Spontaneous deep vein thrombosis (DVT)
and pulmonary embolism (PE) are all recognized causes of morbidity and mortality
in adults and have been studied
extensively. These two events are relatively rare in children but, when present, also cause significant morbidity and occasionally,
death(1) for which there is paucity of information available in the Indian literature. In this communication, we report three cases of DVT, one of them with PE.
Case Reports
Case
1: A 12-year-old female child was
admitted with complaints of fever, and pain in the left hip joint and thigh of 15 days duration. She developed throbbing chest pain and palpitation 12 hours after admission. There was no history suggestive of rheumatic fever
or rheumatic heart disease. The subject was toxic and had coated tongue, tachycardia, tachypnea, congested throat and normal blood pressure. She was
pale, had no signs of rheumatic arthiritis or infective endocarditis. Liver and spleen were just palpable, both being soft and non-tender. Investigations revealed Hb of 12.5 g/dl, TLC of
10,200 cells/cu mm (Polymorphs-82%), ESR of 59 mm fall in 1st hour. Urine showed trace albumin with 8-10 WBCs/HPF, 4-5 RBCs/HPF and granular casts. Urine and multiple blood cultures did not grow any organism. BUN was 31 mg/ dl, S. Creatinine was 0.8 mg/dl, total S. bilirubin was 4.7 mg/dl (Direct 3.3 mg/dl), ASLO was 200 IU and PT was 13 see (control 26 see). Widal and Brucella Agglutination tests were negative, ECG showed Rsr pattern in leads V2and V3. Chest X-ray showed pulmonary venous congestion with right upper zone wedge shaped consolidation and features of pulmonary edema. use of abdomen did not show any evidence of septic focus anywhere. Echocardiography revealed evidence of pulmonary hypertension with dilation of right sided chambers secondary to pulmonary
embolism. Color Doppler study of lower limbs, showed sub totally occluding
thrombus in the left common femoral vein measuring 4.3 mm x 18.5 mm. The child
received symptomatic treatment, in the form of frusemide, antibiotics and low molecular weight heparin subcutaneously with regular monitoring of PI and was later treated with warfarin for three months. She recovered without any sequelae. One year follow up was uneventful.
Case 2: A 10-year-old female child was admitted with intermittent type of moderate degree fever, blood and mucus loose stools and non-bilious, non-projectile vomiting. She was admitted previously to the same hospital
at the age of 7 years and was
treated for ascitic type of abdominal tuberculosis. On examination, she was febrile, toxic, pale and had lymphadenopathy, Grade II clubbing, bilateral pitting pedal edema, Bitot's spots in the eyes, flacky paint dermatosis over lower limbs and generalized muscle wasting with normal vital signs. Systemic examination revealed hypotonia of all four limbs with decreased deep tendon reflexes and normal plantars.
She was given symptomatic and supportive care. On the 7th day of her stay in the hospital, she complained of pain in the left leg. On examination, the leg was swollen, tender,' warm and the left dorsalis was weak. Moss's sign was positive. Investigations revealed anemia (Hb 9.0 g/dl). TLC of 10,000 cells/cu mm (polymorphs 74%), 10% band forms, ESR 5mm fall in 1st hour, no malarial parasites. Widal and blood culture were negative. BT was 1'30", CT 2'30", Mantoux test was 22 x 17 mm, urine was normal and Chest X-ray showed multiple small bilateral calcifications. Color doppler study of lower limbs showed thrombus in the left femoral vein measuring 4.0 mm x 14.0 mm. With bed rest, analgesics, antipyretics, antibiotics, anti-tubercular drugs and heparin, the child improved in 2 weeks without any sequelae, but the follow-up was not available.
Case 3.: A 10-year-old female child was brought with history of abdominal pain and generalized swelling of body of 3 and 2 months duration, respectively, followed by progressive weakness. She sustained injury to her legs one week prior to admission. On examination she was conscious, pale, unable to walk, had bilateral pitting lower limb edema, more on right side and vital signs were normal-systemic examination showed soft, non-tender hepatomegaly of 3 cms, hypotonia and decreased deep tendon reflexes in all four limbs with normal plan tars, no meningeal signs, no spinal
deformity or tenderness. Both dorsalis pedis arteries were well felt. There was severe tenderness, redness and increased temperature in the right leg. Investigations showed anemia (Hb 7.7 g/dl), TLC of 16,900 cells/cu mm (Polymorphs 43% Lymphocytes 57%), BUN 26 mg/dl, S. creatinine 1 mg/dl, BT 2'00", PT 19" (control 14"). Blood culture grew E. coli which was sensitive to Amikacin, Cefuroxime and Ceftizoxime. Urine examination and chest X-ray were normal. X-ray of right thigh showed no evidence of osteomyelitis or fracture. Doppler study showed DVT of femoral and popliteal veins on the right side with no flow in both the veins and normal arterial flow. Child was treated with antibiotics and warfarin. In 14 days, she improved and was discharged after three weeks of treatment with warfarin. She did not develop any complications or sequelae during the followup treatment with warfarin for three months.
Discussion
Case reports and case series dearly document that DVT occurs in children as do pulmonary
embolisms(1). Anti-coagulants thrombolytic therapy are used in children to treat DVT arid PE which are extrapolated from recommendations for
adults(1). This practice has arisen because DVT and its consequences are infrequent management dilemmas that require therapeutic intervention. A recent review of all case reports of DVT and PE in children in French and English literatures from 1975- 92 reported, 308 children with DVT of extremities or PE or
both(1), while a prospective study by Canadian registry of DVT and PE from 1990 for four years recorded an incidence of DVT /PE as 5.3/ 10,000 hospital admissions or 0.07/10,000 child population in Canada (137 patients). Thirty six cases of thromboembolism (10 DVT) were reported during 1971-75(2) and
prior to 1971, only
28 cases were reported(3). Medline search shows one or two studies every year since
1984, and not
a single of them from India. The age distribution of DVT and PE in 199 out of 214 cases demonstrated more
occurrence of DVT in adolescence than in children (probably due to their referrals to adult clinics)(4) and in children less than 1 year old(4). All the three cases that we saw were
in the age group
of 10-12 years. Reports
from the-literature show equal sex distribution(1,3,4). However, our three
cases were
all females.
In contrast to adults, children with DVT,
have
a serious underlying disorder or predisposing factor
in 96%(4) to 98%(1).
Associated conditions seen are CHD(4), malignancy(4), trauma(1,4), immobilization(3), CVP line(1,4), nephrotic syndrome(4), surgery(1,3,4), VA shunts(4),
SLE(1), and infection(1,3). However, in our cases, no identifiable cause was found in
case 1. Of the
other two; the second case
had abdominal tuberculosis and third case had trauma and septicemia. There is no mention in current text books of the
occurrence of
spontaneous
DVT in children
with tuberculosis. Diagnostic criteria for spontaneous DVT includes exclusion of: (i)
Local predisposing factors like lymphangitis, cellulitis or ulcers;
(ii)
Ostemoyelitis by X-ray, local tenderness and bone marrow
culture sensitivity;
and (iii)
Trauma,
surgery and immobilization.
Pathogenesis
Venous thrombi are intravascular
deposits
of
fibrin, red cells, platelets and
leukocytes usually formed in the regions of slow or disturbed flow in large venous sinuses and the valve cusp pockets in the deep veins of calf or venous segments exposed to trauma; the balance between the
thrombogenic stimuli and protective mechanisms being crucial factors for formation, growth
and
dissolution
of
venous
thrombi. Vascular damage leads to formation of venous thrombosis through direct trauma and also through the cytokines activated from endothelial cells as a result
of
injury. Blood coagulation is activated by
intravascular stimuli both from local vessal wall damage and from remote site. The cytokine stimulates the endothelial cells to synthesize tissue factor and plasminogen
activator inhibitor-I, which reduces the protective functions of endothelium.
The coagulation mechanism gets amplified by stasis and stasis also decreased the
clearance of
activated
coagulation factors.
Clinical
Features
The most frequent clinical findings include local tenderness, increased size of the involved limb, local warmth, palpable venous cord, and positive Homan's sign(3). Clinical diagnosis of
DVT in
children is complicated by the widely diverse locations in which clots occur, the small size of the patients, underlying disorders and lack of validated non-invasive diagnostic radiographic tests. Clinical diagnosis of DVT is equally non-specific in adults too!
Investigations
The radiographic techniques for the diagnosis of DVT can be considered as non-invasive (doppler USG) and invasive (angiographic studies). Unfortunately, one cannot determine from the literature which
vessels
were
most frequently involved'
in pediatric patients because a detailed description is rarely given(1). Upper system is involved more in children due to CVP
lines(1), however, all the three cases
of
ours
had DVT of lower system and one patient (Case 1) had PE. PE is usually diagnosed with lung scan or angiography or both and our case was diagnosed by clinical and
typical radiographic finding
of wedge
shaped homogenous, opacity and right sided volume overload of heart with failure and evidence of pulmonary hypertension. The finding of a Hampton hump (a semi-circular opacity with the base abutting the pleural surface) is strongly suggestive of pulmonary infarction(5). The other radiographic features that can be seen are pleural effusion, sub-segmental atelectais, pulmonary infiltrate, raised hemidiaphragm, regions of apparent oligemia and prominent
pulmonary vascular shadow at the hilum. However, none of these are diagnostic of PE because they can be seen in pulmonary infection, atelectasis and obstructive lung disease. Literature has documented
PE in three out of 50 DVTs in upper system and 11 out of 79 in lower system with ventilation/perfusion (VQ) scans(4).
D-Dimer Test:
Activation of blood coagulation
leads to thrombin generation which binds to fibrinogen and liberates fibrinopeptides
A and B. This forms fibrin monomers and polymers. This fibrin network is stabilized (Cross-linked) by activated factor XIII. Plasmin induces lysis of cross 'linked fibrin and leads to liberation of various fibrin degradation products (FOPs) including
D-dimer (DD)(6) and DD epitopes. This DD can be easily detected and measured in
both whole blood and plasma using monoclonal antibodies directed against epitopes located in the
DD fragment. The DD testing
has been established as
useful aid in
diagnosis of venous thromboembolisin (VTE)(7).Various assay methods are available for measurement of
DD(8). Rapid single test, quantitative DD assays and more reliable latex tests can be used in emergency
department to rule out DVT and PE if the concentration of the DD falls below
certain assay dependent cut-off. Further the DD test is used in diagnosis of VTE in symptomatic patients, in screening asymptomatic high risk patients and to rule out suspected recurrent VTE.
Treatment
In the past, majority of the DVT in children were treated with heparin (85%)(4) and only a minority with thrombolytic
therapy. The objectives of treating venous thrombosis and PE are to prevent
local extension of the thrombus, prevent embolization and in some circumstances accelerate fibrinolysis. Of the 2 anticoagulants in current use, heparin acts immediately while coumarins act much slowly. Standard text books say heparin is to be used in full doses for 7 to 10 days with warfarin
added for an additional 2 to 3 months in patients with proximal (above knee)
venous thrombosis while patients with calf vein thrombosis should be treated
with heparin for 7 days and then with warfarin or subcutaneous heparin for an additional 6 weeks period(9). As per current recommendations; in adults
DVT is treated' aggressively to prevent PE, sudden death, recurrence and post-phlebitic syndrome with heparin followed by three months oral anti-coagulant therapy. In children, so far there is no convincing evidence that risks of
DVT in pediatric patients are any less than in adults. The therapeutic options include:
(i)
Heparin followed by oral anticoagulant
therapy;
and (ii)
Thrombolytic therapy
followed by anticoagulant therapy.
As per the information from a Statement by the Council on Thrombosis(5),
children older than 2 months who have DVT or PE should be treated with IV heparin (bolus 75 U/Kg), maintenance of 20 U /Kg/h so as to prolong the aPTT to a range that corresponds of an antifactor Xa
level of 0.3 to 0.7 U / ml. Treatment with hepatin is continued for 5-10 days and oral anti-coagulation overlapped with heparin for 4-5 days. In many patients both can be started together and heparin is discontinued on day-6. Long term anticoagulants are continued for atleast 3 months(5,10), with
oral agents in a dose of 0.2 mg/kg/ day to prolong PT to an INR of 2.0-3.0. In children with PE, heparin therapy is used for a longer period. In recurrences or a continued risk factor, either indefinite warfarin
therapy, a low dose anticoagulant therapy or a close monitoring should be considered.
Newborns with central venous line should receive IV heparin in doses of 1-5 units/h through the catheter. If anti-coagulation is indicated, a 10-14 days course of IV heparin (75 units/kg bolus, 28 units/kg/h maintenance) should be used. Use of thrombolytic
agents in management of VTE in newborns is uncertain and for definitive recommendations further clinical investigation is needed.
Heparin: Heparin is initiated with a dose of 75 units/Kg for 10 minutes followed by an infusion beginning at 22 units/Kg/h. Four to six hours after the initial dose, heparin activity is measured with APTI
(calibrated to heparin levels) or by heparin levels. A 5-7 day course is usually
sufficient. Treatment with warfarin can be instituted within 48 hour of heparin therapy.
Low Molecular Weight Heparins (LMWHs): LMWHs
are an important new class of
antithrombotic agents. They differ from standard unfractionated heparin in having a high ratio of anti-factor Xa to anti-factor
IIa activity, greater biovaliability, longer half life and a more predictable anti-coagulant response when administered sub-cutaneously in fixed dose(11). The added advantages of
LMWH
is less heparin induced thrombocytopenia and possibly less osteoporosis(12). Two recently concluded studies state that LMWH and unfractionated heparin are equally effective and safe in unselected patients with confirmed DVT with or without PE. In addition, LMWH permits treatment regimens to be simplified so that hospital stays can be shortened
and suitable patients can be treated on an out patient basis(13-15). LMWH can also be given as a single dose. This is equally effective and has less side effects than warfarin and can be given without laboratory monitoring(13). These LMWH have replaced unfractionated heparin in many parts of Europe, and are now finding a place in North America(15). Their use is likely to increase in the next few years.
Warfarin:
Many studies have evaluated
dose requirement of warfarin in children(5,16,17). Treatment is initiated with 0.2 mg/Kg (maximum 10 mg) for two days and then modified
according to the INR values. The hemorrhagic risks are similar to adults. The drug can be discontinued after three months unless an underlying cause of DVT is still present or recurs in which case a longer course would be needed.
Thrombolytic
Therapy:
This is used in low
doses usually to re-establish catheter patency or in systemic doses in children with extensive DVT /massive PE. Two to three ml of urokinase (5000 units/ml) for 2-4 hours or 150 units/kg/h for 8 hours is used. However, it is more expensive than heparin and is associated with a high risk of bleeding.
Surgical Treatment:
Surgical removal of the
thrombus (venous thrombectomy) or the embolus (embolectomy) is rarely indicated. In patients with DVT, PE is prevented effectively with anti-coagulant therapy. PE can also be prevented by inserting a filter into the vena cava, but only if anticoagulant therapy is contraindicative due to bleeding or PE has
occurred inspite of adequate treatment with anticoagulants(5). Mortality due to DVT or PE has been reported to be 3.4 to 9.5%(3,4) either due to PE or other complications or due to the primary underlying disease. Though all our three patients recovered well, they need to
be followed up for recurrence, postphlebitic syndrome, patient's compliance and bleeding complications. The risk of recurrent VTE is increased by the presence of malignancy, coagulation abnormalities and reduced in patients who have reversible risk factors like surgery, trauma and fracture(5). Investigations like protein C and 5, antithrombin III, plasminogen and fibrinogen
activities should be done to find out inherent susceptibility. These investigations are hi-tech and are not available in every center and were hence not performed in our cases. The management in our three patients was modified according to the availability and afford ability of the drugs.
In conclusion, although infrequent, a diagnosis of DVT should be suspected in an appropriate clinical setting. Considering
the paucity of literature in Indian children,
regular reporting from multiple centers, metanalysis of these reports and
establishing a registry at National level may be of great help in formulating diagnostic and management protocol.
Acknowledgements
The authors are grateful to The Medical Director and Chief Executive of K.L.E. Society's Hospital and Medical Research Center, Belgaum and District Surgeon, District Hospital, Belgaum for their help.
