What is prekallikrein deficiency?
Prekallikrein deficiency is a rare coagulation deficiency that presents itself with a prolonged PTT and a normal PT. It was first identified in 4 of the 11 Fletcher family children in 1965, coincidentally when one of the Fletcher children was undergoing a workup for an adenoidectomy.
How is prekallikrein deficiency diagnosed?
Diagnosis is based on the presence of a great prolongation of partial thromboplastin time and normal prothrombin time and thrombin time. The long partial thromboplastin time is fully corrected by the addition of normal plasma or normal serum and presents the unusual feature of shortening on long incubation times.
What factor is prekallikrein?
Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to produce kallikrein by activated Factor XII (Hageman factor).
How is Hageman factor activated?
The activation of Hageman factor initiates the intrinsic coagulation pathway by conversion of precursor plasma thromboplastin antecedent (pre- PTA) to activated PTA,l kinin generation by conversion of prekallikrein to kallikrein2 and fibrinolysis by conversion of plasminogen proactivator to plasminogen activator.
What is Prekallikrein activator?
Prekallikrein activator (PKA) is a contaminating enzyme found in therapeutic albumin and immunoglobulin products.
Which coagulation factors are vitamin K dependent?
Prothrombin, FVII, FIX, protein C, and protein S are vitamin K-dependent clotting factors or proteins strictly related to blood coagulation.
Is prekallikrein a clotting factor?
Causes. Prekallikrein deficiency is caused by mutations in the KLKB1 gene, which provides instructions for making a protein called prekallikrein. This protein, when converted to an active form called plasma kallikrein in the blood, is involved in the early stages of blood clotting .
What is Fletcher factor deficiency?
A diminished rate of Hageman factor activation caused by absence of prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic activity, and kinin generation.
What is factor12 deficiency?
Summary. Factor XII deficiency is a rare genetic blood disorder that causes prolonged clotting (coagulation) of blood in a test tube without the presence of prolonged clinical bleeding tendencies.
What is the function of Hageman factor?
Factor XII, originally called Hageman factor, plays an important role in the kallikrein-kinin system by activating prekallikrein. In the 1960s, a platelet activity that promoted factor XII activation was identified but its biochemical nature remained unknown.
Where is Hageman factor produced?
Coagulation Factor XII (Hageman factor, FXII) is produced and secreted by the liver. It is the product of a single gene that maps to chromosome 5 [4]. The gene for Factor XII is 12kb and is composed of 13 introns and 14 exons [5].
Where is Hageman factor found?
Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 3.4. 21.38) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene.
What is the standard dilution for fibrinogen assay?
37. A fibrinogen assay is performed on the fibrometer using the standard 1:10 dilution with Owren's buffer. The seconds obtained do not read on the standard curve. An alternate 1:20 dilution is performed and is 400 mg/dL when read off the curve. The concentration of fibrinogen to be reported in mg/dL is
What happens to the optical density of platelets as they aggregate?
B. Change in optical density: As platelets aggregate, the optical density of the platelet-rich plasma decreases.
Who recommends reporting INR on patients?
C. The World Health Organization recommends reporting the INR on patients
Is platelet aggregation directly proportional to the difference in platelet counts performed before and after platelet?
Platelet aggregation is directly proportional to the difference in platelet counts performed before and after platelet-rich plasma is passed through a column of glass beads.
How is prekallikrein converted to active kallikrein?
The conversion of prekallikrein (85/88 kDa) to active kallikrein is accomplished by serine protease cleavage, generally by factor XIIa, where Arg371-Ile372 is split, generating a heavy chain of 371 amino acids and a light chain of 248 amino acids held together by a disulfide bond. Under western analysis conditions, kallikrein comigrates with prekallikrein. In plasma, C1inh or α2-macroglobulin, either of which forms a 1:1 inhibitory complex with kallikrein, and inactivates kallikrein. Therefore, an activated contact system might be accompanied by a normal or decreased prekallikrein/kallikrein band with or without kallikrein/protease inhibitor complexes. Decreased prekallikrein bands were observed in most SLE patients ( Fig. 4 C, lanes 2–11 compared to the control lane 1), which is consistent with the consumption of contact system proteins in SLE patient plasmas.
What is the zymogen of kallikrein?
Plasma prekallikrein (PPK), the zymogen of the serine protease plasma kallikrein (PK, EC 3.4.21.34), is a single-chain glycoprotein, which is the product of the gene KLKB1 located on chromosome 4q34–q35. The PPK synthesized in hepatocytes is secreted into the blood where it circulates at a concentration of 35–50 mg l − 1 mainly as a complex with high-molecular-weight kininogen (HMWK). Two forms of PPK with different carbohydrate contents ( Mr 85 and 88 kDa) exist in blood plasma. PPK is a single-chain protein with 619 amino acids. Conversion to active PK is achieved by cleavage of the peptide bond Arg371-Ile372 on negatively charged surfaces by activated factor XII (FXII, Hageman factor) with HMWK as cofactor ( Schmaier, 2016 ). Alternatively, when PPK is linked to surface-bound HMWK on endothelial cells, it can be activated by prolyl-carboxypeptidase. A disulfide bond holds the two chains of active PK together. The N-terminal heavy chain contains four tandemly arranged apple domains of 90 or 91 amino acids, which are important for the interaction with proteins. The light chain contains the catalytic domain and is homologous to the members of the chymotrypsin family of peptidases.
What is plasma prekallikrein?
Plasma prekallikrein is a single chain globulin encoded by a single gene and is synthesized and secreted by hepatocytes as an inactive proenzyme. Activated plasma kallikrein acts on high molecular weight (HMW) kininogen at two sites, Lys-Arg and Arg-Ser, to release BK, a peptide consisting of nine amino acids with arginine at both the amino- and the carboxyterminal ends (Figure 1 ).
How many amino acids are in prekallikrein?
Plasma prekallikrein is synthesized as a zymogen precursor of 638 amino acids with a molecular mass of 71,369 daltons. It has a 19 amino acid propeptide and the mature secreted protein is 619 amino acids. Figure 1 is a configuration of the mature, secreted protein. Its mRNA codes for a 371 amino acid heavy chain and a 248 amino acid light chain, which are held together by a disulfide bond Chung et al (1986). The sequence has 58% sequence homology to factor XI Asakai et al (1987). The protein has four tandem repeats in the aminoterminal portion of the molecule due to the linking of the first and sixth, second and fifth, and third and fourth half cysteine residues present in each group of 90 and 91 amino acids that are arranged in “apple domains” McMullen et al (1991) ( Fig. 1 ). In Fig. 1, the letters A 1 to A 4 represent the apple domains of prekallikrein′s heavy chain. The notation “Factor XIIa” and arrow at arginine 371 represents the factor XIIa activation site on prekallikrein. Histidine 415, aspartic acid 464, and serine 559 represent kallikrein's active site. The areas in apple domains 1 and 4 with the darkened amino acids ( Fig. 1) represent part of the discontinuous high-molecular weight kininogen-binding site Herwald et al (1996). Further investigations have shown that in addition to apple domains 1 and 4, which as isolated species bind high-molecular weight kininogen with equal affinity, apple domain 2 binds high-molecular weight kininogen with highest affinity Renne et al (1999). Unlike factor XI, plasma prekallikrein does not have a cysteine at position 326 that allows it to dimerize with other prekallikrein molecules Gailani et al (2001).
Where is prekallikrein synthesized?
Plasma prekallikrein is synthesized in the liver, but mRNA has also been detected in the human and rat kidney, adrenal and placenta [35]. PK is a fast γ-globulin with a pI between 8.5 and 9.0. It circulates in blood with an estimated concentration of 35–50 μg/ml. Approximately 75% circulates bound to HK [36,37], and only 25% is free. The molecular mass of human plasma PK, as assessed by gel filtration, is approximately 100 kDa. By SDS-PAGE, PK consists of two components of Mr 85 000 and 88 000 that probably differ in the degree of glycosylation. PK can be purified by column chromatography [38] or by an immunoaffinity method [30].
Where are factor XII and PK located?
They are synthesized in the liver along with HK. PK also forms a complex with HK and factor XI. This complex is located on endothelial cells. PK, through its activation to kallikrein, is responsible for breaking down HK to bradykinin, which is a potent vasodilator. Factor XII plays a key part in the intrinsic pathway in the presence of HK and PK through contact activation. Contact activation occurs in both contact between proteins as well as contact of proteins with negatively charged surfaces. Kallikrein, formed by the breakdown of PK by a carboxypeptidase, activates factor XII that initiates fibrinolysis by activating urokinase. The contact factors are required for a normal aPTT since plasma containing these factors interacts in vitro with reagents used in this test that provide a negatively charged surface, for example, kaolin or ellagic acid. In animal models, deficiency of factor XII appears to have a greater association with thrombosis than bleeding. Thus, factor XII, HK, and PK appear to be required for normal aPTT but not for hemostasis.