Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

Users Online : 32357

AbstractCase ReportDiscussionConclusionReferencesDOI and Others
Article in PDF How to Cite Citation Manager Readers' Comments (0) Audio Visual Article Statistics Link to PUBMED Print this Article Send to a Friend
Advertisers Access Statistics Resources

Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Case Series
Year : 2024 | Month : August | Volume : 18 | Issue : 8 | Page : ER01 - ER05 Full Version

Multiple Coagulation Factor Deficiency: A Series of Eight Cases


Published: August 1, 2024 | DOI: https://doi.org/10.7860/JCDR/2024/70239.19697
Abhijith Lakshman, Febe Renjitha Suman, Gramani Arumugam Vasugi

1. Postgraduate Student, Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India. 2. Professor, Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India. 3. Associate Professor, Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India.

Correspondence Address :
Dr. Febe Renjitha Suman,
Professor, Department of Pathology, Sri Ramachandra Medical College, Mount Poonamallee Road Porur, Chennai-600116, Tamil Nadu, India.
E-mail: febemd@gmail.com

Abstract

Multiple Coagulation Factor Deficiency (MCFD) is an uncommon haematological disorder characterised by simultaneous deficiency of multiple clotting factors, which leads to an increased risk of bleeding and compromised haemostasis. The present series aimed to provide a comprehensive analysis of MCFD, shedding light on its aetiology, clinical manifestations, and potential therapeutic interventions in a case-by-case manner, highlighting the individualised treatment options that are needed for many of these cases. A prospective combined clinical and laboratory study was performed on all patients who presented with bleeding tendencies and were subsequently diagnosed with MCFD. Clinical records and laboratory data of all these patients were reviewed to identify commonalities and variations among affected individuals. Haematological assays were performed to quantify the extent of coagulation factor deficiencies. The present series identified a diverse cohort of eight individuals (2 females and 6 males) with MCFD, showcasing variability in age of onset, severity of symptoms, and potential underlying genetic mutations. Clotting factor assays revealed deficiencies of Factor V and Factor VIII (F5F8D), Vitamin K-dependent clotting factor deficiency, and failure of synthesis of clotting factors of hepatic origin. Clinically, patients presented with a spectrum of bleeding phenotypes, ranging from mild to severe, requiring tailored therapeutic strategies. The present series provides an overview of some of the presentations of MCFD, emphasising the need for a multidisciplinary approach in its diagnosis and management. Clinicians should be vigilant in recognising the varied clinical presentations of MCFD and consider genetic testing for precise diagnosis and management.

Keywords

Clotting disorder, Factor V, Factor VIII, Multiple factor deficiency, Vitamin K

Multiple Coagulation Factor Deficiency (MCFD), both inherited and acquired, is a rare and intricate haematological disorder denoted by simultaneous deficiency of multiple clotting factors essential for proper coagulation function. Unlike more common single-factor deficiencies, MCFD represents a unique confluence of deficiencies in Factors II, V, VII, IX, X, and occasionally others, creating a complex clinical scenario that demands a nuanced understanding. Multiple factor deficiencies can be either familial or acquired and are further divided into two types: the first represents a simultaneous occurrence of more than one single-factor hereditary state, while the second is a single inheritable disorder associated with a deficiency of more than two factors (1). Acquired causes, on the other hand, need to be investigated and treated appropriately. Understanding MCFD is crucial for optimising diagnostic strategies, tailoring therapeutic interventions, and ultimately improving patient outcomes (2).

Case Report

Case 1

An 18-year-old female patient presented with recurrent mucosal bleeds since childhood, as well as prolonged bleeding following a tooth extraction 8 years ago. Her brother was diagnosed with haemophilia A. Her parents also revealed that she was easily bruised after minor trauma. Laboratory investigations showed prolonged clotting time as well as depleted levels of factor V and VIII, and a combined factor V and VIII deficiency was suspected. The patient was started on Desmopressin {1-deamino-8-D-arginine vasopressin (DDAVP)} and factor VIII concentrates and showed a satisfactory response to treatment. She is doing well and was advised regarding the nature of the disease.

Case 2

A 47-year-old male presented with swelling in the knee joints following minor trauma one week ago. He also revealed that he had similar complaints of epistaxis and joint bleeds for many years, which were symptomatically managed in a local nursing home. No significant family history was noted. Complete blood count showed thrombocytopenia (Platelet count-27,000/cumm). Coagulation screen revealed reduced levels of factors V (9.4%) and VIII (22.2%). He was advised prophylactic DDAVP as well as Fresh Frozen Plasma (FFP). Repeat coagulation screen showed correction of FVIII values (57.3%), while factor V remained slightly deranged (43.4%). The patient is currently asymptomatic and responded well to the treatment.

Case 3

An 11-year-old male patient complained of bloating and passing bulky stools, which were observed to float, aggravated by eating heavy meals since three months. He also complained of intermittently present over three years and ecchymotic patches over the anterior abdomen, measuring 4 cm in greatest dimension, which had developed six months ago. The coagulation profile showed low levels of factors II (15.5), VII (<5%), IX (34.3%), and X (14.6%). An ultrasound of the abdomen revealed cholecystitis with numerous gallstones (Table/Fig 1), which, in turn, had resulted in lipid malabsorption and subsequently Vitamin K malabsorption. He underwent cholecystectomy for the same, following which he was administered 10 mg of Vitamin K. He responded well to the treatment and procedure, showing complete remission of symptoms after four weeks, while the ecchymotic patches resolved after three days.

Case 4

A 59-year-old female complains of petechial spots and bruises over her chest since one month and a single ecchymotic patch over her lower back for five days. Past history revealed a high-grade fever associated with chills and rigours for three weeks, which was relieved on taking over-the-counter medications. She was then referred to a hospital due to the persistence of symptoms and was diagnosed with septicaemia. Blood culture was performed which was positive for Klebsiella sp. Following her current admission, complete blood counts revealed no abnormalities, while the coagulation screen depicted reduced levels of factors II (15.7%), VII (21.4%), IX (8.5%), and X (9.5%). Repeat blood cultures showed no growth. Vitamin K was administered, resulted in the resolution of her symptoms.

Case 5

A 47-year-old male patient presents with sharp pain over the right hip joint since one week, which aggravates on walking and subsides with Non Steroidal Anti-inflammatory Drugs (NSAIDs), along with numerous reddish patches on his right thigh for one year. He had also taken various alternative medications of unknown brands to prevent Coronavirus Disease-2019 (COVID-19). Past history also revealed a fractured neck of the right femur, for which a bipolar prosthetic implant was inserted. Following this procedure, he was lost to follow-up and presented with his current complaints. Local examination revealed a few ecchymotic patches on the right thigh, with the largest measuring 5 x 4 cm. The right hip joint was swollen but non tender. The coagulation screen revealed deficiencies in factors II (24.6%), VII (<5%), IX (7.9%), and X (23.3%). He was advised against the use of NSAIDs without medical supervision and was administered Vitamin K (10 mg). The patient responded well to the treatment, and his coagulation parameters normalised after three days.

Case 6

A 63-year-old male presented with epistaxis, haematuria, and melena for the past six months and had undergone previous surgeries without blood transfusion. The coagulation screen revealed reduced levels of factor V (29.5%) and X (35.8%). Bone marrow aspirate revealed the presence of numerous plasma cells (72%), while serum electrophoresis showed an M band of 1.9 g/dL, consistent with a diagnosis of multiple myeloma, suggested a possibility of myeloma-induced clotting factor deficiency due to excess light chain production. Bony lytic lesions were also noted in the lumbar spine on Computed Tomography (CT) abdomen. A bone marrow biopsy and aspirate were performed, as seen in (Table/Fig 2),(Table/Fig 3). Increased plasma cells, plasmablasts, and binucleate forms were noted. He was initiated on the CyBor-D chemotherapy regimen and was followed-up with coagulation profiles and serum free light chain assay for six months. After three months, there was no detectable M band, and his symptoms were in remission.

Case 7

An 18-year-old male patient presented with ecchymosis over the back and shoulder for one year, along with chest pain and palpitations on strenuous exercise since five years. His Electrocardiogram (ECG) was unremarkable, while the echocardiogram showed left ventricular outflow tract obstruction in the form of Aortic Stenosis (AS). Haematological evaluation, which included a coagulation screen, showed reduced levels of von Willebrand factor (vWF) (16.4%) and factor XI (23.3%). These features were suggestive of Heyde syndrome, due to the presence of acquired von Willebrand syndrome and AS. He was treated with DDAVP and planned for balloon valvuloplasty. He withstood the surgery well and is currently on prophylactic DDAVP. He was also advised against taking part in contact sports.

Case 8

A 26-year-old male patient complained of prolonged bleeding from a skin tag, along with persistent thrombocytopenia for six months (Platelet count- 50,000/μL), as tested at another centre. The coagulation panel revealed depletion of all clotting factors except factor VIII and vWF, both of which have an extrahepatic site of synthesis. Factor VIII was elevated in this case (FVIII- 158.1%). Further investigations also showed deranged liver function tests. An ultrasound of the abdomen demonstrated moderate splenomegaly and cirrhosis of the liver. He was administered three units (750 mL) of FFP, which showed a slight elevation in the deficient factor levels (Factor II- 46.2%, Factor V- 53.6%, Factor VII- 57.4%, Factor IX- 42.3%, Factor X- 58.5%, Factor XI- 48.7%, Factor XII- 46.5%), and was stable on subsequent follow-up.

The eight cases are summarised in the table below with salient presenting features (Table/Fig 4). A coagulation panel and bleeding work-up were done for all these cases, and the laboratory findings of each patient are summarised in (Table/Fig 5). The individual details and relevant findings of each of these cases are further elucidated below.

Discussion

The exact cause of MCFD can be either inherited or acquired (2). They can range over a wide variety of aetiologies, which can include infections, inflammatory states, nutritional deficiencies, amyloidosis, sepsis, Disseminated Intravascular Coagulation (DIC), autoimmune diseases, liver diseases, or malignancies. While the prevalence of MCFD is comparatively low, the condition’s rarity should not undermine its clinical importance (1),(3).

The first two patients, cases 1 and 2, were found to have concomitant factor V and factor VIII deficiency (F5F8D). Soff and Levin classified Familial Multiple Factor Deficiencies (FMFD) into six types, and F5F8D is classified as FMFD I (4). The first case of F5F8D was diagnosed in 1954 in a pair of Swiss siblings, and since then, less than 200 cases have been reported, with an estimated incidence of 1:1,000,000.

Recently, there has been significant progress in understanding the underlying molecular mechanisms of these disorders (5),(6),(7). For instance, F5F8D is primarily caused by mutations in two different genes (LMAN1 and MCFD2) that encode components of a stable protein complex. Overall, 33 LMAN1 and 17 MCFD2 pathogenic mutations have been detected so far (8). This complex is linked and present in the secretory pathway of the cell and likely functions in transporting newly synthesised FV and FVIII, and perhaps other proteins, from the endoplasmic reticulum to the Golgi apparatus.

Clinically, they present with very mild symptoms and may be incidentally detected. As such, treatment options such as FFP are administered only if indicated, such as in both of the cases. Desmopressin acetate (DDVAP) may also be administered, though this raises only Factor VIII levels (9).

The next 3 cases (cases 3, 4, and 5) presented with bleeding disorders in the form of ecchymosis, and the coagulation panel revealed reduced levels of factors II, VII, IX, X, all of which are Vitamin K-dependent clotting factors. Despite the common laboratory picture, each case presented with a unique set of complaints and pathogenesis as highlighted in (Table/Fig 6).

Acquired causes of vitamin K deficiency should be evaluated and ruled out first due to their incidence. As seen in the present cases, they can have various causes including dietary insufficiency, drug intake, metabolic defects, liver diseases, malabsorption syndrome, sepsis, and altered gut bacteria. Inherited Vitamin K Clotting Factor Deficiency (VKCFD) can be caused by mutations in the genes encoding γ-carboxylase or vitamin K epoxide reductase (10). These two enzymes are key components of the carboxylation reactions which are vitamin K-dependant. Deficiency in either protein leads to under-carboxylation and hampers the activity of all the vitamin K-dependent coagulation factors, as well as several other proteins. In our case, the patient responded well to Vitamin K therapy, and due to the paucity of other systemic manifestations that are normally seen in inherited causes, acquired causes must first be considered and ruled out (11).

Multiple myeloma is known to interfere with the coagulation cascade, as the light chains bind with fibrinogen molecules, reducing functional activity. Additionally, they may bind with and interfere with both factors V and X. Multiple myeloma has a strong association with amyloidosis, which can also entrap factor X within the beta-pleated fibrils. However, factor X deficiency can occur in amyloid-negative multiple myeloma as well, as in case 6 (12).

Case 7 is a case of Heyde syndrome, a multisystem disorder characterised by the triad of gastrointestinal bleeding, acquired von Willebrand syndrome, and AS (13). The high molecular weight multimers of von Willebrand factor are ineffectively cleaved due to obstruction to outflow, resulting in consumption and subsequent bleeding. In people with stenosis of the aortic valve, the valve becomes increasingly narrowed, which results in an increase in the speed of the blood through the valve to maintain cardiac output, in accordance with the Hagen-Poiseuille law. This combination of a narrow opening and a higher flow rate results in increased shear stress on the blood (14). The von Willebrand normally uncoils into its active form at a site of damaged endothelium, further amplifying the haemostatic cascade. The higher shear stress seen in the narrowed valvular orifice in AS causes von Willebrand factor to uncoil as it would on encountering an injury site, albeit at a faster rate. Following this, it is degraded by its catabolic enzyme ‘A disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs’ (ADAMTS13). This results in an unusable vWF, which is unable to bind to the collagen exposed at the site of injury (15). As the amount of viable von Willebrand factor progressively decreases, the incidence of bleeding tendencies dramatically increases (8).

Liver disease results in various alterations in all three phases of haemostasis, as seen in case 8. This altered dynamic manifests as a fall in clotting factor levels, accompanied by a parallel fall in anticoagulant proteins. The liver plays a major role in blood coagulation, as it is the common site of synthesis of all clotting factors and their associated inhibitors, except for von Willebrand factor (8). As a result, liver damage is commonly associated with impairment of coagulation. Overall, the haemostatic cascade must precisely balance between antithrombotic and prothrombotic processes to prevent excessive blood loss from injured sites on one extreme end and to prevent spontaneous thrombosis on the other. Liver failure causes multiple changes in the haemostatic system, as discussed earlier, because of reduced plasma levels of procoagulant and anticoagulant factors synthesised by the residual intact liver. Additionally, vitamin K deficiency may also co-exist in this state, resulting in defective or reduced gamma-carboxylation of vitamin K-dependent clotting factors and inhibitors.

Portal hypertension, with the development of collaterals and secondary splenomegaly, causes the sequestration of platelets within the spleen, resulting in thrombocytopenia. There may also be associated impairment in platelet function. Complications of cirrhosis, such as sepsis or variceal bleeding, may further accelerate the initiation of bleeding. Even though the liver is damaged, the ability of sinusoid endothelial cells to produce factor VIII remains intact. This may be due to increased production outside the liver, possibly as a response to the injury or as a side-effect of inflammation triggered by endotoxins. Additionally, the high levels of vWF can be explained by its non-hepatic origin, decreased breakdown by the liver, and reduced activity of ADAMTS13 (9). These features suggest clotting factor deficiencies secondary to hepatic dysfunction. Elevated factor VIII levels were noted, which were explained by a compensatory production due to hepatocyte injury.

The prognosis and long-term management of MCFD depend on various factors, including the severity of the deficiency, the underlying cause, and the effectiveness of treatment. Contrary to single-factor deficiencies, which require a significant reduction in factor levels to produce bleeding symptoms, multiple factor deficiencies can produce a similar clinical picture even with mildly deranged values (6). Regular monitoring of coagulation factor levels and the management of underlying conditions are crucial in preventing complications and improving outcomes.

Conclusion

In the present case series, the treatment approach varied depending on whether the deficiency was inherited or acquired. For inherited MCFD, replacement therapy with specific deficient factors was the mainstay of treatment. However, for acquired MCFD, addressing the underlying condition or removing the triggering factor was found to be effective in normalising coagulation factor levels.

References

1.
Preisler B, Pezeshkpoor B, Banchev A, Fischer R, Zieger B, Scholz U, et al. Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a large cohort of patients- A single-center experience in genetic diagnosis. J Clin Med. 2021;10(2):347. [crossref][PubMed]
2.
Zhang B, Ginsburg D. Familial multiple coagulation factor deficiencies: New biologic insight from rare genetic bleeding disorders. J Thromb Haemost. 2004;2(9):1564-72. [crossref][PubMed]
3.
Guy JE, Wigren E, Svärd M, Härd T, Lindqvist Y. New insights into multiple coagulation factor deficiency from the solution structure of human MCFD2. J Mol Biol. 2008;381(4):941-55. [crossref][PubMed]
4.
Lenting PJ, VAN Schooten CJ, Denis CV. Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost. 2007;5(7):1353-60. [crossref][PubMed]
5.
Cheney G. Vitamin K. Deficiency in a case of gall bladder disease without clinical jaundice or hepatitis+. American Journal of Digestive Diseases. 1940;7(12):521-23. [crossref]
6.
Corrigan JJ Jr. Vitamin K-dependent coagulation factors in gram-negative septicaemia. Am J Dis Child. 1984;138(3):240-42. [crossref][PubMed]
7.
Dahlberg S, Schött U, Kander T. The effect of vitamin K on prothrombin time in critically ill patients: An observational registry study. J Intensive Care. 2021;9(1):11. [crossref][PubMed]
8.
Groeneveld DJ, Poole LG, Luyendyk JP. Targeting von Willebrand factor in liver diseases: A novel therapeutic strategy? J Thromb Haemost. 2021;19(6):1390-408. [crossref][PubMed]
9.
Madeira CL, Layman ME, de Vera RE, Fontes PA, Ragni MV. Extrahepatic factor VIII production in transplant recipient of hemophilia donor liver. Blood. 2009;113(21):5364-65. [crossref][PubMed]
10.
Kankirawatana S, Berkow R, Marques M. A neonate with bleeding and multiple factor deficiencies. Laboratory Medicine. 2006;37(2):95-97. [crossref]
11.
Jennings I, Kitchen DP, Kitchen S, Woods TA, Walker ID. Investigation of a prolonged APTT. Different approaches taken by laboratories to achieve the same diagnosis. Int J Lab Hematol. 2012;35(2):177-82. [crossref][PubMed]
12.
Sallah AS, Angchaisuksiri P, Roberts HR. Use of plasma exchange in hereditary deficiency of factor V and factor VIII. Am J Hematol. 1996;52(3):229-30. 3.0.CO;2-A>[crossref]
13.
Marshalek JP, Yashar D, Huynh K, Tomassetti S. Case of concurrent factor VII and factor XI deficiencies manifesting as spontaneous lower extremity compartment syndrome. Clin Case Rep. 2022;10(4):e05710.[crossref][PubMed]
14.
Banerjee S, Kapoor S, Mathur NB. Vitamin K deficiency bleeding. Journal of Neonatology. 2003;17(1):22-30. [crossref]
15.
Ndour DD, Mbaye M. Vitamin K deficiency bleeding: A case revealed by intracranial haemorrhage. Acad J Ped Neonatol. 20 17;6(2):555737.

DOI and Others

DOI: 10.7860/JCDR/2024/70239.19697

Date of Submission: Feb 20, 2024
Date of Peer Review: Mar 25, 2024
Date of Acceptance: May 07, 2024
Date of Publishing: Aug 01, 2024

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Feb 21, 2024
• Manual Googling: Mar 28, 2024
• iThenticate Software: May 06, 2024 (11%)

ETYMOLOGY: Author Origin

EMENDATIONS: 6

JCDR is now Monthly and more widely Indexed .
  • Emerging Sources Citation Index (Web of Science, thomsonreuters)
  • Index Copernicus ICV 2017: 134.54
  • Academic Search Complete Database
  • Directory of Open Access Journals (DOAJ)
  • Embase
  • EBSCOhost
  • Google Scholar
  • HINARI Access to Research in Health Programme
  • Indian Science Abstracts (ISA)
  • Journal seek Database
  • Google
  • Popline (reproductive health literature)
  • www.omnimedicalsearch.com