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].

• 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]

• Delayed Gastric Emptying

  Albums GF086 Hyperemesis / Hypoprothrombinemia Hyperemesis / Hypoprothrombinemia - Gastric Marginal Ulcers After Pancreaticoduodenectomy With Pancreaticogastromy Due To Delayed Gastric Emptying And Helicobacter Pylori Infection / Cystic Lesions Of The [discogs.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]

  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]

  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]

  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]

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]

• Vitamin K Decreased

  A vitamin K-dependent clotting factor is seldom seen as a contributor to inherited prothrombin deficiencies, but lack of Vitamin K decreases the synthesis of prothrombin in liver cells.Acquired underlying causes of this condition include severe liver [en.wikipedia.org]

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]

Prognosis for patients varies and is dependent on severity of the condition and how early the treatment is managed. With proper treatment and care, most people go on to live a normal and healthy life. [en.wikipedia.org]

[…] lupus anticoagulant levels. 5 There are no guidelines indicating what the best treatment is for LAHS, most treatment being based on corticoids with another immunosuppressor. [revistanefrologia.com]

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]

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

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]

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]

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

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

[…] 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]

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]

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]

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]

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

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]

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]

Symptoms - Acquired hypoprothrombinemia Causes - Acquired hypoprothrombinemia Prevention - Acquired hypoprothrombinemia Not supplied. Diagnosis - Acquired hypoprothrombinemia Not supplied. [checkorphan.org]

1. Meeks SL, Abshire TC. Abnormalities of prothrombin: a review of the pathophysiology, diagnosis, and treatment. Haemophilia. 2008;14(6):1159-1163.
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.