Edit concept Question Editor Create issue ticket

Acquired Prothrombin Deficiency

Acquired Hemophilia

Acquired prothrombin deficiency, which is also referred to as acquired factor II deficiency (AFIID), is a rare coagulation disorder of autoimmune origin. It is most frequently diagnosed in the presence of lupus anticoagulants, then constituting the so-called lupus anticoagulant-hypoprothrombinemia syndrome (LAHS). Isolated AFIID is increasingly rare but has been described. AFIID therapy is based on the compensation for blood loss, immunosuppression, and treatment of any underlying disorder.


Presentation

The clinical presentation of AFIID depends on the extent of the deficiency. While minor deficiencies of prothrombin may go unnoticed, the near-complete inactivation of this coagulation factor may lead to extensive hemorrhages [1].

The formation of hematoma after minor trauma is most commonly observed. Hematoma may form in subcutaneous tissues, muscles, or joints [2]. In the long term, recurrent hemarthrosis may induce degenerative changes of joint structures and disabling hemophilic arthropathy [3]. Furthermore, AFIID patients tend to bleed for prolonged periods of time after sustaining a penetrating injury, and they may report a propensity to gum bleeding, epistaxis, and other forms of mucosal hemorrhages. Women in fertile age may suffer from menorrhagia [1]. Fortunately, AFIID isn't typically associated with life-threatening hemorrhages of the gastrointestinal tract or central nervous system [4]. Hematuria is rather common, though [1].

It should be noted that AFIID is generally diagnosed in pediatric patients suffering from systemic lupus erythematosus or viral infections [1]. Thus, their general condition may be determined by the primary disorder or by acquired hemophilia. The primary disorder may be associated with a prothrombotic state that may be restored upon the resolution of AFIID [5] [6].

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]
  • Symptoms include excessive umbilical cord bleeding, easy bruising, frequent nosebleeds and hemorrhaging after surgery or trauma. Women with FII deficiency experience menorrhagia, heavy menstrual bleeding, and postpartum hemorrhage after childbirth.[hemophilia.org]
  • Common symptoms Nosebleeds (epistaxis) Easy bruising Heavy or prolonged menstrual bleeding (menorrhagia) Bleeding into joints (hemarthrosis) Muscle bleeds Bleeding in the mouth, particularly after dental surgery or tooth extraction Other reported symptoms[haemophilia.ie]
  • Symptoms include: Umbilical stump bleeding at birth (for those severely affected) Nose bleeds Mouth bleeds Easy bruising Swelling, pain, or warmth around a joint Inability to straighten or bend a joint normally Headache or neck ache Drowsiness or loss[rarebleedingdisorders.com]
Prolonged Bleeding
  • Without it, people experience clotting failures and prolonged bleeding. However, thanks to vitamin K injections given before birth, this form of hypoprothrombinemia remains relatively rare, though still less rare than its inherited counterpart.[patientworthy.com]
  • In case of an antibody-mediated inactivation of AFIID, this procedure will not correct prolonged bleeding times and thereby confirm the presence of an inhibitor, namely lupus anticoagulant or an inhibitor of factorsor prothrombin.[symptoma.com]
  • A person with mild hemophilia may first discover the disorder with prolonged bleeding following a surgical procedure or injury.[encyclopedia.com]
  • Symptoms of the deficiency include prolonged bleeding, especially after an injury or after surgery. Women with prothrombin deficiency may have heavy menstrual bleeding.[rarediseases.info.nih.gov]
  • 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]
Anemia
  • […] can interfere with factor VII include: liver disease myeloma sepsis aplastic anemia vitamin K deficiency Symptoms vary from mild to severe, depending on your levels of usable factor VII.[healthline.com]
  • Sub Menu Disorders Bleeding Disorders Rare Bleeding Disorders Factor I Factor II Factor V Factor VII Factor VIII Factor X Factor XI Factor XIII Clotting Disorders Anemia (Also known as Prothrombin Deficiency) Factor II deficiency is quite rare, with only[ilbcdi.org]
  • Investigations revealed raised APTT and PT levels along with microcytic, hypochromic anemia. Fibrinogen level, platelet count, routine urine microscopy, and other hematological and biochemical parameters were within normal range.[e-ijd.org]
  • Seventeen patients were given packed RBCs because of severe anemia. No patient was given fresh frozen plasma. Although CT scan head was clinically indicated in 30 (72%) cases, it could be done in 28.[indianpediatrics.net]
  • Postoperatively, the surgery team suspected formation of a deep hematoma due to persistent anemia despite transfusion of 5 additional units of red cells over 6 days.[clinchem.aaccjnls.org]
Pallor
  • Bleeding (intracranial), pallor, poor suck, seizures and bulging anterior fontanelles were the most common clinical manifestations.[herdin.ph]
  • Hemorrhagic diathesis, pallor and mild hepatomegaly were the major manifestations. The incidence of intracr anial bleeding was strikingly high (63 per cent) particularly with subdural and subarachnoid hemorrhage.[ncbi.nlm.nih.gov]
  • Nearly 2/3rd of the patients had pallor on examination.[indianpediatrics.net]
  • General and systemic examination failed to reveal any abnormality, except pallor. Investigations revealed raised APTT and PT levels along with microcytic, hypochromic anemia.[e-ijd.org]
Pallor
  • Bleeding (intracranial), pallor, poor suck, seizures and bulging anterior fontanelles were the most common clinical manifestations.[herdin.ph]
  • Hemorrhagic diathesis, pallor and mild hepatomegaly were the major manifestations. The incidence of intracr anial bleeding was strikingly high (63 per cent) particularly with subdural and subarachnoid hemorrhage.[ncbi.nlm.nih.gov]
  • Nearly 2/3rd of the patients had pallor on examination.[indianpediatrics.net]
  • General and systemic examination failed to reveal any abnormality, except pallor. Investigations revealed raised APTT and PT levels along with microcytic, hypochromic anemia.[e-ijd.org]
Ecchymosis
  • The common manifestations of late HDN reported are evidence of intracranial hemorr-hage, deep ecchymosis, bleeding from GI tract and/or bleeding from mucus membrane, skin punctures or surgical incisions(11,12).[indianpediatrics.net]
Fatigue
  • Some patients show none of these symptoms but complain of fatigue and general weakness. There are several causes of thrombocytopenia, which is more commonly acquired as a result of another disorder.[encyclopedia.com]
Suggestibility
  • Our study suggests that prothrombin complex concentrates have predictable effectiveness in acquired hypoprothrombinemic bleeding episodes only when coagulation deficiencies are limited to the prothrombin complex (coagulation factors II, VII, IX, and X[annals.org]
  • Some centres keep a list of suggested medications; ask if the centre has one Diagnosis - Acquired prothrombin deficiency Prothrombin ( factor II) is one of the approximately 15 clotting proteins that is needed to stop us from bleeding.[checkorphan.org]
  • A low vitamin K intake by infants is suggested to have a major role in the pathogenesis. To reduce the incidence of this syndrome, its risk factors have to be identified.[ncbi.nlm.nih.gov]
  • If anamnestic and clinical data suggest hemophilia, coagulation studies have to be carried out.[symptoma.com]
  • An isolated PT prolongation suggests a deficiency or inhibition of the extrinsic pathway (FVII), but mild factor X, V, and II deficiencies are also possible causes.[clinchem.aaccjnls.org]
Epistaxis
  • Furthermore, AFIID patients tend to bleed for prolonged periods of time after sustaining a penetrating injury, and they may report a propensity to gum bleeding, epistaxis, and other forms of mucosal hemorrhages.[symptoma.com]
  • […] and gum bleeding Late vitamin K deficiency bleeding usually presents as mucosal haemorrhages. [2] Epistaxis is the bleeding from the nose and oral mucosal bleeding result in gum bleeding.[explainmedicine.com]
  • 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]
  • Common symptoms Nosebleeds (epistaxis) Easy bruising Heavy or prolonged menstrual bleeding (menorrhagia) Bleeding into joints (hemarthrosis) Muscle bleeds Bleeding in the mouth, particularly after dental surgery or tooth extraction Other reported symptoms[haemophilia.ie]
  • See Bleeding Symptoms of Rare Clotting Factor Deficiencies Common symptoms nosebleeds (epistaxis) easy bruising heavy or prolonged menstrual bleeding (menorrhagia) bleeding into joints (hemarthrosis) muscle bleeds bleeding in the mouth, particularly after[wfh.org]
Hematuria
  • Hematuria is rather common, though. It should be noted that AFIID is generally diagnosed in pediatric patients suffering from systemic lupus erythematosus or viral infections.[symptoma.com]
  • […] in the gut (gastrointestinal hemorrhage) bleeding from the umbilical cord stump at birth abnormal bleeding during or after injury, surgery, or childbirth Rare symptoms bleeding in the central nervous system (the brain and spinal cord) blood in urine (hematuria[wfh.org]
  • Menorrhagia Excess menstrual bleeding may be found in females. [6] Hematuria Urogenital bleeding may present as haematuria. [6] Suburothelial bleeding may result in obstructive uropathy. [6] Pathological fractures Vitamin K is essential for the bone metabolism[explainmedicine.com]
  • Blood in the urine (hematuria) is rare. Bleeding in the gut (gastrointestinal hemorrhaging) has been reported usually in relation to an underlying disease rather than the factor deficiency itself.[rarediseases.org]
Intracranial Hemorrhage
  • The diagnosis of APCD was made based on prolonged prothrombin times and proven intracranial hemorrhage on brain CT-scan. All subjects were treated with vitamin K injections for 5 days and offered craniotomy procedures.[ingentaconnect.com]
  • Intracranial hemorrhage was noted in 50 percent of patients. Fifty two percent of patients died.[herdin.ph]
  • All the scans revealed large intracranial hemorrhage. The majority of the patients showed hemorrhage at more than one site (75%).[indianpediatrics.net]
  • Severe forms may present intracranial hemorrhage or umbilical bleeding. The severity of the bleeding manifestations correlates with the FII levels.[orpha.net]
  • Intracranial hemorrhages due to late-type vitamin K deficiency bleeding. Childs Nerv Syst 2008;24:821-5. 3. Nagi NA, Al-Dubooni HM, Al-Shirkat SA. Nodular purpura in infancy. Postgrad Med J 1982;58:274-8. [ PUBMED ] 4.[e-ijd.org]
Irritability
  • The most common signs and symptoms were bleeding (80 percent), pallor (76 percent), poor suck (70 percent), seizure (60 percent), and irritability (56 percent).[herdin.ph]

Workup

If anamnestic and clinical data suggest hemophilia, coagulation studies have to be carried out. These include the assessment of platelet count, plasma fibrinogen concentration, activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). While APTT reflects the integrity of the intrinsic cascade and common pathway of coagulation, PT depends on the extrinsic cascade and common pathway. In order to measure TT, thrombin is added to the plasma sample, so the result doesn't depend on the conversion of factor II to factor IIa. Hence, prolonged APTT and PT would be expected in AFIID patients, whereas their TT should be in the reference range [4] [7]. Platelet count and plasma fibrinogen concentration are not altered by AFIID.

Prolonged APTT and PT may also be obtained in those who suffer from a deficiency of factors I, V, or X, or vitamin K, from liver disease or disseminated intravascular coagulation, so all these conditions should be ruled out [7] [8]. Similarly, therapy with anticoagulants like warfarin may induce a prolongation of APTT and PT. The patient's medical history, hemogram, and blood chemistry should implicate a coagulation disorder, and this suspicion is most easily confirmed by the detection of an endogenous inhibitor. Therefor, the patient's plasma is mixed with normal plasma [4]. In case of an antibody-mediated inactivation of AFIID, this procedure will not correct prolonged bleeding times and thereby confirm the presence of an inhibitor, namely lupus anticoagulant or an inhibitor of factorsor prothrombin. The presence of AFIID antibodies that accelerate the factor's clearance but don't interfere with its activation may result in a normalization of PT upon mixing [1].

Testing for lupus anticoagulant is the next step and carried out as the dilute Russell’s Viper Venom Test or Staclot LA. Its results depend on the etiology of AFIID in the index case. In LAHS patients, lupus anticoagulant is present; in the rare cases of isolated AFIID, it cannot be detected. Lupus anticoagulant is typically related to venous and arterial thrombosis, so its association with a tendency to bleed should raise suspicion as to LAHS and warrants the assessment of factor II activity [9]. If the test for lupus anticoagulant yields negative results, the activities of coagulation factors I, V, and X, should also be measured. In AFIID, the activity of prothrombin is below the reference range, and a determination of the factor II inhibitor titer becomes necessary [8].

The diagnosis of AFIID may be followed by studies aiming at the identification of the underlying disorder if it hasn't been defined until this point. Laboratory analyses of blood samples may yield valuable hints at a primary autoimmune disease, so the presence of anti-beta-2-glycoprotein, anticardiolipin, anti-double-stranded DNA, antinuclear, antimitochondrial, and antineutrophil cytoplasmic antibodies should be reviewed [8]. Due to a possible link to malignancy, patients should undergo a general cancer screening.

Treatment

Because of the rarity of AFIID, there are no standardized recommendations for treatment [9]. According to the general condition of the patient and their particular needs, either of the strategies listed below may be followed.

  • Symptomatic therapy is based on the transfusion of plasma and red blood cells and aims at compensating for severe blood loss. Platelet concentrates are rarely required, but if hemorrhages can't be controlled, the administration of prothrombin complex concentrates may be indicated. The risk of thrombosis due to the concomitant increase of factors IX and X should be considered before making this decision [8] [10] [11]. The supplementation of vitamin K may help to restore homeostasis [1].
  • On the other hand, immunosuppressive therapy is indicated to inhibit the autoimmune reaction generating antibodies against factor II. Most patients receive high-dose corticosteroid therapy with prednisone or methylprednisolone as a first-line treatment, but other immunosuppressants such as cyclophosphamide, azathioprine, and rituximab may also be applied [9]. Some patients receive intravenous immunoglobulins. In refractory cases, the need for combination therapy may arise. Corticosteroids should be tapered slowly, and coagulation studies should be repeated after therapy to quantify the patient's response to treatment [1].
  • If an underlying disorder is identified, adequate treatment of this condition is indicated.

Prognosis

AFIID is a potentially curable disease, and even spontaneous resolution has been described. The latter is likely to occur in patients developing AFIID due to the transient formation of lupus anticoagulants, e.g., in the scope of a viral infection. If the underlying disorder persists, relapses are to be expected. AFIID-related hemorrhages may be life-threatening, and fatal cases have been reported [1] [9]. Death may also occur from the primary disorder [10].

Etiology

AFIID is provoked by autoantibodies directed against coagulation factor II. These antibodies may partially or completely neutralize the function or activation of prothrombin, or accelerate its clearance [12]. Similar to other autoimmune disorders, the precise triggers of the immune response against prothrombin remain unknown. Certain pathological conditions, however, seem to predispose to AFIID. There is a high prevalence of systemic lupus erythematosus and viral infections among AFIID patients, and a causal relation is very likely. AFIID has also been related to lymphoma and other types of malignancy [10] [13]. In some cases, though, no primary disease can be identified, and AFIID is deemed idiopathic [8].

Epidemiology

AFIID is a rare disorder affecting two groups of patients:

  • On the one hand, there are pediatric patients or young adults with systemic lupus erythematosus, viral infections, or, rarely, lymphoma, who develop LAHS-related AFIID. More than half of affected individuals are younger than 16 years, and the patients' median age at the time of symptom onset is 13 years. Females are affected more frequently than males [1].
  • On the other hand, there are elder adults with AFIID. They may suffer from malignancies, but there's also a general trend towards an increased incidence of autoimmune disorders in individuals of advanced age [8].
Sex distribution
Age distribution

Pathophysiology

The conversion of prothrombin to thrombin constitutes the first step of the common pathway of coagulation. It is preceded by the intrinsic and extrinsic cascades, so irrespective of whether endothelial lesions or tissue damage trigger clotting, it always relies on the presence of factor II and its activation to factor IIa [11]. Thus, AFIID may cause extensive, potentially life-threatening hemorrhages.

An interesting phenomenon can be observed in LAHS patients. These patients' blood contains autoantibodies binding to plasma proteins that have an affinity for phospholipid surfaces, such as prothrombin. The antibody-prothrombin complexes are rapidly cleared, thereby decreasing factor II levels and causing a hemorrhagic diathesis - which is in contrast to the more common prothrombotic phenotype of patients with antiphospholipid syndrome. The hepatic clearance of the antibody-prothrombin complexes is even faster in pediatric patients, which may explain why LAHS is preferentially observed in the young. Somewhat surprisingly, antibody binding doesn't interfere with the activiation of prothrombin, so PT may normalize after mixing the patient's plasma with normal plasma. As implied above, antiphospholipid antibodies may also bind to anticoagulative components of the coagulation system, thereby inducing a prothrombotic state [9]. This is the pathogenesis of antiphospholipid syndrome, a frequent complication of systemic lupus erythematosus. The antibodies' affinity to prothrombin seems to determine whether a patient develops LAHS or antiphospholipid syndrome [1].

Prevention

Few recommendations can be given to prevent the onset of AFIID. The precise triggers of the disease remain elusive, and effective measures to prevent the primary disorders predisposing to AFIID have not been described. However, regular follow-ups may allow for the early identification of high-risk patients, e.g., those suffering from systemic lupus erythematosus who test positive for antiphospholipid antibodies. These individuals may subsequently be informed about the symptoms of a coagulation disorder, so that they can react faster in case of hemorrhages or thromboembolism [14]. In general, patients should stay up to date with screenings for cancer, so malignancies can be diagnosed and treated in a timely manner.

Summary

AFIID is a rare coagulation disorder. The deficiency of factor II interrupts the coagulation cascade in the common pathway, so neither the intrinsic nor the extrinsic activation of coagulation are successful. The severity of the disease varies largely, but AFIID patients may experience life-threatening hemorrhages. Disease onset is triggered by an autoimmune reaction leading to the generation of antibodies against prothrombin. The causes of this autoimmune reaction remain unknown, but patients suffering from systemic lupus erythematosus, viral infections, or lymphoma seem to be predisposed. Still, many cases of AFIID are deemed idiopathic because no primary disorder can be identified.

The diagnosis of AFIID relies on standard coagulation studies. Common findings are prolonged APTT and PT, which may or may not normalize when the patient's plasma is mixed with normal plasma. Depending on the etiology of AFIID, lupus anticoagulant may yield positive or negative results: AFIID may occur as a complication of systemic lupus erythematosus and be associated with the formation of lupus anticoagulants, and the patient is then diagnosed with LAHS. On the other hand, AFIID may develop in the absence of lupus anticoagulant, resulting in the rare entity of isolated AFIID.

AFIID treatment is based on the rapid compensation for blood loss, the suppression of the causative autoimmune reaction, and, if feasible, therapy of the primary disease. If cure of the underlying disorder can be achieved, chances are the patient will also recover from AFIID.

Patient Information

The formation of blood clots is tightly regulated by a complex network of factors favoring or inhibiting coagulation. Prothrombin is one of these factors and is also called factor II. It is required for one of the final steps of the coagulation cascade, and patients with a factor II deficiency have a propensity to bleed. Such a deficiency may be congenital, when certain mutations are inherited, or acquired. Acquired prothrombin deficiency manifests if the patient's body generates antibodies that bind to factor II and accelerate its degradation. But why are those antibodies produced?

This question could not yet be answered satisfactorily. Acquired prothrombin deficiency is most commonly diagnosed in children and adolescents who suffer from systemic lupus erythematosus. Individuals who recently recovered or are still suffering from a viral infection are at increased risks, too. Deficiency of factor II may occasionally affect the elderly, and while the disease may be related to cancer in this age group, no cause is identified in the majority of patients. Indeed, studies aiming at the identification of an underlying disorder are an integral part of the diagnosis, which is otherwise based in standard coagulation tests.

Treatment relies on three pillars: the transfusion of blood products to immediately compensate for possibly life-threatening blood loss, the administration of immunosuppressive drugs to inhibit the production of autoantibodies, and an adequate therapy of the primary disease if it can be identified. Unless the underlying disorder is associated with a poor outcome, patients diagnosed with acquired prothrombin deficiency have a favorable prognosis. In the majority of individuals, especially in children, spontaneous resolution occurs.

References

Article

  1. 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.
  2. Peyvandi F, Palla R, Menegatti M, Mannucci PM. Introduction. Rare bleeding disorders: general aspects of clinical features, diagnosis, and management. Semin Thromb Hemost. 2009; 35(4):349-355.
  3. Melchiorre D, Manetti M, Matucci-Cerinic M. Pathophysiology of Hemophilic Arthropathy. J Clin Med. 2017; 6(7).
  4. Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood. 2015; 125(13):2052-2061.
  5. Abdo L, Mekinian A, Riviere S, Fain O. A case of lupus anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus. Joint Bone Spine. 2016; 83(5):589-590.
  6. Vinet E, Rich E, Senécal JL. Thromboembolism complicating the treatment of lupus anticoagulant hypoprothrombinemia syndrome. J Rheumatol. 2006; 33(10):2088-2090.
  7. Campbell SE, Bolton-Maggs PH. Congenital and acquired bleeding disorders in infancy. Early Hum Dev. 2015; 91(11):637-642.
  8. Huang LW, Anand S, Hassan S, Onwuemene O. Bruised Black and Blue: Acquired Hypoprothrombinemia. Am J Med. 2015; 128(11):e7-e11.
  9. Cetin Gedik K, Siddique S, Aguiar CL. Rituximab use in pediatric lupus anticoagulant hypoprothrombinemia syndrome - report of three cases and review of the literature. Lupus. 2018; 27(7):1190-1197.
  10. Alamelu J, McCormick A, Moore GW, Madan B. Acquired prothrombin deficiency in a patient with follicular lymphoma. Haemophilia. 2008; 14(3):634-636.
  11. Hurwitz A, Massone R, Lopez BL. Acquired bleeding disorders. Emerg Med Clin North Am. 2014; 32(3):691-713.
  12. Kessler CM, Knöbl P. Acquired haemophilia: an overview for clinical practice. Eur J Haematol. 2015; 95 Suppl 81:36-44.
  13. Lee ES, Hibsman BK, Liebman HA. Acquired bleeding disorder in a patient with malignant lymphoma: antibody-mediated prothrombin deficiency. Cancer. 2001; 91(4):636-641.
  14. Doria A, Arienti S, Rampudda M, Canova M, Tonon M, Sarzi-Puttini P. Preventive strategies in systemic lupus erythematosus. Autoimmun Rev. 2008; 7(3):192-197.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-07-11 20:08