Acquired Coagulation Disorders Caused by Inhibitors

Introduction and Overview

In 1941 Lawrence and Johnson described a “circulating anticoagulant” in a patient with hemophilia who became refractory to blood transfusions for the treatment of bleeding. Over the next several years, they and others determined that this substance was an antibody contained within the γ-globulin fraction of blood and directed against antihemophilic factor, a precursor term used to describe the deficient clotting factor in patients with hemophilia. Concurrent with these observations, reports emerged of an anticoagulant identified in blood from adults—often female, none with a personal or family history of bleeding—associated with serious bleeding. Affected individuals were diagnosed with acquired antibodies (inhibitors).

Over the next 70-plus years, acquired inhibitors have been described for nearly all known coagulation factors. Primarily polyclonal immunoglobulin G (IgG) autoantibodies (usually IgG and IgG ; rarely IgA or IgM ), these autoantibodies bind to epitopes on the clotting factor molecule and are referred to as inhibitors when they partially or completely neutralize clotting function and predispose to bleeding. Acquired inhibitors are clearly distinct from inhibitors associated with congenital bleeding disorders, in which alloantibodies may be generated following exposure to factor replacement therapy.

Acquired coagulation disorders are quite rare; uncommonly affect children; are sometimes linked to drug exposure or underlying conditions, including autoimmune disease, cancer, or pregnancy; and typically present as abnormal bleeding in persons with a negative personal or family history of bleeding. The acquired coagulopathy with the highest—albeit still extremely low—prevalence is acquired hemophilia A (AHA). Acquired von Willebrand syndrome (AVWS) occurs with a far lower frequency, and even more uncommon are acquired inhibitors to factors (F) II, V, VII, IX, X, XI, and XIII and to fibrinogen.

The importance of an accurate diagnosis, which relies on a high index of suspicion confirmed by prompt expert laboratory testing and interpretation, cannot be overstated because patients with acquired inhibitors frequently have unpredictable, severe, and sometimes life-threatening bleeding. After the diagnosis is established, management requires a two-pronged, usually parallel approach: (1) control bleeding and (2) eradicate the inhibitor, which may take weeks or months and entail immunosuppression and treatment of any contributing underlying pathology ( Fig. 5.1 ).

Because these coagulation disorders are so uncommonly encountered in clinical practice, their diagnosis is often delayed (by several days to weeks ) or missed. Treatment may be inadequate, and bleeding complications may develop during invasive procedures aimed at controlling hemorrhage. Immediate consultation with a physician at a specialty coagulation treatment center experienced in the diagnosis and care of inhibitor patients is recommended whenever an acquired coagulopathy is suspected, whether or not bleeding is present.

Laboratory Assessment of Inhibitors

The presence of an inhibitor typically prolongs the prothrombin time (PT), partial thromboplastin time (PTT), or both, depending on the specific coagulation factors inhibited. A mixing study, typically a 1 : 1 mixture of patient plasma and pooled normal plasma, is performed to determine whether prolongation results from a clotting factor deficiency or an inhibitor interfering with factor functioning. In the case of a factor deficiency, the PT or PTT of the mix corrects, owing to a full complement of clotting factors in the normal plasma. If an inhibitor is present, it neutralizes the specific clotting factor contained in the normal plasma, and the PT or PTT fails to correct after incubation.

Mixing study samples are incubated for 2 hours at 37°C (body temperature) before interpretation. Because some coagulation proteins are heat labile, the PTT should be reassessed at the end of incubation in the patient plasma, normal plasma, and the 1 : 1 mix. A mix showing less than a 50% to 60% correction or failure of the mix to correct to within 5 seconds of the PTT for normal plasma are two criteria used for inhibitor detection.

When the presence of an inhibitor is suspected on the basis of a noncorrecting mixing study, the next step is to determine the specificity of the inhibitor. A lupus anticoagulant, which results in prolongation of the PTT and lack of correction in a 1 : 1 mixing study ( Table 5.1 ), must be ruled out. Confirmatory testing for the lupus anticoagulant is discussed in Chapter 20 .

After eliminating lupus anticoagulant (LA) from the differential diagnosis, the inhibited clotting factor is identified using specific factor assays. Because anti-FVIII autoantibodies are the most common, an FVIII assay should be performed whenever a patient has bleeding symptoms and a prolonged, noncorrecting PTT. If the factor FVIII level is normal, other factors in the intrinsic and common pathways (i.e., factors I, II, V, IX, X, and XI) should be assayed. If there is a prolonged, noncorrecting PTT and a prolonged PT, then those factors in the common pathway (i.e., factors I, II, V, and X) should be assayed. In the case of a prolonged, noncorrecting PT with a normal PTT, FVII should be assayed.

The final step in the laboratory assessment of an acquired antibody is quantification of the inhibitor titer, because this value may guide treatment decisions and allows monitoring of inhibitor eradication therapy. The Bethesda assay is most commonly used and measures residual FVIII activity in a mixture of control (normal) plasma with dilutions of patient plasma incubated at 37°C for 2 hours. One Bethesda unit (BU) is defined as the amount of antibody that destroys 50% of FVIII in the mixture. The Bethesda assay can be modified to measure inhibitors affecting other clotting factors.

Acquired Hemophilia a (Acquired FVIII Inhibitors)

Epidemiology and Associated Conditions

AHA affects approximately 1.5 individuals per million per year. Annual incidence rises with age, from 0.045 per million in children younger than 16 years to 14.7 per million in people older than 85 years. In the European Acquired Haemophilia (EACH2) registry, the largest reported observational database that has collected prospective data for 501 AHA patients treated in 90 hemophilia centers in 11 countries, the average age at presentation was 73.9 years (interquartile range: 61.4 to 80.4), with a slight preponderance of males. Among 28 pediatric AHA cases (separately reviewed), the median age at presentation was 5 years (range: 2 to 17). A retrospective review of AHA demographics in the United States gleaned from the Hemostasis and Thrombosis Research Society (HTRS) registry found women and men were equally affected, median age was 70 years, and 61% were non-Hispanic whites (61%).

Approximately 50% of all AHA cases are idiopathic; the remainder are associated with comorbidities. In the EACH2 registry, 13% of patients had another autoimmune disorder; 16% had various underlying conditions (e.g., infection, dermatologic disorders); 12% had hematologic or solid malignancies; 8% were pregnant; and in 3%, antibiotics or other medications were linked to the development of AHA ( Fig. 5.2 ). In the HTRS registry, 28% had concomitant autoimmune disease, 15% had cancer, and 3% of cases were pregnancy related.

Clinical Presentation

AHA is characterized by spontaneous (77.4%) or provoked (trauma: 8.4%, surgery: 8.2%) bleeding. Fewer than 7% of patients enrolled in the EACH2 registry were asymptomatic at diagnosis, with the disorder discovered incidentally during routine blood testing. As opposed to the hemarthroses that are the hallmark of congenital hemophilia A, bleeding associated with AHA usually presents as extensive bruising and subcutaneous hematomas, although muscle bleeding, hematuria, epistaxis, and gastrointestinal or even intracranial hemorrhage (ICH) may also occur. Of the 474 initial bleeding episodes reported in the EACH2 registry, 53% were skin hematomas, 32% were mucosal bleeds, and only 5% were hemarthroses ( Fig. 5.3 ). Bleeding is severe in 70% to 97% of cases.

Hemostatic Therapy

The need for hemostatic therapy in patients with AHA is determined by bleeding site and severity. The inhibitor titer provides little guidance for clinical hemostatic decision-making because it does not correlate with bleeding severity. Unlike the alloantibodies associated with hemophilia A, which inactivate FVIII in direct proportion to their concentration (type 1 kinetics), acquired inhibitors exhibit type 2/nonlinear kinetics, whereby rapid initial inactivation is followed by a slower phase of equilibrium ( Fig. 5.4 ). Some measurable FVIII (usually <10% of normal) is often detected in patients with high-titer anti-FVIII autoantibodies (>5 BU), but this small amount of residual circulating FVIII offers no protection from bleeding. In fact, residual FVIII activity levels as high as 10%, levels that would rarely trigger spontaneous bleeding in congenital hemophilia, have been associated with severe hemorrhage in patients with AHA.

Minor Bleeding

In patients with low-titer (≤5 BU) acquired inhibitors who have no/minimal bleeding and do not require surgery, observation and laboratory monitoring may be sufficient. Despite its dramatic presentation, extensive subcutaneous hemorrhage can usually be safely managed without treatment, although patients may be hospitalized to facilitate close monitoring. Although some inhibitors, primarily those associated with pregnancy and antibiotic therapy, may spontaneously disappear over several months, active immunosuppression is nonetheless indicated to minimize the risk for bleeding.

Should minor bleeding require treatment, initial interventions include routine nonpharmacologic hemostatic techniques (e.g., rest, ice, compression, elevation); avoidance of invasive procedures; and discontinuation of any therapies that can exacerbate bleeding (i.e., antiplatelet or anticoagulant drugs), if possible. For patients with an FVIII level greater than 5% and a very low-titer inhibitor (<2 BU), desmopressin acetate (DDAVP) may cause a transient rise in FVIII levels capable of controlling minor bleeding. Human (h) FVIII is more likely than DDAVP to achieve hemostasis in patents with low-titer inhibitors, but large, even massive doses may be required to saturate the autoantibody.

Major Bleeding

Severe bleeding symptoms on presentation are common and can be life- or limb-threatening (e.g., ICH, retroperitoneal hemorrhage, compartment syndrome); they have been reported in up to 72% of patients and require the prompt initiation of hemostatic therapy.

FVIII replacement.

hFVIII concentrates may have some value as first-line treatment in patients with low-titer inhibitors, but for those with high-titer (>5 BU) autoantibodies, FVIII replacement is likely to be completely ineffective.

A recombinant porcine sequence FVIII B-domain–deleted product (rpFVIII; OBIZUR, Shire) is currently approved for bleed management in AHA. The pivotal phase 2/3 registration study showed that rpFVIII was effective in controlling life- and limb-threatening bleeding in patients with high-titer hFVIII inhibitors who did not have significant cross reactivity to rpFVIII (i.e., anti-porcine FVIII inhibitor ≤20 BU) and could be monitored in real time using standard FVIII assays (e.g., one-stage assay, chromogenic substrate assay). Although clinical experience with this relatively new drug is limited, a recently published retrospective chart review of seven patients with AHA found infusions of rpFVIII achieved good and durable hemostatic efficacy. Another report described successful control of bleeding in two patients with AHA treated with rpFVIII after the failure of bypassing therapy (see next section) to achieve hemostasis.

Bypassing therapy.

Bypassing therapy with agents that circumvent the need for FVIII is an effective first-line approach for major bleeding in patients with AHA and high-titer inhibitors. Two bypassing agents are available: plasma-derived activated prothrombin complex concentrate (aPCC; FEIBA, Shire) containing factor II and activated factors VII, IX, and X; and recombinant activated FVII (rFVIIa; Novo Seven, Novo Nordisk). Both achieve hemostasis by generating thrombin at the site of bleeding in the absence of FVIII but differ with respect to their biochemical properties and pharmacokinetics. In particular, aPCC has a longer half-life of 4 to 7 hours compared with approximately 2 hours for rFVIIa.

Good and equivalent success rates have been reported for aPCC and rFVIIa used for hemostatic management in AHA. In the EACH2 registry, bleeding was controlled in 60 of 64 patients (93%) treated with aPCC first line and 159 of 174 (91%) of those treated with rFVIIa first line. Yet the efficacy of bypassing therapy is unpredictable, and studies in patients with congenital hemophilia A show that some respond better to one drug than the other. Furthermore, no standard measures of coagulation (e.g., PT, PTT) or validated laboratory tests are available to monitor the therapeutic efficacy of bypassing agents or guide dosing. Although global hemostatic assays (e.g., thromboelastography, thrombin generation, clot waveform analysis) have been evaluated as strategies for measuring thrombin generation after the application of bypassing therapy, they do not reliably correlate with clinical efficacy or bleed resolution. Moreover, none of these assays is likely to detect overcoagulation and a resultant elevated risk for arterial and venous thrombosis, a particular concern in AHA patients with underlying conditions that increase thrombotic potential, especially cardiovascular disease, advanced age, cancer, and pregnancy. Owing to such risk, the use of higher than recommended doses of aPCC (100 U/kg per dose or 200 U/kg per day) or rFVIIa (90 µg/kg every 2 hours) should be considered only under exceptional circumstances.

Other therapies.

Plasmapheresis and extracorporeal immunoadsorption are used for antibody removal in a variety of autoimmune diseases and has been successful in eradicating FVIII inhibitors. However, high cost and limited access to necessary materials limit the application of extracorporeal immunoadsorption.