Friday, August 15, 2008

Dog Fur Discoloration Stomach

INTRODUCTION

History
von Willebrand disease was first described in 1926 by physicist Eric Adolf von Willebrand disease. His first patient was Hjördis, a five year old girl who suffered from recurrent bleeding lips, nose and ankles. It was not the first case in her family, four of his brothers had died of uncontrolled bleeding early. At age 13 she died at menarche. [1] Dr. von Willebrand
distinguished this case of hemophilia after realizing that the injuries caused by the VWD differed from those caused by haemophilia because it is the first external bleeding and internal bleeding in the second case. When analyzing the bleeding time and capillary fragility test scored abnormal values. In turn, studies of platelet count and clotting time results were within the range considered normal, which would not have happened if it had been a case of hemophilia. That is why the doctor concluded that it was modified morphological changes of platelet function and called it "pseudohemofilia."
In 1928, Dr. George Minot of Boston described five cases in which the bleeding time was high but contrary to that obtained by Dr von Willebrand, capillary fragility test was negative. Continuing research
was assigned to the disease the name "vascular hemophilia" because it is a disorder of blood vessels. In the 1950's it was discovered that hemophilia is sex-linked so it affects only men (women are carriers but do not have the disease). This was known a new difference between the two diseases. Also noticed that members of a family of hemophiliacs had similarly low levels of FVIII, while a family who suffered from von Willebrand disease, the values \u200b\u200bof this factor varied.
At that time he began to use the plasma transfusion. We performed a transfusion of a patient with hemophilia A in a VWD, causing a slow increase of FVIII, which remained a few days and then decline.



However, the plasma transfusion in reverse (a hemophiliac VWD) FVIII values \u200b\u200bremained the same. It was discovered that in cases of VWD was in a new factor deficiency could be restored by normal or haemophilic plasma.
In the 1960's found that ristocetin, an antibiotic, stimulated platelet aggregation in normal subjects or hemophiliacs but not in people with VWD. If adding platelet-poor plasma from a normal or hemophilic VWD a patient with a platelet-rich plasma, the antibiotic worked. So the discovery of a new test to detect the VWF, which was not yet known as such.
When they semi-purified FVIII injected a group of rabbits, they produced an antibody that recognizes a substance found in people suffering from hemophilia A. This substance was called "antigen factor VIII (FVII: Ag). Later it was discovered that two different factors: the factor VIII and VWF, which could be separated.
In 1985, VWF was cloned and sequenced for the first time and was able to study the relationship between their structure and function. [2]




Physiology of hemostasis
Upon endothelial injury starts primary hemostasis: platelets adhere to subendothelial structures, interacting with specific receptors and exposing their receptors for VWF and fibrinogen, this process leads to platelet adhesion and aggregation and release the contents of their granules (a and dense) with platelet plug formation, in turn activates the coagulation cascade, which together with activated platelets produce coagulation activation.
in blood clotting plasma proteins involved many known as "factors" (F), which circulate as zymogens which, when activated have enzymatic activity, and in many cases serinoproteasas and cofactors of coagulation. This process also presents a chain reaction leading to the amplification process, called "coagulation cascade" and self-limiting reactions that operation (natural anticoagulants).
The process of extrinsic pathway is initiated by tissue factor (TF) exposed to circulating FVII to form an activating complex to FVIIa. This complex, FT-VIIa, activates FX.
The intrinsic pathway involves the activation of FXII to FXII, which activates FXI to FXIa happens. This, in turn, activates FIX to FIXa happens. The FIXa forms a complex with FVIII activator, platelet-derived phospholipids and calcium. This complex acts on the FX to activate, combining both approaches. FXa binds to FVa and acts on prothrombin (FII), producing thrombin (FIIa). Thrombin activates FV and FVIII, generating FVa and FVIII and fibrinogen producing fibrin, which strengthens the platelet plug to form a stable clot by the support of fibrin (Figure 1).


This stabilizing action is carried out by FXIII. This knowledge in haemostasis have been acquired from the analysis of congenital deficiencies of various clotting factors that are associated with a hemorrhagic syndrome florida. Hemophilia A is given by a deficiency of FVIII: C, Hemophilia B FIX deficiency (described by the Argentine Alfredo Pavlovsky) and the present one, the VWD by VWF deficit with initial contributions of Dr core group Pavlovsky since 1957, first director of the Instituto de Investigaciones Hematologic "Mariano R Castex", where we develop this work. [3]


Synthesis and structure of
VWF VWF is a multimeric glycoprotein. The number of subunits varies from one molecule to another. Each subunit contends two thousand and fifty to twenty amino acids and carbohydrate side chains carbon. The units are joined in pairs by disulfide bonds, forming dimers of 500 kD.
The VWF gene is 180 kb and contains fifty-two exons. It is located on the short arm of chromosome 12. The primary
RNA translation gives the pre-pro-VWF, a polypeptide twenty-eight hundred thirteen amino acids. The newly synthesized protein consists of a signal peptide of twenty amino acids, the peptide of seven hundred forty-one amino acids and the mature subunit, two thousand fifty amino acids. [4] The protein is synthesized in endothelial cells and megakaryocytes. From there it is released into the subendothelium and plasma. Is deposited in the granules to platelets, in Weibel-Palade bodies of endothelial cells in the subendothelium. [5] (Figure 2)
The pre-pro-VWF becomes pro-VWF to get the signal peptide. Then glycosylated with simple sugars for transport to the Golgi apparatus. The pro-VWF monomers associate to form dimers. The noncovalent association of regions of propeptides promotes multimerization through disulfide bonds in the D3 domain of the amino terminal. Once completed the multimerization, the VWF is stored in storage organelles. In endothelial cells VWF stored in Weibel-Palade bodies. In megakaryocytes and platelets are stored in a -Granules. Propeptide dimers are removed before the secretion of VWF. This peptide was originally known as "von Willebrand antigen II." There are two secretory pathways: one constitutive (related to the synthesis) and a regulated pathway that involves the release of VWF-mediated secretagogues (activators of secretion). The VWF in megakaryocytes and platelets derived from the regulated pathway. The VWF circulating in plasma is of endothelial (constitutive pathway). [4]
VWF consists of a series of homologous segments (domains), each of which is repeated two to four times [6]. There are 3 repetitions of A, 3 B, 2 C and 4 D. Link the various functions of VWF appears to be localized in these domains. The site of interaction with GPIb is located in the A1 domain [7]. Also, within such domain, there is a binding site for collagen and a binding site for heparin [8]. The binding domain for factor VIII (FVIII) has been located in the fragment comprising 272 aa in the N-terminal region, corresponding to the domains D 'and part of D3 [9]. In the A2 domain is the ultimate proteolytic site (Figure 3).


The A3 domain is another binding site for collagen [10] and it has been suggested that this is the physiological site of interaction with collagen [11]. The tetrapeptide RGDS, which mediates the binding of VWF to the complex IIBB 3 (GPIIb-IIIa) to activated platelets, is located near the C-terminal C2 domain [12].


function
VWF VWF has three main functions: on the one hand it promotes the adhesion of platelets to subendothelial structures at the site of vascular injury. Here the VWF binds to collagen exposed through the A3 domain, this causes a conformational change in the VWF A1 domain that exposes the binding sites of GP Ib on platelets. On the other hand protects FVIII from inactivation and rapid catabolism, by training a noncovalent complex with it, through the D'-D3 domains, FVIII binding site. It also promotes platelet-platelet interaction by binding to platelet GP Ib and GP IIb-IIIa. This link not only depends on the presence of VWF and its quality, but also of other adhesive proteins such as fibronectin, laminin, thrombospondin, and different types of collagen. [1]


Classification of von Willebrand disease
Von Willebrand disease is caused by a deficiency of VWF cualitatitva or quantitative, which prevents platelet plug formation. VWD is currently
the most common bleeding disorder, with prevalence ranging between 0.8 and 1.3% of the population.
has been subdivided into two major categories reflecting the pathophysiology of the disease: quantitative and qualitative variants, types 1 and 3 are quantitative variants, refer respectively to the total or partial reduction of VWF whereas type 2 refers to deficiencies qualitative. Sadler [13] suggested in the revised classification introduced in 1994, subdivided into 4 type 2 variants (2 A, 2B, 2M, 2N or Normandy) according to specific details of the phenotype.


quantitative VWF defect:
• Type 1: partial quantitative deficiency of VWF in plasma and / or platelets.
• Type 3: complete deficiency of VWF in plasma and platelets.
The most common form of the disease is type 1 (70-80% of cases), characterized by comparatively low levels of FVIII: C, VWF antigen (VWF: Ag) and ristocetin cofactor activity ( VWF: RCo), produced by a decrease in the synthesis, with normal multimeric composition. The decrease in FVIII: C in this case is secondary to reduced VWF. The platelet VWF is present but may be decreased or normal.
Option 3 is the least common, but clinical symptoms presented severe. Represents 5-10% of the cases studied. It is characterized by undetectable levels of VWF: Ag and VWF: RCo with greatly reduced levels of FVIII: C.


Influence of blood group on plasma VWF levels
normal individuals were described with group 0 have lower levels of FVIII: C and / or VWF lower than those with other blood types. Although no one knows the reasons for this, the physiological basis of these differences are probably related to the type or amount of glycosylation of VWF, leading to a shortened survival itself. Gill et al (27) assessed the prevalence of each blood in patients with Group 0, finding that 77% of patients with type 1 had group 0, which is higher than the prevalence of this group in the general population. No significant differences in the prevalence of group 0 among patients with type 2 and 3.

qualitative VWF deficiency (type 2):
With decrease in high molecular weight multimers:
• 2A: Decreased affinity for platelet GP Ib
• 2B: Increased affinity for platelet GP Ib.
with normal multimeric structure:
• 2M: Decreased affinity for platelet GP Ib.
• 2N: marked decrease in affinity for FVIII.
type 2A is characterized by a qualitative change, which would be much diminished or absent multimers of high and intermediate molecular weight, both in plasma and platelets in plasma are decreased or absent VWF: RCo, with slightly reduced or normal levels of VWF: Ag and FVIII : C. 2B
type plasma has the same pattern, with a decrease of large multimers in plasma, but present in platelets. Multimeric structure in this case has a greater affinity for GPIb. This phenomenon can cause thrombocytopenia. In this case, the differential diagnosis of type 2B capacity to agglutinate platelets in the presence of low doses of ristocetin (0.3 ug / mL).
The presents type 2M VWF: RCo greatly diminished or absent levels of VWF: Ag and FVIII: C slightly decreased or normal, with normal multimeric pattern.
2N variant is characterized by an impaired ability to bind to the FVIII: C, with a consequent decrease in its half-life and low plasma levels of FVIII: C and VWF: Ag and VWF: RCo normal.
recently Lethagen reported that a significant number of patients diagnosed as type 1, mutations that would require to be reclassified as type 2. It further suggests that some patients would be helped at the clinic for the DDAVP [14]. Castamir described a lack of association between genotypes, history of bleeding and VWF: RCo in many families diagnosed with type 1 mild. This leads to consider that therapeutic decisions could not be based solely on phenotypic variants. [15]


Alternative 2N
This subtype that is caused by inherited recessive mutations in the domains D 'and part of the D3, that modulates the binding site of VWF to FVIII. Patients may be homozygous for substitution mutations or compound heterozygous for two different mutations. They may also have mutations in the binding site or a null mutation. About twenty mutations have been described. Most of them are located between exons 18 and 20, affecting the FVIII binding domain. Other mutations have been described in exons 17 and 21 to 27 who are outside the FVIII binding site and are also responsible for the decrease in binding capacity between VWF and FVIII. The R854Q mutation is the most frequently reported.
Bibliography
[1] Von Willebrand disease update: diagnostic dilemmas and Treatment . Bolton-Maggs PHB, D. Lillicrap, J. Goudemand, E. Berntorp. 2008
[2] Von Willebrand disease - and introductory discussion for young physicians. Carol K. Kasper, Los Angeles. October 2005
[3] Foundations for the practical use in the laboratory of haemostasis.
CAHT
Group [4] New perspectives on VWF functions in hemostasis and thrombosis. Loredana Mendolicchio Grazia, M. Zaveri Ruggeri. 2005
[5] Von Willebrand disease. Wagner. 1990
[6] Bonthron et al, 1986, Verweij et al, 1986; INLO Shelton et al, 1987
[7] Mohri et al, 1988; Mohri et al, 1989, Vicente et al, 1990; Sugimoto et al, 1991
[8] Pareti et al, 1986; Roth et al, 1986; Fujimura et al, 1987; Mohri et al, 1989
[9] Foster et al, 1987; Takahashi et al, 1987; Bahou et al, 1989
[10] Roth et al, 1986; Kalafatis et al, 1987
[11] Cruz et al, 1995; Lankhof et al, 1996
[12] Beacham et al, 1992
[13] Sadler JE.1994
[14] Lethagen S, et al, 1998
[15] Castaman G et al, 1999

Thursday, August 14, 2008

Whats A Good Phrase For A Soccer Themed Party



Today's meeting is dedicated to find the information we needed and finish writing the introduction to our final project.