Thrombosis in rare bleeding disorders

Abstract

Inherited deficiencies of blood coagulation factors are usually associated with lifelong bleeding tendency. In addition to Hemophilias A and B and von Willebrand disease, congenital deficiencies of such factors as fibrinogen, prothrombin (FII)), FV, FVII, FX, FXI, FXIII, and combined deficiencies occur and can lead to a diversity of clinical conditions. Paradoxically, for some of these disorders associated with significant bleeding tendency there are reports of thrombotic events, both arterial and venous. Thrombosis in hemophilia patients has a multifactorial pathogenesis and the main conditions associated with this complication are the use of long-term central venous catheters, intensive replacement therapy usually in the setting of surgical procedures, the use of bypassing agents or the coexistence of acquired or inherited prothrombotic risk factors. Regarding other rare bleeding disorders, thrombotic phenomena has been described particularly in patients with afibrinogenemia, FXI and FVII deficiency and the events can occur even in young patients, in the presence of concomitant risk factors or spontaneously. Replacement therapy must be individualized and should take into account past history of haemostatic challenges, family history of bleeding and thrombosis, just like the level of factor. For mild deficiencies when patients are asymptomatic the use of antithrombotic prophylaxis must be considered with or without concomitant use of replacement therapy. In patients with history of thrombosis it may be helpful to perform a thrombophilia screening to exclude coexisting prothrombotic defects and for all patients it is recommended to control known cardiovascular disease risk factors.

Keywords:

• Rare bleeding disorders
• Thrombosis
• Bleeding

General Features of Rare Bleeding Disorders (RBDs)

Inherited deficiencies of blood coagulation factors are usually associated with lifelong bleeding tendency. Although Hemophilias A and B and von Willebrand disease are the most common coagulation disorders, congenital deficiencies of all the other clotting factors occur and can lead to a diversity of clinical conditions, which may cause diagnostic and therapeutic difficulties. These RBDs include the inherited deficiencies of such factors as fibrinogen, prothrombin (FII), FV, FVII, FX, FXI, FXIII, combined FV+FVIII, and multiple deficiency of vitamin K-dependent factors.1 On the recently published 2009 Global Survey of the World Federation of Haemophilia (www.wfh.org), factor VII and factor XI deficiencies are the most frequent explaining ∼50% of RBDs.

Almost all RBDs are transmitted as autosomal recessive traits; only individuals who are either homozygotes or compound heterozygotes have a severe deficiency and develop hemorrhagic manifestations whereas those who are heterozygotes for a mutation are usually asymptomatic. On the other hand, dysfibrinogenemia is transmitted on an autosomal dominant manner, with most patients heterozygous for the causative mutation. Other common characteristic is their low prevalence in the general population varying from 1∶300 000 for FVII deficiency to 1∶2 000 000 for prothrombin and FXIIII deficiencies. Some geographical variation has been described; the prevalence is higher in areas of the world with high incidence of consanguinity and for FXI deficiency which is particularly common in Ashkenazi Jews in whom the heterozygous frequency is 8%.1

A clinical, biological, and genetic heterogeneity is a characteristic of these hemorrhagic diseases. Affected individuals show a variable bleeding phenotype whose severity is usually inversely proportional to the degree of factor deficiency. The most frequent symptom, common to all RBDs, is the occurrence of excessive bleeding at the time of invasive procedures. Mucocutaneous bleeding particularly epistaxis and menorrhagia is also described. Hemarthroses, soft tissue hematomas, and more severe symptoms such as intracranial, umbilical cord bleeding, and hemoperitoneum during ovulation may also occur in patients with afibrinogenemia or severe prothrombin, factor X, factor VII, and factor XIII deficiencies.

Thrombosis in Inherited Bleeding Disorders

Paradoxically for some of these disorders associated with significant bleeding tendency, there are reports of thrombotic events, both arterial and venous. As a matter of fact, as in many countries life expectancy has increased for individuals with hemophilia, patients are more prone to suffer age-related medical problems such as cardiovascular diseases.2 Although it may be that severe deficiency of FVIII or FIX may offer relative protection against thromboembolic events, there is evidence that atherosclerosis and ischemic heart disease can occur in patients with severe hemophilia or type 3 von Willebrand disease. Myocardial infarction and other arterial occlusions in hemophilia have been reported; most occurred in older individuals and after intensive treatment associated with major surgical procedures.3

Thrombosis in hemophilia patients has a multifactorial pathogenesis4 and the main conditions associated with this complication are:

1. use of long-term central venous catheters;

2. coagulation factor concentrate therapy: It has even been reported in patients with mild hemophilia A, von Willebrand disease and mainly in elderly patients after using intensive replacement therapy usually in the setting of surgical procedures;

3. use of bypassing agents, recombinant FVIIa or activated prothrombin complex concentrates which have been linked to thrombotic events;

4. coexistence of acquired or inherited prothrombotic risk factors: major surgery as total knee or hip arthroplasty, malignancies, or prothrombotic mutations.

Thrombosis in RBD

Regarding other RBDs, thrombotic phenomena have been described particularly in patients with afibrinogenemia, and FXI and FVII deficiency. So far, it has never been described in patients with factor II or factor X.3 Thromboembolic events can occur even in young patients, in the presence of concomitant risk factors such as surgery, replacement therapy or coinherited thrombophilias or spontaneously. There are reports of myocardial infarction, ischemic stroke, arterial occlusions, disseminated intravascular coagulation, and venous thromboembolism including unusual sites as portal systems, cerebral sinuses, and inferior vena cava.

Inherited Fibrinogen Disorders

Congenital abnormalities of fibrinogen may be classified as quantitative or qualitative disorders. The first group includes afibrinogenemia and hypofibrinogenemia while the second one is defined as the presence of an abnormal fibrinogen variant or dysfibrinogenemia.5

In afibrinogenemia, despite the absence of fibrinogen, patients can develop severe thromboembolic disease both venous and arterial.5,6 These complications can occur in the presence of concomitant risk factors after replacement therapy or without any known risk factor. Patients with afibrinogenemia are able to generate thrombin in the absence of fibrinogen; the excess of circulating thrombin could activate platelets and smooth muscle cell migration and proliferation, particularly in the arterial vessel wall. There is experimental evidence using in vivo thrombosis models in fibrinogen-deficient mice that thrombous formation is maintained but thrombus is unstable and with a tendency to embolize. An antithrombin role has also been attributed to fibrinogen as the clearance of thrombin is impaired in its absence, and fibrin acts as antithrombin I by modulating thrombin activity.7

Dysfibrinogenemia is characterized by the presence of functionally abnormal plasma fibrinogen. It has been stated that of the reported cases 55% were asymptomatic, 25% were associated with bleeding diathesis, and 20% show a predisposition to thrombosis. On the contrary, patients with venous thrombosis had a 0·8% prevalence of congenital dysfibrinogenemia.5

The molecular abnormalities have been found throughout the three fibrinogen genes. Some mutations such as BbetaArg14Cys or AalphaArg554Cys have been reported in several unrelated families in association with thrombophilia, so the identification of these variants might influence clinical management of the affected subjects. Thrombosis of these patients may arise from the clot structure consisting of very thin fibers, defective binding of thrombin by the abnormal fibrinogen molecule and impaired fibrinolysis.

Patients can present deep vein thrombosis, thrombophlebitis, and pulmonary embolism at a young age. The thrombotic risk increases in the presence of additional congenital or acquired risk factors.6

Factor VII Deficiency

Clinical features are variable ranging from mild or even asymptomatic forms to lethal cerebral hemorrhages which are poorly correlated with residual FVII coagulant activity.8 Thrombosis in association with FVII deficiency has been reported although the mechanism is unclear.

Thrombotic episodes, particularly deep vein thrombosis have been reported in 3–4% of patients even in severe deficient patients. The majority of the events occurred in the context of treatment to cover surgery but spontaneous events may occur as well. This complication has been described in two series and it has been examined in international registries (www.rbdd.org) and more recently in the EUHASS project, a prospective adverse event reporting program running in Europe (www.euhass.org).8,9 This surveillance program has identified five serious arterial and venous thrombotic episodes following concentrate treatment in five patients with FVII level <18%. It has been suggested that factor VII deficiency does not offer protection against venous or arterial thrombosis and it is also recommended to provide an individually tailored treatment.

Factor XI Deficiency

Factor XI deficiency usually leads to excessive hemorrhage after surgery or trauma particularly during surgery at sites with increased local fibrinolysis like tooth extractions, tonsillectomy, nasal surgery, and prostatectomy. Spontaneous bleeds are rare and hemorrhage into joints and muscles uncommon. Severe factor XI deficiency probably is protective against ischemic stroke but not against acute myocardial infarction.10

The relation between factor XI deficiency and thrombosis is mainly related to replacement therapy, and arterial and venous thrombotic events have been reported either after infusion of plasma-derived FXI concentrate or standard doses of recombinant FVIIa, especially associated with other risk factors as surgery. Recombinant FVIIa at low doses (15–30 μg/kg) seems to be safe treatment regimen in patients with severe FXI deficiency and inhibitors undergoing surgeries.

Conclusions

Some severe factor coagulation deficiencies do not seem to offer protection from strong thrombosis risk factors such as surgery and replacement therapy.

The risk of thrombosis should be taken into account in evaluating the need and the dose of replacement therapy especially when surgical procedures are planned.

Replacement therapy must be individualized and should take into account past history of hemostatic challenges, family history of bleeding and thrombosis, just like the level of factor. It is advisable to avoid peaks of coagulation factor activity or higher than needed doses.2,6

For mild deficiencies when patients are asymptomatic, the use of antithrombotic prophylaxis must be considered, either mechanical and/or pharmacological, with or without concomitant use of replacement therapy.8

In patients with history of thrombosis, it may be helpful to perform a thrombophilia screening to exclude coexisting prothrombotic defects and for all patients, it is recommended to control known cardiovascular disease risk factors.

Currently the usefulness of global assays such as thromboelastography is under investigation which may provide a better evaluation of hemostatic state and optimize the management of the patient.