1
A PROSPECTIVE OBSERVATIONAL STUDY ON
ABNORMAL UTERINE BLEEDING IN WOMEN
WITH BLEEDING DISORDERS
Registration number 221716401
A dissertation submitted to Tamil Nadu
DR.M.G.R Medical university, Chennai, in partial
fulfillment of the rules and regulations for the degree
M.S. in Obstetrics and Gynaecology, to be held in May 2020
2
CERTIFICATE
This is to certify that the dissertation “A study on abnormal uterine bleeding in
women with bleeding disorders” is a bonafide work of Dr. Eunice Susanna Abraham that
was carried out under my guidance and supervision for the M.S. (Obstetrics and
Gynaecology) examination of the Tamil Nadu DR.M.G.R. Medical university, to be held
in May 2020.
Dr. Jessie Lionel
Professor of Obstetrics and Gynaecology –Unit I
Christian Medical College & Hospital,
Vellore-632004.
3
CERTIFICATE
This is to certify that the dissertation “A study on abnormal uterine bleeding in
women with bleeding disorders” is a bonafide work of Dr. Eunice Susanna Abraham
that was carried out under my guidance and supervision for the M.S. (Obstetrics and
Gynaecology) examination of the Tamil Nadu DR.M.G.R. Medical university, to be held
in May 2020.
Dr. Jiji Elizabeth Matthews
Professor and Head, Department of Obstetrics and Gynaecology
Christian Medical College & Hospital,
Vellore-632004. Tamil Nadu.
4
CERTIFICATE
This is to certify that the dissertation “A study on abnormal uterine bleeding in
women with bleeding disorders” is a bonafide work of Dr. Eunice Susanna Abraham
that was carried out under my guidance and supervision for the M.S. (Obstetrics and
Gynaecology) examination of the Tamil Nadu DR.M.G.R. Medical university, to be held
in May 2020.
Dr.Anna Pulimood
The Principal
Christian Medical College & Hospital
Vellore-632004, Tamil Nadu.
5
DECLARATION
I hereby declare that this dissertation titled “A study on abnormal uterine bleeding
in women with bleeding disorders” is carried out by me under the guidance and supervision
of Dr.Jessie Lionel, Professor of Obstetrics and Gynaecology Unit-I, Christian Medical
College, Vellore. This dissertation is submitted in partial fulfillment of the requirements
for the degree of M.S in Obstetrics and Gynaecology examination of the Tamil Nadu
Dr.M.G.R. Medical University to be held in May 2020.
Dr.Eunice Susanna Abraham
Registration number-221716401
PG Registrar,
Department of Obstetrics and Gynaecology
Christian Medical College,
Vellore- 632004
Tamil Nadu, India.
6
PLAGIARISM CERTIFICATE
This is to certify that this dissertation work titled “Study on Abnormal uterine bleeding in
women with bleeding disorders” of the candidate Dr. Eunice Susanna Abraham, with
registration number 221716401 for the award of MS Obstetrics and Gynaecology. I
personally verified the www.urkund.com website for the purpose of plagiarism check. I
7
found that the uploaded thesis file contains from introduction to conclusion pages and the
results show 3% of plagiarism in the dissertation.
Dr. Jessie Lionel
Professor
Department of Obstetrics and Gynaecology
Christian Medical College, Vellore- 632004
8
ACKNOWLEGMENTS
Throughout the writing of this dissertation I have received a great deal of support
and assistance. I would like to express my sincere gratitude to my guide, Dr. Jessie Lionel,
Professor of Obstetrics and Gynaecology-Unit I, Christian Medical College and Hospital,
whose expertise was invaluable in the formulating of this research topic and methodology
in particular. I would also like to thank her, for her valuable help, guidance and support in
this endeavor.
I would like to thank my co guides Dr. Alok Srivastava, Professor of Hematology,
Dr. Fouzia NA, Associate professor of haematology, Dr.Beena, Associate Professor of
Obstetrics and Gynaecology, Dr.Tulasi Geevar, Assistant professor of transfusion
medicine for their valuable advice.
My heartfelt gratitude to Mrs. Grace Rebecca, Department of Bio -statistics, Mr.
Madhan, from department of CEU, Mr.Abraham from the department of haematology for
their help and assistance.
I thank my husband Dr. Judson and my parents for their support and sympathetic
ear. Above all I would like to thank Lord Jesus for His strength throughout this endeavor
and for helping me to complete this project with success.
9
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL LETTER
10
11
12
1
TABLE OF CONTENTS
1) Introduction 6
2) Aim and objectives 8
3) Review of literature 9
4) Materials and methodology 40
5) Results 46
6) Discussion 80
7) Limitations 88
8) Conclusions 89
9) Bibliography 90
10) Annexures 97
2
INDEX OF TABLES
Table 1. 1- Bleeding patterns 18
Table 1. 2-Classification of bleeding disorders. 19
Table 1. 3-Treatment of AUB in women with bleeding disorders 35
Table 2. 1- Age distribution of patients 46
Table 2. 2-Haematological diagnosis 47
Table 2. 3-Distribution of haematological disease among women requiring hospital
admission 53
Table 2. 4-Distribution of haematological diagnosis and infertility 55
Table 2. 5-Quality of life at class,work and social life 57
Table 2. 6-Number of patients who used second line managment 64
3
INDEX OF FIGURES
Figure 1. 1-PALM COEIN FIGO classification for AUB 10
Figure 1. 2-Extrinsic and intrinsic pathway 13
Figure 1 .3-Pictorial blood loss assessment chart 41
Figure 1 .4 Symptoms at diagnosis 49
Figure 1. 5-Menstrual bleeding patterns 50
Figure 1. 6-Haematological diagnosis and HMB 51
Figure 1. 7-Percentage of patients who required hospital admission and blood 52
Figure 1. 8-Infertility among women with bleeding disorders 54
Figure 1. 9-Number of women with APH and PPH 56
Figure 1. 10 -Percentage of women who have taken treatment for HMB 58
Figure 1. 11-Distribution of first line medication 59
Figure 1. 12-Percentage of relief of symptoms with OCP’s and progesterone only pills 60
Figure 1. 13-Number of patients who used OCP’s and progesterone only pills 61
Figure 1 .14-Number of patients who used DMPA and tranemexic acid
62
Figure 1 .15-number of women on treatment referred to Gynaecology OPD 63
Figure 1. 16-Number of patients referred to Gynaecology OPD 65
Figure 1 .17-Number of ITP patients with HMB and prolonged cycles with HMB 66
Figure 1 .18-Quality of life in women with ITP 67
Figure 1 .19-Number of patients with HMB and prolonged cycle with HMB among
women with vWD 69
Figure 1 .20-Number of patients who required hospital admissons and blood transfusion
70
Figure 1 .21-Quality of life among women with vWd 71
Figure 1 .22-Treatments used for patients with vWD 72
4
Figure 1 .23-Number of patients who required hospital admissions and blood transfusion
for HMB among patients with factor deficiencies. 73
Figure 1 .24-Percentage of women with miscarriage and infertility among those with
factor deficienies 74
Figure 1 .25-Number Of women with APH and PPH among those with factor
deficiencies 75
Figure 1 .26-Quality of life among women with factor deficiencies 76
Figure 1 .27-Treatments taken by women with factor deficiencies 77
Figure 1 .28-Hospital admission and blood transfusion for HMB among women with
factor deficiencies. 78
Figure 1 .29-Treatments given for women with qualitative platelet dysfunction 79
5
ABBREVIATIONS
AUB -Abnormal uterine bleeding
FIGO -International Federation of Gynaecology and Obstetrics
HMB -Heavy menstrual bleeding
ITP-Immune thrombocytopenic purpurae
APTT -Activated partial thromboplastin time
ASH -American society of Haematology
IVIg - Intravenous Immunoglobulin
COC’s -Combined oral contraceptives
OCP’s - Oral contraceptive pills
PPH -Post partum haemorrhage
APH -Antepartum Haemorrhage
DMPA -Depot medroxy progesterone acetate
6
INTRODUCTION
The haemostatic system plays an important role in regulating the amount and the
duration of menstrual bleeding. It is reported that the prevalence of bleeding disorders
among women with heavy menstrual bleeding is 10%-20%(1).Some of the common
bleeding disorders which are associated with abnormal uterine bleeding include
quantitative platelet disorders like immune thrombocytopenia, factor deficiencies,
vonWillebrands disease.
Prolonged or profuse bleeding tend to occur in a large number of women affected
by bleeding disorders. Severe acute bleeding, heavy menstrual bleeding at menarche and
chronic heavy menstrual bleeding during the entire reproductive life are usually seen in
these women with inherited bleeding disorders and women with platelet dysfunction.
The first line management for abnormal uterine bleeding in women with bleeding
disorders includes medical managements with antifibrinolytics like tranemexic acid,
hormonal medications like oral contraceptive pills, progesterone only pills, depot medroxy
progesterone acetate. Second line managments include levonorgesterol intrauterine device,
danazol.
7
Abnormal uterine bleeding affects about 30% of women in reproductive age
group.(2).Studies have shown that 20% of women in UK and 30% in the USA, have
hysterectomy before the age of 60years and heavy menstrual bleeding was the chief
compliant in many of these women.(3) In approximately 50% of these women no organic
cause was determined.(2)
While studies in western countries have showed that von Willebrands disease to be
the most common inherited bleeding disorder, data regarding the Indian population is
sparse.
Erratic medical management and inappropriate use of first line medications for
abnormal uterine bleeding (AUB) in women with bleeding disorders has led to
unnecessary surgical interventions including hysterectomy in younger age groups.
Women with bleeding disorders should embark on pregnancy with
multidisciplinary support of combined specialty clinics along with prenatal diagnosis,
which is an important aspect of pregnancy care as pregnancy in these women is at high
risk with complications of antepartum haemorrhage, post-partum haemorrhage.
8
AIM AND OBJECTIVES
AIM
To define the current practice and management for abnormal uterine bleeding in
women with bleeding disorders.
OBJECTIVES
1. To study the menstrual patterns in women with bleeding disorders
2. To study the reproductive outcome and quality of life in women with bleeding
disorders
3. To assess the treatment modalities used for HMB in women with bleeding
disorders.
9
REVIEW OF LITERATURE
The international Federation of Gynaecology and Obstertrics (FIGO) classified
AUB into structural and non-structural causes.The acronym PALM-COEIN is used with
the PALM group including the structural entities which can be diagnosed by imaging and
or histopatology and the COEIN group consists of entities that cannot be defined by
imaging or histopathology.
The acronym PALM COEIN stands for: Polyp; Adenomyosis; Leiomyoma;
Malignancy and Hyperplasia; Coagulopathy; Ovulatory dysfunction; Endometrial;
Iatrogenic; and Not yet classified.
10
Figure 1. 1-PALM COEIN FIGO classification for AUB
When a patient presents with heavy menstrual bleeding, a detailed history should
be taken and examination should be done. Structural causes for AUB have to be considered
first like polyp, adenomyosis and leiomyoma. About 30-50% of women in perimenopausal
age have leiomyomas. After looking for structural causes, pathology related to the
hypothalamic-pituitary ovarian axis has to ruled out. Then the possibility of coagulation
disorders has to be considered. In the adolescent age group possibility of coagulation
disorders like factor deficiencies have to be kept in mind and in the older age group the
possibility of quantitative platelet disorders.
11
A detailed history and examination would help one to consider systemic
coagulopathy related disorders .The haemostatic process can be divided into three
phases.(4)
1. Formation of the platelet plug (primary hemostasis),
2. Stabilization of the platelet plug through, fibrin deposition (secondary hemostasis)
3. Orderly dissolution of the blood clot (fibrinolysis)
Defects in primary hemostatic process usually presents as mucocutaneous bleeding
such as epistaxis, gingival bleeding or heavy menstrual bleeding. The bleeding time is
characteristically prolonged in these patients.
Abnormalities in secondary hemostasis leads to bleeding into soft tissues such as
muscles and joints. In the context of surgery, defective primary hemostasis causes
excessive bleeding that is often evident intraoperatively to the surgeon. In contrast to the
above, defects in the coagulation cascade, results in abnormal bleeding starting several
hours after surgery. The activation of coagulation cascade leads to stabilization of the
primary platelet plug.
Similarly, disorders of the fibrinolytic system result in delayed-onset bleeding that
may first become evident one or more days after surgery.
12
PRIMARY HAEMOSTASIS AND AUB
Abnormalities of primary hemostasis results from quantitative platelet
abnormalities, from defects in von Willebrand factor (vWF), or from abnormal blood
vessel wall components. Uterine hemostasis that happens during menstruation involves the
formation of a platelet plug and this is a critical step in the regulation of blood flow.(5)
It is also noted that at menarche the menstrual bleeding is very severe.(6)
Historically the first patient diagnosed with von Willlebrand disease by Dr. Erik von
Willebrand in 1926 had eventually died of uncontrollable heavy menstrual bleeding at age
13 years.
13
DISORDERS OF SECONDARY HAEMOSTASIS AND AUB
Secondary haemostasis involves the extrinsic and intrinsic pathways of coagulation.
Figure 1. 2-Extrinsic and intrinsic pathway
14
The coagulation cascade on activation leads to stabilization of the primary platelet
plug. In general it is known that coagulation factor deficiencies lead to bleeding in soft
tissues and joints .It has been reported that factor deficiencies VIII, XIII are associated
with heavy menstrual bleeding and postpartum haemorrhage(7).Heavy menstrual bleeding
has also been documented in patients receiving oral anticoagulant therapy.(8)
DISORDERS OF FIBRINOLYSIS AND AUB
The fibrinolytic system consists of plasminogen, which is converted to the
enzymatically active plasmin and regulatory proteins. The main physiologic activator of
plasminogen is tissue plasminogen activator. Plasminogen Activator inhibitor -1(PAI-1)
and alpha 2 antiplasmin play an important role in down regulation of fibrinolytic activity.
Recent studies has shown that there is relationship between locally enhanced fibrinolysis
and heavy menstrual bleeding(9)
15
DEFINITIONS
Disturbance of the normal menstrual cycle can present in different ways.
Abnormal uterine bleeding (AUB)
AUB is a terminology used to describe any departure from normal menstruation or
normal menstrual pattern. Key characteristics include
1. Regularity
2. Frequency
3. Amount / Quantity of flow
4. Duration of flow.
DISTURBANCE OF REGULARITY
Regular cycles are defined as cycles in which the shortest to longest variation is of
7-9 days depending on the age based on the revisied FIGO AUB system.(10) (18–25 years
≤9 days; 26–41 years ≤7 days; 42–45 years ≤9 days) Amenorrhea is defined as no bleeding
in a 90 day period according to the FIGO Recommendations on terminology published in
2011.(11)
16
FREQUENCY
• Infrequent menstrual bleeding is defined as one or two episodes of bleeding in a
90 day reference period.(11)
• Frequent menstrual bleeding is more than four episodes of bleeding in a 90 day
reference period.(11)
QUANTITY/AMOUNT OF FLOW
Heavy menstrual bleeding
The National Institute of Health and Clinical Excellence of the United Kingdom
defines heavy menstrual bleeding as excessive menstrual blood loss which interferes with
the woman’s physical, emotional,social and material quality of life, and which can occur
alone or in combination with other symptoms.(12)
Light menstrual bleeding
This is usually identified based on patient’s complaint of having less amount of
bleeding in terms of number of pads a day, duration of bleeding and is rarely related to
any pathology.(11). These patients have bleeding for less than 2 days during their cycles.
17
DURATION OF FLOW
Prolonged menstrual bleeding-This terminology is recommended to be used when
menstrual bleeding exceeds 8 days in duration on a regular basis(11)
Shortened menstrual bleeding is defined as bleeding lesser than 2 days in duration
and usually will be light in volume. Patients with intrauterine adhesions and endometrial
tuberculosis can present with shortened menstrual bleeding.(11)
Intermenstrual bleeding-defined as irregular episodes of bleeding, usually of short
duration and light in volume, occurring between normal menstrual periods.(11)
Acute AUB is defined as an episode of bleeding in a woman of reproductive age
that is of sufficient quantity requiring immediate intervention to prevent further menstrual
blood loss.(13)
18
CHRONIC ABNORMAL UTERINE BLEEDING
Menstrual bleeding that is abnormal in duration, volume and or frequency and has
been present for the majority of the last 6 months is referred to as chronic AUB.(13)
Recommendation for bleeding patterns based on data of >1000 normal women(14)
Table 1. 1- Bleeding patterns
No bleeding No days of bleeding through out the
reference period
Prolonged bleeding ≥10 days in one episode
Frequent bleeding >4 episodes in a 90 day reference period
Infrequent bleeding <2 episodes ina 90 day reference period
Irregular bleeding Range of varying lengths of bleeding free
intervals >17 days in a 90-day reference
period.
19
COAGULATION FACTOR DEFICIENCIES
Table 1. 2-Classification of bleeding disorders.
Coagulation factor
deficiencies
von Willebrands disease
Factor XI deficiency
Haemophilia A carrier
Haemophilia B carrier
Factor V deficiency
Factor VII deficiency
Factor II deficiency
Factor X deficiency
Fibrinogen disorders
20
Platelet disorders Quantitative
Immune Thrombocytopenic purpurae
Qualitative
Glanzmann thrombasthenia
Bernard souldier syndrome
vON WILLEBRANDS DISEASE
According to western data vWD is the most common inherited bleeding disorder.
Studies have shown that 10.7% of women with HMB have vWD as a cause of their heavy
bleeding(15).von Willebrands disease has been classified into three major categories:
• Type 1 partial quantitative deficiency of von Willebrand factor (vWf)
• Type 2 qualitative defect of von Willebrand molecule
• Type 3 total deficiency of vWf
21
Type 1 vWD is known as an autosomal dominant disease, Type 2 vWD may be autosomal
dominant or recessive, and Type 3 vWD is autosomal recessive. vWf has two important
roles in the hemostatic pathways:
1) Binding of platelets to subendothelium at sites of vascular injury;
2) stabilizating and protecting coagulation factor VIII (16). Heavy menstrual bleeding,
epistaxes and bleeding after dental extraction have been found to be the most prominent
symptoms, and are present in about 60% of affected patients.(17) Another study showed
that 35% of patients with von Willebrands disease present with heavy menstrual
bleeding.(18)
Investigation of vWD includes a complete blood count which may show evidence
of iron deficiency anaemia, and a low platelet count. The clotting tests may show
prolongation of the activated prothrombin time (APTT) in moderate and severe disease,
but can be normal in mild forms. The primary diagnosis of vWD is done by analyzing vWf
antigen, which is a quantitative measurement. Functional assays such as the Ristocetin
cofactor activity, which reflect von Willebrand factor function, tests the binding ability of
the vWf to platelets and is usually decreased in both cases of quantitative and qualitative
disease.(1)
22
The United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO)
recommends to measure vWf antigen and function on at least two occasions before the
diagnosis of vWD is ruled out .
There is no sufficient evidence to say that vWD, impairs fertility in affected women
or that miscarriages are more common in these patients than in women without vWD(19).
During pregnancy, women with vWD tend to normalize their factor VIII, von Willebrand
antigen level and the ristocetin cofactor activity and thus it is shown that these women are
unlikely to bleed during pregnancy; however, these women may start having bleeding by
day 4–5 postpartum when the levels start dropping(20) .
First line treatment with combined oral contractive pills in women with heavy
menstrual bleeding due to von Willebrands disease was found useful in 73% of the women
.(21).It is shown that when tranemexic acid was used in a dose of 1g four times daily for
4-5 days there was 50% reduction of blood loss in these women(22).Concentrated
desmopressin nasal spray was found to be effective in 92% of the treatment days it was
used in (23).
23
FACTOR DEFICIENCIES
FACTOR II PROTHROMBIN DEFICIENCY
Factor II is a single chain protein and is vitamin K dependent, synthesized by the
liver. It is inherited as autosomal recessive disease with an incidence of 0.5 per million in
the general population (24).There are two clinical types which are known: Type I
deficiency in which both prothrombin antigen and activity are reduced to the same degree;
and Type II in which prothrombin activity is reduced while the antigen levels remain
normal.
Common clinical presentation are episodes of bleeding into muscle and joints, mild
mucosal bleeding, rarely intracranial bleeding. Prothrombin complexes are the treatment
of choice; the majority have three factors – II, IX and X; some have four factors (including
factor VII)(25).
FACTOR V DEFICIENCY
Factor V is produced by hepatocytes and megakaryocytes. Platelets have about 20%
of the total circulating factor V. This factor deficiency is a autosomal recessive bleeding
disorder with an incidence in the population of about one per million.
24
Common clinical presentations are easy bruising, mucous membrane bleeding from
the oral cavity and nose. Haemoarthrosis and haematomas are seen but not spontaneous in
nature, unlike in haemophilia. Other less frequently seen presentations are of
gastrointestinal bleeding, haematuria, and postpartum haemorrhage.
Diagnosis is suspected when there is prolonged prothrombin time and APTT.
Confirmatory test is usually done by a prothrombin time-based factor V assay or by an
immunological factor V assay. Fresh frozen plasma is currently the mainstay of treatment
for this deficiency.
COMBINED FACTOR V AND VIII DEFICIENCY
Combined factor V and VIII is an autosomal recessive disorder which occurs due
to a single gene defect which is located on chromosome 18 .(26,27)It is observed that in
this deficiency the production of the Factors are normal within the cell and the defective
gene causes the failure of secretion of the factors into the blood circulation.
The commonest bleeding presentation seen in this condition is during postoperative
periods, for example like in post dental extraction procedure, and trauma. Heavy menstrual
bleeding and post partum haemorrhage are commonly seen in affected women (28).
25
In combined Factor V and VIII deficiency both prothrombin time and APTT are
prolonged; the prolongation in APTT is not proportionate to that in prothrombin time. The
levels of Factor V and VIII are normally noted to be to between 5 and 20 IU/dl.(1)
Recombinant factor VIII and virally inactivated Fresh frozen plasma are the treatment of
choice for this deficiency.
FACTOR VII DEFICIENCY
Factor VII is a vitamin K-dependent glycoprotein and is inherited as an autosomal
recessive disorder (29), with an incidence of two to three per million (30). Acquired Factor
deficiency can occur in patients with liver disease, vitamin K deficiency and those on
warfarin therapy.
The commonest symptoms for this deficiency include heavy menstrual bleeding,
epixstasis, gum bleeding.(31)
In Factor VII deficiency diagnosis is usually suspected when there is prolonged
prothrombin time. The APTT, thrombin time and fibrinogen are all normal. The final
confirmation of factor VII deficiency is done by performing a prothrombin time-based
factor VII assay.(1)
26
In women with mucosal bleeding, heavy menstrual bleeding tranemexic acid can
be used. In patients with severe bleeding Factor VII concentrates, prothrombin complexes
and recombinant factor VII a (NovoSeven) can be used.(1)
HAEMOPHILIA A AND B CARRIERS
Haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency)
are X-linked recessive disorders with a prevalence in the general population of one to two
per 10, 000 and one to two per 100 000, respectively(32)
Symptomatic female carriers can present with heavy menstrual bleeding due to the
inappropriate inactivation of the normal X chromosome, this phenomenon is known as
lyonization (33)
Symptomatic haemophilia A carriers can be treated with Desmopressin and less
often factor VIII concentrates. In symptomatic haemophilia B carriers Tranemexic acid
and factor IX concentrate are useful agents.(1)
27
FACTOR X DEFICIENCY
Factor X s synthesized by the liver and the deficiency of this factor is an autosomal
recessive disorder.The incidence of this deficiency is one per million of the general
population.(31)
The most common presentations include epistaxes, heavy menstrual bleeding,
(which occurs in half of the affected women), haemoarthrosis, severe postoperative
bleeding and intracranial bleeding.(1)
Prolonged prothrombin time and APTT, which corrects after a 50 : 50 mix with
normal plasma should suggest the possibility of factor X deficiency.
Fibrinolytic agents, for example tranexamic acid, plasma factor IX, prothrombin
complexes and recombinant factor VIIa are the currently used treatment options for these
patients.(25)
28
FACTOR XI DEFICIENCY
Factor XI deficiency is an autosomal recessive disorder which affects about 4.3–
11% of Ashkenazi Jews (34) . The incidence of severe deficiency in the general population
is estimated to be one per million. Recent studies have shown that this deficiency was
identified in 4% of women with menorrhagia (35).Women with heterozygous trait can
have heavy bleeding during childbirth or menstruation. The measurement of plasma factor
XI activity is a reliable indicator of the disease.
Tranemexic acid can be used in women with heavy menstrual bleeding (1) and
Fresh frozen plasma can be used for treatment of symptomatic severe cases.
FIBRINOGEN DISORDERS
Fibrinogen is a protein which is synthesized in the liver. Distinct gene mutation
can lead to :
• hypofibrinogenaemia (reduced level of fibrinogen),
• afibrinogenaemia (absolute deficiency)
• dysfibrinogenaemia (normal level but defective fibrinogen)
29
This disorder is inherited as an autosomal recessive gene with an incidence of one
per million in the general population(36). It is observed that in areas with increased
incidence of consanguineous marriage, afibrinogenaemia has its highest incidence.
Afibrinogenaemia and hypofibrinogenaemia have been found to be associated with
recurrent miscarriages, heavy menstrual bleeding, antepartum haemorrhage and
postpartum haemorrhage (37,38).The clinical presentation in a compilation of 250 patients
with dysfibrinogenaemia showed that 53% were asymptomatic, 26% had haemorrhage
and 21% had thrombosis(39).
If the prothrombin time, APTT and thrombin time are markedly prolonged then
afibrinogenemia should be immediately suspected. The definitive diagnosis of fibrinogen
deficiencies can be made after demonstrating the molecular defect.
Tranexamic acid can be used in cases of mucosal bleeding, such as heavy menstrual
bleeding but , it increases the risk of thrombosis and therefore preferable should not be
used in patients where there is personal or family history of
thrombosis.(31)Cryoprecipitate is a very rich source of fibrinogen but is not virally
inactivated, hence it should be given only in an emergency situation.
30
QUANTITATIVE PLATELET DISORDER
IMMUNE THROMBOCYTOPENIA PURPURAE
This is an autoimmune disease where autoantibody is produced against one’s own
platelets causing peripheral destruction of platelets by the reticuloendothelial system. In
England the childhood incidence of ITP was seen to be between 10 and 40 new cases per
million population per year (40). The incidence among adults is more, with 66 new cases
per million per year, with female predominance.
The symptoms experienced by these patients are purpura, heavy menstrual
bleeding, epistaxes and gingival bleeding.
ITP has to be suspected in patients when there is isolated thrombocytopenia and
after ruling out other causes of thrombocytopenia. Bone marrow examination is not
required always to make the diagnosis but if blood counts and smear reveal other
abnormalities with thrombocytopenia or if patient fails to respond to standard therapies
then it can be done. In ITP on bone marrow examination there would be increased number
of megakaryocytes.
31
ITP AND PREGNANCY
(ITP) occurs in one or two of every 1,000 pregnancies(41), and accounts for 5% of
cases of pregnancy-associated thrombocytopenia. One study that reviewed the experience
of 92 women with ITP during 119 pregnancies over an 11 year period found that women
who were previously diagnosed with ITP were less likely to require therapy for ITP than
those with newly diagnosed with ITP.(42)
The most useful means of coming to a diagnosis of ITP is, the antenatal history.
A history of prior thrombocytopenia, underlying autoimmune disease or severe
thrombocytopenia (< 50,000/μl) makes the diagnosis of ITP highly likely. In the absence
of any documentation of platelet count prior to pregnancy, significant thrombocytopenia
in the first trimester, with a declining platelet count as pregnancy progresses, is also highly
consistent with ITP. In contrast, mild thrombocytopenia which develops in the second or
third trimester and is not associated with hypertension or proteinuria will most likely be
incidental thrombocytopenia.
The clinical management of pregnant patients with ITP requires close collaboration
between the obstetrician and hematologist. These patients should be seen monthly in the
first and second trimester, then every 2 weeks after 28 weeks, and weekly after 36
weeks.(43)
32
Treatment has been recommended for women with a platelet count below 10,000/μl
at any time during pregnancy, or when the platelet counts are below 30,000/μl in the
second or third trimester or when associated with any episode of bleeding.(44,45)
Many consider corticosteroids to be first line treatment for ITP in pregnancy due to
their efficacy and low cost. The therapeutic dosage of prednisone is 1 mg/kg/day (based
on the pre-pregnancy weight), which, after achieving adequate response, is gradually
titrated down. Some of the side effects which are known with corticosteroids in pregnancy
include such as gestational diabetes, weight gain, acceleration of bone loss, hypertension
and possibly placental abruption and premature labor(46).
Some studies have found out that the use of corticosteroids in the first trimester is
associated with congenital anomalies, such as orofacial clefts.(47).Some have suggested
that Immunoglobulin (IVIg) should be the first line therapy for pregnancy patients with
ITP, especially when a long duration of therapy is not required (48) American Society of
Haematology (ASH) guidelines considers IVIg to be an appropriate first line agent for
severe thrombocytopenia, or thrombocytopenic bleeding in the third trimester (49).
However, responses to IVIg tend to be transient, and multiple courses of therapy may be
required at significant cost and patient inconvenience.splenectomy may be beneficial in
selected cases.
33
QUALITATIVE PLATELET DISORDERS
GLANZMANN THROMBASTHENIA
This is an inherited platelet dysfunction with autosomal recessive trait. There is a
female preponderance of 1.5 : 1, with heavy menstrual being a chief presenting symptom
in females.(1)
This disease is a result of a deficiency or abnormality of the platelet membrane
glycoprotein IIb/IIIa complex, which acts as the fibrinogen receptor.
PFA-100 is very specific and sensitive and aids in confirming the diagnosis.
Combined oral contraceptive pills and tranemexic acid is useful to manage heavy
menstrual bleeding in this condition.
BERNARD SOULIER SYNDROME
This is a rare hereditary disorder characterised by decreased platelet adhesiveness
to the subendothelium due to abnormality in the platelet glycoprotein Ib/IX complex (CD
42). This is an autosomal recessive disorder. On peripheral blood smear there is the
34
presence of giant platelets and other features are pronounced thrombocytopenia and a
prolonged bleeding time.
Desmopressin , tranemexic acid and combined oral contraceptive pills have been
found to be useful for heavy menstrual bleeding in these patients.(50)
.
35
TREATMENT OF AUB IN WOMEN WITH BLEEDING DISORDERS
TREATMENT MODALITIES
Medical methods Surgical methods
1)First line management 1)Conservative
2)Second line management 2)Definitive
Table 1. 3-Treatment of AUB in women with bleeding disorders
MEDICAL
METHODS
First line management 1)Tranemexic acid
2)Oral contraceptive pills
3)Progesterone only pills
4)Depot medroxy progesterone acetate
Second line management 1)Levonogestrol intrauterine device
2)Danazol
3)Gonadotrophin releasing hormone
analoges
4)Desmopressin
SURGICAL METHODS
Conservative methods-Endometrial ablation
Definitive method-Hysterectomy
36
NON-HORMONAL TREATMENTS
ANTIFIBRINOLYTIC AGENTS
Antifibrinolytic agents like tranemexic acid decreases the fibrinolytic capacity of
menstrual blood, stabilizing the clot, therefore reducing menstrual blood loss on the
average by approximately 50%.(51).It is found to be effective in both women with and
without bleeding disorders. The major advantage of this drug is that it needs to be taken
during the menstrual period only.(52)
With respect to drug interactions, tranexamic acid and concomitant use of hormonal
contraception may further exacerbate the increased thrombotic risk associated with
combination hormonal contraceptives. Tranexamic acid is not recommended in people
taking factor IX complex concentrates due to high chances of thromboembolic
phenomenon.
MEFENAMIC ACID
This is a non-steroidal anti-inflammatory drug (NSAID) which acts as a
prostaglandin inhibitor. Prostagladin inhibitors have been found to reduce heavy menstrual
bleeding by 30% to 50%. (53).NSAID can lead to platelet aggregation. Thus, in heavy
37
menstrual bleeding caused by vWD and other bleeding disorders it can lead to increased
bleeding. The exceptions are the COX-2 inhibitors (e.g., Celebrex, Vioxx), which do not
cause platelet dysfunction.(54)
DESMOPRESSIN
This drug can be given intranasally, subcutaneously, or by intravenous infusion. It
causes the release of vWF from storage sites within the endothelial cells thereby increasing
the vWF, and then results in an increase in plasma levels of factor VIII. Desmopressin can
be used in patients with mild coagulation disorders, namely mild vWD, mild hemophilia
A, and mild platelet function disorders.(55). Tachyphylaxis has been reported with
repeated doses of desmopressin, a therapeutic response of 70% of the initial increment is
still achieved.
COMBINED ORAL CONTRACEPTIVES (COC’S)
COC’s are effective for heavy menstrual bleeding and reduces menstrual blood
loss by approximately 50%(56).These agents partly cause rise of factor VIII and vWF.
The combination oral contraceptives is the ideal treatment for HMB in women with
vWD and who also require effective contraception .COC’s suppress ovulation thus
alleviating the severe mid cyclical pain which is more commonly experienced by women
38
with vWD. OCP’s when given as extended cycle helps in preventing blood loss and
correcting anemia.
PROGESTERONES
These drugs lead to decidualization of stroma with granulocytes and thin sinusoidal
blood vessels.
DEPOT MEDROXY PROGESTERONE ACETATE- DMPA is given as an
intramuscular injection once every 3 months. Amenorrhea is the expected outcome, but as
many as 1/3 of women experience ongoing spotting or bleeding during treatment. In
patients with a bleeding disorder, after an intramuscular injection is given, pressure should
be applied at the site for 15 min.
LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM-This
suppresses the endometrial growth and significantly decreases bleeding. Studies showed
that use of this device decreased menstrual blood loss by between 74% and 97% and
resulted in 64% to 82% of women subsequently cancelling their hysterectomies, when it
was used in women awaiting hysterectomy surgery.(57,58). There is limited data on uses
of these devices in women with bleeding disorders but it is considered an appropriate
therapeutic option.(59)
39
DANAZOL
This drug is a synthetic steroid with mild androgenic properties and has anti-
gonadotrophic effects on the pituitary gland. Oligomenorrhoea and amenorrhoea can be
induced with a dose of 100mg per day given over 3 months. Side effects include weight
gain, irritability, musculoskeletal pain, hot flushes and breast atrophy . Long-term
treatment with danazol may cause side effects in the liver (including benign hepatic
adenomas).
GONADOTROPHIN RELEASING HORMONE ANALOGS
These drugs cause hypoestrogenism which results in endometrial thinning usually
to the point of amenorrhea. Side effects include bone loss and menopausal symptoms such
as hot flashes and vaginal dryness. Furthermore, in vWD patients, these drug can lead to
hypoestrogenism which further lowers FVIII and vWF levels, predisposing to even more
bleeding.
40
MATERIALS AND METHODOLOGY
The study was a prospective observational study which was conducted in Christian
Medical College Hospital, Vellore between April 2018 and August 2019 in the department
of Haematology, Transfusion medicine and Obstetrics and Gynaecology. An institutional
ethics committee approval was obtained.
Patients with bleeding disorders were recruited from the above-mentioned
departments. Detailed history was collected to identify bleeding patterns.
A detailed questionnaire was made and all information regarding the symptoms the
patient had presented when the haematological diagnosis was made. Data was collected
on frequency and duration of menstrual cycles based on which the bleeding pattern was
identified. History of previous hospital admissions for heavy menstrual bleeding and blood
transfusions for heavy menstrual bleeding was recorded. Details regarding reproductive
outcomes like infertility, miscarriage, antepartum or post-partum haemorrhage was noted
.Quality of life at class, work, and social life was taken into consideration. Treatment
history with respect to first line drugs like oral contraceptive pills, progesterone only pills,
Depot medroxy progesterone acetate, tranemexic acid and second line like levonorgesterol
intrauterine device, danazol with respect to the symptoms was collected. Inappropriately
treated patients were identified based on pictorial blood loss assessment chart and finally
referred to Gynaecology OPD.
41
Pictorial blood loss assessment chart
Figure 1 .3-Pictorial blood loss assessment chart
This chart is made with a table with each row representing a day of the month, then
the number of sanitary pads and/or tampons used are counted. A score is calculated for
each day, then the score at the end of the month is added up. The results were analyzed to
determine the current medical practices for treatment of abnormal uterine bleeding in
women with bleeding disorders.
42
PARTICIPANTS
ELIGIBILITY CRITERIA
• Women with bleeding disorders
• Age group of post menarche-40 years
• Women who had attained menarche
EXCLUSION CRITERIA
• Girls who have not attained menarche
OUTCOMES
Menstrual patterns-
• Duration of menstrual cycle
• Frequency of menstrual cycle
Reproductive outcomes
• Infertility
• Ante partum haemorrhage
Post partumhaemorrhage
Quality of life-
• Ability to go to school and work
• Ability to go for social gathering
43
Treatment given and Relief of symptoms
SAMPLE SIZE
SAMPLE SIZE CALCULATION
Women with bleeding disorders were recruited from transfusion
medicine,haematology OPD,Obstertrics and Gynaecology OPD
Detailed questionnaire was filled by the investigator
If PBAC score was >100 then patient was referred to
Gynecological OPD for further evaluation
Patients who are referred to Gynecology OPD will be followed up
44
SAMPLE SIZE CALCULATION
Single Proportion - Absolute Precision
Expected Proportion 0.57
Precision (%) 7.5
Desired confidence level (1- alpha) % 95
Required sample size 167
According to Kadir et al the Menstrual disorder present among women with
Bleeding disorder was found to be 57% with a precision at 7.5% and a desired confidence
interval at 95% .We needed to study atleast 167 women with bleeding disorder who attend
the Hematology OPD in CMC Vellore.
45
Statistical methods:
Data entry and data analysis was done using SPSS 16. Descriptive statistics was
reported using Mean ± SD for continuous variables such as age. Categorical data was
reported using frequency and percentage. Pattern of menstrual disorder among women
with bleeding disorder was reported using frequency and percentage. Tests of association
was checked with chisquare tables.
46
RESULTS
Patient demographics-Age
Table 2. 1- Age distribution of patients
Age group Number (%)
≤15 years
9(11.1%)
16-25 years
32(39.5%)
26-35 years
31(38.2%)
≥36 years
9(11.1%)
The mean age of the patient recruited was 26±7 years.The age group range was from 11
years to 41 years
In this study we found that the maximum number of women were in the age group of 16-
25 years(39.5%) , in 26-35 years 31 women(38.2%), in ≥36 year 9 women and in ≤15
years 9 girls.
47
Hematological diagnosis
Table 2. 2-Haematological diagnosis
PLATELET
DYSFUNCTION NUMBER %
Quantitative
ITP 36 44.4
Qualitative
Bernard soulier syndrome 1 1.2
Glanzmann thromasthenia 5 6.1
FACTOR
DEFICIENCIES
von Willebrand disease 14 17.2
Factor VII deficiencies 4 4.9
Factor VIII deficiencies 4 4.9
Factor X deficiencies 2 2.4
Factor XIII deficiencies 4 4.9
Combine Factor V and VIII
deficiencies 1 1.2
48
Of the 81 women recruited, 36 women had ITP which accounted for 44%. The next highest
being von Willebrands disease (17.2%). There were 6 patients with qualitative platelet
dysfunction and a total of 15 patients with various factor deficiencies.
FIBRINOGEN
DEFICIENCIES
Afibrinogenemia 1 1.2
Hypodysfibrinogenemia 1 1.2
OTHERS
AIHA 2 2.4
Aplastic anemia 2 2.4
Hypoplastic anemia 1 1.2
Lupus anticoagulant
hypothrombinemia
deficiency
1 1.2
Thalessemia 1 1.2
Evans syndrome 1 1.2
There were two patients with fibrinogen deficiencies. Patients with others disease
conditions which were included in this study were Autoimmune haemolytic anemia,
Aplasticanemia, Hypoplasticanemia, Lupus anticoagulant hypothrombinemia and
thalassemia.
49
SYMPTOMS AT DIAGNOSIS
-Figure 1 .4 Symptoms at diagnosis
23.4% of the patients had presented with heavy menstrual bleeding at diagnosis whereas
29.6% of the patients had history of gum bleeding, bleeding on dental extraction and
Heavy menstrual bleeding
23%
0%
Bleeding while extracting
tooth,delivery,gum bleeding
30%
History of treatment of anemia
11%
Family history of bleeding disorders
4%
Rashes4%
Bleeding from trauma
5%
Fever6%
Others17%
SYMPTOMS AT DIAGNOSIS
50
bleeding after delivery.4% had family history of bleeding disorder, 6% had history of fever
at diagnosis, 11% had history of treatment of anemia, 4% had history of rashes.
MENSTRUAL BLEEDING PATTERNS
Figure 1. 5-Menstrual bleeding patterns
0 5 10 15 20 25 30 35 40 45 50
Normal
Heavy menstrual bleeding
Prolonged
Infrequent
Frequent
Prolonged and heavy menstrual cycle
46.9
22.2
4.9
7.4
4.9
13.5
Menstrual bleeding patterns
%
51
Among the 81 women recruited 22.2% had heavy menstrual bleeding and 13.5% had
prolonged and heavy menstrual bleeding. Hence totally 35% of women had heavy
menstrual bleeding.46.9% had normal bleeding pattern the rest of them had other bleeding
patterns as depicted in the diagram.
HAEMATOLOGICAL DIAGNOSIS AND HMB
Figure 1. 6-Percentage of women with HMB in various bleeding disorders
Among 29 women with heavy menstrual bleeding,9 patients had von willebrands disease,7
women had ITP and 4 women had Bernard soulier and glansmann thrombasthenia,4
19.4
64.266.6
26.6
0
10
20
30
40
50
60
70
ITP von Willebrands disease Glanzmann thrombastheniaand BSS
Factor deficiencies
Incidence of HMB in different haematological diagnosis
52
women had factor deficiencies. Others included patients with Evans syndrome,
hypoplastic anemia,Lupus anticoagulant hypothrombinemia.
HOSPITAL ADMISSION AND BLOOD TRANSFUSIONS
Figure 1. 7-Percentage of patients who required hospital admission and blood
transfusions for HMB
Among the 81 patients recruited, 32 required hospital admission for HMB of which 29
required blood transfusion.
35.80%
39.50%
Blood transfusions Hospital admission for HMB
Hospital admission for HMB and blood transfusions
53
DISTRIBUTION OF HOSPITAL ADMISSION IN DIFFERENT
HAEMATOLOGICAL DISEASE
Table 2. 3-Distribution of hospital admission in different haematological
disease
Among the women who required hospital admission for HMB, 12 (37.5%) patients had
ITP and 7(21.8%) had Von willebrands disease.4 patients had factor deficiencies,3 had
Glanzmann thrombasthenia, one each in afibrinogenemia, aplastic anemia, evan’s
syndrome, hypoplastic anemia and lupus anticoagulant hypothrombinemia deficiency.
DISEASE NUMBER/THE TOTAL %
von Willebrands disease 7/14 50
ITP 12/36 37
Quantitative platelet
disorders
3/6 50
54
REPRODUCTIVE OUTCOMES
Among the 81 patients ,52(64.2%) were married.
Among the married 12 patients had history of infertility which accounts for23% of
married women.
9 women had history of miscarriage which is 11.1%.
Figure 1. 8-Infertility among women with bleeding disorders
55
DISTRIBUTION OF HAEMATOLOGICAL DIAGNOSIS AMONG
WOMEN WITH INFERTILITY.
DISEASE NUMBER/THE TOTAL %
von Willebrands disease 1/7 14.2
ITP 6/27 16.6
Glanzmann thrombasthenia 1/3 20
Factor deficiencies 4/10 40
Table 2. 4-Distribution of haematological diagnosis and infertility . Among the
12 patients with infertility, 6 patients had ITP,4 had factor deficiencies.The
percentage was calculated taking into account total number of patient with each
bleeding disorder.
56
ANTEPARTUM (APH) AND POSTPARTUM HAEMORRHAGE (PPH)
Figure 1. 9-Number of women with APH and PPH
Among the 52 married women 3 patients had history of APH and 14 had PPH. One patient
required caesarian hysterectomy, pre-operative the patient was not diagnosed with
bleeding disorder. 19 of the patients required blood transfusion In antepartum or
postpartum period
57
QUALITY OF LIFE
Quality of life was assessed based on difficulty while attending class, going for work or
going for social functions. The assessment was done based on patient opinion if quality of
life was not affected, occasionally affected or affected often or very often. Based on
patients opinion 19 patients felt the quality of life was affected very often at class and 18
patients felt that quality of life was affected very often at work and social functions.
Table 2. 5-Quality of life at class, work and social life
Quality of life Not affected occasionally Often Very often
Class 54(66.6%) 5(6.2%) 3(3.7%) 19(23.5%)
Work 53(65.4%) 7(8.6%) 3(3.7%) 18(22.2%)
Social 55(67.9%) 5(6.2%) 3(3.7%) 18(22.2%)
58
TREATMENTS GIVEN
The first line agents were combined contraceptive pills, progesterone only pills, DMPA,
Tranemexic acid. The first line treatments were taken by 34 the patients.
Figure 1. 10 Percentage of women who have taken treatment for HMB
Of the women with heavy menstrual bleeding 6 women had not taken any treatment that
is 20.3% of the women.
59
DISTRIBUTION OF FIRST LINE MEDICATION
Figure 1. 11-Distribution of first line medication
Among women who used first line medications,6 patients used OCP’s,15 patients used
progesterone only pills,17 patients used tranemexic acid and 2 patients used DMPA.
Among the above-mentioned patients some of them took combination of drugs such as
progesterone only pills and tranemexic acid, OCP’s and tranemexic acid.
OCP's15%
Progesterone only pills37%
Tranemexic acid43%
DMPA5%
DISTRIBUTION OF FIRST LINE MEDICATION
OCP's Progesterone only pills Tranemexic acid DMPA
60
ORAL CONTRACEPTIVE PILLS
A total of 6 patients took oral contraceptive pills (17.6%). The duration of treatment
extended from 6 months to 180 months. The median percentage of relief was 87.5%. Of
the two patients who took OCP’s ,one had only 50% relief hence was started on Danazol
for 1 year and she had 100% relief and another patient was started on OCP’s and
tranemexic acid for 3 months,she had 75% relief,then she took DMPA and still did not
have sufficient relief of symptoms with PBAC score more than 100. Among patients who
took OCP’s only one patient was referred to Gynae OPD. Hence only one patient required
a second line agent.
Figure 1. 12Percentage of relief of symptoms with OCP’s and progesterone
only pills
61
PROGESTERONE ONLY PILLS
Progesterone only pills was used by 15 patients (44.1%). The durations of treatment ranged
from 2 days to 264 months. The median percentage of relief was 55%. There was one
patient with Factor X deficiency on progesterone only pills who took the treatment for 10
years, but due to inadequate relief required hysterectomy. Another patient on progesterone
only pills had only 60% relief of symptoms and on adding Tranemexic acid had 80% of
relief with PBAC score <100. 5 patients who were on progesterone only pills had
inadequate relief of symptoms and with PBAC>100, was referred to Gynae OPD.
Figure 1. 13-Number of patients who used OCP’s and progesterone only pills
62
DEPOT MEDROXY PROGESTERONE ACETATE (DMPA)
This drug was used by 2 patients in this study (5%). The first patient diagnosed with ITP
had used DMPA for 15 months and had 100% relief of symptomswith the final PBAC
<100. The second patient was diagnosed with von Willebrands disease and used DMPA
after using OCP’s and tranemexic acid and still did not find adequate relief of symptoms
with PBAC>100, hence she was referred to Gynae OPD.
Figure 1 .14-Number of patients who used DMPA and tranemexic acid
2
17
0
2
4
6
8
10
12
14
16
18
DMPA Tranemexic acid
63
TRANEMEXIC ACID
A total of 17 patients took this drug accounting for 47% of the first line treatment. The
duration of the range of treatment extended from 1 month to 240 months. The median
percentage of relief of symptoms was 55%.7 of the patients had more than or equal to 75%
relief of symptoms. One patient was given tranemexic acid along with OCP’s and 3
patients were given along with progesterone only pills.7 patients who had taken
Tranemexic acid had to be referred to OG OPD.
Figure 1 .15 -number of women on treatment referred to Gynaecology OPD
64
SECOND LINE MANAGEMENT
The different drugs used as second line agents are levonorgestrel intrauterine device
(Mirena), Danazol, hysterectomy. Mirena was used by one patient who was diagnosed
with ITP, she had 50% relief of symptoms. The PBAC score after using Mirena was <100.
One patient who used OCP and did not have sufficient relief of symptoms took danazol
for 1 year and had 100% relief of symptoms. 2 patients required hysterectomy, one patient
was diagnosed with Factor X deficiency and did not respond to progesterone only pills and
finally required hysterectomy. The second patient had severe factor XIII deficiency and
and she required a caesarian hysterectomy. She was not diagnosed with bleeding disorder
prior to the surgery .One of the patient took ayurvedic treatment for AUB and she had
adequate relief of symptom with PBAC <100.
SECOND LINE TREATMENT
Mirena 1
Danazol 1
Hysterectomy 1
Table 2. 6-Number of patients who used second line managment
65
FOLLOW UP
Of the 81 women recruited, 19 patients were referred to Gynae OPD in view of PBAC
score >100. Among these four patients were pregnant.15 patients were advisied to follow
up. Eight patients followed up.3 patients were started on OCP’s like the extended OCP
regimen.One patient was started on Danzol,One was given Mirena, One was started on
progesterone only pills, One was started on T.Tranemexic acid.
Figure 1. 16-Number of patients referred to Gynaecology OPD
66
HAEMATOLOGICAL DISEASE AND AUB
ITP
There were 36 patients with ITP, of these 3 patients had HMB and 4 had prolonged cycles
and heavy menstrual bleeding. Hence 19.4% patients had HMB.
Figure 1 .17 -Number of ITP patients with HMB and prolonged cycles with
HMB
12 patients required hospital admission (33.3%) and 10 had blood transfusion.
6 patients (16.6%) had history of infertility.
3
4
0
1
2
3
4
5
HMB Prolonged cycle with HMB
67
QUALITY OF LIFE
Figure 1 .18 -Quality of life in women with ITP
The y axis represents the percentage of women with ITP whose quality of life was affected
at class, work and social life. 4 patients with ITP (11.1%) complained that their life was
affected at class, work and social aspects very often.
68
TREATMENT
First line treatments were taken by 12 patients. 5 patients took tranemexic acid and had
relief of symptoms of 50%. 3 patients were given progresterone only pills and had relief
of symptoms ranging from 50-100%.One patient took DMPA and one took OCP and both
had 100% relief. One patient required use of second line agent with levnorgestrel
intrauterine device
69
vON WILLEBRANDS DISEASE
They were 14 patients with vWD
Figure 1 .19 -Number of patients with HMB and prolonged cycle with HMB
among women with vWD
The y axis represents the number of women with von Willebrands disease who had heavy
menstrual bleeding and prolonged cycles with HMB.
70
Heavy menstrual bleeding was there in 8 patients and prolonged cycle with HMB in 1
patient. Hence a total of 64.2% had heavy menstrual bleeding
HOSPITAL ADMISSION AND BLOOD TRANSFUSION
Figure 1 .20 -Percentage of patients who required hospital admissions and
blood transfusions
7 patients (50%) needed hospital admission and 7 required blood transfusion.
71
QUALITY OF LIFE
Figure 1 .21-Quality of life among women with vWD
Among patients with von Willebrands disease, quality of life was very often affected at
class, work and social gathering among 4 women (28.5%).
72
TREATMENT
First line treatment was given to 10 patients.
Figure 1 .22-Treatments used for patients with vWD
2 patients were given OCP’s with 75% of symptom relief.
5 patients were given progesterone only pills with relief of symptoms ranging from 60-
100% .7 patients used tranemexic acid..4 patients were referred to Gynaecological OPD.
73
FACTOR DEFICIENCIES
They were total 15 patients with factor deficiencies. Among these 3 patients had HMB and
1 patient had prolonged cycle withHMB. That is 26.6% patients had HMB.
Figure 1 .23 -Number of patients who required hospital admissions and blood
transfusion for HMB among patients with factor deficiencies.
74
OUTCOMES IN FACTOR DEFICIENCIES
5 patients required hospital admission for HMB and 4 patients required blood transfusion
Figure 1 .24 -Percentage of women with miscarriage and infertility among
those with factor deficienies
Among patients with factor deficiencies 4 patients (26.6%) had abortions and 4 had history
of infertility.
75
OBSTETRIC BLEEDING IN FACTOR DEFICIENCIES
-Figure 1 .25 -Number Of women with APH and PPH among those with factor
deficiencies
1 patient had APH and 3 patients had PPH. One of the patient with factor XIII deficiency
required caesarian hysterectomy.
0
1
2
3
4
APH PPH
76
QUALITY OF LIFE
Among women with factor deficiencies, 5 women felt their quality of life was affected
very often at class, work and social life.
Figure 1 .26 -Quality of life among women with factor deficiencies
77
TREATMENT
First line treatment was used by 6 patients for AUB. 3 patients was put on progesterone
only pills with relief of symptoms ranging from no relief to 100%.2 patients were
tranemexic acid. One of the patient on progesterone on pills continued to have AUB and
required hysterectomy. 4 patients were referred to Gynae OPD.
Figure 1 .27 -Treatments taken by women with factor deficiencies
3
2
0
1
2
3
4
Progesterone only pills Tranemexic acid
Treatment given to women with factor deficiencies
78
QUALITATIVE PLATELET DISORDERS-BERNARD SOULIER AND
GLANZMANN THROMBASTHENIA
There were 6 patients with these disorders. Among these 2 patients had HMB and 2 had
prolonged and HMB cycle.Hence 66.6% had HMB. 3 patients required hospital admission
for HMB and 3 required blood transfusion.
Figure 1 .28 -Hospital admission and blood transfusion for HMB among
women with factor deficiencies.
79
QUALITY OF LIFE
Among women with platelet dysfunction, quality of life was affected very often at class in
2 patients, work-1 patient and social aspects-1 patient.
TREATMENT GIVEN
Figure 1 .29 -Treatments given for women with qualitative platelet
dysfunction
3 patients required first line treatment.2 patients were given tranemexic acid and 1 was
given progesterone only pill.2 of the patients with HMB were not given any treatment,
hence was referred to Gynae OPD.
2
1
2
0
1
2
3
Tranemexic acid Progesterone only pills No treatments taken
80
DISCUSSION
In women of reproductive age group menstruation and ovulation are unique
haemostatic challenges.
Women with bleeding disorders, where the haemostatic system is affected suffer
significant morbidity and impaired quality of life during the menstrual cycles.
In our study we recruited 81 patients with different bleeding disorders who
presented to our haematology OPD, Obstetrics and Gynaecology OPD and transfusion
medicine department. Western literature has showed that von Willebrands disease is the
most common bleeding disorder among women who present with heavy menstrual
bleeding(60).
In an Indian study ,1100 women with heavy menstrual bleeding were evaluated and
23 were found to have bleeding disorders with von Willebrands disease being the
highest.(61).In our study where we recruited women in the age group of post menarche to
40 years with bleeding disorders we found that ITP was the most common, constitiuting
36 patients out of the 81. The second highest was von Willebrands disease.Philipp et al
has shown that in black women with bleeding disorders, platelet dysfunction was more
common compared to white women.(62)
81
The mean age of the patients in this study was 26±7.42years. Kadir et al showed
that the median age of women with von Willebrands disease who presented with HMB
was 40 years.(60)
Among the women recruited 19(23%) of them had heavy menstrual bleeding as
symptom at diagnosis. The rest of them had presented with symptoms like bleeding
following minor dental procedures, gum bleeding and trauma. Kadir et al found that 65%
of women with bleeding disorders in his study had heavy menstrual bleeding since
menarche.
In our study we noted that the prevalence of heavy menstrual bleeding among women with
bleeding disorders was 35% Most of the other studies were done in women who presented
with HMB and found that 10- 20% of them had bleeding disorders (1)
The World Federation of Hemophilia (WFH) reported that the prevalence of heavy
menstrual bleeding in women with various bleeding disorders as:
• vWD 74% to 92%
• Bernard Soulier syndrome 51%
• Glanzmann thrombasthenia 98%
• Factor XI deficiency 59%
• carriers of haemophilia 57%
82
• other rare factor deficiencies 35% to 70% (63)
In our study we found that the prevalence of HMB in various bleeding disorders were
• ITP 19.4%
• von Willebrands disease 64.2%
• factor deficiencies 26.6%
• qualitative platelet dysfunction disorders 66.6%
HMB was found to be highest among women with qualitative platelet dysfunction
like Glanzmann’s thrombasthenia and Bernard souldier disease.
We found that 32 (39.5%) patients gave history of requiring hospital admissions for
heavy menstrual bleeding and 29(35.8%) of them required blood transfusions for heavy
menstrual bleeding.50% of patients with von Willebrands disease and quantitative platelet
disease required hospital admission. A retrospective cohort study done in Children’s
Medical Centre among patients with HMB found that 43% received blood transfusions.
(64).
83
REPRODUCTIVE OUTCOMES
Infertility
In our study 52 of the patients were married and 12(23%) patients among them had
history of infertility. In the general population infertility affects about 8-12% of couples.
So, there is increased incidence of infertility in women with bleeding disorders.
Miscarriage
9(17%) patients had history of miscarriage of which 4 had factor deficiencies and
3 had ITP and 2 had von Willebrands disease. Coagulation defects and platelet defects are
known to be associated with recurrent pregnancy loss causing about 55 to 62% of the
recurrent miscarriage(65,66).Factor XIII deficiency, factor XII defects , factor X
deficiency, factor VII deficiency , factor V deficiency, factor II (prothrombin)
deficiency,von Willebrand syndrome, carriers of hemophilia and fibrinogen defects are
disorders known to be associated with early pregnancy loss (66).
84
Obstetric Haemorrhage
Incidence of PPH is reported as 2-4% in vaginal delivery and 6% after caesarean
section in general population. In our study there were 14 (23.3%) patients who had history
of post-partum haemorrhage and 3 patients with antepartum haemorrhage. The prevalence
of PPH among women who went through pregnancy were:
• ITP 33.3%
• von Willebrands disease 40%
• factor deficiencies 50%
19 patients required blood transfusions during antepartum and postpartum periods.
A study done recently in women with bleeding disorders showed that primary PPH was
significantly greater among these women (P < 0.001). 48% of hemophilia carriers, 32% of
patients with VWD and 44% of women with rare bleeding disorders experienced primary
PPH as compared to only 7.5% of controls(67). The complication of obstetric bleeding is
more among women with bleeding disorders as compared to general population.
In our study we found that one patient required caesarian hysterectomy, she was a
30 year old lady who had regular normal menstrual cycles and was asymptomatic till
delivery. She delivered by a caesarian section and intra operatively there was severe PPH
85
because of which she required a hysterectomy. And later on evaluation she was found to
have Factor XIII deficiency.
QUALITY OF LIFE
Studies has shown that heavy menstrual bleeding affects quality of life in women
with bleeding disorder as compared to women with normal haemostasis.(68) We assessed
the quality of life based on the opinion of the patient whether menstrual bleeding affected
her activities at class, work and social life. 23.4% felt quality of life was very often affected
at class and 22.2% at work and social life. 33% of women with factor deficiencies felt their
quality of life was affected which was the maximum
TREATMENT
Even though women experienced HMB, 20% of women did not take any drugs for
treatment of bleeding. The first line treatment taken into consideration for this study was
Combined contraceptive pills, Tranemexic acid, Progesterone only pills, Depot medroxy
progesterone acetate. The first line treatment was taken by 34 patients.
86
TRANEMEXIC ACID
17(43%) of the patients used tranemexic acid as first line treatment. In a few
patients this was given as a combination with OCP’s and progesterone only pills. The
median relief of symptoms with this drug was 50%.7 patients were referred to
Gynaecology OPD as their PBAC scoring after treatment was >100.Previous literature also
shows that relief of symptoms with tranemexic acid about 50%.(51)
PROGESTERONE ONLY PILLS
This was used by 15(44.1%) patients. The median percentage of relief of symptoms
with progesterone only pills was 55%.5 patients were referred to Gynaecology OPD due
to PBAC score >100.One of the patients with Factor X deficiency took Progesterone only
pills for 10 years but there was not adequate relief of symptoms and finally required
hysterectomy.It was also noted that when progesterone only pills was taken along with
tranemexic acid the relief of symptoms was more. DMPA was used by one patient with
ITP and she had complete relief of symptoms.
87
ORAL CONTRACEPTIVE PILLS
There were 6(17.6%) patients who used OCP’s. They had a median percentage of
relief of symptoms of 87.5%.1 patient who took treatment with OCP’s did not have
adequate relief hence was referred to Gynaecology OPD. Studies have shown that with
OCP’s the reduction in menstrual blood loss is about 50%.(56)
The second line agents used by patients were levonogesterol intrauterine device and
danzol. Levonogesterol intrauterine device was used by one patient. She had good relief
of symptom after use leading to a PBAC score less than 100. One patient who used OCP
and did not have sufficient relief of symptoms took danazol for 1 year and had 100% relief
of symptoms.
88
LIMITATIONS
1)This was a prospective observational study done in a tertiary referral care hospital, the
profile may not be representative of the exact profile in the community.
2)The desired sample size required for this study could not be completed due to lack of
time.
3)As many of our patients were recruited from haematology OPD, the problem associated
with their primary pathology seemed to outweigh the need for treatment of menstrual
irregularity according to the patients.
4)The quality of life among women with bleeding disorders was assessed according to
patients own understanding rather than a standardizied questionnaire.
5)The possibility of interviewier bias has to be kept in mind in these type of cross sectional
studies.
6)The gold standard to measure menstrual blood loss is alkaline hematin extraction which
is a very time consuming and stressful method. Hence PBAC scoring was used to diagnose
women with HMB.
89
CONCLUSION
1) Immune thrombocytopenic purpurae was the most common bleeding disorder among
the women we recruited.
2) The prevalence of heavy menstrual bleeding among women with bleeding disorders was
35% Earlier suspicion and diagnosis of these diseases have better outcomes and lesser
morbidity.
3) Women with qualitative platelet dysfunction had maximum incidence of heavy
menstrual bleeding.
4) Women with bleeding disorder have increased incidence of infertility as compared to
normal population
5) Pregnancy in women with bleeding disorders should be carried out in close
collaboration with haematologist and obstetricians. Postpartum haemorrhage and
antepartum haemorrhage were more among women with bleeding disorders as compared
to general population.
6) Obstetric haemorrhage is found to be very severe in women with factor deficiencies as
we found in our study that one patient required caesarian hysterectomy
7) Quality of life was maximum affected among women with factor deficiencies.
90
BIBLIOGRAPHY
1. El-Hemaidi I, Gharaibeh A, Shehata H. Menorrhagia and bleeding disorders. Curr
Opin Obstet Gynecol. 2007 Dec;19(6):513–20.
2. Oehler MK, Rees MCP. Menorrhagia: an update. Acta Obstet Gynecol Scand. 2003
May;82(5):405–22.
3. Clarke A, Black N, Rowe P, Mott S, Howle K. Indications for and outcome of total
abdominal hysterectomy for benign disease: a prospective cohort study. Br J Obstet
Gynaecol. 1995 Aug;102(8):611–20.
4. Hawiger J. Formation and regulation of platelet and fibrin hemostatic plug. Hum
Pathol. 1987 Feb;18(2):111–22.
5. Davies J, Kadir RA. Endometrial haemostasis and menstruation. Rev Endocr Metab
Disord. 2012 Dec;13(4):289–99.
6. Ward CL. Hemorrhaging at menarche: a case report. J Fam Pract. 1992
Mar;34(3):351–4.
7. Katz D, Beilin Y. Disorders of coagulation in pregnancy. Br J Anaesth. 2015 Dec
1;115:ii75–88.
8. van Eijkeren MA, Christiaens GC, Haspels AA, Sixma JJ. Measured menstrual blood
loss in women with a bleeding disorder or using oral anticoagulant therapy. Am J
Obstet Gynecol. 1990 May;162(5):1261–3.
9. Gleeson N, Devitt M, Sheppard BL, Bonnar J. Endometrial fibrinolytic enzymes in
women with normal menstruation and dysfunctional uterine bleeding. Br J Obstet
Gynaecol. 1993 Aug;100(8):768–71.
10. Munro MG, Critchley HOD, Fraser IS. The two FIGO systems for normal and
abnormal uterine bleeding symptoms and classification of causes of abnormal uterine
bleeding in the reproductive years: 2018 revisions [Internet]. International Journal of
Gynecology & Obstetrics. 2018 [cited 2019 Aug 3]. Available from:
https://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/ijgo.12666
11. Fraser I, Critchley H, Broder M, Munro M. The FIGO Recommendations on
Terminologies and Definitions for Normal and Abnormal Uterine Bleeding. Semin
Reprod Med. 2011 Sep;29(05):383–90.
91
12. Heavy menstrual bleeding (NICE clinical guideline 44) [Internet]. Royal College
of Obstetricians & Gynaecologists. [cited 2019 Aug 3]. Available from:
https://www.rcog.org.uk/en/guidelines-research-services/guidelines/heavy-menstrual-
bleeding-nice-clinical-guideline-44/
13. Munro M, Broder M, Critchley H, Matteson K, Haththotuwa R, S Fraser I. An
International Response to Questions about Terminologies, Investigation, and
Management of Abnormal Uterine Bleeding: Use of an Electronic Audience
Response System. Semin Reprod Med. 2011 Sep 1;29:436–45.
14. Belsey EM, Machin D, d’Arcangues C. The analysis of vaginal bleeding patterns
induced by fertility regulating methods. World Health Organization Special
Programme of Research, Development and Research Training in Human
Reproduction. Contraception. 1986 Sep;34(3):253–60.
15. Dilley A, Drews C, Miller C, Lally C, Austin H, Ramaswamy D, et al. von
Willebrand disease and other inherited bleeding disorders in women with diagnosed
menorrhagia. Obstet Gynecol. 2001 Apr;97(4):630–6.
16. Simon D, Bandinelli E, Roisenberg I. Polymorphism in the promoter region of
von Willebrand factor gene and von Willebrand disease type 1. Genet Mol Biol. 2003
Dec;26(4):397–401.
17. Miller CH, Graham JB, Goldin LR, Elston RC. Genetics of classic von
Willebrand’s disease. I. Phenotypic variation within families. Blood. 1979
Jul;54(1):117–36.
18. Nishino M, Yoshioka A. The revised classification of von Willebrand disease
including the previously masqueraded female hemophilia A (type 2N). Int J Hematol.
1997 Jul;66(1):21–30.
19. Mannucci PM. How I treat patients with von Willebrand disease. Blood. 2001 Apr
1;97(7):1915–9.
20. Govorov I, Löfgren S, Chaireti R, Holmström M, Bremme K, Mints M.
Postpartum Hemorrhage in Women with Von Willebrand Disease – A Retrospective
Observational Study. PLoS ONE [Internet]. 2016 Oct 25 [cited 2019 Aug 5];11(10).
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079555/
21. Lavabre-Bertrand T, Navarro M, Blanc P, Larrey D, Michel H, Rouanet C. Von
Willebrand’s disease, digestive angiodysplasia, and estrogen-progesterone treatment.
Am J Hematol. 1994 Jul;46(3):254–5.
22. Health D of. On the state of public health: Annual report of the Chief Medical
Officer 2006 [Internet]. 2007 [cited 2019 Aug 5]. Available from:
92
https://webarchive.nationalarchives.gov.uk/20130105021748/http://www.dh.gov.uk/e
n/Publicationsandstatistics/Publications/AnnualReports/DH_076817
23. Rose EH, Aledort LM. Nasal spray desmopressin (DDAVP) for mild hemophilia
A and von Willebrand disease. Ann Intern Med. 1991 Apr 1;114(7):563–8.
24. Peyvandi F, Mannucci PM. Rare coagulation disorders. Thromb Haemost. 1999
Oct;82(4):1207–14.
25. United Kingdom Haemophelia Centre Doctors’ Organisation. Guidelines on the
selection and use of therapeutic products to treat haemophilia and other hereditary
bleeding disorders. Haemoph Off J World Fed Hemoph. 2003 Jan;9(1):1–23.
26. Nichols WC, Seligsohn U, Zivelin A, Terry VH, Arnold ND, Siemieniak DR, et
al. Linkage of combined factors V and VIII deficiency to chromosome 18q by
homozygosity mapping. J Clin Invest. 1997 Feb 15;99(4):596–601.
27. Neerman-Arbez M, Antonarakis SE, Blouin JL, Zeinali S, Akhtari M, Afshar Y,
et al. The locus for combined factor V-factor VIII deficiency (F5F8D) maps to
18q21, between D18S849 and D18S1103. Am J Hum Genet. 1997 Jul;61(1):143–50.
28. Peyvandi, Tuddenham, Akhtari, Lak, Mannucci. Bleeding symptoms in 27 Iranian
patients with the combined deficiency of factor V and factor VIII. Br J Haematol.
1998;100(4):773–6.
29. Bartosh NS, Tomlin T, Cable C, Halka K. Newly diagnosed congenital factor VII
deficiency and utilization of recombinant activated factor VII (NovoSeven®). Clin
Pharmacol Adv Appl. 2013 Mar 15;5:53–8.
30. Fadel HE, Krauss JS. Factor VII deficiency and pregnancy. Obstet Gynecol. 1989
Mar;73(3 Pt 2):453–4.
31. Bolton‐Maggs PHB, Perry DJ, Chalmers EA, Parapia LA, Wilde JT, Williams
MD, et al. The rare coagulation disorders – review with guidelines for management
from the United Kingdom Haemophilia Centre Doctors’ Organisation. Haemophilia.
2004;10(5):593–628.
32. Greer IA, Lowe GD, Walker JJ, Forbes CD. Haemorrhagic problems in obstetrics
and gynaecology in patients with congenital coagulopathies. Br J Obstet Gynaecol.
1991 Sep;98(9):909–18.
33. Lyon MF. Sex Chromatin and Gene Action in the Mammalian X-Chromosome.
Am J Hum Genet. 1962 Jun;14(2):135–48.
93
34. Seligsohn U. High gene frequency of factor XI (PTA) deficiency in Ashkenazi
Jews. Blood. 1978 Jun 1;51(6):1223–8.
35. Peyvandi F, Lak M, Mannucci PM. Factor XI deficiency in Iranians: its clinical
manifestations in comparison with those of classic hemophilia. Haematologica. 2002
May;87(5):512–4.
36. Mansouritorghabeh H, Manavifar L, Banihashem A, Modaresi A, Shirdel A,
Shahroudian M, et al. An investigation of the spectrum of common and rare inherited
coagulation disorders in North-Eastern Iran. Blood Transfus. 2013 Apr;11(2):233–40.
37. Kobayashi T, Kanayama N, Tokunaga N, Asahina T, Terao T. Prenatal and
peripartum management of congenital afibrinogenaemia. Br J Haematol. 2000
May;109(2):364–6.
38. Aygören-Pürsün E, Martinez Saguer I, Rusicke E, Louwen F, Geka F,
Ivaskevicius V, et al. Retrochorionic hematoma in congenital afibrinogenemia:
Resolution with fibrinogen concentrate infusions. Am J Hematol. 2007
Apr;82(4):317–20.
39. Hanss M, Biot F. A Database for Human Fibrinogen Variants. Ann N Y Acad Sci.
2001;936(1):89–90.
40. Walker RW, Walker W. Idiopathic thrombocytopenia, initial illness and long term
follow up. Arch Dis Child. 1984 Apr 1;59(4):316–22.
41. Provan: Idiopathic thrombocytopenic purpura in adults - Google Scholar
[Internet]. [cited 2019 Aug 6]. Available from:
https://scholar.google.com/scholar_lookup?journal=J+Pediatr+Hematol+Oncol&title
=Idiopathic+thrombocytopenic+purpura+in+adults&author=D+Provan&author=A+N
ewland&volume=25&issue=Suppl+1&publication_year=2003&pages=S34&pmid=1
4668637&
42. Webert KE, Mittal R, Sigouin C, Heddle NM, Kelton JG. A retrospective 11-year
analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood. 2003
Dec 15;102(13):4306–11.
43. Stavrou E, McCrae KR. Immune Thrombocytopenia in Pregnancy. Hematol
Oncol Clin North Am. 2009 Dec;23(6):1299–316.
44. Letsky EA, Greaves M. Guidelines on the investigation and management of
thrombocytopenia in pregnancy and neonatal alloimmune thrombocytopenia.
Maternal and Neonatal Haemostasis Working Party of the Haemostasis and
Thrombosis Task Force of the British Society for Haematology. Br J Haematol. 1996
Oct;95(1):21–6.
94
45. Chosamata B. The management of immune thrombocytopenic purpura. Malawi
Med J. 2015 Sep;27(3):109–12.
46. Fujimura K, Harada Y, Fujimoto T, Kuramoto A, Ikeda Y, Akatsuka J-I, et al.
Nationwide study of idiopathic thrombocytopenic purpura in pregnant women and
the clinical influence on neonates. Int J Hematol. 2002 May;75(4):426–33.
47. Pradat P, Robert-Gnansia E, Di Tanna GL, Rosano A, Lisi A, Mastroiacovo P, et
al. First trimester exposure to corticosteroids and oral clefts. Birt Defects Res A Clin
Mol Teratol. 2003 Dec;67(12):968–70.
48. Gill KK, Kelton JG. Management of idiopathic thrombocytopenic purpura in
pregnancy. Semin Hematol. 2000 Jul;37(3):275–89.
49. Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP).
Blood. 2005 Oct 1;106(7):2244–51.
50. Cuthbert RJ, Watson HH, Handa SI, Abbott I, Ludlam CA. DDAVP shortens the
bleeding time in Bernard-Soulier syndrome. Thromb Res. 1988 Mar 15;49(6):649–
50.
51. Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding.
Cochrane Database Syst Rev. 2000;(4):CD000249.
52. Demers C, Derzko C, David M, Douglas J, Society of Obstetricians and
Gynecologists of Canada. Gynaecological and obstetric management of women with
inherited bleeding disorders. J Obstet Gynaecol Can JOGC J Obstet Gynecol Can
JOGC. 2005 Jul;27(7):707–32.
53. van Eijkeren MA, Christiaens GC, Geuze HJ, Haspels AA, Sixma JJ. Effects of
mefenamic acid on menstrual hemostasis in essential menorrhagia. Am J Obstet
Gynecol. 1992 May;166(5):1419–28.
54. Avouac B, Combe B, Darné B. [Prescription of NSAIDs in patients treatment
with platelet inhibitors or anticoagulants]. Presse Medicale Paris Fr 1983. 2003 Nov
22;32(37 Pt 2):S38-43.
55. DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet
dysfunction. Am J Hematol. 1990 Jan;33(1):39–45.
56. Irvine GA, Cameron IT. Medical management of dysfunctional uterine bleeding.
Baillieres Best Pract Res Clin Obstet Gynaecol. 1999 Jun;13(2):189–202.
95
57. Stewart A, Cummins C, Gold L, Jordan R, Phillips W. The effectiveness of the
levonorgestrel-releasing intrauterine system in menorrhagia: a systematic review.
BJOG Int J Obstet Gynaecol. 2001 Jan;108(1):74–86.
58. Lethaby AE, Cooke I, Rees M. Progesterone/progestogen releasing intrauterine
systems versus either placebo or any other medication for heavy menstrual bleeding.
Cochrane Database Syst Rev. 2000;(2):CD002126.
59. Siegel JE, Kouides PA. Menorrhagia from a haematologist’s point of view. Part
II: management. Haemoph Off J World Fed Hemoph. 2002 May;8(3):339–47.
60. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Frequency of inherited
bleeding disorders in women with menorrhagia. Lancet Lond Engl. 1998 Feb
14;351(9101):485–9.
61. Kushwaha R, Kumar A, Mishra KL, Sankhwar PL, Singh R. Haemostatic
Disorder in Women with Unexplained Menorrhagia: A Tertiary Care Centre
Experience from Northern India. J Clin Diagn Res JCDR. 2017 May;11(5):EC46–9.
62. Philipp CS, Dilley A, Miller CH, Evatt B, Baranwal A, Schwartz R, et al. Platelet
functional defects in women with unexplained menorrhagia. J Thromb Haemost.
2003;1(3):477–84.
63. Non-surgical interventions for treating heavy menstrual bleeding (menorrhagia) in
women with bleeding disorders. - PubMed - NCBI [Internet]. [cited 2019 Aug 20].
Available from: https://www.ncbi.nlm.nih.gov/pubmed/25426776
64. Iron Deficiency Anemia: Common in Adolescents With Heavy Menstrual
Bleeding [Internet]. [cited 2019 Aug 20]. Available from:
https://www.medpagetoday.com/resource-centers/focus-on-iron-deficiency-
anemia/iron-deficiency-anemia-common-adolescents-heavy-menstrual-bleeding/1651
65. Bick RL. Recurrent miscarriage syndrome and infertility caused by blood
coagulation protein or platelet defects. Hematol Oncol Clin North Am. 2000
Oct;14(5):1117–31.
66. Bick RL, Hoppensteadt D. Recurrent Miscarriage Syndrome and Infertility Due to
Blood Coagulation Protein/Platelet Defects: A Review and Update. Clin Appl
Thromb. 2005 Jan;11(1):1–13.
67. Shahbazi S, Moghaddam-Banaem L, Ekhtesari F, Ala FA. Impact of inherited
bleeding disorders on pregnancy and postpartum hemorrhage. Blood Coagul
Fibrinolysis Int J Haemost Thromb. 2012 Oct;23(7):603–7.
96
68. Von Mackensen S. Quality of life in women with bleeding disorders. Haemoph
Off J World Fed Hemoph. 2011 Jul;17 Suppl 1:33–7.
97
ANNEXURES 1
Information sheet
STUDY ON ABNORMAL UTERINE BLEEDING IN WOMEN WITH
BLEEDING DISORDER
PATIENT INFORMATION SHEET
You are being invited to take part in a research study on abnormal menstrual
bleeding in women with bleeding disorders.
Before you decide it is important for you to understand why the research is being
done and what it will involve. Please take time to read the following information
carefully. Ask us if you need more information. Take time to decide whether you
wish to be part of this study.
Among women with bleeding diseases 67% of them present with abnormal
menstrual bleeding.40-50% of them have limitation of daily activities during their
menstrual cycles. There are no proper treatment protocols for abnormal menstrual
bleeding in women with bleeding diseases. Hence this study aims to collect data on
treatment given in the past for abnormal uterine bleeding to women with bleeding
diseases and make treatment protocols.
Once you are recruited in our study, a questionnaire will be filled by the investigator
and if you are inadequately treated you will be referred to Gynecology OPD for
evaluation and treatment.
There will be no additional cost to the patient because of this study.
Only the investigator and co investigators will have access to the information of the
study and the details will be kept confidential. Your participation in the study is
entirely voluntary and you are free to withdraw from the study even after it starts.
Thank you for taking part in this study.
98
99
100
ANNEXURE 2
Consent form
Informed Consent Form for Subjects
STUDY ON ABNORMAL UTERINE BLEEDING IN WOMEN WITH
BLEEDING DISORDERS
Serial Number: ____________
Subject’s Initials: __________________ Subject’s Name:
_________________________________________
Date of Birth / Age: ___________________________
(Subject)
(i) I confirm that I have read and understood the information sheet dated ____________ for
the above study and have had the opportunity to ask questions. [ ]
(ii) I understand that my participation in the study is voluntary and that I am free to withdraw
at any time, without giving any reason, without my medical care or legal rights being
affected. [ ]
(iii) I understand that the investigator and co-investigators, the Ethics Committee and the
regulatory authorities will not need my permission to look at my health records both in
respect of the current study and any further research that may be conducted in relation to
it, even if I withdraw from the trial. I agree to this access. However, I understand that my
identity will not be revealed in any information released to third parties or published. [ ]
101
(iv) I agree not to restrict the use of any data or results that arise from this study provided such
a use is only for scientific purpose(s). [ ]
(v) I agree to take part in the above study. [ ]
Signature (or Thumb impression) of the Subject/Legally Acceptable
Date: _____/_____/______
Signatory’s Name: _________________________________ Signature:
Or
Representative: _________________
Date: _____/_____/______
102
Signatory’s Name: _________________________________
Signature of the Investigator: ________________________
Date: _____/_____/______
Study Investigator’s Name: _________________________
Signature or thumb impression of the Witness: ___________________________
Date: _____/_____/_______
Name & Address of the Witness: ______________________________
103
ANNEXURE 3
Questionaire
STUDY ON ABNORMAL UTERINE BLEEDING IN WOMEN WITH BLEEDING
DISORDERS
Serial number-
Name-
Hospital number-
Age-
Phone number-
Address-
1)Haematological diagnosis
Symptoms at diagnosis
Heavy menstrual bleeding-
Bleeding while extracting tooth,surgery,abortion,delivery-
History of treatment of anemia-
Family of bleeding disorders-
2)Menstrual bleeding patterns
Duration of bleeding
Frequency of bleeding
Number of pads/clothes used per day
History of passage of clots-
If history is suggestive of AUB then the menstrual pattern-
History of admission in hospital due to HMB-
History of blood transfusion due to HMB-
3)Reproductive outcomes-
Married/unmarried-
Obstetric score-
History of infertility-
History of antepartum haemorrhage
History of post partumhaemorrhage-
If patient required blood transfusion antepartum or post partum-
4)Quality of life
If AUB has interfered with
Ability to attend classes
Ability to go for work
Ability to attend social gatherings
Occasionally/often/very
often
5)Treatment used-
First line treatment given-
104
Combined contraceptive pills-
Progesterone only pills-
DMPA-
Tranemexic acid-
Levonogesterol intrauterine device-
Duration of treatment-
Percentage of relief of symptoms-
6)If second line treatment-
Combined contraceptive pills-
Progesterone only pills-
DMPA-
Tranemexic acid-
Levonogesterol intrauterine device
Duration of treatment-
Percentage of relief of symptom-
History of using conservative surgery like thermal ballon ablation-
History of use of definitive surgery like hysterectomy-
If the patient is inappropriately treated
PBAC scoring
Is the patient referred to Obstetrics and Gynaecology department for
appropriate management-
105
106
ANNEXURE 4
THESIS DATA
107
108
109
