Reduction of contact factors in sickle cell disease

doi:10.1016/S0022-3476(85)80669-7

The Journal of Pediatrics

Volume 106, Issue 3, March 1985, Pages 427-430

https://doi.org/10.1016/S0022-3476(85)80669-7 Get rights and content

Surface-mediated reactions of clotting were compared in 21 black children with homozygous sickle cell disease, 12 age-matched controls, and 15 adults. Both the coagulant and antigen titers of Hageman factor (factor XII) were decreased in asymptomatic patients compared with those in the control groups. These findings were associated with slight but significant reduction in the plasma titers of prekallikrein and high molecular weight kininogen. A further decrease from the initially low titers of these contact factors was observed during vaso-occlusive crises. Additionally, we observed a disparate relationship between Hageman factor coagulant activity and its antigen titers. These data provide evidence for reduction of the contact factors in patients with homozygous sickle cell disease.

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Cited by (21)

Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease
2023, Blood
A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD). Coagulation factor XII (FXII) triggers activation of the contact system that is known to be involved in both thrombosis and inflammation, but not in physiological hemostasis. Therefore, we investigated whether FXII contributes to the prothrombotic and inflammatory complications associated with SCD. We found that when compared with healthy controls, patients with SCD exhibit increased circulating biomarkers of FXII activation that are associated with increased activation of the contact pathway. We also found that FXII, but not tissue factor, contributes to enhanced thrombin generation and systemic inflammation observed in sickle cell mice challenged with tumor necrosis factor α. In addition, FXII inhibition significantly reduced experimental venous thrombosis, congestion, and microvascular stasis in a mouse model of SCD. Moreover, inhibition of FXII attenuated brain damage and reduced neutrophil adhesion to the brain vasculature of sickle cell mice after ischemia/reperfusion induced by transient middle cerebral artery occlusion. Finally, we found higher FXII, urokinase plasminogen activator receptor, and αMβ2 integrin expression in neutrophils of patients with SCD compared with healthy controls. Our data indicate that targeting FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that FXII inhibition may provide a safe approach for interference with inflammation, thrombotic complications, and vaso-occlusion in patients with SCD.
High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease
2020, Journal of Thrombosis and Haemostasis
Sickle cell disease (SCD) is characterized by chronic hemolytic anemia, vaso‐occlusive crises, chronic inflammation, and activation of coagulation. The clinical complications such as painful crisis, stroke, pulmonary hypertension, nephropathy and venous thromboembolism lead to cumulative organ damage and premature death. High molecular weight kininogen (HK) is a central cofactor for the kallikrein‐kinin and intrinsic coagulation pathways, which contributes to both coagulation and inflammation.
We hypothesize that HK contributes to the hypercoagulable and pro‐inflammatory state that causes end‐organ damage and early mortality in sickle mice.
We evaluated the role of HK in the Townes mouse model of SCD.
We found elevated plasma levels of cleaved HK in sickle patients compared to healthy controls, suggesting ongoing HK activation in SCD. We used bone marrow transplantation to generate wild type and sickle cell mice on a HK‐deficient background. We found that short‐term HK deficiency attenuated thrombin generation and inflammation in sickle mice at steady state, which was independent of bradykinin signaling. Moreover, long‐term HK deficiency attenuates kidney injury, reduces chronic inflammation, and ultimately improves survival of sickle mice.
The role of platelets in sickle cell disease
2019, Platelets
Sickle cell disease is caused by the homozygous mutation in the beta globin gene that leads to erythrocyte sickling, rigidity, dehydration, impaired rheology and premature hemolysis. Growing evidence suggests that platelet activation in SCD contributes to the progression of major complications such as acute systemic painful vaso-occlusive crisis, chronic organ damage, acute chest syndrome and pulmonary hypertension. Erythrocyte- and tissue-derived damage associated molecular patterns molecules released in SCD promote platelet activation by regulating nitric oxide signaling, reactive oxygen species generation, toll-like-receptor-4-dependent innate immune signaling, purinergic signaling, and coagulation. Activated platelets adhere to leukocytes, sickle erythrocytes and endothelium to promote vaso-occlusion and/or vascular thrombosis. The knowledge of the platelet-dependent pathophysiology has led to the development of new therapies for SCD, by targeting different processes leading to platelet activation in SCD.
How I diagnose and treat venous thromboembolism in sickle cell disease
2018, Blood
Citation Excerpt :
Decreases in anticoagulant proteins, such as proteins C and S, have been reported in SCD and likely contribute to the hypercoagulable state.8,14 Finally, the possible role for iron in hypercoagulability has been suggested by decreased ex vivo measures of clotting, as measured by thromboelastography, in the plasma of SCD patients after iron chelation.34 Platelet activation may further promote clot formation.
The incidence of venous thromboembolism (VTE) in adult patients with sickle cell disease (SCD) is high. However, overlapping features between the clinical presentation of VTE and SCD complications and a low index of suspicion for thrombosis can influence patient management decisions. VTE in SCD can therefore present management challenges to the clinical hematologist. Herein, we present 3 distinct clinical vignettes that are representative of our clinical practice with SCD patients. These vignettes are discussed with specific reference to the hypercoagulable state in SCD patients, recent VTE diagnosis and anticoagulant therapy guidelines from the general population, and evaluation of the risk of bleeding as a result of long-term exposure to anticoagulant therapy. We examine current diagnostic and treatment options, highlight limitations of the existing clinical prognostic models that offer personalized guidance regarding the duration of anticoagulation, and propose a clinical approach to guide the decision to extend anticoagulation beyond 3 months.
Thrombin generation and cell-dependent hypercoagulability in sickle cell disease
2016, Journal of Thrombosis and Haemostasis
Click to hear Dr Hillery discuss coagulation and vascular pathologies in mouse models of sickle cell disease.
Sickle cell disease (SCD) is a hypercoagulable state with chronic activation of coagulation and an increased incidence of thromboembolic events. However, although plasma pre‐thrombotic markers such as thrombin‐anithrombin complexes and D‐dimer are elevated, there is no consensus on whether global assays of thrombin generation in plasma are abnormal in patients with SCD. Based on our recent observation that normal red blood cells (RBCs) contribute to thrombin generation in whole blood, we hypothesized that the cellular components in blood (notably phosphatidylserine‐expressing erythrocytes) contribute to enhanced thrombin generation in SCD.
Whole blood and plasma thrombin generation assays were performed on blood samples from 25 SCD patients in a non‐crisis ‘steady state’ and 25 healthy race‐matched controls.
Whole blood thrombin generation was significantly elevated in SCD, whereas plasma thrombin generation was paradoxically reduced compared with controls. Surprisingly, whole blood and plasma thrombin generation were both negatively correlated with phosphatidylserine exposure on RBCs. Plasma thrombin generation in the presence of exogenous activated protein C or soluble thrombomodulin revealed deficiencies in the protein C/S anticoagulant pathway in SCD. These global changes were associated with significantly lower plasma protein S activity in SCD that correlated inversely with RBC phosphatidylserine exposure.
Increased RBC phosphatidylserine exposure in SCD is associated with acquired protein S deficiency. In addition, these data suggest a cellular contribution to thrombin generation in SCD (other than RBC phosphatidylserine exposure) that explains the elevated thrombin generation in whole blood.
Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies
2016, Blood Reviews
Citation Excerpt :
While this may reflect the contribution of endothelial and sub-endothelial TF at sites of vascular injury that is not measured in blood, it may also reflect a contribution of activation of the intrinsic pathway to in vivo thrombin generation. Indeed, plasma levels of contact system proteins, including factor XII, prekallikrein and high molecular weight kininogen have been shown to be decreased in patients with SCD at “steady state” compared with control subjects, with further decreases during acute painful episodes [50–52]. Autoactivation of contact system proenzymes is known to occur on negatively charged surfaces.
Sickle cell disease (SCD) is a hypercoagulable state. Patients exhibit increased platelet activation, high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis “steady state.” Furthermore, SCD is characterized by an increased risk of thrombotic complications. The pathogenesis of coagulation activation in SCD appears to be multi-factorial, with contributions from ischemia–reperfusion injury and inflammation, hemolysis and nitric oxide deficiency, and increased sickle RBC phosphatidylserine expression. Recent studies in animal models suggest that activation of coagulation may contribute to the pathogenesis of SCD, but the data on the contribution of coagulation and platelet activation to SCD-related complications in humans are limited. Clinical trials of new generations of anticoagulants and antiplatelet agents, using a variety of clinical endpoints are warranted.

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^†: Supported in part by Grants HL0166 and HL28348 from the National Heart, Lung, and Blood Institute, the National Institutes of Health, and by a grant-in-aid from the American Heart Association and its Northeast Ohio Affiliate. Dr. Gordon is the recipient of a New Investigator Research Award from the National Institutes of Health.

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Original articleReduction of contact factors in sickle cell disease†

Blood

Am J Med

Blood

Thrombos Res

Blood

Thrombos Res

Disseminated intravascular coagulation: A clinical/laboratory study of 48 patients

Ann NY Acad Sci

The syndrome of disseminated intravascular coagulation

Rev Surg

Pathophysiology of generalized intravascular coagulation

Semin Thrombos Haemost

The clinical challenge of disseminated intravascular coagulation

N Engl J Med

Consumption of serum factors and prothrombin during intravascular clotting in rabbits

Scand J Haematol

Radioimmunoassay of human Hageman factor (factor XII)

J Lab Clin Med

Human plasma prekallikrein (Fletcher factor) clotting activity and antigen in health and disease

J Lab Clin Med

Rheological aspects of sickle cell disease

Arch Intern Med

Hemostatic alterations accompanying sickle cell pain crisis

J Lab Clin Med

A plasma inhibitor of ristocetin-induced platelet aggregation in patients with sickle hemoglobinopathies

Am J Hematol

Platelet function and survival in sickle cell disease

J Lab Clin Med

Factor VIII (antihaemophilic factor) activity in sickle-cell anemia

Br J Haematol

Original article
Reduction of contact factors in sickle cell disease†