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Re: DVT and PregnancyFrom: Efrain Ramirez (eramirez@icepr.com)Mon Feb 26 15:34:38 2001
No Steve - prior DVT *is* an indication for low dose heparin prophylaxis -- we can argue about dose but hardly on the indications - Risk Factors for Deep Vein Thrombosis and Thromboembolic Disorders Hereditary Thrombophilia (prevalence in general population) Factor V Leiden mutation (5-9%)* AT-III deficiency (0.02-0.2%) Protein C deficiency (0.2-0.5%) Protein S deficiency (0.08%) Hyperhomocystinemia (1-11%) Prothrombin gene mutation (2-4%) ***Prior history of deep vein thrombosis*** Mechanical heart valve Atrial fibrillation Trauma/prolonged immobilization/major surgery Other familial hypercoagulable states Antiphospholipid syndrome *For African Americans, about 1%; for Caucasians, 6-11%. Data from Lockwood CJ. Heritable coagulopathies in pregnancy. Obstet Gynecol Surv 1999;54:754-765 Clinical Considerations and Recommendations "Who are candidates for thromboprophylaxis in pregnancy? Thromboprophylaxis is defined as administration of anticoagulants because of an increased risk of VTE during pregnancy rather than treatment for an acute event. Often this can be accomplished using relatively low doses, which have a minimal effect on laboratory measures of coagulation. Such low-dose prophylaxis carries fewer risks than full therapeutic anticoagulation. There are certain high-risk conditions that require dosage adjustments to achieve higher therapeutic levels of anticoagulation (adjusted-dose heparin prophylaxis). Each patient's regimen should be individualized once the risks of heparin therapy are weighed against the benefits (31). Patients with the following conditions are at highest risk and should have adjusted-dose heparin prophylaxis (12): Artificial heart valves (some investigators recommend warfarin therapy after the first trimester in certain circumstances) (26-29) Antithrombin-III (AT-III) deficiency (with or without a history of thrombosis; also referred to as "anti-thrombin deficiency") (32, 33) Antiphospholipid syndrome (some investigators recommend low-dose prophylaxis for this condition if there is no history of DVT) (34, 35) History of rheumatic heart disease with current atrial fibrillation (36) Homozygous factor V Leiden mutation, homozygous prothrombin G20210A mutation Patients receiving chronic anticoagulation for recurrent thromboembolism Patients who are identified carriers of other inherited thrombophilias who do not have a history of thrombosis but have a strong family history of thrombosis (36) and noncarriers with a history of thromboembolic events before the current pregnancy (34) appear to be at lower risk and may be candidates for low-dose prophylaxis. However, no data exist to support or refute this approach. It is not clear whether patients with a history of thrombosis identified with a protein C or protein S deficiency should receive low-dose or adjusted-dose heparin prophylaxis during pregnancy. It is also not known whether asymptomatic women who have been identified as carriers of inherited thrombophilia (except AT-III or homozygosity to the factor V Leiden or prothrombin G20210A mutation) and who are without a personal or family history of thromboembolism should receive heparin prophylaxis because there is marked variation in the penetrance of the thrombotic trait. Patients with a history of idiopathic thrombosis, extensive or life-threatening thrombosis, recurrent thrombosis, thrombosis related to a high estrogen state, or who have an underlying thrombophilia or postthrombotic syndrome are likely to be at a higher risk of recurrence in pregnancy than patients with a definite transient provocation (orthopedic trauma or surgery) without any of these risk factors. The former group should consider antepartum thromboprophylaxis beginning in the first trimester and continuing until 6 weeks postpartum. It is unclear whether patients who have sustained VTE from a transient and highly thrombogenic provocation (eg, orthopedic trauma) and who have no other risk factors may benefit from antepartum prophylaxis. Their risk of recurrence is likely higher than the baseline population, and an increasing number of thrombophilic states are being identified in patients who sustain thromboses in the setting of recognized transient provocations (37). Although data are limited, some experts recommend that, at minimum, such patients be given postpartum prophylaxis with warfarin" American Journal of Obstetrics and Gynecology Volume 173 • Number 6 • December 1995 Copyright © 1995 Mosby-Year Book, Inc. P1869 Obstetrics Heparin levels to guide thromboembolism prophylaxis during pregnancy Linda A. Barbour MD, MSPH Jeffrey M. Smith MD Richard A. Marlar PhD Denver, Colorado Departments of Internal Medicine, Obstetrics and Gynecology, and Pathology, University of Colorado Health Sciences Center, and Laboratory Services, Denver Veterans Administration Medical Center. OBJECTIVE: Our purpose was to determine the dose of heparin required in pregnant women to achieve the same heparin levels as standard doses of 5000 units given subcutaneously every 12 hours in the nonpregnant population. STUDY DESIGN: Fourteen pregnant women placed on heparin prophylaxis for a history of thromboembolism had blood drawn for 64 anti-Xa level determinations in the second and third trimesters. Heparin doses were adjusted in an attempt to achieve a midinterval or peak level of 0.05 to 0.25 U/ml, which corresponds to the range seen in nonpregnant patients given standard doses of 5000 units subcutaneously every 12 hours. RESULTS: A standard heparin dose of 5000 units given subcutaneously every 12 hours was inadequate to achieve the desired range in this pregnant population. In five of nine second-trimester pregnancies 7500 units given subcutaneously every 12 hours was inadequate to attain this range. In six of 13 third-trimester pregnancies, >10,000 units subcutaneously every 12 hours was needed. CONCLUSIONS: Heparin requirements may increase and are highly variable in patients during pregnancy. Until appropriate clinical outcomes trials can determine optimal dosing, measuring anti-Xa activity may be useful to guide therapy. (A M J O BSTET G YNECOL 1995;173:1869-73.) Key words: Thromboembolism pregnancy prophylaxis heparin levels Received for publication October 31, 1994; revised February 14, 1995; accepted April 12, 1995. Reprint requests: Linda Barbour, MD, MSPH, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Box B-180, Denver, CO 80262. 6/1/65582 In England and Wales thromboembolism is the leading cause of maternal mortality [1] and is the leading cause of maternal death after a live birth in the United States. [2] ******Women with a prior history of a thromboembolic event are at significant risk of recurrence in the subsequent pregnancy, [3] [4] so the majority of consensus panels in the United States and the United Kingdom recommend heparin prophylaxis. [5] [6] [7] Recent data suggest that antepartum events are at least as common as postpartum events and are nearly equally distributed throughout all trimesters. [4] [8] [9] [10] [11] Thus pregnant women are exposed to heparin and its possible osteopenic side effect throughout the majority of pregnancy.********* [12] [13] [14] [15]
Controversy persists among the consensus panels regarding the optimal dose of heparin to adequately confer prophylaxis to pregnant women at risk, because there are no large clinical outcome trials to guide therapy. Although 5000 units every 12 hours given subcutaneously is usually effective prophylaxis for nonorthopedic nonpregnant patients, changes in the metabolism and clearance of heparin during pregnancy might significantly reduce bioavailability. Increases in heparin-binding proteins, plasma volume, renal clearance, and heparin degradation by the placenta may result in reduced bioavailability of subcutaneous heparin. [16] [17] Because prophylactic doses of heparin usually do not increase the activated partial thromboplastin time (APTT), we used an anti-Xa heparin assay to guide heparin dosing during pregnancy. Material and methods Fourteen pregnant patients referred to the high-risk obstetric clinic at the University of Colorado Health Sciences Center were judged at significant risk for a thromboembolic event during pregnancy and advised to receive low-dose (prophylactic) heparin. None of the patients had a known hereditary hypercoagulable state and 12 of the 14 had been evaluated by protein S, protein C, and antithrombin III assays. Eleven of the 14 patients were given heparin prophylaxis because of previous thromboembolic episodes. The events were associated with oral contraceptive use alone in five women, with pregnancy alone in two women, and with both the postpartum period and oral contraceptive use in three women. One woman had no known provocation. Indications for heparin prophylaxis in the three remaining women included acute deep venous thrombosis early in pregnancy, which had initially been treated with therapeutic heparin for 3 months, P1870 Figure 1. Frequency distribution of heparin levels in controls given 5000 U subcutaneously twice daily. nephrotic syndrome with tense edema and chronic venous stasis, and the antiphospholipid syndrome characterized by recurrent fetal loss. Plasma levels of heparin were determined by a commercial clinical assay (ACA, DuPont, Wilmington, Del.) by using factor Xa as the enzymatic source. Each patient's plasma was incubated with factor Xa for 30 seconds, and the amount of factor Xa remaining was determined with a chromogenic substrate. The residual factor Xa was inversely proportional to the amount of heparin present in the patient's plasma. For each assay positive and negative controls were run and had to be in the established control range. A prophylactic range of 0.05 to 0.25 U/ml was established on the basis of midinterval levels in 74 nonpregnant men and women receiving heparin at 5000 units subcutaneously every 12 hours for prophylaxis against deep venous thrombosis associated with orthopedic or abdominal surgery or prolonged bed rest. Fig. 1 displays the distribution of heparin levels in this control group, which had a mean heparin level of 0.116 ± 0.096 U/ml. None of the control patients had undetectable levels with this dose. The amount of heparin necessary to achieve but not exceed this range 2 to 6 hours after injection (peak to midinterval) during each trimester was documented. If a pregnant patient's level achieved this range even one time during a given trimester, that heparin dose was considered the ``least heparin dose required.'' If a patient later in the same trimester required a higher dose of heparin to maintain the prophylactic range, that heparin dose was considered the ``highest heparin dose required.'' Only peak or midinterval heparin levels were considered. A total of 64 heparin levels in 14 patients were evaluated, resulting in an average of four to five levels from each patient. All dosing decisions were based on anti-Xa levels rather than the APTT and adjustments were made to achieve the desired range. Results None of the 14 women had recurrent thromboembolic events during this pregnancy, and all had favorable perinatal outcomes. Bleeding during delivery was not increased, and no decrease in platelet count was demonstrated. Nine of the 14 women entered prenatal care early enough to start heparin therapy in the second trimester. Compliance with heparin was assumed in all patients studied on the basis of bruising witnessed from repeated subcutaneous injections and the monitoring of heparin vials. Figs. 2 to 5 display the frequency distributions of heparin doses required to achieve the desired level during each trimester. A dose of 5000 units given subcutaneously every 12 hours did not give desired levels in any of the patients studied. A dose of 7500 units given subcutaneously every 12 hours resulted in a prophylactic level in four of nine patients initially (``least heparin dose required''), but one of these patients needed 10,000 units every 12 hours later in the second trimester to maintain it (``highest heparin dose required''). The other five patients required >7500 units every 12 hours in the second trimester, and in two patients the desired level could not be attained before the third trimester (Figs. 2 and 3) . One P1871 Figure 2. Percent of patients in prophylactic range in second trimester. B.I.D., Twice daily. Figure 3. Percent of patients in prophylactic range in second trimester. B.I.D., Twice daily. patient with exceedingly high requirements reached the lower limit of the prophylactic range (0.05 U/ml) with 12,500 units every 12 hours but within a month was below this range, with 15,000 units every 12 hours (<0.02 U/ml). The desired range could not be attained until she was finally placed on a dose of 20,000 units every 12 hours at 29 weeks' gestation, at which point she had a heparin level of 0.06 U/ml. Thirteen of the 14 patients studied had heparin levels measured during the third trimester. Three of 13 patients had a desired level with 7500 units given subcutaneously every 12 hours, but one of these patients needed a dosage increase to 10,000 units every 12 hours by the end of the third trimester to maintain levels in the prophylactic range. A dose of 10,000 every 12 hours resulted in four of 13 patients with levels in the desired range, but almost half the patients (six of 13) required doses beyond 10,000 every 12 hours, including a patient whose heparin levels never reached the desired range before delivery (Figs. 4 and 5) . There was a trend toward levels rising again during the last 4 to 6 weeks of gestation in spite of a previous level within the desired range. In four of five patients who had levels redrawn between 32 and 38 weeks the levels had increased in spite of the patients' being maintained on Figure 4. Percent of patients in prophylactic range in third trimester. B.I.D., Twice daily. Figure 5. Percent of patients in prophylactic range in third trimester. B.I.D., Twice daily. the same dosage. Two of these patients' levels rose above the prophylactic range. APTT values were not determined concurrently with each heparin level because it was our experience that APTT measurements were inconsistently elevated with prophylactic levels of heparin and that they vary considerably in their sensitivity to heparin. Dahlman et al. [17] also noted no significant prolongation in the APTT in two thirds of the samples among 26 pregnant women given an average heparin dose of 8200 units every 12 hours. However, APTT measurements were drawn concurrently on 21 occasions when the peak-to-midinterval heparin levels were within the desired range for prophylaxis (0.05 to 0.25 U/ml). In nine of 21 patients the APTT was still within the normal range (24 to 34.1 seconds) or slightly lower. In the remaining 12 cases the APTT was between 34.6 and 41.5 seconds. In only two of the 12 cases with an APTT elevation were the heparin levels in the higher half of the desired prophylactic range (0.15 to 0.25 U/ml), and there was no significant correlation between APTT elevation and anti-Xa levels in this range. No consistent relationship could be found between maternal weight and heparin dosage required to obtain desired levels. Although the heaviest woman in the P1872 group exhibited the highest heparin requirement, three of the four women with the highest requirements had body weights 11 to 23 kg less than the mean of the entire group. Comment ****The American Academy of Chest Physicians now recommends heparin prophylaxis throughout pregnancy for patients with a prior thromboembolic event. ********[5] However, their recommendation of 5000 units given subcutaneously every 12 hours throughout pregnancy is a significant change from their previous recommendation of heparin therapy in the third trimester to achieve an APTT of 1.5 times control. Other consensus panels from the United Kingdom disagree with this recommendation and believe that 5000 units every 12 hours is likely to be inadequate [6] [7] for the entire duration of pregnancy. The British Society of Haematology Guidelines recommends heparin prophylaxis with 5000 units every 12 hours in the first and second trimesters and increasing heparin in the third trimester to prolong the midinterval APTT 1.5 times control. Alternatively, they advocate using 10,000 units every 12 hours throughout pregnancy unless the heparin level by anti-Xa activity is >0.3 U/ml. [6] The Maternal and Neonatal Hemostasis Working Party of the Hemostasis Thrombosis Task recommends that, if heparin prophylaxis is elected, 7500 to 10,000 units every 12 hours be used throughout pregnancy. [7] Dahlman et al. [17] also noted that during pregnancy heparin requirements seemed to increase. In 26 pregnant women given prophylactic heparin the mean dose required to achieve a plasma concentration of 0.08 to 0.15 IU/ml measured as anti-Xa activity was approximately 8200 units given subcutaneously every 12 hours. Our data are consistent with those of Dahlman et al., which suggests that heparin requirements increase throughout pregnancy. None of our patients had a thromboembolic event while receiving prophylactic therapy. In five of nine patients 7500 units every 12 hours was inadequate to achieve prophylactic levels in the second trimester. In six of 13 patients 10,000 units every 12 hours resulted in levels below the prophylactic range in the third trimester. Like Dahlman et al., we also noted a trend for heparin levels to rise late in the third trimester in four of five women studied, possibly as a result of decreasing placental heparinase activity from placental aging. Confirming that the APTT is not significantly elevated at term may be prudent given recent data suggesting that the APTT may be elevated as long as 24 hours after a subcutaneous dose of therapeutic heparin. [18] We did not find any correlation between maternal weight and heparin prophylaxis. Although Dahlman et al. expressed the average heparin requirement for prophylaxis during pregnancy in their cohort of 26 women as 234 IU/kg, we found no correlation between weight and required heparin dosage. A number of changes occur in pregnancy that may decrease the bioavailability of heparin and may not be closely correlated with maternal weight. Increases in heparin binding proteins, including platelet factor IV and von Willebrand's factor, may serve to change the saturation kinetics of heparin clearance and decrease the bioavailability of standard heparin. Substantial changes in plasma volume may increase the volume of distribution of all types of heparin, and significant increases in glomerular filtration rates may result in more rapid renal clearance. The placenta appears to have a heparinase that degrades heparin, and the activity of this enzyme may not be static throughout pregnancy. All these changes would serve to increase the dose required for adequate heparin prophylaxis and could be highly variable among patients and independent of weight. There are no clinical outcomes trials with a sufficient sample size to resolve the efficacy of heparin prophylaxis during pregnancy nor the optimal dose required. Experience with anti-Xa levels to guide prophylaxis is limited to animal data and from observing the levels that result when nonpregnant patients are given a standard dose of 5000 units subcutaneously every 12 hours. Five thousand units every 12 hours often results in nondetectable levels in pregnant women by peak or midinterval sampling, and this dose may not confer adequate prophylaxis given the hypercoagulable state of pregnancy. Two prophylactic failures reported by Tengborn et al. [4] in a study of 87 women with a prior history of thromboembolism occurred in patients receiving 5000 units every 12 hours during the second trimester. Although dosing heparin to raise the APTT might confer adequate anticoagulation, it is probably excessive anticoagulation for prophylactic purposes; APTT assays vary considerably in their sensitivity to heparin. Concerns that heparin-induced osteoporosis is dose related justify the attempt to minimize heparin exposure in spite of a prospective trial suggesting that it is not dose related and may affect up to one third of patients exposed. [14] Only a large clinical outcome trial can ascertain what dose of heparin confers adequate prophylaxis, if any. However, hundreds of pregnant patients with previous thromboembolic events would need to be enrolled to have sufficient numbers to answer this question; this is beyond the scope of any single center. Keen interest in the use of low-molecular-weight heparin for prophylaxis during pregnancy is certainly warranted because its bioavailability and half-life is longer because it does not significantly bind to plasma proteins, endothelium, or macrophages.19-26 Monitoring may also be unnecessary. [19] Given the hypercoagulable state of pregnancy and the reduced bioavailability of standard heparin P1873 during pregnancy, we believe that 5000 units given subcutaneously every 12 hours is unlikely to confer adequate prophylaxis for many pregnant women. A dose of 7500 to 10,000 units given subcutaneously every 12 hours may be reasonable in the second and third trimesters as long as the APTT is not significantly elevated. However, the extreme variability in individual responses to a given dose of heparin may result in the optimal heparin dose differing among patients and may be independent of body weight. The use of heparin levels in an attempt to attain a measurable heparin effect without elevating the APTT may be a rational approach for prophylaxis until the appropriate multicenter efficacy trial can be completed. We thank Dr. Mark Earnest and Dr. Steve Kick for their contributions in the graphic illustration of the data.
>From the Department of Obstetrics and Gynaecology, Trinity
At Mon, 26 Feb 2001, Steve & Eryl Raymond wrote:
>
-- "Life is neither the notes nor the silence between the notes, but the music that arises out of sound and silence felt as a living whole. Stop choosing...between chaos and order, and live at the boundary between them, where rest and action move together..." David Whyte
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