Thrombotic Events in Patients with Congenital Prekallikrein Deficiency: A Critical Evaluation of All Reported Cases

Girolami, Antonio; Allemand, Emanuele; Bertozzi, Irene; Candeo, Nicole; Marun, S; Girolami, Bruno

doi:10.1159/000313361

Cited by 24 publications

(28 citation statements)

References 73 publications

(48 reference statements)

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“…Twenty-one out of the 89 patients had hypertension or hypertension-related conditions [6,8,12,14,15,[17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Twelve were men and nine women (Table 1).…”

Section: Resultsmentioning

confidence: 99%

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Prevalence of hypertension and its complications in congenital prekallikrein deficiency

Girolami¹,

Ferrari²,

Cosi³

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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The extra coagulation effects of prekallikrein and of the other factors of the contact phase of blood clotting have received great attention in the past few years.The clinical observation that hypertension was present in two families with congenital prekallikrein deficiency prompted a survey of all reported cases of this disorder.Altogether, 89 cases of proven prekallikrein deficiency have been described in the literature. Hypertension or vascular complications of it were found in 21 patients (12 men and nine women). If the analysis is limited to patients over 25 years of age, the number becomes 21 out of 64 cases (38.2%).This prevalence is much higher than that seen for other conditions occasionally found in patients with prekallikrein deficiency, namely hyperthyroidism, lupus erythematosus, chronic lymphocytic leukemia, kidney malformation, peptic ulcer, and myelofibrosis (1-2%).These results indicate the need to investigate further the relation between prekallikrein deficiency and hypertension.

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Section: Resultsmentioning

confidence: 99%

“…Thrombotic events have been occasionally reported in patients with prekallikrein deficiency [17], but no study has ever been dedicated to the prevalence of hypertension and its complications in these patients.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of hypertension and its complications in congenital prekallikrein deficiency

Girolami¹,

Ferrari²,

Cosi³

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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“…There is scant data on a role for PKK in human thromboembolism. Only ϳ 75 cases for congenital PKK deficiency have been published, 7,8,29 precluding meaningful epidemiologic analysis, and an association between elevated PKK levels and thrombosis has not been established. 49 Small molecule inhibitors, antibodies and ASOs targeting fXI or fXIa are currently under development for therapeutic use.…”

Section: Discussionmentioning

confidence: 99%

“…Humans and other animals deficient in a contact activation protein are largely asymptomatic. 4,[6][7][8] However, the contact system may play an important role in thrombotic disease, as pharmacologic inhibition of fXIIa or ablation of the fXII or HK genes can protect mice from experimentally induced thrombosis in a variety of models. [9][10][11][12][13] Interestingly, fXII deficiency confers somewhat greater protection from thrombosis than fXI deficiency in some models, 11 implying that fXII may contribute to thrombus formation through additional pathways distinct from fXI-dependent intrinsic pathway activation.…”

Section: Introductionmentioning

confidence: 99%

Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding

Revenko

Gao

Crosby

et al. 2011

Blood

195

183

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Recent studies indicate that the plasma contact system plays an important role in thrombosis, despite being dispensable for hemostasis. For example, mice deficient in coagulation factor XII (fXII) are protected from arterial thrombosis and cerebral ischemia-reperfusion injury. We demonstrate that selective reduction of prekallikrein (PKK), another member of the contact system, using antisense oligonucleotide (ASO) technology results in an antithrombotic phenotype in mice. The effects of PKK deficiency were compared with those of fXII deficiency produced by specific ASO-mediated reduction of fXII. Mice with reduced PKK had ϳ 3-fold higher plasma levels of fXII, and reduced levels of fXIIa-serpin complexes, consistent with fXII being a substrate for activated PKK in vivo. PKK or fXII deficiency reduced thrombus formation in both arterial and venous thrombosis models, without an apparent effect on hemostasis. The amount of reduction of PKK and fXII required to produce an antithrombotic effect differed between venous and arterial models, suggesting that these factors may regulate thrombus formation by distinct mechanisms. Our results support the concept that fXII and PKK play important and perhaps nonredundant roles in pathogenic thrombus propagation, and highlight a novel, specific and safe pharmaceutical approach to target these contact system proteases. (Blood. 2011; 118(19):5302-5311) IntroductionThe blood coagulation system responds to vascular injury with local production of a clot formed of fibrin mesh and activated platelets. While this process is essential for hemostasis, dysregulated coagulation can lead to blood vessel occlusion (thrombosis), precipitating life-threatening events such as myocardial infarction, stroke and venous thromboembolism. In the classic view of blood coagulation, thrombin generation and fibrin formation can be initiated by 2 distinct mechanisms referred to as the extrinsic and intrinsic pathways. 1,2 The extrinsic pathway involves binding of plasma factor VIIa (fVIIa) to extravascular tissue factor (TF) at a site of vessel injury. 3 The first step in the intrinsic pathway requires the surface-dependent activation of plasma factor XII (fXII) to fXIIa in a process called contact activation. 4,5 Contact activation involves 2 other proteins, prekallikrein (PKK) and high molecular weight kininogen (HK). HK serves as a docking molecule for PKK on the contact surface. PKK is cleaved by fXIIa to form the protease ␣-kallikrein, which in turn cleaves fXII to generate additional fXIIa. Collectively, fXII, PKK and HK comprise the plasma contact system. FXIIa generated by contact activation can activate factor XI (fXI) to fXIa, triggering a series of proteolytic cleavage events that culminates in thrombin generation and fibrin clot formation.While the contact system can clearly trigger coagulation in vitro, it is not required for hemostasis. Humans and other animals deficient in a contact activation protein are largely asymptomatic. 4,[6][7][8] However, the contact system may play an important r...

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“…In addition to the mechanistic relevance of PKK and f12 in HAE, our rationale for targeting these proteins via antisense drugs is enhanced by the limited pathophysiology associated with deficiencies of either of these proteins in humans. Humans with complete deficiencies of PKK are asymptomatic (Girolami et al, 2010a;Girolami et al, 2010b); f12 deficiency has been correlated with a predisposition towards increased venous thrombosis (Ratnoff, 1980), though the mechanism by which this occurs remains to be elucidated, as other prothombotic factors may be involved (Girolami et al, 2004). Moreover, case-controlled studies have not found an association between f12 deficiency and adverse outcomes (Koster et al, 1994;Zeerleder et al, 1999) and severe f12 deficiencies are not associated with increased mortality (Endler et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Vascular Permeability by Antisense-Mediated Inhibition of Plasma Kallikrein and Coagulation Factor 12

Bhattacharjee

Revenko

Crosby

et al. 2013

Nucleic Acid Therapeutics

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Hereditary angioedema (HAE) is a rare disorder characterized by recurrent, acute, and painful episodes of swelling involving multiple tissues. Deficiency or malfunction of the serine protease inhibitor C1 esterase inhibitor (C1-INH) results in HAE types 1 and 2, respectively, whereas mutations in coagulation factor 12 (f12) have been associated with HAE type 3. C1-INH is the primary inhibitor of multiple plasma cascade pathways known to be altered in HAE patients, including the complement, fibrinolytic, coagulation, and kinin-kallikrein pathways. We have selectively inhibited several components of both the kinin-kallikrein system and the coagulation cascades with potent and selective antisense oligonucleotides (ASOs) to investigate their relative contributions to vascular permeability. We have also developed ASO inhibitors of C1-INH and characterized their effects on vascular permeability in mice as an inducible model of HAE. Our studies demonstrate that ASO-mediated reduction in C1-INH plasma levels results in increased vascular permeability and that inhibition of proteases of the kinin-kallikrein system, either f12 or prekallikrein (PKK) reverse the effects of C1-INH depletion with similar effects on both basal and angiotensin converting enzyme (ACE) inhibitor-induced permeability. In contrast, inhibition of coagulation factors 11 (f11) or 7 (f7) had no effect. These results suggest that the vascular defects observed in C1-INH deficiency are dependent on the kinin-kallikrein system proteases f12 and PKK, and not mediated through the coagulation pathways. In addition, our results highlight a novel therapeutic modality that can potentially be employed prophylactically to prevent attacks in HAE patients.

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Thrombotic Events in Patients with Congenital Prekallikrein Deficiency: A Critical Evaluation of All Reported Cases

Cited by 24 publications

References 73 publications

Prevalence of hypertension and its complications in congenital prekallikrein deficiency

Prevalence of hypertension and its complications in congenital prekallikrein deficiency

Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding

Inhibition of Vascular Permeability by Antisense-Mediated Inhibition of Plasma Kallikrein and Coagulation Factor 12

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