there is a disproportionate inactivation of the normal X chromosome, you can have a female with hemophilia A. Clinically, then experience bruising, muscle hematomas and hemarthrosis. It is a functional abnormality or deficiency of factor VIII. Unlike von Willebrand's disease, platelet aggregation is normal, because there are normal levels and normal functioning of the von Willebrand factor. It is a qualitative rather than a quantitative defect in factor VIII that results in the prolonged PTT. Treatment involves factor VIII concentrate or cryoprecipitate and DDAVP can also be used. Hemophilia B is also known as Christmas disease; it is factor IX deficiency. Again, it is an X-linked recessive and it is much less common than hemophilia A.

Thrombophilia means any propensity to thrombosis. It should be considered in a young patient who experiences atraumatic thrombosis, in patients who have a family history of thrombosis, in cases of recurrent thrombosis, especially when someone is already anticoagulated, when thrombosis occurs at an unusual site, or when there is warfarin-induced skin necrosis. It should also be considered, for our purposes, in patients who have recurrent pregnancy loss, unexplained IUFD's and early severe IUGR.

The first one is antithrombin III deficiency. This is an autosomal-dominant condition. It affects 1 in 250 to 1 in 500 individuals. Type I is a deficiency state and type II is reduced functional activity. The clinical manifestation is thrombosis. It may be an acquired deficiency in patients who have DIC, nephrotic syndrome, liver disease, pre-eclampsia, during oral contraceptive use and during heparin therapy.

Protein C deficiency is also autosomal dominant. This is the next thrombophilia. It occurs in 1 in 200 individuals, although the penetrance is variable. Type I has a reduction in amount and function and type II has a reduction in function only. When thrombin binds to thrombomodulin, it ceases to function as a procoagulant. It then becomes an anticoagulant. The thrombin-thrombomodulin complex activates protein C to become activated protein C. Activated protein C is a serine protease which cleaves activated factor V and VIII, thereby decreasing thrombin formation and functions as an anticoagulant. Protein C works best in the presence of its cofactor, protein S. There is less risk of thrombosis with protein C deficiency than with antithrombin III deficiency. The risk seems to be the greatest in the post partum period. That is why whether or not therapeutic anticoagulation is required during pregnancy is mixed.

Protein S deficiency is also autosomal dominant, even more rare, occurring in 1 in 20,000 individuals. It is only the forty percent that is free that is functionally active as a cofactor to the anticoagulant effects of activated protein C. The classic deficiency state is marked by a fifty percent reduction of total protein S antigen and protein S functional activity.

Factor V Leiden mutation is the next thrombophilia I want to talk about. It is also known as activated protein C resistance and we will talk about why it is given that name. It is autosomal dominant and it results from a single base pure substitution in the factor V molecule. The mutant factor, which is referred to as the factor V Leiden.

The last thrombophilia I want to talk about is new and you probably won't even find it in a textbook - it's prothrombin gene mutation. It is autosomal dominant; it is not recessive. It results from a single base pure substitution. Again, it has homozygous and heterozygous states. It can be synergistic with factor V Leiden mutation. So the patient who has both factor V mutation and prothrombin mutation is at extremely high risk for thromboembolism.

Let's talk about the acquired disorders that lead to bleeding. These include DIC, vitamin K deficiency, liver disease, uremia and after massive transfusion. DIC results from the pathologic generation of thrombin ; that activates platelets, converts fibrinogen to fibrin thrombi and activates several coagulation factors. Thrombi in the microcirculation activates the fibrinolytic process and leads to the release of fibrin degradation products, which inhibit normal coagulation. The consumption of platelets and coagulation factors, as well as the above described inhibition of normal coagulation, leads to both hemorrhagic and thrombotic consequences.

Acquired disorders that lead to thrombosis include antiphospholipid syndrome. I am only going to touch on this briefly. It should be considered with recurrent thrombosis, unexplained recurrent pregnancy loss, IUGR or stillbirth. It has no prolongation of any coagulation tests. It is diagnosed by the presence of IgA, IgG and IgM antibodies.

The other acquired disorder that lead to thrombosis is lupus anticoagulant, which is a misnomer, because it is not necessarily related to lupus and it is not an anticoagulant; it is actually a procoagulant. This is an acquired anticoagulant that inhibits coagulation tests in vivo, despite normal clotting factors. Of course, not all patients have associated rheumatologic conditions such as lupus.

Doppler duplex: Doppler duplex is used to detect the absence of either spontaneous flow or the normal variation seen with respiration. It has a sensitivity and specificity for proximal veins of ninety percent. The combination of continuous-wave Doppler and real-time imaging results in a ninety-eight percent detection of proximal deep vein thrombosis with a ninety-five percent specificity compared to venography. At least fifty percent of small calf thrombi will be missed secondary to collateral circulation.

Impedance plethysmography: Impedance plethysmography measures the changes in electrical resistance seen with changes in blood volume. It is highly sensitive to proximal thrombosis.

Venography: Venography, which is the diagnostic gold standard, is expensive and invasive. An injection of dye into the veins is painful. A quarter of patients will experience minor side effects, including pain, swelling and erythema. The fetal exposure for venography is three millirads.

VQ scan: VQ scan is done by the infusion of technetium labeled albumin while the patient is supine and then images taken while the patient is upright in multiple positions. It is highly sensitive and a normal scan can almost completely exclude the diagnosis of pulmonary embolism. The ventilation component will increase the specificity. The problem is that very few will come back as normal, a great majority will come back as indeterminate, and then there is low, moderate and high probability. The reliability of diagnosis of pulmonary embolism is ninety percent. The fetal dose is two millirads.

One of the new things that some of you may be hearing about now is spiral or helical CT. This is best for evaluation of the proximal pulmonary vasculature. It may miss small peripheral lesions, but it is less likely than a VQ scan.

Treatment options.

Heparin: The high molecular weight and negative charge prevents passage of heparin to the fetus, which is why we love heparin. It potentiates the action of antithrombin III which we talked about before; it can be given IV or subcu., it has a half life of 1 to 2-1/2 hours with an immediate anticoagulant effect. The goal is a PTT of 1-1/2 to 2-1/2 times normal. You can also monitor heparin levels or inhibition of factor X. The usual dose is 100 units per kilogram loading for deep vein thrombosis and 150 units per kilogram loading for pulmonary embolism, followed by 15 to 25 units per kilogram per hour and

Coumadin inhibits the action of vitamin K, which is required to carboxylate the glutamic acid residues on II, VII, IX, X and protein C. As you know, it easily crosses the placenta and for the most part is contraindicated during pregnancy. Warfarin embryopathy, including nasal hypoplasia, depression of the bridge of the nose and epiphyseal stippling can occur at highest risk with exposure from four to nine weeks. Second and third-trimester exposure is associated with central nervous system and

Many drugs can potentiate the action of Coumadin. Common ones that we might use would include Cimetidine, metronidazole, nonsteroidals and dilantin.

Some drugs antagonize the action of Coumadin, including common things that we might use in pregnancy; antacids, antihistamines, corticosteroids, so that needs to be kept in mind when the patient is on Coumadin.

Generally, treatment for deep vein thrombosis is for three months. Treatment should continue for at least six weeks post partum if this occurs during pregnancy and it should be longer than that if there is a thrombophilia present or other risk factor. Generally,

Heparin prophylaxis: 5000 to 10,000 units subcu every 12 hours with a gradual increase through the pregnancy; 5000 in the first trimester, 7500 in the second trimester and 10,000 in the third trimester. This is call low or mini-dose heparin. Mini-dose heparin enhances antithrombin III, inhibits activated factor X and thus diminishes thrombin formation. It requires less heparin to inhibit factor X than to prevent clotting once

Protamine sulfate can be used to reverse low molecular weight heparin, but low molecular weight heparin is less effective than standard heparin by the action of protamine sulfate. It is administered in a weight-dependent dose, so therapeutic anticoagulation is 1 mg per kilogram subcu every 12 hours and prophylactic is