A retrospective
clinicopathological study of inherited bleeding disorders in a tertiary care
centre of Uttar Pradesh
Deepa Rani1,
Pawan Pandey2, Anu Singh3*, Sandip Kumar4
1Associate Professor, Department of Pathology, IMS BHU, Varanasi India.
2Technical Assistant, Hematology Section, Department of Pathology, IMS
BHU, Varanasi India.
3Assistant Professor, Department of Pathology, IMS BHU Varanasi India.
4Professor & Head, Department of Pathology, IMS BHU, Varanasi India.
*Corresponding Author E-mail: anusinghbangalore@gmail.com
ABSTRACT:
BACKGROUND:
Inherited Bleeding Disorders (IBD) include various
disease that reflect abnormalities of primary and secondary hemostasis. The
pathophysiology of these disorders can be explained on the basis of vessel wall
abnormalities, platelet disorders and coagulation factor defects. To further
elaborate and enhance our understanding on these disorders, a 6-year
retrospective study (2014-2020) was conducted on the patients referred to
the coagulation section of the Hematology Department (Department of Pathology,
IMS BHU). These included the ones who had suffered from bleeding tendencies at
one or more sites with other relevant clinical history. AIM: - The
objective of this study was to assess the prevalence, clinical spectrum, and
haematological profile of inherited bleeding disorder among patients of Eastern
UP and Bihar. It also focussed on various epidemiological factors including
age, sex, family inheritance and consanguinity. MATERIALS AND METHODS: Three
hundred and two patients matched our criteria. The age of these patients ranged
from neonate to 50. A detailed relevant clinical history was taken for all the
patients. These categories of patients were screened with routine tests like
platelet count, Prothrombin Time (PT), Active Partial Thromboplastin Time
(APTT), Breathing Time (BT), Clotting Time (CT) and a Complete Blood Cell Count
(CBC). A factor assay was performed if indicated by the results of the
screening assays. RESULTS: Out of 302 patients, 280patients (92.70%) were
diagnosed with factor VIII deficiency. This category further comprised
of 63.57% Hemophilia A cases (n=192), and 12.58%hemophilia B cases
(n=38). Another cluster of 16.55% were diagnosed as Von Willebrand Disease
(n=50). Also, a subset of the total patient population (7.30%) was diagnosed
with an entity called Rare Inherited Coagulation Deficiency (RICD) which was
further designated on the basis of specific factor assays. Most common clinical
feature encountered was hematoma followed by ecchymosis, hemarthrosis, gum
bleeding and epistaxis. CONCLUSION: The most common IBD was Hemophilia A
in this subcategory of patients. Children under 5 year age were most affected making it the most
vulnerable age group amounting to 38.73% of all recorded cases. Male population
was more affected forming majority of the patients. Sporadic cases were more
common than the inherited ones.
KEYWORDS: Bleeding
disorders, Factor assays, Inherited, RICD.
INTRODUCTION:
Inherited
bleeding disorder (IBD) includes various disease that
reflect abnormalities of primary and secondary hemostasis. The pathophysiology
of these disorders can be explained on the basis of vessel wall abnormalities,
platelet disorders and coagulation factor defects. Disorders of primary
hemostasis include vessel wall aberrations and platelet disorders (Qualitative
and Quantitative). However, secondary hemostasis defects are associated with
coagulation factor disarrays. The most common inherited bleeding disorders are
Hemophilia A and B, which are relatively rare among other haematological
abnormalities.1 In our study, we elaborated
a new entity termed as RICD. To understand any pathology, first we need to know
the normal physiology. After any trauma or injury to blood vessel, there is a
spontaneous arrest of bleeding from the severed vessel by the process of
hemostasis. The basic mechanisms are vascular constriction, formation of a
platelet plug followed by clot formation produced by the constituents of blood
at the site of injury. This hemostatic plug is formed within few minutes of
trauma involving activation of the blood coagulation cascade.2,3 The final step is fibrous organization and clot
retraction.
Any
defect in the above mechanisms explained can lead to life-long bleeding
disorders [4]. An elaborate clinical history of patient is required including
duration, site and severity of previous episodes of bleeding. Also,
requirements for blood transfusion, nature of the injury, reaction of
hemostatic factors on exposure to previous haemostatic challenges (such as
surgery, tooth extraction, childbirth) and presence of a family history if any
is noted. Any drug history or nutritional deficiency should be excluded. A
basic initial workup includes a complete blood count (CBC) with peripheral
blood smear review, BT, CT, platelet count, prothrombin time (PT)/international
normalised ratio (INR) and partial thromboplastin time (PTT), According to
these findings, further investigations are warranted. In many cases, however,
the routine use of a small battery of screening tests has merit because it
usually saves time, and the results direct the course of further study.4
MATERIALS AND
METHODS:
The study included
patients with history of bleeding tendencies referred to the coagulation
section of the Hematology Department (Department of Pathology, IMS BHU) from
2014 to 2020. An elaborate history of bleeding episodes including duration,
site and severity was taken. Also, requirements for blood transfusion, nature
of the injury, reactionof hemostatic factors on
exposure to previous haemostatic challenges (such as surgery, tooth extraction,
childbirth) was covered. Further, consanguinity, drug intake and family history
of bleeding disorder were noted. Individuals who had a past history of intake
of any drugs affecting platelet function in the previous four weeks were
excluded from the study. None of these patients showed signs of acute Leukemia,
Uraemia, Myelodysplastic syndrome, Myeloproliferative disorders,
Dysproteinaemias, Cardiopulmonary bypass or any other secondary systemic
disorders. A basic initial workup was done including complete blood count (CBC)
with peripheral blood smear review, BT, CT, platelet count, prothrombin time
(PT)/international normalised ratio (INR) and partial thromboplastin time
(PTT), Based on the above derangements, individual coagulation factor assays
were performed. All the tests of hemostasis were performed within 4 hours of
blood collection. 2ml of venous blood was collected in EDTA vial for CBC tests
and platelet counts. A peripheral blood smear was prepared from direct finger
prick. After Leishman staining, slide was observed for any morphological
abnormalities in platelets. For performing coagulation tests, Blood was
collected in 3.2% sodium citrate vacutainer (blue cap) vial. One part of 3.2%
sodium citrate buffer and nine parts of blood was taken (i.e. 0.1ml of
anticoagulant for a 0.9ml specimen). Bleeding time (BT) was performed by Ivy’s
modified template method, Additional tests performed were clot solubility test,
PF3 availability and platelet aggregation tests. For performing platelet
studies, platelet rich plasma was prepared and coagulation studies were done on
platelet poor plasma. Platelet-rich plasma was prepared by 600 rpm for 3
minutes while platelet-poor plasma was prepared by 2,500 rpm for 10 minutes for
the coagulation profile Platelet aggregation test with adenosine diphosphate
(ADP) and adrenaline was done to detect platelet function defects. Both
semi-automated and fully automated Stago equipment and reagents were used for
factor assays. Correction experiment was also performed to know the specific
factor deficiency or inhibitors present, with normal plasma, normal-aged serum,
and Al(OH)3 adsorbed plasma. On the basis of these
assay, specific factor assay was performed further. If all the coagulation
tests were normal, then factor XIII assay (urea solubility test) was performed.
Test for vWD detected Von Willebrand factor antigen (vWFAg) by enzyme-linked
immunosorbent assay (Diagnostica Stago, France),.
OBSERVATION AND
RESULTS:
Table 1: Prevalence
(%) of inherited bleeding disorder in the present study (n=302)
|
Diagnosis |
Frequency |
Percent |
|
Hemophilia –A |
192 |
63.57 |
|
Hemophilia –B |
38 |
12.58 |
|
Vonwillebrand |
50 |
16.55 |
|
Platelet Disorder |
13 |
4.30 |
|
Factor XIII |
6 |
1.98 |
|
Factor X |
2 |
0.66 |
|
Factor VII |
1 |
0.33 |
|
Total |
302 |
100.00 |
Table 2: Severity
|
Severity |
Frequency |
Percent |
|
Severe |
191 |
63.24 |
|
Moderate |
55 |
18.21 |
|
Mild |
56 |
18.54 |
|
Total |
302 |
100.00 |
Table 3: Age
distribution
|
Age |
Frequency |
Percent |
|
<1 |
25 |
8.27 |
|
1-5 |
92 |
30.46 |
|
6-10 |
47 |
15.56 |
|
11-20 |
92 |
30.46 |
|
21-30 |
27 |
8.94 |
|
>31 |
19 |
6.29 |
|
Total |
302 |
100.00 |
Table 4: Sex
distribution
|
SEX |
Frequency |
Percent |
|
Male |
253 |
83.77 |
|
Female |
49 |
16.22 |
|
Total |
302 |
100.00 |
Table 5: Inheritance
|
FAMILY HISTORY |
Frequency |
Percent |
|
Present |
122 |
40.39 |
|
Absent |
180 |
59.60 |
|
Total |
302 |
100.00 |
Table 6:
Consanguinity
|
Consanguinous |
Frequency |
Percent |
|
Present |
22 |
7.28 |
|
Absent |
280 |
92.71 |
|
Total |
302 |
100.00 |
Table 8: District
via distribution of inherited bleeding disorder
|
District |
Frequency |
Percent |
|
Allahabad |
5 |
1.65 |
|
Azamgarh |
23 |
7.61 |
|
Ballia |
23 |
7.61 |
|
Basti |
6 |
1.98 |
|
Bhadohi |
20 |
6.62 |
|
Chandauli |
22 |
7.28 |
|
Deoria |
13 |
4.30 |
|
Ghazipur |
19 |
6.29 |
|
Gorakhpur |
2 |
0.66 |
|
Jaunpur |
30 |
9.93 |
|
Kaushambi |
1 |
0.33 |
|
Kushinagar |
12 |
3.97 |
|
Maharajgunj |
12 |
3.97 |
|
Mau |
34 |
11.25 |
|
Mirzapur |
21 |
6.95 |
|
Sonbhadra |
14 |
4.63 |
|
Sultanpur |
3 |
0.99 |
|
Varanasi |
42 |
13.90 |
|
Total |
302 |
100.00 |
Varanasi
13.90%, Mau 11.25%, Jaunpur 9.93%, being higher prevalence area while
Gorakhpur, Kaushambi, Sultanpurstaying<1%.
Table 7: Clinical
Presentation
|
Clinical Presentation |
Present |
Absent |
||
|
No. |
% |
No. |
% |
|
|
Umblical cord bleeding |
6 |
1.98 |
296 |
98.01 |
|
Purpura |
11 |
3.64 |
291 |
96.35 |
|
Epistaxis |
75 |
24.83 |
227 |
75.16 |
|
Petechiae |
23 |
7.61 |
279 |
92.38 |
|
Ecchymosis |
158 |
52.31 |
144 |
47.68 |
|
Epistaxis |
75 |
24.83 |
227 |
75.16 |
|
Malena |
33 |
10.92 |
269 |
89.07 |
|
Hematemesis |
8 |
2.64 |
294 |
97.35 |
|
Hematuria |
22 |
7.28 |
280 |
92.71 |
|
Hemarthrosis |
158 |
52.31 |
144 |
47.68 |
|
Haematoma |
201 |
66.55 |
101 |
33.44 |
|
Menorrhagia |
31 |
10.26 |
271 |
89.73 |
|
Gum Bleeding |
78 |
25.82 |
224 |
74.17 |
RESULTS:
On the basis of clinical history and screening
parameters, three hundred and two individual patients were entitled for the
study. After detailed analysis, these patients were labelled under the broad
spectrum of inherited bleeding disorders. As mentioned in Table 1, Out of 302
patients, 280patients (92.70%) were diagnosed with factor VIII deficiency.
These category further comprised of 63.57% Hemophilia A cases
(n=192), and 12.58% Hemophilia B cases (n=38). Another cluster of 16.55%
were diagnosed as vWD (n=50). A subset of the total patient population (7.30%)
were diagnosed with an entity called Rare Inherited Coagulation Deficiency
(RICD). Among these, Platelet function disorders was found in 13 individuals
amounting for 4.30% of the total percentage, Factor XIII deficiency was in 6
(1.98%), Factor X deficiency in 2 (0.66%) and Factor VII deficiency in 1
(0.33%). The proportion of Hemophilia A: B was 5:1. Majority of the cases
showed severe signs and symptoms (63.24%) of all the cases (Table 2). Delayed
presentation and diagnosis was a common feature. Children under 5 year age were
most affected making it the most vulnerable age group amounting to 38.73% of
all recorded cases (Table 3). After analysing sex incidence, it was observed
that males had higher frequency of coagulation factor defects than females,
frequency being 83.77 percent (Table 4). 40.39% of patients had family
history of bleeding manifestations.(Table 5). As mentioned in Table 6,
consanguinity was present in minor percentage (7.28%) The most common
presenting feature was hematoma (66.55%) followed by ecchymosis (52.31%)
and hemarthrosis (52.31%) jointly (Table 7). Hallmark feature of umbilical cord
bleeding was reported in patients with factor XIII deficiency (1.98%). (Table 7).
We also tabulated (Table 8) district wise distribution of inherited bleeding
disorders by analysing individual records of each patient. However, this
interpretation was biased due to lack of awareness and accessibility among
patients and ignorance of health services in few districts.
DISCUSSION:
In the current study, Hemophilia was most
prevalent bleeding disorder followed by vWD. Incidence of Hemophilia A is
approximately 1 in 10000 people and it is five times more common than
Hemophilia B. [4] Similar findings were noted in our study. HA and
HB are X linked diseases and genes for HA is located in the tip of the long arm
of X chromosomes in band Xq28 and for HB in band Xq27. Majority of severe HA
have large deletions or inversions (intron 22, intron 1) leading to major
defects of factor VIII.4 Factor VIII (hemophilia A), Factor IX (hemophilia B), and von
Willebrand's factor deficiency are the most common inherited coagulation
defects. Both hemophilia A (HA) and hemophilia B (HB) show X-linked recessive
inheritance. Factor XI deficiency also called hemophilia C is rarer, milder,
and autosomally inherited.5 In about 59.60% of the total 302
patients in the current study, there was no family history, could have been due
to spontaneous mutations or transfers by mildly affected or carrier parents who
were asymptomatic and undiagnosed.The current study data suggests the scattered
nature of disease as a result of spontaneous genetic mutation. Nearly 2/3rd of
all Hemophilia who underwent factor assay had acute disease suggestive of
prevalence of severe Hemophilia in the North Indian population, although
referral bias due to past presentation of severe cases to health care facility
could be another possible ground. Few studies have been carried out in India to
show the prevalence of bleeding disorders associated with factor deficiencies
and their clinical manifestations.6-11 this particular study was
carried out to help best define the frequency of these bleeding disorders in
this area of the world. Similar to available literature from Indian
subcontinent 6-10 as well as Middle East Asia11 and
Pakistan12,13, our study showed Hemophilia A to be the commonest
bleeding disorder. A large number of patients in our country with inherited
bleeding disorders remain undiagnosed because of the limitation of coagulation
laboratories and lack of awareness among health care professionals and family
members. Henceforth, the figures presented in this study do not reflect the
actual burden of the bleeding disorders in our community. 14
In current study, the incidence of PFD and vWD
was found to be around 4.30% and 16.55% respectively as compared to the
previous studies which reported incidence of PFD and vWD from 12.8 to 39.4% 8,
13 and 6.5 to 20% 11, 15 respectively. Also, a recent study
[16] showed incidence as 7.5% and 4.4% respectively. Plausible
explanation for dipping incidence could be that PFD and vWD are autosomal
disorders and have been caught to have higher incidence in communities where
consanguinity is customary. The consanguinity in our evaluated population was
low (7.28%) in contrast to national level study which was (10.6%)17.
Common sites of bleeding were mucocutaneous and hemathrosis. The low numbers of
patients getting replacement treatment is because of underreporting and may not
be the real depiction of the consumption of health resources at our institute
and as well of the resources used by the bleeding diathesis patients in their
life time, as most of these patients were advised to be followed up at local
public health centres for minor bleeds and replacement therapy. Therapy with
fresh frozen plasma is the most frequently used therapy modality with factor
replacement therapy used only in a smaller fraction. Majority of the patients
were lost to follow up after first visit.
CONCLUSION:
In our findings, prevalence of inherited
bleeding disorder were as follows, 63.57% through Hemophilia A , 12.58% via
Hemophilia B, Factor XIII deficiency 1.98%, Factor X deficiency 0.66% and a
single case of factor VII deficiency 0.33%. vWD was present in 16.55% of all
cases while Platelet function disease was spotted in 4.30% cases. Most of the
recorded cases in the study resulted due to sporadic mutations. Children under
5 years of age were most affected making it the most vulnerable age group
amounting to 38.73% of all recorded cases. There is a need to keep a check on
bleeding manifestations in childhood and should be attended carefully on time.
Connection between an individual and its family member is rare and happens only
in emergencies due to migration for work. Due to less number of coagulation
laboratories and lack of knowledge among healthcare practitioners and family
members, a substantial number of patients with inherited bleeding disorders go
undetected and thus the data presented in this study do not represent the
actual burden of the disease condition in our state. These patients receive
diagnostic and therapeutic care through NGOs and get very little assistance
from the establishment. The administration should ensure adequate
infrastructure for detection as well as funding for the treatment and
management of these patients so that more and more patients across the state
live well.
CONFLICTS OF INTEREST:
There are no conflicts of interest.
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Received on 09.07.2022
Modified on 19.08.2022
Accepted on 13.09.2022
© RJPT All right reserved
Research J. Pharm. and Tech 2022; 15(10):4772-4776.
DOI: 10.52711/0974-360X.2022.00801