Clinical review

Antithrombotic therapy in special circumstances. Ipregnancy and cancer

Bernd Jilma, Sridhar Kamath, Gregory Y H Lip. 

	Antithrombotic therapy during pregnancy

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Pregnancy predisposes to venous thromboembolism for several reasons. These include a change in the balance between procoagulant and anticoagulant factors in the blood. Any conditions that predispose a woman to thromboembolism when she is not pregnant will also predispose her to thromboembolism when she is pregnant.

Disorders during pregnancy for which antithrombotic therapy is commonly considered Prophylaxis and treatment of venous thromboembolism Prophylaxis in patients with valvar disease (for example, mitral stenosis) Prophylaxis in patients with mechanical prosthetic valves Antiphospholipid syndrome Prophylaxis against pregnancy induced hypertension and intrauterine growth retardation

Potential risks of antithrombotic therapy during pregnancy Maternal disadvantages and risks Unfractionated heparin Haemorrhage (uteroplacental, especially during labour) Heparin induced thrombocytopenia Osteoporosis Regular monitoring Low molecular weight heparin Bleeding risk, especially during labour Warfarin Bleeding Regular monitoring Risk to the fetus or child Heparin Seems to be safe Low molecular weight heparin Seems to be safe Warfarin Embryopathy, especially if mother is exposed between 6 and 12 weeks Central nervous system malformations during any time of the gestation Low dose aspirin Potential risk of birth defects and bleeding risk in the first trimester  Safe in second and third trimester

Generally, antithrombotic therapy started in a non-pregnant patient for a particular disorder needs to be continued during the pregnancy and in the puerperium. The use and type of antithrombotic therapy depends on the risk:benefit ratio, taking into consideration the potential harm to the mother and the fetus.

The potential risks of antithrombotic therapy during pregnancy can be divided into maternal and fetal risks, and include teratogenicity and bleeding. Unfractionated heparin and low molecular weight heparins do not cross the placenta and are probably safe for the fetus, although bleeding at the uteroplacental junction is possible. Nevertheless, data are sparse for low molecular weight heparin, with no reliable comparative trials or convincing dose assessment.

In contrast to heparin, coumarin derivatives cross the placenta and can cause both bleeding in the fetus and teratogenicity. Coumarin derivatives can cause an embryopathy (which consists of nasal hypoplasia or stippled epiphyses or both) after in utero exposure during the first trimester of pregnancy. In addition, central nervous system abnormalities can occur after exposure to such drugs during any trimester. The main risk of embryopathy occurs if coumarin derivatives are taken between six weeks and 12 weeks of gestation. At the time of delivery, the anticoagulant effect in the fetus can lead to bleeding in the neonate.

Heparin and low molecular weight heparins are not secreted into breast milk and can probably be given safely to nursing mothers. High dose aspirin should be avoided, as it could (theoretically) impair platelet function and produce hypoprothrombinaemia in the infant, if neonatal vitamin K stores are low, as well as cause Reye's syndrome. Warfarin does not induce an anticoagulant effect in an infant who is breast fed and therefore could be used safely in the postpartum period; thus, patients who are receiving long term heparin treatment could be switched over to warfarin post partum if and when considered appropriate. With regard to other agents, phenindione should be avoided, and acenocoumarol requires prophylactic vitamin K for the infant.

View larger version (22K): [in this window] [in a new window]   Diagnosis of suspected deep vein thrombosis in pregnancy

Venous thrombosis and pulmonary embolism
Antithrombotic prophylaxis for the prevention of venous thromboembolic disorders in pregnancy is indicated when a patient has experienced a previous thromboembolic episode or is considered to be at particularly high risk because of a predisposing condition.

Unfractionated heparin 5000 IU twice daily is generally adequate in non-pregnant women. Heparin requirements can be highly variable in pregnancy. A once daily dose of low molecular weight heparin is a useful alternative to unfractionated heparin and has been shown to be safe and effective in pregnancy.

Patients who develop thromboembolism during pregnancy could be treated initially with at least five days of intravenous heparin treatment, followed by a twice daily subcutaneous dose of unfractionated heparin. The dose is adjusted by maintaining the activated partial thromboplastin time (APTT) within the therapeutic levels. Heparin could temporarily be stopped immediately before delivery and then resumed in the postpartum period to minimise the risk of haemorrhage during labour. The duration of antithrombotic therapy in the postpartum period should be maintained for a minimum of three months, possibly up to six months.

View larger version (21K): [in this window] [in a new window]   Distribution of warfarin dose and poor outcome according to order of pregnancy. The risk of pregnancy complication in patients treated with warfarin is higher when the mean daily dose exceeds 5 mg (P<0.001)

Patients with prosthetic heart valves
The precise safety of warfarin during pregnancy continues to be debated, but it is probably appropriate to withhold warfarin between six and 12 weeks of gestation and for the latter half of the third trimester, because of the risk of causing embryopathy and postpartum haemorrhage respectively. Based on this, the recommended options for use of antithrombotic therapy in patients with a mechanical heart valve during pregnancy include:

Antiphospholipid syndrome in pregnancy: a randomised controlled trial of aspirin v aspirin plus heparin Low dose aspirin (n=47) Low dose aspirin plus heparin (n=51) Live birth rate (%) 72 78 Mean (SD) birth weight (g):  Range    3221 (781)890-5300    3127 (657)718-4319 Gestation at delivery (%):  <30 weeks       1       1   30-36 weeks 3 1   >36 weeks 30 38 Embryo loss (%) 9 3 Fetal loss (%) 4 8

• Adjusted dose of unfractionated heparin twice daily or low molecular weight heparin to maintain the APTT within therapeutic range throughout the pregnancy
• Warfarin throughout the pregnancy, except for the first trimester (either for the entire trimester or between six and 12 weeks) and for the latter half of the third trimester (when warfarin should be replaced by unfractionated or low molecular weight heparin).

The risks and benefits of this approach should be explained to patients, who should be allowed to make an informed choice. There are real concerns over the incidence of abortions and fetal malformations in patients treated with warfarin in the first trimester. Concerns over long term heparin treatment in pregnant women include heparin induced thrombocytopenia and osteoporosis.

Antithrombotic therapy in antiphospholipid syndrome Scenario Management History of pregnancy loss Aspirin plus heparin (APTT in therapeutic range) History of thromboembolism but no pregnancy loss Heparin alone (APTT in therapeutic range) No history of adverse events Heparin alone 5000 IU twice daily; close observation

Prepregnancy counselling is vital for patients who are receiving long term warfarin treatment, and a cardiologist and obstetrician should explain the risks to patients. Patients who are established on long term warfarin treatment and plan to become pregnant could then take twice daily heparin before getting pregnant. Alternatively, and assuming that the risk of warfarin to the fetus in the first six weeks of gestation is not worrisome, they could continue taking warfarin and have frequent checks to see if they are pregnant. If they are they should immediately switch over to heparin. Again, close liaison between obstetrician, midwife, general practitioner, cardiologist, and neonatologist is vital.

Antiphospholipid syndrome
Antiphospholipid syndrome predisposes a pregnant woman to thromboembolism and pregnancy losses. Abortion in a previous pregnancy predisposes to further abortions or stillbirths in subsequent pregnancies. A combination of aspirin and heparin to prolong the APTT to within the therapeutic range (APTT ratio 2.0-3.0) thoughout the pregnancy would substantially decrease pregnancy losses and other complications. However, one recent trial suggested that low dose aspirin (75 mg) may suffice (see box).

Pre-eclampsia and intrauterine growth retardation
On the basis of small, retrospective studies, low dose aspirin (<150 mg daily) was thought to be useful as prophylaxis in patients with a history of pre-eclampsia and intrauterine growth retardation in preventing similar adverse events during the current pregnancy. However, a large (nearly 10 000 women) randomised controlled trial (CLASP) of aspirin 60 mg compared with placebo, reported that, although aspirin was associated with a 12% reduction in the incidence of pre-eclampsia, this was not significant nor was there any substantial impact on intrauterine growth retardation, stillbirth, or neonatal death. Thus, routine use of low dose aspirin is not recommended. However, some experts recommend its use in patients who are liable to develop early onset (before 32 weeks) pre-eclampsia or in high risk groups for pre-eclampsia, such as women with type 1 diabetes, chronic hypertension, multiple pregnancies, or previous pre-eclampsia. However, the safety of higher doses of aspirin and aspirin ingestion during the first trimester remains uncertain.

View larger version (32K): [in this window] [in a new window]   Effect of aspirin in preventing pre-eclampsia: meta-analysis of randomised trials showing numbers of cases of pre-eclampsia

	Antithrombotic therapy in cancer

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Venous thromboembolism is a frequent complication in patients with cancer, and it is a common clinical problem. It can even precede the diagnosis of cancer by months or years. Patients with cancer are nearly twice as likely to die from pulmonary embolism in hospital as those with benign disease, and about 60% of these deaths occur prematurely. Thromboembolism seems to be particularly predominant in patients with mucinous carcinoma of the pancreas, lung, or gastrointestinal tract. Therapeutic interventions in patients with cancer, such as surgery or hormone based treatment (such as oestrogens for prostatic cancer), further increase the risk for thrombosis. Unfortunately, no standardised protocols exist for the management of patients with cancer and the approaches vary.

Risk factors for thromboembolism in patients with cancer   Prolonged immobility   Surgical procedures   Chemotherapy   Indwelling vascular   catheters

Primary prophylaxis
In patients with cancer who are confined to bed or having low risk surgical procedures a low dose of unfractionated heparin or low molecular weight heparin is administered subcutaneously, along with physical measures, as primary prophylaxis to reduce thromboembolic risk. Patients having major abdominal or pelvic surgery for cancer are recommended to receive adjusted dose heparin, low molecular weight heparin, or oral anticoagulants (therapeutic international normalised ratio (INR) 2.0-3.0) similar to those for major orthopaedic surgery.

View larger version (29K): [in this window] [in a new window]   Overview of coagulation, fibrinolysis, and angiogenesis in cancer. The activation of platelets leads to their swelling and the release of angiogenic factors. These affect the vascular endothelia of healing and tumour tissues. The blue arrows facilitate angiogenesis and the red arrows are inhibitory (ATIII=antithrombin III, F1 + 2=prothrombin fragments, PAI=plasminogen activator inhibitor, PDGF=platelet derived growth factor, PF4=platelet factor 4, TF=tissue factor, TFPI=tissue factor pathway inhibitor, TSP1/2=thrombospondin 1 and 2, tPA=tissue type plasminogen activator, uPA=urokinase type plasminogen activator, VEGF=vascular endothelial growth factor)

A low dose warfarin regimen is recommended for patients receiving chemotherapy or those with indwelling venous catheters to decrease the incidence of thromboembolism. For example, one double blind randomised study of patients with metastatic breast cancer receiving chemotherapy showed that a very low dose (1 mg/day) of warfarin for six weeks followed by a dose to maintain the INR at 1.3-1.9 was effective. Low dose low molecular weight heparin (for example, daltaparin 2500 IU/day) is an alternative for patients with indwelling venous catheters.

Treatment and secondary prevention
Patients with cancer who develop a thromboembolism should be treated in a similar manner to patients without cancer. An initial period of therapeutic unfractionated heparin or low molecular weight heparin which is overlapped and followed by warfarin for a minimum of three months is recommended. Anticoagulation should be continued in patients who have active disease or who receive chemotherapy while these risk factors last. The dose should maintain an INR of between 2.0 and 3.0.

Risk of haemorrhage
Patients with cancer who are receiving antithrombotic therapy are thought to be at higher risk of bleeding than patients without cancer. This assumption has been disputed, however, in light of the evidence from some studies in which the risk of major bleeding did not differ greatly between the two groups of patients. For practical purposes, the recommended therapeutic levels of anticoagulation remain the same as long as patients are educated about the risks and the anticoagulation levels are strictly monitored.

Concerns about antithrombotic therapy in cancer Recurrent venous thromboembolism Increased tendency for minor and major bleeds Inconsistency in therapeutic anticoagulant levels Procoagulant effects of chemotherapy (for example, endothelial cell dysfuntion)

Definite conclusions cannot be drawn about the safety of antithrombotic therapy in patients with primary or secondary brain malignancy. Some small studies report that it is probably safe to give these patients anticoagulants. However, definite decisions about anticoagulation in such patients have to be individualised and carefully considered. Anticoagulation should probably be avoided in patients with brain metastasis because of the chances of renal cell carcinoma or melanoma, as these tumours are highly vascular.

Further reading Barbour LA. Current concepts of anticoagulation therapy in pregnancy. Obstet Gynecol Clin North Am 1997;24:499-521[CrossRef][ISI][Medline] CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet 1994;343:619-29[CrossRef][ISI][Medline] Cumming AM, Shiach CR. The investigation and management of inherited thrombophilia. Clin Lab Haem 1999;21:77-92[CrossRef][ISI][Medline] Coomarasamy A, Papaioannou S, Gee H, Khan KS. Aspirin for the prevention of preeclampsia in women with abnormal uterine artery Doppler: a meta-analysis. Obstet Gynecol 2001;98:861-6[Abstract/Free Full Text] Cotrufo M, De Feo M, De Santo LS, Romano G, Della Corte A, Renzilli A, et al. Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet Gynecol 2002;99:35-40[Abstract/Free Full Text] Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 2001:119;S122-31 Farquarson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 2002;100:408-13[Abstract/Free Full Text] Letai A, Kuter DJ. Cancer, coagulation, and anticoagulation. Oncologist 1999;4:443-9[Abstract/Free Full Text] Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, et al. Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994;343:886-9[CrossRef][ISI][Medline] Lip GYH, Chin BSP, Blann AD. Cancer and the prothrombotic state. Lancet Oncol 2002;3:27-34 Prandoni P. Antithrombotic strategies in patients with cancer. Thromb Haemost 1997;78:141-4[ISI][Medline] Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavanne-Pardlonge E, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999;81:668-72[ISI][Medline] Chan W-S, Ginsberg JS. Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy. Thromb Res 2002;107:85-91[CrossRef][ISI][Medline]

Recurrent venous thromboembolism
Patients with cancer are at a higher risk than non-cancer patients of recurrence of thromboembolism despite adequate anticoagulation. Again, no strict evidence based guidelines exist for the management of these patients. The recommended options include maintenance of a higher level of anticoagulation (INR 3.0 to 4.5), substitution with adjusted dose heparin or low molecular weight heparin (some evidence suggests heparin is probably better in this situation), and placement of inferior venacaval filters with or without anticoagulation.

	Acknowledgments

The figure showing diagnosis of deep vein thrombosis is adapted from Chan W-S et al, Thromb Res 2002;107:85-91. The table showing the results of aspirin v aspirin plus heparin in treating antiphospholipid syndrome in pregnancy is adapted from Farquharson RG et al, Obstet Gynecol 2002;100:408-13. The table showing Virchow's triad in cancer is adapted from Lip GYH et al, Lancet Oncol 2002;3:27-34. The histogram showing distribution of warfarin dose and poor outcome according to order of pregnancy is adapted from Cotrufo M et al, Obstet Gynecol 2002;99:35-40. The meta-analysis showing the effect of aspirin in preventing pre-eclampsia is adapted from Coomarasamy A et al, Obstet Gynecol 2001;98:861-6. The figure showing the overview of coagulation, fibrinolysis, and angiogenesis in cancer is adapted from Nash G et al, Lancet Oncol 2001;2:608-13.

	Footnotes

Bernd Jilma is associate professor in the department of clinical pharmacology, Vienna University Hospital, Vienna, Austria; Sridhar Kamath is research fellow and Gregory Y H Lip is professor of cardiovascular medicine at the haemostasis, thrombosis, and vascular biology unit, university department of medicine, City Hospital, Birmingham.

The ABC of antithrombotic therapy is edited by Gregory Y H Lip and Andrew D Blann, senior lecturer in medicine at the haemostasis, thrombosis, and vascular biology unit, university department of medicine, City Hospital, Birmingham. The series will be published as a book in spring 2003.