Factor V Inhibitors: A Diagnostic and Therapeutic Challenge.
The clinical manifestations of FV inhibitors vary; however, most people will have bleeding symptoms. The most common sites of hemorrhage are mucosal surfaces such as the gastrointestinal and genitourinary tracts. (1,7) Less frequently, patients present with intracranial or retroperitoneal hemorrhages but rarely do hemarthroses occur. (1,7) When inhibitors develop postoperatively, bleeding at the surgical site usually occurs 7 to 10 days following surgery. (11) Up to 20% of patients will have no bleeding symptoms at diagnosis, (6) and there are reports of patients presenting with thrombosis. (8,12,13) For example, an FV inhibitor was identified in a patient with limb gangrene due to extensive microvascular thrombosis, (8) and development of deep vein thrombosis has been reported after treatment for an FV inhibitor. (14,15)
Factor V is in the common pathway of the coagulation cascade (Figure 1), thus FV inhibitors will typically manifest with prolongation of both the prothrombin time (PT) and activated partial thromboplastin time (aPTT). (11) The thrombin time (TT) is usually normal; however, when the patient has been exposed to bovine thrombin, it can be prolonged. (6) Fibrinogen levels are often normal to slightly increased, and in rare cases patients have developed thrombocytopenia. (13)
The prolonged clotting times will not correct in mixing studies with normal plasma, and in contrast to the more common acquired factor VIII inhibitors, FV inhibitors do not show initial clotting time correction with subsequent prolongation after incubation. In fact, FV inhibitors are generally evident immediately upon mixing, with several studies showing inhibition anywhere from immediately to 15 minutes after mixing with normal plasma. (8,16,17)
Specific coagulation factor assays are required to confirm the presence of an FV inhibitor; FV activity will be decreased, often to less than 1%. (1,2,6) Factor V inhibitor activity is assessed by using a modification of the Bethesda assay for quantitation of factor VIII inhibitors (18) and is expressed in Bethesda Units (BU) with one BU defined as the amount of inhibitor that will neutralize 50% of FV in normal plasma. Dilutions of patient plasma with pooled normal plasma are made and assayed for residual FV activity. The quantity of inhibitor present is calculated by taking the reciprocal of the dilution that results in 50% residual FV activity. Reports of FV inhibitors have described marked variation in inhibitor titers, ranging from barely detectable to greater than 250 BU. (2)
Occasionally an FV inhibitor will display lupus anticoagulant (LA) activity with apparent inhibition of multiple coagulation factors. In this situation, the FV activity is usually decreased out of proportion to the other affected coagulation factors and improves only marginally with dilution as compared to the other factors. (12,19,20) For example, Kamphuisen et al (12) reported a case of a patient with undetectable levels of FV activity, as well as suppression of factors II, VII, and X. All factors returned to normal after 1:160 dilution with normal plasma with the exception of FV, which remained undetectable. A similar phenomenon has been observed recently. (21)
Screening coagulation study abnormalities associated with FV inhibitors are not specific. The PT and aPTT will usually be prolonged but the TT will be normal. If the TT is also prolonged, then hypofibrinogenemia, dysfibrinogenemia, anticoagulant use (direct thrombin inhibitor), and exposure to bovine thrombin must be considered. Diagnostic considerations for PT and aPTT prolongations with a normal TT include congenital or acquired coagulation factor deficiencies or inhibitors. These may involve either a single coagulation factor in the common pathway (factor II, V, X or fibrinogen) or multiple coagulation factors in both pathways (eg, due to liver disease, vitamin K deficiency, disseminated intravascular coagulation, or nonspecific inhibition by an LA). Narrowing the diagnostic possibilities is straightforward with a mixing study inasmuch as combined PT and aPTT prolongations that do not correct with mixing should immediately raise the suspicion of an inhibitor involving the common pathway or an LA. Distinguishing between an FV inhibitor and an LA can be challenging; however, most FV inhibitors do not show LA activity in modern assays. For example, though FV inhibitors will prolong the dilute Russell viper venom time, the clotting time will typically not correct after addition of excess phospholipid. Although some FV inhibitors can have LA-like properties, patients with LA rarely have bleeding complications (2) and, if anything, are more prone to thrombosis. Nevertheless, patients with FV inhibitors can present with thrombosis, adding to the diagnostic challenge. Resolving the question may require determination of individual coagulation factor activity levels at several dilutions, as specific inhibition of FV may only be evident after serial dilutions if more than 1 factor is affected as we have observed. (21)
Historically, if a patient has demonstrated a prolonged PT and aPTT with a normal TT, this is thought to be pathognomonic for an FV inhibitor. (22) However, antibodies to factor X, although exceedingly rare, may produce a similar profile, and some of the newly developed oral direct factor Xa inhibitor medications will prolong the PT and aPTT but not the TT and will show an inhibitor pattern in a mixing study. (23)
Factor V is a structurally unique coagulation factor (24) composed of a heavy chain and a light chain, joined by a connecting region (Figure 2). The exact mechanism by which FV autoantibodies develop is incompletely understood and in one study, (9) investigators identified multiple binding sites for inhibitors of FV. All patients with bleeding symptoms in that study, however, were found to have inhibitors that bound to the C2 domain of the light chain, thus disrupting the interaction between FV and the phospholipid membrane. Loss of light-chain binding to phospholipid results in dramatic loss of FV affinity for factor Xa, which in turn reduces the efficiency of conversion of prothrombin to thrombin. (25)
Despite the fact that FV is an essential cofactor for efficient conversion of prothrombin to thrombin, the level of FV inhibitor activity does not correlate with clinical bleeding. (3) Some patients may be asymptomatic with undetectable levels of FV, while others with modest suppression develop bleeding complications. A possible explanation for this is that FV, in addition to circulating in plasma, is stored in platelet alpha granules and is protected from circulating inhibitors. When the platelets are activated, they release FV locally at the site of bleeding and this FV can be used before being affected by the inhibitor. (26)
Alternatively, some have proposed that platelet FV is different from its circulating counterpart. Tracy et al (27) described a family with a severe bleeding diathesis despite normal coagulation studies, other than a mild decrease in plasma FV activity. The extent of FV suppression did not correlate with the degree of bleeding, and when the platelet FV was tested specifically, the investigators documented severely depressed activity levels. In another study, (28) IgG isolated from patients with FV inhibitors showed marked inhibition of prothrombinase complex activity. However, when the inhibitors were mixed with factor Xa and normal platelets, there was only partial inhibition.
The differences between circulating and platelet FV appear to be both structural and functional. Though both forms of FV are synthesized in the liver, the fraction of FV that is taken up by megakaryocytes is cleaved to a partially active state, which renders it resistant to protein C inactivation. (29) This partially active FV is then stored in platelet alpha granules, where it appears that this partial activation also renders platelet FV resistant to circulating inhibitors.
TREATMENT AND PROGNOSIS
The management of FV inhibitors requires a 2-step approach consisting of controlling bleeding and eradicating the inhibitor. Asymptomatic patients generally do not require treatment with hemostatic agents but may benefit from immunosuppression to eliminate the inhibitor. Bleeding in patients with FV inhibitors may be difficult to treat, since FV inhibitors interfere with the prothrombinase complex and are difficult to bypass with currently available coagulation factor concentrates. Fresh frozen plasma, prothrombin complex concentrates, and recombinant activated factor VII have been used to treat acute hemorrhage in FV inhibitor cases with varying outcomes. (3,6) Treatment with platelet transfusions has had a reported success rate ranging from 35% to 71%. (3,6) A report by Perdekamp et al (16) noted a 98% reduction in urine red blood cells in a patient with an FV inhibitor and hematuria after transfusion of 1 unit of platelets. No recommendation on the number of platelet units to administer can be made, as this depends on the extent and nature of the bleeding and should be individualized. For example, some have reported success with transfusing 1 unit per day in a patient with a kidney hematoma, (30) while others administered 2 units of platelets per day in a patient with a chest hematoma and diffuse bleeding. (26)
Though FV inhibitors may remit spontaneously and observation may be appropriate in some asymptomatic patients, immunosuppression may be required to eradicate the inhibitor. Treatment with chemotherapy and/or corticosteroids has a reported success rate of 83%, though intravenous immunoglobulin and therapeutic plasma exchange may be used as adjunct or alternative treatments. (1) In patients with severe bleeding, a multimodality approach may be required. (6)
It is important to identify any potential agents (eg, medications such as antibiotics, valproic acid, tacrolimus) that may have triggered FV inhibitor production. (1) In many cases this is not feasible, however, as it is difficult to determine whether a given agent is causative or incidental. Nevertheless, if an FV inhibitor develops shortly after beginning a new drug, it would be prudent to discontinue its use.
The prognosis with an acquired FV inhibitor largely depends on the extent and location of bleeding. The mortality rate appears to be about 12% to 14% with a favorable prognosis for those who develop an inhibitor on an idiopathic basis and an adverse prognosis with FV inhibitors associated with autoimmune disorders and cancer. (1,6) Not surprisingly, the highest mortality rates have been observed in patients who developed central nervous system bleeding or hemolytic uremic syndromes. (7) In these cases, bleeding was severe and usually resulted in death.
Factor V inhibitors are rare and are likely underrecognized. With the declining use of bovine thrombin, a larger proportion of FV inhibitors will have an unclear etiology and must remain a diagnostic consideration in cases of unexplained prolongations of the PT and aPTT with a normal TT. Because some FV inhibitors may have LA activity, multiple coagulation factors will appear to be suppressed in those cases, though FV may be suppressed out of proportion to the others. It is important to remember that FV inhibitors may not behave clinically like other coagulation factor inhibitors and may be associated with thrombosis rather than bleeding. Treatment of hemorrhage in patients with FV inhibitors can be challenging because, unlike FVIII inhibitors, bypassing agents are often ineffective but platelet transfusions may promote effective hemostasis.
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(3.) Streiff MB, Ness PM. Acquired FV inhibitors: a needless iatrogenic complication of bovine thrombin exposure. Transfusion. 2002;42(1):18-26.
(4.) Shastri KA, Ho C, Logue G. An acquired factor V inhibitor: clinical and laboratory features. J Med. 1999;30(5-6):357-366.
(5.) Diesen DL, Lawson JH. Bovine thrombin: history, use, and risk in the surgical patient. Vascular. 2008;16(suppl 1):S29-S36.
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(8.) Kapur A, Kelsey PR, Isaacs PE. Factor V inhibitor in thrombosis. Am J Hematol. 1993;42(4):384-388.
(9.) Ortel TL, Moore KD, Quinn-Allen MA, et al. Inhibitory anti-factor V antibodies bind to the factor V C2 domain and are associated with hemorrhagic manifestations. Blood. 1998;91(11):4188-4196.
(10.) Favaloro EJ, Bonar R, Duncan E, et al. Identification of factor inhibitors by diagnostic haemostasis laboratories: a large multi-centre evaluation. Thromb Haemost. 2006;96(1):73-78.
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(20.) Ahmadinejad M, Roushan N. Acquired factor V inhibitor developing in a patient with esophageal squamous cell carcinoma. Blood Coagul Fibrinolysis. 2013;24(1):97-99.
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(26.) Motwani P, Howard L, Ali SS. Successful management of a possible antibiotic-related acquired factor V inhibitor: a case report and review of the literature. Acta Haematol. 2013;129(3):182-184.
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(28.) Nesheim ME, Nichols WL, Cole TL, et al. Isolation and study of an acquired inhibitor of human coagulation factor V. J Clin Invest. 1986;77(2):405-415.
(29.) Gould WR, Simioni P, Silveira JR, Tormene D, Kalafatis M, Tracy PB. Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet-derived cofactor. J Thromb Haemost. 2005;3(3):450-456.
(30.) Ardillon L, Lefrancois A, Graveleau J, et al. Management of bleeding in severe factor V deficiency with a factor V inhibitor. Vox Sang. 2014;107(1):97-99.
Nicholas J. Olson, MD; Deborah L. Ornstein, MD
Accepted for publication November 14, 2016.
From the Department of Pathology & Laboratory Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Nicholas J. Olson, MD, Department of Pathology & Laboratory Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756 (email: email@example.com).
Caption: Figure 1. Activated coagulation factor X (FXa) and activated factor V (FVa) assembled on a phospholipid surface comprise the prothrombinase complex that cleaves prothrombin to produce thrombin. FVa is essentially a receptor for FXa on a cell or phospholipid surface and, in the presence of calcium ions, accelerates the FXa-mediated conversion of prothrombin by incompletely understood mechanisms. FV inhibitors interfere with binding of FV to the phospholipid surface and therefore with assembly of an effective prothrombinase complex.
Caption: Figure 2. Coagulation factor V (FV) consists of 6 protein domains (A1, A2, B, A3, C1, and C2) assembled into a heavy chain (A1 and A2) and a light chain (A3, C1, and C2) joined together by a connecting region (B).24 Activation of FV to FVa requires cleavage of the B-domain. Inhibitors to FV, associated with the most severe bleeding, bind to the C2 domain of the light chain, inhibiting FV binding to phospholipids.
[Please Note: Illustration(s) are not available due to copyright restrictions.]
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|Author:||Olson, Nicholas J.; Ornstein, Deborah L.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Dec 1, 2017|
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