Keywords
anticoagulation - assessment - effectiveness - monitoring - thrombosis - warfarin
Introduction
Thrombophilia describes conditions of the hemostatic processes that tend to predispose
individuals to clotting. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are
common examples and are collectively referred to as venous thromboembolism (VTE).[1]
There are genetic and acquired forms of thrombophilia. The genetic forms are associated
with deficiencies or abnormalities in mechanisms that control clotting, such as mutant
factor V Leiden, protein C and S deficiencies, defective fibrinogen, and prothrombin
allele G20210A mutation.[1]
[2] The acquired forms are associated with conditions that render individuals susceptible
to clotting such as lengthy hospitalization, pregnancy, malignancy, inflammation,
and immobility. Other blood disorders such as myeloproliferative disease and blood
viscosity are now known to cause clotting.[1] Thrombophilia is a major cause of mortality; therefore, early diagnosis and treatment
are vital.
Diagnosis of thrombophilia includes clinical findings and specific laboratory tests.
Laboratory diagnosis includes tests that identify both genetic and acquired forms
of thrombophilia. The major treatment formulae for thrombophilia are anticoagulation
using heparin and/or warfarin. Heparin is given intravenously because it is not absorbed
through the gut, while warfarin is given orally.[3]
[4]
[5]
Warfarin prevents blood clotting by inhibiting vitamin K–dependent coagulation factors
(II, VII, IX, and X).[1]
[6]
[7] However, despite its effectiveness, warfarin has several contraindications. Therefore,
warfarin activity should be carefully monitored to avoid contraindications that may
lead to bleeding or thrombosis. Careful monitoring of warfarin is usually done using
prothrombin time, activated partial thromboplastin time, and international normalized
ratio (INR). Monitoring of warfarin administration ensures that patients are taking
adequate and safe doses of the drug. A high INR predisposes patients to an increased
risk of bleeding, while an INR below therapeutic target indicates that the dose of
warfarin is insufficient to protect against thromboembolic events.[1]
[8]
[9]
The absence of a centralized coagulation clinic in Zimbabwe makes it difficult to
monitor warfarin therapy in patients with thrombophilia. Patients are usually managed
under individual specialized systems. There is also no standardized approach for the
management of warfarin therapy. The increasing burden of thrombophilia now requires
effective systems in place for monitoring warfarin therapy. The study aimed at assessing
the effectiveness and identifying gaps in warfarin monitoring systems in the country.
Materials and Methods
The present study was performed after approval from the local Joint Research Ethics
Committee of the Parirenyatwa Group of Hospitals and University of Zimbabwe College
of Health Sciences (JREC/387/16). Access to patients visiting various outpatient clinics of the Parirenyatwa Group
of Hospitals and laboratory test results was granted by the clinical director and
chief medical laboratory scientist, respectively, and each participant was required
to give a written consent.
The study had a mixture of prospective and retrospective components from a cross-section
of clinical and laboratory datasets. The study focused on outpatients who had been
on warfarin therapy (following an event) for at least 1 year. The inclusion criteria were: patients on warfarin for at least 1 year; over 18 years of age; and a confirmed
diagnosis of thrombophilia. The exclusion criteria were: patients with chronic disorders or malignancies involving the bone marrow as
well as those below the age of 18 years.
Demographic and laboratory data were collected from 47 adult patients on warfarin
who attended various outpatient clinics from January to April 2017. Questionnaires
were administered to assess participants' knowledge of warfarin therapy, as well as
its effects and recommendations on centralized warfarin clinic for ease of monitoring.
Coagulation test results performed by qualified and registered medical laboratory
scientists on the STA-R Max (Stago) analyzer were accessed from the hematology laboratory
information system. Data were captured on the Epi info and Microsoft Excel. Statistical
analysis was done using the Graft Paired Prism software. Responses from participants
were also captured into the Epi info for analysis.
Results
A total of 50 questionnaires were administered to patients on warfarin and 47 participants
fully and legibly answered the questionnaires, giving a return rate of 94%. The demographic
distribution of participants showed that more female (61.7%) participants than males
(38.3%) were on warfarin and that the majority (34%) of them were elderly (>50 years
of age; [Table 1]). The age range of patients on warfarin was 24 to 71 years, with a median of 44
years.
Table 1
Demographic distribution of patients on warfarin therapy
|
Variable
|
Frequency
|
Percentage
|
|
Gender
|
Female
|
29
|
61.70%
|
|
Male
|
18
|
38.30%
|
|
Age (y)
|
20–30
|
8
|
17.02%
|
|
31–40
|
15
|
32.92%
|
|
41–50
|
8
|
17.02%
|
|
>50
|
16
|
34.04%
|
Twenty-nine (61.7%) of the 47 participants on warfarin indicated that they were not
aware of the need for regular check-ups. Eighteen (38.3%) of the 47 had at some point
missed their warfarin medication, while 12 (25.5%) had taken an overdose of warfarin
at some point. Sixteen (34.0%) and 11 (23.4%) admitted taking alcohol and smoking,
respectively.
Assessment of the warfarin administration systems at Parirenyatwa Group of Hospitals
indicated that 35 (74.5%) of the participants were not asked to change their medication
(if they were taking any contraindicated medicines) or their diet, according to the
dictates of warfarin management. These warfarin patients were being managed by physicians
and nurses under different clinics—some as medical patients and others as postsurgical
patients.
Questionnaire responses on appointment frequency indicated that 4 (8.5%), 9 (19.2%),
and 34 (72.3%) had appointments set at once in 3 days, once a week, and once monthly,
respectively. Responses on the effects of warfarin indicated that 24 (51.1%) and 20
(42.6%) had experienced symptoms of clotting (chest pain, shortness of breath, and
painful arms or legs) and unusual bleeding episodes, respectively. Twenty-one (44.7%)
were on other long-term medication besides warfarin.
DVT was the most common clinical indication for warfarin administration in all age
groups, peaking in young adults (31–40-year-olds) and the elderly. Although PE and
VTE were the most common conditions in all age groups, they were found to be highest
in young adults. Atrial fibrillation was only found in the elderly age group ([Fig. 1]). There were statistically significant differences (p < 0.001) between patients' INR results for the three groups when divided into monthly
intervals; one-month intervals from the initiation of warfarin therapy demonstrated
a steady decline ([Fig. 2]) indicating stabilization of the INR due to warfarin therapy.
Fig. 1 Distribution of warfarin indications by age groups of patients.
Fig. 2 Effects of warfarin on INR results on three 1-month intervals.
Discussion
The present study was performed over 4 months across different outpatient clinics
where 50 questionnaires were administered and 47 responses were received. The responses
to the administered questionnaires were good (94%), considering the duration over
which the study was performed. This could be attributed to the country's high literacy
rate.
There were more female participants than males, which could be a reflection of the
country's demographic distribution as revealed by the last census figures. Other studies
have shown a higher risk of VTE in women of childbearing ages. The increasing use
of oral contraceptives also puts women at higher risk of thrombophilia than men.[1]
[10] Although the elderly formed the majority of patients on warfarin, a combined figure
of all the younger patients (under 40 years) was highest. It can also be argued that
age tends to limit mobility in the elderly, thereby putting them at higher risk of
thrombophilia.[11]
Questionnaire responses revealed that the majority (61.7%) of those on warfarin indicated
that they were not aware of the need for regular check-ups, with 38% of the participants
having missed their warfarin medication at least once and 25% taking warfarin overdose.
These are some of the challenges contributing to the lack of adherence to medications.
Due to these circumstances, warfarin monitoring and disease management in Zimbabwe
becomes a big challenge.[12]
[13]
Thirty-four percent of the participants admitted to taking alcohol while 23.4% indicated
that they did not quit smoking after commencing warfarin therapy. Alcohol intake and
smoking are known to increase and inhibit the effects of warfarin, respectively. While
alcohol intake is linked to increased warfarin metabolism, smoking is known to be
associated with increased warfarin dosage requirements.[1]
[8]
[14] Therefore, patients who admitted to indulging in these habits were increasing their
risk of bleeding or thrombosis, respectively.
An assessment of the effectiveness of warfarin administration showed that a high number
of patients were neither monitored for any concomitant contraindicated drugs nor advised
on proper noncontraindicated diet. For example, foods with high vitamin K content
(such as the Zimbabwean green vegetables: bowora, tsunga, and spinach) are known to reverse the effects of warfarin. Therefore, monitoring
of warfarin treatment and maintaining the recommended diet are paramount in the effective
drug action. Most of the patients on warfarin had monthly appointment dates, although
it is recommended that patients on warfarin should be observed by their doctor or
nurse after every 3 days following a 10-mg daily dose unless they are computer managed.[15]
DVT was the main indication for warfarin therapy of all thrombophilia events, with
highest prevalence among young adults and the elderly. The risk of venous thrombosis
(comprising DVT) is known to increase sharply above the age of 45. This could explain
why the majority of patients in the present study were in this age group. The major
outcomes of venous thrombosis are death, postthrombotic syndrome, and excessive bleeding.[16] Therefore, it is particularly important to monitor warfarin therapy to avoid these
outcomes.
[Fig. 2] shows the general trend of participants' first 3 monthly consecutive INR values.
These results were used as a tool to assess the effects of warfarin currently being
prescribed at Parirenyatwa Group of Hospitals via the use of patients' INRs. The results
showed a significant relationship among the differences of all the three classes,
namely INR1 (first visit), INR2 (second visit), and INR3 (third visit). There was
a statistically significant difference between INR1 and INR2 with a p-value < 0.0001, and similarly there was also a statistically significant difference
between INR2 and INR3 (p < 0.001). This is a good indication as the median INR pattern generally decreases
as treatment moved from INR1 to INR3 eventually falling into therapeutic range, with
targets of 2.5 (2–3 target range). This shows a glimpse of hope that despite all the
negative pointers to the system, the warfarin is benefiting some of the patients.
Conclusion
It can be concluded that patients who followed their treatment schedules for warfarin
responded to the study very well. More females were on warfarin therapy than males.
Most patients did not know about the benefits of regular check-ups, with some even
missing their appointments or prescribed medications, or taking overdose. The monitoring
system of patients on warfarin therapy appeared to be inadequate, which calls for
a review of the current practice and need for a centralized system. However, the INR
results showed that, if effectively monitored, warfarin therapy can be beneficial
to thrombophilic patients if successfully managed.
Limitations
This study was limited by the small number of patients who volunteered to take part
as well as the short duration of 4 months, which was just one season.
Recommendations
-
A follow-up study should be conducted using larger sample size and a longer period,
taking into consideration seasonal variations in thrombophilia diseases.
-
It is strongly recommended that stand-alone facility to deal with thrombophilia challenges
in Zimbabwe be established.
-
A national standard model of care for warfarin therapy services should be agreed upon.
This will handle all challenges and requirements for optimal anticoagulation therapy
in general and warfarin specifically.
-
Patient education and information sheets for the patients and their physicians would
need to be prepared and made available.
