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Deep Vein Thrombosis: Prevalence of Etiologic Factors and Results of Management in 100 Consecutive Patients
Deep vein thrombosis (DVT) is a significant clinical problem seen in many medical specialties. Although many etiologic factors have been identified, it remains unclear what the prevalence of each factor is in the gen eral population. Also, management is controversial and ideal treatment remains to be defined. The etiologic fac tors associated with DVT are conveniently divided into clinical conditions, hereditary blood defects, and ac quired blood defects. The clinical factors commonly as sociated with DVT include malignancy, stasis, the post operative state, sepsis, use of estrogen-containing compounds, trauma, heart disease, and burns. 1-5 Hered itary blood protein defects associated with thrombosis include antithrombin-III (AT III) deficiency, protein C, protein S, plasminogen, heparin cofactor II, and tissue plasminogen activator (t-PA) deficiencies, dysfibrinogenemia, and cystathionine β-synthetase deficiency.6-13 Acquired blood defects associated with DVT include polycythemia, benign or malignant thrombocytosis, lu pus anticoagulant, anticardiolipin antibodies, elevated t-PA-inhibitor type 1 and acquired deficiencies of AT III, protein C, protein S, heparin cofactor II, plasminogen, and t-PA. 14-24 Also, Factor XII deficiency and possibly elevated Factor VII, fibrinogen, and lipoprotein a may be associated with DVT. 25-28 Despite appreciating these as sociations, the prevalence of each of these hereditary and acquired defects and disorders, which may account for development of DVT in the general population, is un
From the Regional Cancer and Blood Disease Center of Kern and Department of Medicine, Division of Hematology/Oncology, UCLA Center for the Health Sciences, Bakersfield and Los Angeles, Califor nia. Reprint requests: Dr. Bick, Clinical Professor of MedicineUCLA, P.O. Box 580, Bakersfield, CA 93302-0580.
clear. We have assessed the clinical and laboratory char acteristics of 100 consecutive patients referred for con sultation for DVT to ascertain prevalence of associated clinical and blood defects accounting for thrombosis in these patients. All patients were treated by a uniform multimodality protocol. The results of this analysis, in cluding clinical, are herein presented.
METHODS Patient Population The patient population consisted of 100 consecutive patients referred to our consultative service for evaluation of DVT. All patients were subjected to careful clinical evaluation and confirmation of DVT by ascending con trast venography or ascending thromboscintography, us ing technetium-99 labeled macroaggregated albumin. All patients with suspected pulmonary embolus were sub jected to pulmonary ventilation perfusion scans or pul monary angiography.
Laboratory Evaluation At presentation, all patients underwent complete blood and platelet count and differential white count, SMA 18/60 biochemistry survey including glucose, blood urea nitrogen, creatinine, cholesterol, bilirubin, SGOT, SGPT, GGT, gamma glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), alkaline phos phatase, uric acid, total protein, albumin, globulin, so dium, potassium, chloride, calcium, bicarbonate, and amylase. At presentation, all patients underwent hemostasis testing, which consisted of the following: AT III, 29
Copyright © 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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RODGER L BICK, M.D., F.A.C.P., JENNIFER JAKWAY, M.D., and WILLIAM F. BAKER, Jr., M.D., F.A.C.P.
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protein C, 30 protein S,31 plasminogen,32 heparin cofactor II, 33 fibrinogen level by clotting time technique,34 lupus anticoagulant assay,35 anticardiolipin antibody assay (immunoglobulin G, A and M [IgG, IgA, and IgM] isotypes),36 t-PA37 tissue plasminogen activator inhibitortype 1 (PAI-1) assay,38 and baseline prothrombin time and activated partial thromboplastin time (APTT).39 All abnormal hemostasis results were repeated 6 to 8 weeks after the acute event to ascertain the etiologic association of defects initially found. Hemostasis assay methods used are depicted by the references cited.
Treatment Methods All patients with acute DVT were treated with multimodality therapy consisting of anticoagulation, initial bed rest with progressive early ambulation (within 24 hours in the absence of pulmonary embolus [PE]), antiembolic exercises when appropriate and antiembolic stockings when appropriate.40 Initial anticoagulant therapy was subcutaneous calcium heparin (Calciparine, Choay) at a dosage of 5000 U every 6 hours if total body weight was less than 70 kg and 7500 U every 6 hours if body weight was more than 70 kg. APTTs were not obtained for monitoring purposes; each patient had a heparin level41 every AM and the subcutaneous dose adjusted upward, if needed, to assure a plasma heparin level of more than 0.05 U/ml. At the time of discharge, all patients were discharged on 5000 U subcutaneously every 6 hours. Calcium heparin was tapered as follows: after 2 weeks, the dose was decreased to 5000 U every 8 hours, after 4 weeks the dose was decreased to 5000 U every 12 hours, and after 6 weeks the dose was decreased to 2500 U every 12 hours. If the patient had no identifiable continuing risk factor and this was the first event, the calcium heparin was stopped at 12 weeks. If, however, the patient had an identifiable continuing risk factor, such as congenital or acquired blood defect, or if this was a recurrent event, the calcium heparin was continued at 2500 U every 12 hours indefinitely. All patients referred with recurrence while on or after initial warfarin therapy were also treated by this protocol. All patients with upper or lower extremity DVT were instructed in antithrombotic exercises; these were started by 24 hours after diagnosis. Exercises for DVT of the lower extremities consisted of straight leg elevation above the hip joints by 10°, and dorsiplantar flexion of the foot for 5 minutes per leg or until fatigue of calf muscles, done at least six times per day during waking hours. Exercises for DVT of the upper extremities consisted of straight arm elevation above the head with
compression of the fist for 5 minutes, or until muscle fatigue, also done at least six times per day during waking hours. All patients with extremity thrombosis were placed in medium compression stockings (panty hose for lower extremities and sleave stockings for upper extremities) and instructed to use these during waking hours for at least 3 months. Stockings were ordered at the time of diagnosis and were placed on the patient about 48 hours after presentation. After discharge, patients were followed, including clinical examination, weekly for at least 1 month and then every 2 weeks until at least 3 months after the event. After 3 months, patients were followed every 3 to 4 months.
RESULTS Patient Characteristics At presentation 68 patients presented with an acute thrombosis and were placed on heparin as previously described; 20 additional patients presented while on coumarin therapy and of these 13 were referred because of failure, with a new acute event while on adequate doses; these 13 were immediately placed on heparin as earlier noted. The remaining seven referred on coumarin were stable and only referred for an etiologic diagnosis. Nine patients were referred without acute DVT and were not on therapy, having had a thrombosis in the past and requesting an evaluation, and three patients were referred with a history of DVT and were on antiplatelet agents. There were 51 men with a mean age of 52.7 years and 49 women with a mean age of 54.7 years. A total of 81 patients (68 with a new acute thrombosis and 13 coumarin failures with an acute thrombosis) were treated with subcutaneous calcium heparin as described under Methods. During the 3 months of treatment, there were two heparin failures, one following orthopedic surgery and one with congenital AT HI deficiency. Of the 20 patients treated with coumarin, thirteen failed; failures were seen with anticardiolipin antibodies (eight failures), protein S deficiency (one failure), t-PA deficiency (one failure), hereditary spherocytosis (one failure), trauma (one failure), and no defined etiology for DVT (one failure). Thus, the failure rate for subcutaneous calcium heparin given as described was 2 of 81 patients (2.4%) over 3 months of therapy and for patients treated with coumarin was 13 of 20 (65%); however, most of the coumarin failures were in patients having anticardiolipin antibodies, suggesting coumarin to be ineffectual for this situation.
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DEEP VEIN THROMBOSIS—BICK, JAKWAY, BAKER
It was found that by careful clinical evaluation, coupled with carefully chosen laboratory evaluation, an etiology could be defined for 81% of all patients. These associations are divided into plasma defects and nonplasma defects. The plasma defects can be divided into hereditary or acquired.
Nonplasma Defects and Deep Vein Thrombosis Fifty-five patients (55% of the population) had a defined nonplasma defect associated with DVT. These were as follows in descending order of prevalence: 11 patients (11%) had malignancy, ten patients (10%) had arthroscopy, eight patients (8%) had major trauma, seven patients (7%) had orthopedic surgery, six patients (6%) were morbidly obese (more than 20% ideal body weight), three patients (3%) were ingesting Premarin, three patients (3%) had diabetes mellitus, two patients (2%) had giant cavernous hemangiomas of the thrombosed extremity, and one patient each (1%) had hereditary spherocytosis, pregnancy, mitral valve prolapse, chronic immobility, and ingestion of oral contraceptives.
Plasma Defects and Deep Vein Thrombosis Forty-seven patients (47%) had a defined plasma defect associated with hypercoagulability and thrombosis. Of these defects, 28% (28 patients) were acquired and 19% (19 patients) were congenital. Of the acquired defects, 24% (24 patients) had anticardiolipin antibodies and four patients (4%) had a lupus anticoagulant. Of the congenital defects found, eight patients (8%) had protein S deficiency, eight patients (8%) had AT III deficiency, two patients (2%) had protein C deficiency, and one patient (1%) had congenital t-PA deficiency. No cases of plasminogen deficiency, heparin cofactor II deficiency or dysfibrinogenemia were found. Also, no cases of elevated PAI-1 were found. Nonplasma defects were slightly more common than plasma defects, 55% versus 47% of patients presenting. Of the nonplasma defects, malignancy, arthroscopy, trauma, and other orthopedic procedures comprised most of the etiologic disorders associated with venous thrombosis. In patients with a plasma defect, acquired defects are more common than congenital problems and anticardiolipin antibodies were the most common associated hypercoagulable defect found, seen in 24% of this population. Of the hereditary defects, protein S and AT III
TABLE 1. Defects Found Associated with Deep Vein Thrombosis in 100 Consecutive Patients %
Defect Non-plasma defects (55% of patients) Malignancy Arthroscopy Major trauma Orthopedic surgery Obesity Premarin Diabetes Hemangiomas Spherocytosis Pregnancy Mitral valve prolase Immobility Oral contraceptives Plasma defects (47% of patients) Acquired Anticardiolipin antibodies Lupus anticoagulant Hereditary Protein S Antithrombin III Protein C Tissue plasminogen activator
11 10 8 7 6 3 3 2
24 4 8 8 2 1
deficiencies, followed by protein C deficiency, were the most commonly found. Twenty-one patients had both a clinical and plasma defect. These results are summarized in Table 1.
DISCUSSION Confusion and controversy continue over both acute and long-term management of DVT. Both intravenous and subcutaneous heparin have been advocated for acutephase management; recent studies have clearly shown subcutaneous heparin to offer equal efficacy to intravenous heparin for acute management.42-44 Despite these efficacy findings, many continue intravenous heparin for acute-phase treatment of DVT. However, common recommendations for intravenous heparin therapy for acutephase management have been based on only two studies, both seriously flawed, that suggested that the APTT should be prolonged to 1.5 times control. 45-48 The first study suggesting improved efficacy with APTT adjustment to 1.5 times control by Basu et al47 was uncontrolled, wherein the diagnosis of both DVT and PE were based on clinical findings and not accepted radiographic studies. The lack of radiographic evaluation of DVT or PE induces a potential 50% error in the diagnosis.49 Also, this study used a homemade APTT system and, since it is known that many different commercially avail-
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able APTT systems are themselves not comparable, it is unlikely that APTTs from numerous commercial sources are at all comparable to the homemade APTT system used by Basu et al. 50-53 The second study was that of Hull and associates48 who claimed a statistically significant difference in rethrombosis (failure) rates between patients with the APTT longer than or shorter than 1.5 times control; however, in this study, there were three patient failures in the longer APTT group and 11 patient failures in the shorter APTT group. In the failure group, six of the failures (recurrences) happened between 3 weeks and 3 months after presentation while on warfarin, not heparin, therapy and the group included two patients with malignancy, a disorder known to exhibit refractoriness to anticoagulant therapy. One could easily argue that patients rethrombosing after 3 weeks could just as likely be warfarin rather than heparin failures. When removing these warfarin failure patients from both groups, the significance of the differences between the failures in the long APTT (therapeutic) versus shorter APTT (subtherapeutic) groups becomes insignificant (p = 0.24). Another major problem with these and other studies is that most authors fail to account for several important variables. It has been repeatedly shown that prolongation of the APTT by heparin is incredibly variable, depending on the APTT reagents, for example, the activators or phospholipids used. 54-56 Generally, liquid activators, such as ellagic acid or celite, are less sensitive to heparin than are particulate activators, such as kaolin, or micronized silica; also, sensitivity to heparin is variable, depending on the type of partial thromboplastin (phospholipid) used in the APTT.57 Thus, with a given heparin, the degree of APTT prolongation will be highly dependent on reagents (activators and phospholipids) and not necessarily dose of heparin used or plasma heparin level. To complicate the situation further, any given APTT is also dependent on the type of heparin used. It is well known that the more abundant the higher molecular weight subfractions of heparin, the more anti-IIa activity and the more prolonged the APTT, but the more abundant the lower molecular weight heparin subfractions, the more anti-Xa activity and with less anti-IIa activity less prolongation of the APTT may occur.58 Also, the source of heparin (bovine or porcine) and the salt (sodium or calcium) may influence the APTT, for porcine heparin renders more anti-Xa activity than bovine heparin at all molecular weights.59 When given subcutaneously, calcium heparin gives lower blood levels than sodium heparin and calcium heparin gives less prolongation of the APTT than sodium heparin.60 Thus, the APTT prolongation is dependent on particular type of heparin used. Of other significance is that clinical efficacy appears more correlated with anti-Xa activity and less with anti-IIa activity, yet prolongation of the APTT is dependent primarily on
anti-IIa activity.61,62 Consideration of this information leads to the obvious conclusion that without knowing the type of heparin used and the type of APTT used, one cannot draw meaningful conclusions from clinical studies. It is also obvious that clinical trial results cannot be compared unless the APTT systems are the same and the type of heparin used the same. Our results, using calcium heparin subcutaneously at a dose of 5000 or 7500 U every 6 hours during the acute phase render a failure rate of 2.4% of patients. We aimed for a plasma heparin level of more than 0.05 U/ml, but this level was empirically chosen because the minimum required effective plasma heparin level is undefined.63 The long-term treatment after acute-phase DVT likewise is associated with confusion and controversy. Most clinicians continue to use coumarin drugs despite hemorrhagic risks approaching 30 to 40% in some series 64,65 and despite incredibly high failure rates, up to 38% in some reports. 66,67 The high hemorrhage risk and high failure rates, coupled with inconvenience of periodic prothrombin time requirements, have led to exploration of long-term management with subcutaneous heparin. 68-70 Although many have shown a high level of efficacy, dose regimens, like those with acute-phase management, remain confusing and controversial. Obviously, much confusion and controversy results from the same variables as discussed for heparin earlier, dependence on the type of reagents used for the APTT and dependence on the type of heparin used. Thus, it is impossible to compare results of clinical trials unless the APTT systems and types of heparin are similar. Despite these important variables, investigators have advocated long-term subcutaneous fixed dose heparin therapy or long-term dose-adjusted subcutaneous heparin therapy; it is, of course, impossible to compare results of these two different approaches because of the aforementioned variables dependent on heparin used and APTT used. 69,70 Our patient population was given fixed-dose subcutaneous calcium heparin for long-term management. Therapy was stopped if no identifiable continued etiologically associated factor was found and if this was the first event. As will be discussed, however, if an associated continuing etiologic factor was found, long-term management continued indefinitely. Our long-term regimen consists of tapering, as previously depicted, to a minimum fixed dose of 2500 U every 12 hours. Using this regimen, none of our 81 patients has failed during 3 or longer months of long-term therapy; this includes the original 13 patients referred after failing coumarin therapy. The etiology of DVT may dictate both type and duration of anticoagulant therapy. In this series of patients 55% had a definable clinical, nonplasma defect and 47% had a definable plasma defect. Of those with plasma defects, 28% were acquired and 19% were hereditary.
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No studies to date address the incidence of acquired plasma defects in the general population with DVT; however, several have evaluated the incidence of selected hereditary defects in DVT populations. Ben-Tal et al71 estimate the relative frequency of lupus anticoagulant, dysfibrinogenemia, and deficiencies of AT III, protein S, and protein C in a population of 107 patients presenting over a 4-year period. Unfortunately, other blood defects associated with DVT, such as heparin cofactor II, plasminogen deficiency, or t-PA were not assessed. In this study, 21.5% of patients had one of the defects searched for and the remainder were unaccounted for. AT III deficiency was found in 8%, protein C deficiency was found in 5.6%, protein S deficiency was found in 2.8%, dysfibrinogenemia was found in one patient, and lupus anticoagulant was found in 3.7% of patients. In a similar study of 141 patients under 45 years of age Gladson et al72 found 5% to have protein S deficiency, 4% to have protein C deficiency, 3% to have AT III deficiency, 2% to have plasminogen deficiency, and 1% to have dysfibrinogenemia with thrombosis. In a survey of inherited thrombotic disorders in Italy, Tripodi and associates73 queried members of the Italian Society for the Study of Hemostasis and Thrombosis and collected all known cases of congenital thrombosis. Although their method of study did not allow for conclusions regarding the incidence of these defects in the general or DVT population, they concluded that AT III, protein C, and protein S deficiencies were the most common.73 In a similar study, Tabernero and associates74 evaluated the frequency of congenital defects in a general DVT population of 204 patients and found congenital protein defects to account for only 4% of the DVT population; specifically, there were three cases of protein C, three cases of protein S, two cases of plasminogen, and one case of AT III deficiency. Like the other studies cited, this study was also incomplete because heparin cofactor II, fibrinogen, and t-PA defects were not assessed.74 In a study involving 37 Dutch hospitals, a total of 113 unrelated patients with DVT were studied by Briet et al;75 results revealed 35 patients (31%) to have hereditary thrombophilia. In this study, five patients (4.4%) had AT III deficiency, 13 patients (9.7%) had protein C deficiency, 15 patients (13.2%) had protein S deficiency, and two patients (1.7%) had dysfibrinogenemia.75 In a later Dutch study by Engesser et al76 203 patients with thrombosis were assessed for congenital deficiencies associated with thrombosis and 46% had a congenital defect associated with thrombosis; six patients (3%) had AT III deficiency, 14 patients (7%) had protein C deficiency, 16 patients (8%) had protein S deficiency, two patients (1%) had dysfibrinogenemia, and eight patients (4%) had congenital elevation of PAL In a subsequent study assessing a DVT population of 277 consecutive patients in Holland,
271 Heijboer and associates found only 8.3% of the population to have congenital defects; however, only AT III, protein C, protein S, and plasminogen deficiencies were evaluated. Specifically, three of the patients (1.1%) had AT III deficiency, nine patients (3.2%) had protein C deficiency, six patients (2.2%) had protein S deficiency, and four patients (2.2%) had plasminogen deficiency. The authors of this last study concluded that based on their results, screening for hereditary thrombotic disorders was not warranted. However, based on our results, we strongly disagree with this recommendation and are unwilling to accept missing a diagnosis of congenital protein defects associated with thrombosis in 19% of patients presenting with DVT in our series.78 The incidences of congenital defects in these studies, compared with our findings are presented in Table 2. It appears that significant regional differences may occur, accounting for the marked differences in the aforementioned series and results, but the true incidence of many of these congenital defects will not be known with certainty until more complete studies, including assays for all known protein defects leading to congenital thrombophilia, are done. The incidence of acquired plasma defects associated with thrombosis in the general DVT population is even less certain, but appears quite high in selected populations based on the few studies addressing this important issue. 79-82
CONCLUSIONS The etiology of DVT can clearly be defined in greater than 80% of patients if careful clinical assessment combined with equally astute laboratory evaluation is done. The clinical assessment must include a complete history, review of systems, and physical examination and the laboratory evaluation must include a routine complete blood count and platelet count, a routine biochemical survey, and assessment for the more common followed by less common blood protein defects associated with hypercoagulability and thrombosis. Using this combined approach, we found that 55% of patients had a clinical disorder known to be associated with thrombosis and 47% of patients were found to have a plasma defect known to be associated with thrombosis. The plasma defects were more commonly acquired than congenital, but generally the prevalence in descending order of probability is as follows: anticardiolipin antibodies, AT III deficiency, protein S deficiency, lupus anticoagulant, protein C deficiency, and t-PA deficiency. These assays should, therefore, be included in the initial hypercoagulability screening panel used for a patient with clinically unexplained venous thrombosis. If this first panel is negative, the secondary panel should consist of functional
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Deficiency No. patients AT III Protein C Protein S
Brief etal.(1987)
Gladson etal.(1988)
Engesser etal.(1989)
Ben-Tal etal.(1989)
Heijboer etal.(1990)
Tabernero etal.(1991)
Bickand Baker (1991)
113
141
203
107
277
204
100
4.4 11.5
3 4
3 6.8
7.4
1.0
6.5
13.2
5
7.8
2.8
3.2 2.1
NM 0.9 NM NM
NM NM
NM
Plasminogen
0.7
2
NM*
Dysfibrinogenemia
1.7 0.7
1 NM
0.9 NM
0.7
NM
NM
0.7
NM
3.9
33.6
15
22.4
Heparin cofactor II Tissue plasminogen activator High plasminogen activator inhibitor-1 % with defect
17.6
0.5 1.5
8 2
1.5
8
.98 NM
0 0
NM
0
NM
NM
1
NM
NM
0
1.4
7.7
4.5
19
* NM; not measured.
fibrinogen, plasminogen, heparin cofactor II, and PAI-1 assays. A scheme for workup of the patient with thrombosis is given in Table 3. Our results using a uniform fixed dose of subcutaneous calcium heparin for the initial and long-term treatment was associated with a failure rate of 2.4%, generally better than that reported for intravenous heparin, dose-adjusted subcutaneous heparin, or coumarin. However, as earlier discussed, most studies do not depict the type of heparin used or the reagents used for monitoring; therefore our results may not be applicable to different heparin preparations. Of the 20 patients referred for failure of adequate doses of coumarin, 13 (65%) had anticardiolipin antibodies; this finding strongly suggests that coumarin use in DVT associated with anticardiolipin antibodies is associated with a very high failure rate and coumarin drugs are probably not appropriate in this setting. None of these patients failed the aforementioned calcium heparin regimen, suggesting subcutaneous calcium heparin, both initially and long-term, to be the TABLE 3. Laboratory Evaluation of Patients with Unexplained Deep Vein Thrombosis Primary assessment Antithrombin III Anticardiolipin antibodies Lupus anticoagulant Protein C Protein S Tissue plasminogen activator Secondary assessment Heparin cofactor II Plasminogen Plasminogen activator inhibitor-1 Dysfibrinogenemia Factor XII?
therapy of choice for DVT associated with anticardiolipin antibodies. Patients with no continued identifiable associated clinical or plasma defect should be tapered and then calcium heparin stopped after 3 months. However, if a continuing clinical or laboratory defect is present, calcium heparin therapy at 2500 units subcutaneously every 12 hours should be continued indefinitely, as the clinical situation dictates.
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TABLE 2. Published Prevalence (%) of Congenital Blood Defects Associated with Thrombosis
12. Nilsson IM, LA Tengborn: A family with thrombosis associated with high level of tissue plasminogen activator inhibitor. Haemostasis 14:24, 1984. 13. Mammen EF: Fibrinogen abnormalities. Semin Thromb Hemost 9:1, 1983. 14. Berk PD, Goldberg JD, Donovan PB: Therapeutic recommendations in polycythemia rubra vera based on Polycythemia Vera Study Group recommendations. Semin Hematol 23:132, 1986. 15. Schafter AI: Essential thrombocythemia. Prog Hemost Thromb 10:69, 1991. 16. Espinoza LR, RC Hartmann: Significance of the lupus anticoagulant. Am J Hematol 22:331, 1986. 17. Asherson RA, EN Harris: Anticardiolipin antibodies: Clinical associations. Postgrad Med J 62:1081, 1986. 18. Kirschstein W, S Simianer, CE Dempfle: Impaired fibrinolytic capacity and tissue plasminogen activator release in patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA). Thromb Haemost 62:772, 1989. 19. Juhan-Vague I, C Roul, MC Alessi, JP Ardissone: Increased plasminogen activator inhibitor activity in noninsulin dependent diabetic patients-relationship with plasma insulin. Thromb Haemost 61:370, 1989. 20. Thaler E, K Lechner: Antithrombin III deficiency and thromboembolism. Clin Haematol 10:369, 1981. 21. Mannucci PM, S Vigano: Deficiencies of protein C, an inhibitor of blood coagulation. Lancet 2:463, 1982. 22. Griffin JH, MJ Heeb, HP Schwarz: Plasma protein S deficiency and thromboembolic disease. Prog Hematol 15:39, 1987. 23. Chaunsumrit A, MJ Manco-Johnson, WE Hathaway: Heparin cofactor II in adults and infants with thrombosis and DIC. Am J Hematol 31:109, 1989. 24. Paramo JA, MJ Alfaro, E Rocha: Postoperative changes in the plasmatic levels of tissue-type plasminogen activator and its fastacting inhibitor: relationship to deep venous thrombosis and influence of prophylaxis. Thromb Haemost 54:713, 1985. 25. Nagy I, H Losonczy: Haemostatic alterations in lymphomas and tumours. Acta Med Hung 44:71, 1987. 26. Orlando M, O Leri, G Macioce: Factor VII in subjects at risk for thromboembolism: activation or increased synthesis? Haemostasis 17:340, 1987. 27. Mbewu AD, PN Durrington: Lipoprotein A: structure, properties, and possible involvement in thrombogenesis and atherosclerosis. Atherosclerosis 85:1, 1990. 28. Lämmee B, WA Wuillemin, I Huber: Thromboembolism and bleeding tendency in congenital Factor XII deficiency: A study on 74 subjects from 14 Swiss families. Thromb Haemost 65:117, 1991. 29. IL Test: Antithrombin III: chromogenic substrate assay. Package Insert, Instrumentation Laboratory, 1988. 30. Stachrom Protein C Assay. Package Insert, Stago, 1990. 31. Rellplate IED S assay. Package Insert, American Diagnostica 32. IL Test: Plasminogen. Package Insert, Instrumentation Laboratory, 1988. 33. Abildgaard U, M Larsen: Assay of dermatan sulfate cofactor (heparin cofactor II) activity in human plasma. Thromb Res 35:257, 1984. 34. ILTest: PT-Fibrinogen, Instrumentation Laboratory, 1987. 35. Thiagarajan P, V Pengo, S Shapiro: The use of the dilute Russel viper venom time for the diagnosis of lupus anticoagulants. Blood 68:869, 1986. 36. Loisou S, GRV Byron, HJ Engelhart: Association of quantitative anticardiolipin antibody level with fetal loss and time of loss in systemic lupus erythematosus. Q J Med 68:525, 1988. 37. Tissue Plasminogen Activator Assay Package Insert, American Diagnostica, 1990.
273 38. Tissue Plasminogen Activator Inhibitor Assay Package Insert, American Diagnostica, 1990. 39. National Committee for Clinical Laboratory Standards (H28P and H29P): Proposed guidelines for the one-stage prothrombin time and activated partial thromboplastin time. Villanova, PA, 1988. 40. Bick RL: Disorders of Hemostasis and Thrombosis: Principles of Clinical Practice. Thieme, New York, 1985, p 294. 41. Telen AN, M Lie: Evaluation of an amidolytic heparin assay method: Increased sensitivity by adding purified antithrombin III. Thromb Res 10:399, 1977. 42. Bentley PG, VV Kakkar, MF Scully: An objective study of alternative methods of heparin administration. Thromb Res 18:177, 1980. 43. Andersson G, B Fagrell, F Holmgren: Subcutaneous administration of heparin: A randomized comparison with intravenous administration of heparin to patients with deep-vein thrombosis. Thromb Res 27:631, 1982. 44. Doyle DJ, AGG Turple, J Hirsh: Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis. Ann Intern Med 107:441, 1987. 45. Hyers TM, RD Hull, JG Weg: Antithrombotic therapy for venous thromboembolic disease. Chest 89 (Suppl) 26S, 1986. 46. Hyers TM, RD Hull, JG Weg: Antithrombotic therapy for venous thromboembolic disease. Chest 95 (Suppl) 37S, 1989. 47. Basu D, A Gallus, J Hirsh: A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 287:324, 1972. 48. Hull RD, GF Raskob, J Hirsh: Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 315:1109, 1986. 49. Bick RL: Disorders of Hemostasis and Thrombosis; Principles of Clinical Practice. Thieme, New York, 1985, p 288. 50. Ts'ao CH, TS Galluzzo, R Lo: Whole-blood clotting time, activated partial thromboplastin time, and whole-blood recalcification time as heparin monitoring tests. Am J Clin Pathol 71:17, 1979. 51. van den Besselaar AMH, J Meeuwisse-Braun, R Jansen-Gruter: Monitoring heparin therapy by the activated partial thromboplastin time—the effect of preanalytical conditions. Thromb Haemost 57:226, 1987. 52. Poller L, JM Thompson, KF Yee: Heparin and partial thromboplastin time: An international survey. Br J Haematol 44:161, 1980. 53. Hoffmann JJ, PN Meulendijk: Comparison of reagents for determining the activated partial thromboplastin time. Thromb Haemost 39:640, 1978. 54. Bjornsson TD, PV Nash: Variability in heparin sensitivity of APTT reagents. Am J Clin Pathol 86:199, 1986. 55. Naghibi F, Y Han, WJ Dodds, et ah Effects of reagent and instrument on prothrombin times, activated partial thromboplastin times and patient/control ratios. Thromb Haemost 59:455, 1988. 56. Shapiro GA, SW Huntzinger, JE Wilson: Variation among commercial activated partial thromboplastin time reagents in response to heparin. Am J Clin Pathol 67:477, 1977. 57. Brandt JT, DA Triplett: Laboratory monitoring of heparin. Effect of reagents and instruments on the activated partial thromboplastin time. Am J Clin Pathol 76:530, 1981. 58. Choay J: Structure and activity of heparin and its fragments: An overview. Semin Thromb Hemost 15:359, 1989. 59. Thomas DP, S Sagar, JD Stamatakis: Plasma heparin levels after administration of calcium and sodium salts of heparin. Thromb Res 9:241, 1976. 60. Banez EI, DA Triplett, J Koepke: Laboratory monitoring of heparin therapy—the effect of different salts of heparin on the activated partial thromboplastin time. An analysis of the 1978 and
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1979 CAP Hematology Survey. Am J Clin Pathol 74:569, 1980. 61. Bick RL: Disorders of Hemostasis and Thrombosis: Principles of Clinical Practice. Thieme, New York, 1985, p 327. 62. Ofosu FA: Antithrombotic mechanisms of heparin and related compounds. In: Lane DA, U Lindahl (Eds): Heparin: Chemical and Biological Properties, Clinical Applications. CRC Press, Boca Ratan,FL 1989, p 433. 63. Bick RL: Disorders of Thrombosis and Hemostasis: Clinical and Laboratory Practice. ASCP Press, Chicago, 1992 p 291. 64. Hamilton HW, JS Crawford, JH Gardiner, AM Wiley: Venous thrombosis in patients with fracture of the upper end of the femur. J Bone Joint Surg 52B: 268, 1970. 65. Harvald B, T Hilden, E Lund: Long-term anticoagulant therapy after myocardial infarction. Lancet 2:626, 1962. 66. Engelberg H: Actions of heparin relevant to the prevention of atherosclerosis. In: Lundblad RL, WV Brown, KS Mann, HR Roberts (Eds): Chemistry and Biology of Heparin. Elsevier, New York, 1981, p 555. 67. Errichetti AM, A Holden, J Ansell: Management of oral anticoagulant therapy: Experience with an anticoagulant clinic. Arch Intern Med 144:1966, 1984. 68. Fearnside MR, TS Reeve, GA Coupland: Long-term anticoagulation in venous thromboembolic disease by subcutaneous calcium heparin injection. Med J Aust 2:891, 1971. 69. Hull R, T Delmonre, C Carter: Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 306:189, 1982. 70. Bynum LJ, JE Wilson: Low-dose heparin therapy in the long-term management of venous thromboembolism. Am J Med 67:553, 1979. 71. Ben-Tal O, A Zivelin, U Seligsohn: The relative frequency of
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hereditary thrombotic disorders among 107 patients with thrombophilia in Israel. Thromb Haemost 61:50, 1989. Gladson CL, I Scharrer, V Hach, et ah The frequency of type 1 heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost 59:18, 1988. Tripodi A, PM Mannucci: A survey of inherited thrombotic syndromes in Italy. Res Clin Lab 19:67, 1989. Tabernero MD, JF Tomas, I Alberca: Incidence and clinical characteristics of hereditary disorders associated with venous thrombosis. Am J Hematol 36:249, 1991. Briet E, L Engesser, EJP Brommer: Thrombophilia: Its causes and a rough estimate of its prevalence. Thromb Haemost 58:39, 1987. Engesser L, EJP Brommer, C Kluft: Elevated plasminogen activator inhibitor (PAI), a cause of thrombophilia?—a study of 203 patients with familial or sporadic venous thrombophilia. Thromb Haemost 62:673, 1989. Heijboer H, PM Brandjes, HR Buller: Deficiencies of coagulationinhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 323:1512, 1990. Bick RL, WF Baker: Frequency of disorders associated with deep venous thrombosis and pulmonary embolus. Thromb Haemost 65:1170, 1991. Bick RL: Clinical relevance of antithrombin III. Semin Thromb Hemost 8:276, 1982. Meade T: Risk associations in the thrombotic disorders. Clin Haematol 10:391, 1981. Shapiro SS, P Thagarajan: Lupus anticoagulants. Prog Hemost Thromb 6:263, 1982. Asherson RA, EN Harris: Anticardiolipin antibodies: Clinical associations. Postgrad Med J 62:1081, 1986.
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Deep Vein Thrombosis: Prevalence of Etiologic Factors and Results of Management in 100 Consecutive Patients
Deep vein thrombosis (DVT) is a significant clinical problem seen in many medical specialties. Although many etiologic factors have been identified, it remains unclear what the prevalence of each factor is in the gen eral population. Also, management is controversial and ideal treatment remains to be defined. The etiologic fac tors associated with DVT are conveniently divided into clinical conditions, hereditary blood defects, and ac quired blood defects. The clinical factors commonly as sociated with DVT include malignancy, stasis, the post operative state, sepsis, use of estrogen-containing compounds, trauma, heart disease, and burns. 1-5 Hered itary blood protein defects associated with thrombosis include antithrombin-III (AT III) deficiency, protein C, protein S, plasminogen, heparin cofactor II, and tissue plasminogen activator (t-PA) deficiencies, dysfibrinogenemia, and cystathionine β-synthetase deficiency.6-13 Acquired blood defects associated with DVT include polycythemia, benign or malignant thrombocytosis, lu pus anticoagulant, anticardiolipin antibodies, elevated t-PA-inhibitor type 1 and acquired deficiencies of AT III, protein C, protein S, heparin cofactor II, plasminogen, and t-PA. 14-24 Also, Factor XII deficiency and possibly elevated Factor VII, fibrinogen, and lipoprotein a may be associated with DVT. 25-28 Despite appreciating these as sociations, the prevalence of each of these hereditary and acquired defects and disorders, which may account for development of DVT in the general population, is un
From the Regional Cancer and Blood Disease Center of Kern and Department of Medicine, Division of Hematology/Oncology, UCLA Center for the Health Sciences, Bakersfield and Los Angeles, Califor nia. Reprint requests: Dr. Bick, Clinical Professor of MedicineUCLA, P.O. Box 580, Bakersfield, CA 93302-0580.
clear. We have assessed the clinical and laboratory char acteristics of 100 consecutive patients referred for con sultation for DVT to ascertain prevalence of associated clinical and blood defects accounting for thrombosis in these patients. All patients were treated by a uniform multimodality protocol. The results of this analysis, in cluding clinical, are herein presented.
METHODS Patient Population The patient population consisted of 100 consecutive patients referred to our consultative service for evaluation of DVT. All patients were subjected to careful clinical evaluation and confirmation of DVT by ascending con trast venography or ascending thromboscintography, us ing technetium-99 labeled macroaggregated albumin. All patients with suspected pulmonary embolus were sub jected to pulmonary ventilation perfusion scans or pul monary angiography.
Laboratory Evaluation At presentation, all patients underwent complete blood and platelet count and differential white count, SMA 18/60 biochemistry survey including glucose, blood urea nitrogen, creatinine, cholesterol, bilirubin, SGOT, SGPT, GGT, gamma glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), alkaline phos phatase, uric acid, total protein, albumin, globulin, so dium, potassium, chloride, calcium, bicarbonate, and amylase. At presentation, all patients underwent hemostasis testing, which consisted of the following: AT III, 29
Copyright © 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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protein C, 30 protein S,31 plasminogen,32 heparin cofactor II, 33 fibrinogen level by clotting time technique,34 lupus anticoagulant assay,35 anticardiolipin antibody assay (immunoglobulin G, A and M [IgG, IgA, and IgM] isotypes),36 t-PA37 tissue plasminogen activator inhibitortype 1 (PAI-1) assay,38 and baseline prothrombin time and activated partial thromboplastin time (APTT).39 All abnormal hemostasis results were repeated 6 to 8 weeks after the acute event to ascertain the etiologic association of defects initially found. Hemostasis assay methods used are depicted by the references cited.
Treatment Methods All patients with acute DVT were treated with multimodality therapy consisting of anticoagulation, initial bed rest with progressive early ambulation (within 24 hours in the absence of pulmonary embolus [PE]), antiembolic exercises when appropriate and antiembolic stockings when appropriate.40 Initial anticoagulant therapy was subcutaneous calcium heparin (Calciparine, Choay) at a dosage of 5000 U every 6 hours if total body weight was less than 70 kg and 7500 U every 6 hours if body weight was more than 70 kg. APTTs were not obtained for monitoring purposes; each patient had a heparin level41 every AM and the subcutaneous dose adjusted upward, if needed, to assure a plasma heparin level of more than 0.05 U/ml. At the time of discharge, all patients were discharged on 5000 U subcutaneously every 6 hours. Calcium heparin was tapered as follows: after 2 weeks, the dose was decreased to 5000 U every 8 hours, after 4 weeks the dose was decreased to 5000 U every 12 hours, and after 6 weeks the dose was decreased to 2500 U every 12 hours. If the patient had no identifiable continuing risk factor and this was the first event, the calcium heparin was stopped at 12 weeks. If, however, the patient had an identifiable continuing risk factor, such as congenital or acquired blood defect, or if this was a recurrent event, the calcium heparin was continued at 2500 U every 12 hours indefinitely. All patients referred with recurrence while on or after initial warfarin therapy were also treated by this protocol. All patients with upper or lower extremity DVT were instructed in antithrombotic exercises; these were started by 24 hours after diagnosis. Exercises for DVT of the lower extremities consisted of straight leg elevation above the hip joints by 10°, and dorsiplantar flexion of the foot for 5 minutes per leg or until fatigue of calf muscles, done at least six times per day during waking hours. Exercises for DVT of the upper extremities consisted of straight arm elevation above the head with
compression of the fist for 5 minutes, or until muscle fatigue, also done at least six times per day during waking hours. All patients with extremity thrombosis were placed in medium compression stockings (panty hose for lower extremities and sleave stockings for upper extremities) and instructed to use these during waking hours for at least 3 months. Stockings were ordered at the time of diagnosis and were placed on the patient about 48 hours after presentation. After discharge, patients were followed, including clinical examination, weekly for at least 1 month and then every 2 weeks until at least 3 months after the event. After 3 months, patients were followed every 3 to 4 months.
RESULTS Patient Characteristics At presentation 68 patients presented with an acute thrombosis and were placed on heparin as previously described; 20 additional patients presented while on coumarin therapy and of these 13 were referred because of failure, with a new acute event while on adequate doses; these 13 were immediately placed on heparin as earlier noted. The remaining seven referred on coumarin were stable and only referred for an etiologic diagnosis. Nine patients were referred without acute DVT and were not on therapy, having had a thrombosis in the past and requesting an evaluation, and three patients were referred with a history of DVT and were on antiplatelet agents. There were 51 men with a mean age of 52.7 years and 49 women with a mean age of 54.7 years. A total of 81 patients (68 with a new acute thrombosis and 13 coumarin failures with an acute thrombosis) were treated with subcutaneous calcium heparin as described under Methods. During the 3 months of treatment, there were two heparin failures, one following orthopedic surgery and one with congenital AT HI deficiency. Of the 20 patients treated with coumarin, thirteen failed; failures were seen with anticardiolipin antibodies (eight failures), protein S deficiency (one failure), t-PA deficiency (one failure), hereditary spherocytosis (one failure), trauma (one failure), and no defined etiology for DVT (one failure). Thus, the failure rate for subcutaneous calcium heparin given as described was 2 of 81 patients (2.4%) over 3 months of therapy and for patients treated with coumarin was 13 of 20 (65%); however, most of the coumarin failures were in patients having anticardiolipin antibodies, suggesting coumarin to be ineffectual for this situation.
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It was found that by careful clinical evaluation, coupled with carefully chosen laboratory evaluation, an etiology could be defined for 81% of all patients. These associations are divided into plasma defects and nonplasma defects. The plasma defects can be divided into hereditary or acquired.
Nonplasma Defects and Deep Vein Thrombosis Fifty-five patients (55% of the population) had a defined nonplasma defect associated with DVT. These were as follows in descending order of prevalence: 11 patients (11%) had malignancy, ten patients (10%) had arthroscopy, eight patients (8%) had major trauma, seven patients (7%) had orthopedic surgery, six patients (6%) were morbidly obese (more than 20% ideal body weight), three patients (3%) were ingesting Premarin, three patients (3%) had diabetes mellitus, two patients (2%) had giant cavernous hemangiomas of the thrombosed extremity, and one patient each (1%) had hereditary spherocytosis, pregnancy, mitral valve prolapse, chronic immobility, and ingestion of oral contraceptives.
Plasma Defects and Deep Vein Thrombosis Forty-seven patients (47%) had a defined plasma defect associated with hypercoagulability and thrombosis. Of these defects, 28% (28 patients) were acquired and 19% (19 patients) were congenital. Of the acquired defects, 24% (24 patients) had anticardiolipin antibodies and four patients (4%) had a lupus anticoagulant. Of the congenital defects found, eight patients (8%) had protein S deficiency, eight patients (8%) had AT III deficiency, two patients (2%) had protein C deficiency, and one patient (1%) had congenital t-PA deficiency. No cases of plasminogen deficiency, heparin cofactor II deficiency or dysfibrinogenemia were found. Also, no cases of elevated PAI-1 were found. Nonplasma defects were slightly more common than plasma defects, 55% versus 47% of patients presenting. Of the nonplasma defects, malignancy, arthroscopy, trauma, and other orthopedic procedures comprised most of the etiologic disorders associated with venous thrombosis. In patients with a plasma defect, acquired defects are more common than congenital problems and anticardiolipin antibodies were the most common associated hypercoagulable defect found, seen in 24% of this population. Of the hereditary defects, protein S and AT III
TABLE 1. Defects Found Associated with Deep Vein Thrombosis in 100 Consecutive Patients %
Defect Non-plasma defects (55% of patients) Malignancy Arthroscopy Major trauma Orthopedic surgery Obesity Premarin Diabetes Hemangiomas Spherocytosis Pregnancy Mitral valve prolase Immobility Oral contraceptives Plasma defects (47% of patients) Acquired Anticardiolipin antibodies Lupus anticoagulant Hereditary Protein S Antithrombin III Protein C Tissue plasminogen activator
11 10 8 7 6 3 3 2
24 4 8 8 2 1
deficiencies, followed by protein C deficiency, were the most commonly found. Twenty-one patients had both a clinical and plasma defect. These results are summarized in Table 1.
DISCUSSION Confusion and controversy continue over both acute and long-term management of DVT. Both intravenous and subcutaneous heparin have been advocated for acutephase management; recent studies have clearly shown subcutaneous heparin to offer equal efficacy to intravenous heparin for acute management.42-44 Despite these efficacy findings, many continue intravenous heparin for acute-phase treatment of DVT. However, common recommendations for intravenous heparin therapy for acutephase management have been based on only two studies, both seriously flawed, that suggested that the APTT should be prolonged to 1.5 times control. 45-48 The first study suggesting improved efficacy with APTT adjustment to 1.5 times control by Basu et al47 was uncontrolled, wherein the diagnosis of both DVT and PE were based on clinical findings and not accepted radiographic studies. The lack of radiographic evaluation of DVT or PE induces a potential 50% error in the diagnosis.49 Also, this study used a homemade APTT system and, since it is known that many different commercially avail-
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able APTT systems are themselves not comparable, it is unlikely that APTTs from numerous commercial sources are at all comparable to the homemade APTT system used by Basu et al. 50-53 The second study was that of Hull and associates48 who claimed a statistically significant difference in rethrombosis (failure) rates between patients with the APTT longer than or shorter than 1.5 times control; however, in this study, there were three patient failures in the longer APTT group and 11 patient failures in the shorter APTT group. In the failure group, six of the failures (recurrences) happened between 3 weeks and 3 months after presentation while on warfarin, not heparin, therapy and the group included two patients with malignancy, a disorder known to exhibit refractoriness to anticoagulant therapy. One could easily argue that patients rethrombosing after 3 weeks could just as likely be warfarin rather than heparin failures. When removing these warfarin failure patients from both groups, the significance of the differences between the failures in the long APTT (therapeutic) versus shorter APTT (subtherapeutic) groups becomes insignificant (p = 0.24). Another major problem with these and other studies is that most authors fail to account for several important variables. It has been repeatedly shown that prolongation of the APTT by heparin is incredibly variable, depending on the APTT reagents, for example, the activators or phospholipids used. 54-56 Generally, liquid activators, such as ellagic acid or celite, are less sensitive to heparin than are particulate activators, such as kaolin, or micronized silica; also, sensitivity to heparin is variable, depending on the type of partial thromboplastin (phospholipid) used in the APTT.57 Thus, with a given heparin, the degree of APTT prolongation will be highly dependent on reagents (activators and phospholipids) and not necessarily dose of heparin used or plasma heparin level. To complicate the situation further, any given APTT is also dependent on the type of heparin used. It is well known that the more abundant the higher molecular weight subfractions of heparin, the more anti-IIa activity and the more prolonged the APTT, but the more abundant the lower molecular weight heparin subfractions, the more anti-Xa activity and with less anti-IIa activity less prolongation of the APTT may occur.58 Also, the source of heparin (bovine or porcine) and the salt (sodium or calcium) may influence the APTT, for porcine heparin renders more anti-Xa activity than bovine heparin at all molecular weights.59 When given subcutaneously, calcium heparin gives lower blood levels than sodium heparin and calcium heparin gives less prolongation of the APTT than sodium heparin.60 Thus, the APTT prolongation is dependent on particular type of heparin used. Of other significance is that clinical efficacy appears more correlated with anti-Xa activity and less with anti-IIa activity, yet prolongation of the APTT is dependent primarily on
anti-IIa activity.61,62 Consideration of this information leads to the obvious conclusion that without knowing the type of heparin used and the type of APTT used, one cannot draw meaningful conclusions from clinical studies. It is also obvious that clinical trial results cannot be compared unless the APTT systems are the same and the type of heparin used the same. Our results, using calcium heparin subcutaneously at a dose of 5000 or 7500 U every 6 hours during the acute phase render a failure rate of 2.4% of patients. We aimed for a plasma heparin level of more than 0.05 U/ml, but this level was empirically chosen because the minimum required effective plasma heparin level is undefined.63 The long-term treatment after acute-phase DVT likewise is associated with confusion and controversy. Most clinicians continue to use coumarin drugs despite hemorrhagic risks approaching 30 to 40% in some series 64,65 and despite incredibly high failure rates, up to 38% in some reports. 66,67 The high hemorrhage risk and high failure rates, coupled with inconvenience of periodic prothrombin time requirements, have led to exploration of long-term management with subcutaneous heparin. 68-70 Although many have shown a high level of efficacy, dose regimens, like those with acute-phase management, remain confusing and controversial. Obviously, much confusion and controversy results from the same variables as discussed for heparin earlier, dependence on the type of reagents used for the APTT and dependence on the type of heparin used. Thus, it is impossible to compare results of clinical trials unless the APTT systems and types of heparin are similar. Despite these important variables, investigators have advocated long-term subcutaneous fixed dose heparin therapy or long-term dose-adjusted subcutaneous heparin therapy; it is, of course, impossible to compare results of these two different approaches because of the aforementioned variables dependent on heparin used and APTT used. 69,70 Our patient population was given fixed-dose subcutaneous calcium heparin for long-term management. Therapy was stopped if no identifiable continued etiologically associated factor was found and if this was the first event. As will be discussed, however, if an associated continuing etiologic factor was found, long-term management continued indefinitely. Our long-term regimen consists of tapering, as previously depicted, to a minimum fixed dose of 2500 U every 12 hours. Using this regimen, none of our 81 patients has failed during 3 or longer months of long-term therapy; this includes the original 13 patients referred after failing coumarin therapy. The etiology of DVT may dictate both type and duration of anticoagulant therapy. In this series of patients 55% had a definable clinical, nonplasma defect and 47% had a definable plasma defect. Of those with plasma defects, 28% were acquired and 19% were hereditary.
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No studies to date address the incidence of acquired plasma defects in the general population with DVT; however, several have evaluated the incidence of selected hereditary defects in DVT populations. Ben-Tal et al71 estimate the relative frequency of lupus anticoagulant, dysfibrinogenemia, and deficiencies of AT III, protein S, and protein C in a population of 107 patients presenting over a 4-year period. Unfortunately, other blood defects associated with DVT, such as heparin cofactor II, plasminogen deficiency, or t-PA were not assessed. In this study, 21.5% of patients had one of the defects searched for and the remainder were unaccounted for. AT III deficiency was found in 8%, protein C deficiency was found in 5.6%, protein S deficiency was found in 2.8%, dysfibrinogenemia was found in one patient, and lupus anticoagulant was found in 3.7% of patients. In a similar study of 141 patients under 45 years of age Gladson et al72 found 5% to have protein S deficiency, 4% to have protein C deficiency, 3% to have AT III deficiency, 2% to have plasminogen deficiency, and 1% to have dysfibrinogenemia with thrombosis. In a survey of inherited thrombotic disorders in Italy, Tripodi and associates73 queried members of the Italian Society for the Study of Hemostasis and Thrombosis and collected all known cases of congenital thrombosis. Although their method of study did not allow for conclusions regarding the incidence of these defects in the general or DVT population, they concluded that AT III, protein C, and protein S deficiencies were the most common.73 In a similar study, Tabernero and associates74 evaluated the frequency of congenital defects in a general DVT population of 204 patients and found congenital protein defects to account for only 4% of the DVT population; specifically, there were three cases of protein C, three cases of protein S, two cases of plasminogen, and one case of AT III deficiency. Like the other studies cited, this study was also incomplete because heparin cofactor II, fibrinogen, and t-PA defects were not assessed.74 In a study involving 37 Dutch hospitals, a total of 113 unrelated patients with DVT were studied by Briet et al;75 results revealed 35 patients (31%) to have hereditary thrombophilia. In this study, five patients (4.4%) had AT III deficiency, 13 patients (9.7%) had protein C deficiency, 15 patients (13.2%) had protein S deficiency, and two patients (1.7%) had dysfibrinogenemia.75 In a later Dutch study by Engesser et al76 203 patients with thrombosis were assessed for congenital deficiencies associated with thrombosis and 46% had a congenital defect associated with thrombosis; six patients (3%) had AT III deficiency, 14 patients (7%) had protein C deficiency, 16 patients (8%) had protein S deficiency, two patients (1%) had dysfibrinogenemia, and eight patients (4%) had congenital elevation of PAL In a subsequent study assessing a DVT population of 277 consecutive patients in Holland,
271 Heijboer and associates found only 8.3% of the population to have congenital defects; however, only AT III, protein C, protein S, and plasminogen deficiencies were evaluated. Specifically, three of the patients (1.1%) had AT III deficiency, nine patients (3.2%) had protein C deficiency, six patients (2.2%) had protein S deficiency, and four patients (2.2%) had plasminogen deficiency. The authors of this last study concluded that based on their results, screening for hereditary thrombotic disorders was not warranted. However, based on our results, we strongly disagree with this recommendation and are unwilling to accept missing a diagnosis of congenital protein defects associated with thrombosis in 19% of patients presenting with DVT in our series.78 The incidences of congenital defects in these studies, compared with our findings are presented in Table 2. It appears that significant regional differences may occur, accounting for the marked differences in the aforementioned series and results, but the true incidence of many of these congenital defects will not be known with certainty until more complete studies, including assays for all known protein defects leading to congenital thrombophilia, are done. The incidence of acquired plasma defects associated with thrombosis in the general DVT population is even less certain, but appears quite high in selected populations based on the few studies addressing this important issue. 79-82
CONCLUSIONS The etiology of DVT can clearly be defined in greater than 80% of patients if careful clinical assessment combined with equally astute laboratory evaluation is done. The clinical assessment must include a complete history, review of systems, and physical examination and the laboratory evaluation must include a routine complete blood count and platelet count, a routine biochemical survey, and assessment for the more common followed by less common blood protein defects associated with hypercoagulability and thrombosis. Using this combined approach, we found that 55% of patients had a clinical disorder known to be associated with thrombosis and 47% of patients were found to have a plasma defect known to be associated with thrombosis. The plasma defects were more commonly acquired than congenital, but generally the prevalence in descending order of probability is as follows: anticardiolipin antibodies, AT III deficiency, protein S deficiency, lupus anticoagulant, protein C deficiency, and t-PA deficiency. These assays should, therefore, be included in the initial hypercoagulability screening panel used for a patient with clinically unexplained venous thrombosis. If this first panel is negative, the secondary panel should consist of functional
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SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 18, NO. 2, 1992
Deficiency No. patients AT III Protein C Protein S
Brief etal.(1987)
Gladson etal.(1988)
Engesser etal.(1989)
Ben-Tal etal.(1989)
Heijboer etal.(1990)
Tabernero etal.(1991)
Bickand Baker (1991)
113
141
203
107
277
204
100
4.4 11.5
3 4
3 6.8
7.4
1.0
6.5
13.2
5
7.8
2.8
3.2 2.1
NM 0.9 NM NM
NM NM
NM
Plasminogen
0.7
2
NM*
Dysfibrinogenemia
1.7 0.7
1 NM
0.9 NM
0.7
NM
NM
0.7
NM
3.9
33.6
15
22.4
Heparin cofactor II Tissue plasminogen activator High plasminogen activator inhibitor-1 % with defect
17.6
0.5 1.5
8 2
1.5
8
.98 NM
0 0
NM
0
NM
NM
1
NM
NM
0
1.4
7.7
4.5
19
* NM; not measured.
fibrinogen, plasminogen, heparin cofactor II, and PAI-1 assays. A scheme for workup of the patient with thrombosis is given in Table 3. Our results using a uniform fixed dose of subcutaneous calcium heparin for the initial and long-term treatment was associated with a failure rate of 2.4%, generally better than that reported for intravenous heparin, dose-adjusted subcutaneous heparin, or coumarin. However, as earlier discussed, most studies do not depict the type of heparin used or the reagents used for monitoring; therefore our results may not be applicable to different heparin preparations. Of the 20 patients referred for failure of adequate doses of coumarin, 13 (65%) had anticardiolipin antibodies; this finding strongly suggests that coumarin use in DVT associated with anticardiolipin antibodies is associated with a very high failure rate and coumarin drugs are probably not appropriate in this setting. None of these patients failed the aforementioned calcium heparin regimen, suggesting subcutaneous calcium heparin, both initially and long-term, to be the TABLE 3. Laboratory Evaluation of Patients with Unexplained Deep Vein Thrombosis Primary assessment Antithrombin III Anticardiolipin antibodies Lupus anticoagulant Protein C Protein S Tissue plasminogen activator Secondary assessment Heparin cofactor II Plasminogen Plasminogen activator inhibitor-1 Dysfibrinogenemia Factor XII?
therapy of choice for DVT associated with anticardiolipin antibodies. Patients with no continued identifiable associated clinical or plasma defect should be tapered and then calcium heparin stopped after 3 months. However, if a continuing clinical or laboratory defect is present, calcium heparin therapy at 2500 units subcutaneously every 12 hours should be continued indefinitely, as the clinical situation dictates.
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TABLE 2. Published Prevalence (%) of Congenital Blood Defects Associated with Thrombosis
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