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Contact phase of blood coagulation and thrombosis and hypertension: The conundrum has to be clarified

Antonio Girolami

Department of Medicine Silvia Ferrari, University of Padua Medical School, Italy

Silvia Ferrari and Elisabetta Cosi

Department of Medicine Silvia Ferrari, University of Padua Medical School, Italy

DOI: 10.15761/PMCH.1000134

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Dear Sir,

The contact phase of blood coagulation is composed of three clotting proteins, namely FXII or Hageman Factor, Prekallikrein (PK) and High Molecular Weight Kininogen (HMWK) [1]. Since patients with a deficiency of any of these proteins do not show a bleeding tendency, the defects have been often disregarded or under evaluated.

However, this contact phase of blood coagulation has received new attention in recent years.

A body of experimental studies in knockout animals, usually mice, suggest that the contact phase of blood coagulation plays a role in the development and progression of experimentally induced thrombosis [2-5].

Knockout mice are reported to protect against thrombosis. This has stimulated the possibility that anti contact phase drugs could find a therapeutic use in humans since the inhibitory effect would not cause bleeding. In fact, since congenital FXII and PK deficiency are not associated with bleeding, there would be no danger of interfering with the normal hemostatic function.

These observations are in sharp contrast with clinical observations that congenital deficiencies of these factors, present thrombotic events or, better, do not protect from thrombotic events. These thrombotic events seem particularly frequent, in PK deficiency that is also often associated with hypertension [6-9].

The conundrum is unresolved due to the fact that there is no controlled longitudinal study on the incidence of thrombosis in all these patients.

The only studies available concern FXII deficiency and showed that there is no difference in the incidence of venous or arterial thrombosis in patients with congenital severe (1% of normal) or mild (about 50% of normal) FXII deficiency as compared with unaffected family members [10,11].

No similar study is available for PR kallikrein (PK) deficiency or High Molecular Weight Kininogen (HMWK) deficiency.

However, several observations and case series studies indicate that hypertension and its related complications (MI and stroke) seem fairly common in PK deficiency [8,9].

Thrombotic events have been reported even in HMWK deficiency, but the observations are too few to have relevance [1,12].

There is another peculiar observation with regard to PK deficiency: the large majority of thrombotic events concern the arterial system. As the matter of fact, the only venous thrombosis occurred in two sisters who, besides PK deficiency, showed also severe obesity [13].

On the contrary, these is no similar striking difference in FXII deficiency. It seems, in other words, that arterial thrombosis is probably associated with PK deficiency. This action seems mediated by the hypertension which has been frequently found in patients with PK deficiency [6].

Another peculiar fact concerns the observation that African Americans are frequently affected by PK deficiency [6]. It is known that these patients present often hypertension and its complications. The presence of the PK defect could play a role in the known increased mortality rate due to cardiovascular diseases seen among African Americans [14-17].

There is a need to clarify the matter. The only solution is a long-term study with the enrollment of enough patients in comparison with unaffected family members as recently done for FXII deficiency. The major drawback for this type of study is represented 1) by the fact that these patients are usually asymptomatic and therefore often unrecognized; 2) no center has by itself the possibility to accumulate a sufficient number of patients.

It is therefore inevitable a joint effort of several countries and the organization of a steering committee.

Since several animals with congenital PK deficiency have been described, a long-term study in some of these animals (dogs) could also be useful [17].

Due to the heavy cost to society of hypertension and its complications any cost should be faced and accepted.

The problem has been synthesized in the phrase “no contact, no thrombosis” [18]. We think it is safer to state for FXII deficiency “no contact and thrombosis as usual”.

However, the statement for PK deficiency has probably to be changed in “no contact and more thrombosis” [19]. These considerations are based on extensive clinical studies [8,10,19] and are the only important for clinicians.

Finally, we have some doubts about the possibility of hemostasis since, if the contact phase is blocked, there may be a defective or impaired activation and function of FXI and FXI deficient patients do bleed [20].

References

  1. Colman RW (2001) Contact activation pathway: inflammatory, fibrinolytic, anticoagulant, antiadhesive and antiangiogenic activities. In: Colman RW, Hirsh J, Marden VJ, Clowes AW, George JM (eds) Thrombosis and haemostasis, 4th edition. Lippincott, Philadelphia.
  2. Matafonov A, Leung PY, Gailani AE (2014) Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood 123:1739-1746. [Crossref]
  3. Renné T, Pozgajová M, Grüner S, Schuh K, Pauer HU, et al. (2005) Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med. 202: 271-281. [Crossref]
  4. Bird JE, Smith PL, Wang X, Schumacher WA, Barbera F, et al. (2012) Effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice: murine ortholog of the Fletcher trait. Thromb Haemost 107: 1141-1150. [Crossref]
  5.  Merkulov S, Zhang WM, Komar AA, Schmaier AH, Barnes E, et al. (2008) Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis. Blood 111:1274-1281. [Crossref]
  6.  Girolami A, Allemand E, Bertozzi I, Candeo N, Marun S, et al. (2010) Thrombotic events in patients with congenital prekallikrein deficiency: a critical evaluation of all reported cases. Acta Haematol 123: 210-214. [Crossref]
  7.  Girolami A, Ferrari S, Cosi E, Sambado L, Girolami B (2015) Prevalence of hypertension and its complications in congenital prekallikrein deficiency: analysis of all reported cases and clinical significance. Blood Coagul Fibrinolysis 26: 560-563. [Crossref]
  8. Girolami A, Candeo N, De Marinis GB, Bonamigo E, Girolami B (2011) Comparative incidence of thrombosis in reported cases of deficiencies of factors of the contact phase of blood coagulation. J Thromb Thrombolysis 31: 57-63. [Crossref]
  9. Girolami A, Scarparo P, Candeo N, Lombardi AM (2010) Congenital prekallikrein deficiency. Expert Rev Hematol 3: 685-695. [Crossref]
  10.  Girolami A, Ferrari S, Cosi E, Girolami B, Randi ML (2019) Thrombotic events in severe FXII deficiency in comparison with unaffected family members during a long observation period. J Thromb Thrombolysis 47: 481-485. [Crossref]
  11.  Girolami A, Ferrari S, Cosi E, Randi ML (2019) Heterozygous FXII deficiency is not associated with an increased incidence of thrombotic events: Results of a long-term study. Blood Cells Mol Dis 77: 8-11. [Crossref]
  12.  Krijanovski Y, Proulle V, Mahdi F, Dreyfus M, Mu ¨ller-Esterl W, Schmaier AH (2003) Characterization of molecular defects of Fitzgerald trait and another novel high-molecular-weight kininogen-deficient patient: insights into structural requirements for kininogen expression. Blood 101: 4430-4436 [Crossref]
  13.  Goodnough LT, Saito H, Ratnoff OD (1983) Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenia’s: a report of 21 patients and a review of 50 previously reported cases. Medicine (Baltimore) 62: 248-255. [Crossref]
  14.  Mendy VL, Vargas R, Payton M, Sims JN, Zhang L (2019) Trends in the Stroke Death Rate Among Mississippi Adults, 2000-2016. Prev Chronic Dis 16: E21. [Crossref]
  15. Waldron FA, Benenson I, Jones-Dillon SA, Zinzuwadia SN, Adeboye AM, Eris E, Mbadugha NE, Vicente N, Over A (2019) Prevalence and risk factors for hypertensive crisis in a predominantly African American inner-city community. Blood Press 28: 114-123. [Crossref]
  16.  Colantonio LD, Monda KL, Rosenson RS, Brown TM, Mues KE, et al. (2019) Characteristics and Cardiovascular Disease Event Rates among African Americans and Whites Who Meet the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) Trial Inclusion Criteria. Cardiovasc Drugs Ther 33: 189-199. [Crossref]
  17.  Brooks M (1999) A review of canine inherited bleeding disorders: biochemical and molecular strategies for disease characterization and carrier detection. J Hered 90: 112-118. [Crossref]
  18. Meijers JC (2014) No contact, no thrombosis? Blood 123: 1629. [Crossref] 
  19.  Girolami A, Ferrari S, Cosi E, Girolami B (2018) Cardiovascular diseases in congenital prekallikrein deficiency: comparison with other chance-associated morbidities. Blood Coagul Fibrinolysis 29: 423-428. [Crossref]
  20.  Bolton-Maggs PH, Young Wan-Yin B, McCraw AH, Slack J, Kernoff PB (1988) Inheritance and bleeding in factor XI deficiency. Br J Haematol 69: 521-528. [Crossref]

Editorial Information

Editor-in-Chief

Article Type

Letter to Editor

Publication history

Received date: November 10, 2019
Accepted date: November 15, 2019
Published date: November 19, 2019

Copyright

©2019 Girolami A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Girolami A (2019) Contact phase of blood coagulation and thrombosis and hypertension: The conundrum has to be clarified 2: DOI: 10.15761/PMCH.1000134

Corresponding author

Antonio Girolami

Department of Medicine Silvia Ferrari Padua, University of Padua Medical School, Elisabetta Cosi Via Ospedale Civile 105, Italy

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

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