Prothrombin is an essential vitamin K-dependent zymogen that is synthesized in the liver and forms thrombin, with its principal function being the conversion of fibrinogen to fibrin, which is essential for the creation of a stable blood clot [1] [2]. In the literature, hypoprothrombinemia (factor II deficiency) can occur due to both inherited and acquired pathophysiological mechanisms [1] [2] [3] [4] [5]. Inherited factor II deficiency is considered to be the rarest hereditary disorder of coagulation, with estimated incidence rates of 1 in 2,000,000 individuals [1] [2] [5] [6]. The autosomal recessive pattern of inheritance is the mode of its transfer and two types have been identified - type 1, also known as true hypoprothrombinemia, is characterized by very low levels of prothrombin and its functional activity; and type II (dysprothrombinemia), where the synthesis of a dysfunctional protein is observed [2] [5] [6]. Both phenotypes arise from mutations in the gene coding for prothrombin (located on chromosome 11), and the clinical presentation is proportional to the severity of deficiency [2] [6]. Heterozygotes are often asymptomatic, whereas homozygotes and compound heterozygotes may present with excessive bleeding after trauma and surgical procedures, bruising, hemarthrosis and menorrhagia in women [1] [2]. Furthermore, a much higher risk of thrombosis and thromboembolic disease is evident in a certain subtype [1]. In rare cases, chronic musculoskeletal disorders, anemia, and intracerebral hemorrhage have been reported [7]. On the other hand, the pathogenesis of acquired hypoprothrombinemia almost always involves the formation of prothrombin antibodies, principally seen in systemic lupus erythematosus (SLE), but certain viral infections and malignancies are reported as possible etiologies as well [3]. Hence, the term lupus anticoagulant-hypoprothrombinemia syndrome (LA-HPS) is used to describe this rare disorder that is most frequently diagnosed in the pediatric population, with a slight female predominance [3] [4]. The clinical presentation is similar to hereditary hypoprothrombinemia, and patients who develop a severe inflammatory reaction might suffer from sudden and life-threatening hemorrhagic episodes in the absence of adequate treatment [3] [4].

• Asymptomatic

  Heterozygotes are often asymptomatic, whereas homozygotes and compound heterozygotes may present with excessive bleeding after trauma and surgical procedures, bruising, hemarthrosis and menorrhagia in women. [symptoma.com]

  However, the risk of bleeding in asymptomatic individuals cannot be underestimated in circumstantial situations like major surgery [ 20, 26 ]. [mdpi.com]

  120 hours Clinical features Complete deficiency is incompatible with life Severe hemorrhage typically occurs when levels are < 5% Need levels of 10 - 40% for surgical hemostasis Patients have lifelong history or family history of bleeding; varies from asymptomatic [pathologyoutlines.com]

  Mild (> 40% activity): Patients are mostly asymptomatic, but might have problems with bleeding during trauma, a surgical procedure or with pregnancy/delivery Moderate (20-40% activity): Patients may have mild spontaneous bleeding, or bleeding triggered [rarebleedingdisorders.com]

• Falling

  “I spend only 15 or 20 days a month studying, until I fall unconscious in the classroom and the school administration shifts me to a hospital,” she said. “I am not sure where my life is going, but keeping up my courage helps me cope with things.” [tribune.com.pk]

  When the prothrombin level falls to about 10 to 15% of normal, even slight trauma may cause bleeding; when the level is below 10%, spontaneous hemorrhage may occur, in the form of hematoma, hematemesis, hematuria or melena. [rxmed.com]

  Thus, we recommend basing the diagnosis of PIGFD/GHIS on a combination of factors that fall into 4 stages. The first two stages investigate whether a patient with short stature could potentially fall into the PIGFD/GHIS category. [karger.com]

• Easy Bruising

  Common clinical signs include epistaxis, menorrhagia, oral cavity bleedings, mucosal bleeding, soft tissue bleeding, hemarthroses, easy bruising, and prolonged bleeding after tooth extraction, trauma or surgery. [orpha.net]

  As an alternative, they may have a history of a preceding viral infection, usually an upper respiratory infection or gastroenteritis. [7] Symptoms associated with hypoprothrombinemia include the following: Easy bruising Epistaxis Prolonged bleeding with [emedicine.medscape.com]

  bruising, postoperative bleeding, epistaxis, menorrhagia, miscarriage, postpartum hemorrhage, hemarthroses and intracranial bleeding (if severe deficiency) Laboratory Prolonged PT and PTT that correct with mixing study (1:1 mixture of patient and normal [pathologyoutlines.com]

• Bleeding Gums

  Specifically, when the bloodstream has insufficient levels of prothrombin, a patient develops hypoprothrombinemia, a condition characterized by the following symptoms: an increased susceptibility to bruising bleeding gums excessive or prolonged bleeding [checkorphan.org]

  Mild symptoms might include: bruising and soft tissue bleeding longer bleeding time from wounds or dental extractions bleeding in joints nosebleeds bleeding gums heavy menstrual periods In more severe cases, symptoms can include: destruction of cartilage [healthline.com]

• Purpura

  Infants and babies within the first year of life who have homozygous protein S deficiency characteristically have purpura fulminans. [ihtc.org]

  Disorders affecting the vessel walls Henoch-Schonlein purpura : supportive care Thrombotic thrombocytopenic purpura : prompt plasma exchange therapy (see TTP for details) Disorders of secondary hemostasis Disorders of the intrinsic pathway Hemophilia [amboss.com]

  ICD-10-CM Codes › D50-D89 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism › D65-D69 Coagulation defects, purpura and other hemorrhagic conditions › D68- Other coagulation defects › Acquired coagulation [icd10data.com]

  Clinically, catastrophic APS (CAPS) may resemble thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.30 Recurrent thromboembolic events tend to have consistency with respect to site (ie, arterial-arterial, venous-venous). [the-medical-dictionary.com]

  A case of congenital prothrombin deficiency and idiopathic thrombocytopenic purpura in a pregnant female. Blood Coagul Fibrinolysis. 2016 Feb 15. [Medline]. Watson H, Perez A, Ayesu K, Musa F, Sarriera J, Madruga M, et al. [emedicine.medscape.com]

• Epistaxis

  Common clinical signs include epistaxis, menorrhagia, oral cavity bleedings, mucosal bleeding, soft tissue bleeding, hemarthroses, easy bruising, and prolonged bleeding after tooth extraction, trauma or surgery. [orpha.net]

  As an alternative, they may have a history of a preceding viral infection, usually an upper respiratory infection or gastroenteritis. [7] Symptoms associated with hypoprothrombinemia include the following: Easy bruising Epistaxis Prolonged bleeding with [emedicine.medscape.com]

  < 5% Need levels of 10 - 40% for surgical hemostasis Patients have lifelong history or family history of bleeding; varies from asymptomatic to minor bleeding to severe bleeding (depending on the mutation) Also easy bruising, postoperative bleeding, epistaxis [pathologyoutlines.com]

• Hematuria

  In our case, the Factor II level was 29% and only microscopic hematuria was observed. [kjim.org]

  […] an upper respiratory infection or gastroenteritis. [7] Symptoms associated with hypoprothrombinemia include the following: Easy bruising Epistaxis Prolonged bleeding with injury, tooth extraction, or surgery Oral mucosal bleeding Melena Hematochezia Hematuria [emedicine.medscape.com]

  536 Clinical Evaluation Of The Child With Hematuria 537 Isolated Glomerular Diseases Associated With Recurrent Gross Hematuria 538 Multisystem Disease Associated With Hematuria 539 Tubulointerstitial Disease Associated With Hematuria 540 Vascular Diseases [elsevier.com]

  Case report A 36-year-old black male patient was hospitalized in March 2013 after a four-day period of low back pain, bruised hips, macroscopic hematuria, and gingival bleeding. [scielo.br]

• Confusion

  Deficiency symptoms include dermatitis, microcytic hypochromic anemia (small, pale red blood cells), impaired immune function, depression, confusion, and convulsions. [britannica.com]

The rare nature of hypoprothrombinemia suggests that a thorough workup is necessary for the physician to raise clinical suspicion. Firstly, a detailed patient history that will cover the course of symptoms and their progression, but also the presence of similar findings within the family (given the autosomal recessive pattern of inheritance) must be obtained, followed by a complete physical examination. A presumptive diagnosis toward bleeding disorders must be made in the presence of typical signs and symptoms, particularly in the pediatric population, in which case a complete laboratory workup must be conducted immediately [4]. Both partial thromboplastin time (APTT) and prothrombin time (PT) are prolonged in hypoprothrombinemia, while the functional activity of factor II through assay testing is a more specific method to confirm hypoprothrombinemia [1] [3]. Usually, the activity of factor II in hereditary forms will be 10% of normal in homozygotes, and between 40-60% in heterozygotes [5]. Furthermore, genetic testing can be done, both in adults and even prenatally, to yield a solid diagnosis [1] [5]. On the other hand, detection of antiprothrombin antibodies is suggestive for acquired forms of hypoprothrombinemia [3] [4].

• Partial Thromboplastin Time Prolonged

  Prothrombin time Normal Normal Activated partial thromboplastin time Prolonged Normal or prolonged Test Haemophilia VWD Platelet count Normal Normal or reduced Bleeding time Normal Normal or prolonged Prothrombin time Normal Normal Activated partial [academic.oup.com]

No consensus exists for the treatment of LAHPS. Corticosteroids, with or without the addition of vitamin K or blood products, have been a successful first-line treatment. [ncbi.nlm.nih.gov]

Prophylactic Treatment Before Surgery If you are planning any surgeries or invasive procedures, infusions of clotting factor or other treatments may be required to minimize bleeding risks. [healthline.com]

Management and treatment Prothrombin Complex Concentrates (PCCs) or fresh frozen plasma (if PCCs are not available) is usually used to treat hemorrhagic episodes. Prognosis Prognosis is good with early diagnosis and adequate treatment. [orpha.net]

Prognosis Prognosis is good with early diagnosis and adequate treatment. The documents contained in this web site are presented for information purposes only. [orpha.net]

(Outcomes/Resolutions) The prognosis of Factor II Deficiency (both inherited and non-inherited type) is generally good with appropriate treatment The prognosis of non-inherited F II Deficiency may depend on the prognosis of the underlying disorder (such [dovemed.com]

Prognosis - Acquired hypoprothrombinemia The prognosis for patients with inherited prothrombin deficiency varies. [checkorphan.org]

This review summarizes what is currently known about the pathogenesis, clinical features, diagnosis, treatment and prognosis of LA-HPS, and presents two case reports. [ncbi.nlm.nih.gov]

Etiology Inherited FII deficiency is caused by mutations in the F2 gene (11p11-q12) encoding prothrombin. [orpha.net]

This practical text covers disorders of thrombosis and hemostasis in a logical and sequential manner: etiology, pathophysiology, clinical and laboratory diagnosis, and management. [books.google.com]

[…] other hand, the pathogenesis of acquired hypoprothrombinemia almost always involves the formation of prothrombin antibodies, principally seen in systemic lupus erythematosus (SLE), but certain viral infections and malignancies are reported as possible etiologies [symptoma.com]

Treatment - Acquired hypoprothrombinemia The treatment of hypoprothrombinemia depends on the underlying etiology. Plasma-derived products that contain factor II are available. [checkorphan.org]

Summary Epidemiology Factor II deficiency is the most rare coagulation factor deficiency. Prevalence of homozygous forms is estimated at 1/2,000,000. Both sexes are equally affected. [orpha.net]

[…] of prothrombin and is characterized by reduced prothrombin activity and antigen levels Dysprothrombinemia (type II deficiency) is the synthesis of dysfunctional prothrombin molecules and is characterized by reduced activity and normal antigen levels Epidemiology [pathologyoutlines.com]

Healthcare-Acquired Infections 131 Congenital And Perinatal Infections PART XII Adolescent Medicine 132 Adolescent Physical And Social Development 133 Gender And Sexual Identity 134 Gay, Lesbian, And Bisexual Adolescents 135 Transgender Care 136 The Epidemiology [elsevier.com]

Epidemiology Frequency United States Both acquired and inherited hypoprothrombinemia are exceedingly rare in the United States. [emedicine.com]

Abstract Heterocyclic thiol metabolites of cephalosporin antibiotics may play an important role in the pathophysiology of hypoprothrombinemia and hemorrhage in patients treated with these drugs. [ncbi.nlm.nih.gov]

This practical text covers disorders of thrombosis and hemostasis in a logical and sequential manner: etiology, pathophysiology, clinical and laboratory diagnosis, and management. [books.google.com]

In the literature, hypoprothrombinemia (factor II deficiency) can occur due to both inherited and acquired pathophysiological mechanisms. [symptoma.com]

Pathophysiology Thrombin is paramount to proper hemostasis. This powerful protease is at the core of the coagulation cascade. [emedicine.com]

Pathogenetic mechanisms leading to hypoprothrombinemia, its prevention and treatment are discussed. [ncbi.nlm.nih.gov]

Currently, there are no specific methods or guidelines to prevent the inherited form of Factor II Deficiency, since it is a genetic condition Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing [dovemed.com]

A vitamin K deficiency caused by antibiotics and intestinal disorders (that prevent absorption), can cause a temporary FII deficiency. Newborns may be born with a vitamin K deficiency. [hemophilia.ca]

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2. Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood. 2015;125(13):2052-2056.
3. Mulliez SM, De Keyser F, Verbist C, et al. Lupus anticoagulant-hypoprothrombinemia syndrome: report of two cases and review of the literature. Lupus. 2015;24(7):736-745.
4. Carvalho C, Viveiro C, Maia P, Rezende T. Acquired antiprothrombin antibodies: an unusual cause of bleeding. BMJ Case Rep. 2013;2013:bcr2012007948.
5. Girolami A, Scarano L, Saggiorato G, Girolami B, Bertomoro A, Marchiori A. Congenital deficiencies and abnormalities of prothrombin. Blood Coagul Fibrinolysis. 1998;9:557–569.
6. Lancellotti S, Basso M, De Cristofaro R. Congenital prothrombin deficiency: an update. Semin Thromb Hemost. 2013;39(6):596-606.
7. Acharya SS, Coughlin A, Dimichele DM. North American Rare Bleeding Disorder Study Group. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost. 2004;2(2):248-56.