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Summarize role of vWF in clot formation

· Factor VIII is bound to VWF while inactive in circulation
· VWF binds to collagen when it is exposed in endothelial cells due to damage occurring to the blood vessel. Endothelium also releases VWF which forms additional links between the platelets' glycoprotein Ib/IX/V and the collagen fibrils
· VWF binds to platelet gpIb when it forms a complex with gpIX and gpV;
-VWF binds to other platelet receptors when they are activated


Describe the role of factor VIII in hemostasis

· In the blood, it mainly circulates in a stable noncovalent complex with von Willebrand factor.
· Upon activation by thrombin (factor IIa), it dissociates from the complex to interact with factor IXa in the coagulation cascade.
· It is a cofactor to factor IXa in the activation of factor X, which, in turn, with its cofactor factor Va, activates more thrombin.
· Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using factor XIII) into a blood clot.


pathophysiology of vWD, type I

· The anomalies responsible for type 1 VWD generally lead to intracellular retention or rapid clearance of VWF from the circulation.
· Type 1 von Willebrand disease characterized by partial quantitative plasmatic deficiency of an otherwise structurally and functionally normal Willebrand factor.


causes and inheritance patterns of Type 1 vWD

D cases) is a quantitative defect which is heterozygous for the defective gene. It can arise from failure to secrete vWF into the circulation or from vWF being cleared more quickly than normal.


causes and inheritance patterns of Type 2 vWD

is a qualitative defect and the bleeding tendency can vary between individuals. Four subtypes exist: 2A, 2B, 2M, and 2N. These subtypes depend on the presence and behavior of the underlying multimers.


causes and inheritance patterns of Type 2A vWD

quantitatively normal but qualitatively defective. The ability of the defective von Willebrand factors to coalesce and form large vWF multimers is impaired, resulting in decreased quantity of large vWF multimers and low RCoF activity. Only small multimer units are detected in the circulation. Von Willebrand factor antigen (vWF:Ag) assay is low or normal.


causes and inheritance patterns of Type 2B vWD

This is a "gain of function" defect. The ability of the qualitatively defective vWF to bind to glycoprotein Ib (GPIb) receptor on the platelet membrane is abnormally enhanced, leading to its spontaneous binding to platelets and subsequent rapid clearance of the bound platelets and of the large vWF multimers. Thrombocytopenia may occur. Large vWF multimers are reduced or absent from the circulation.


causes and inheritance patterns of Type 2M vWD

Type 2M vWD is a qualitative defect of vWF characterized by its decreased ability to bind to GPIb receptor on the platelet membrane and normal capability at multimerization. The vWF antigen levels are normal. The ristocetin cofactor activity is decreased and high molecular weight large vWF multimers are present in the circulation.


causes and inheritance patterns of Type 2N vWD

This is a deficiency of the binding of vWF to coagulation factor VIII. The vWF antigen test is normal, indicating normal quantity of vWF. The ristocetin cofactor assay is normal. Assay for coagulation factor VIII revealed marked quantitative decrease equivalent to levels seen in hemophilia A. This has led to some vWD type 2N patients being misdiagnosed as having hemophilia A.


causes and inheritance patterns of Type 3 vWD

Type 3 is the most severe form of vWD (homozygous for the defective gene) and is characterized by complete absence of production of vWF. The von Willebrand factor is undetectable in the vWF antigen assay. Since the vWF protects coagulation factor VIII from proteolytic degradation, total absence of vWF leads to extremely low factor VIII level, equivalent to that seen in severe hemophilia A with its clinical manifestations of life-threatening external and internal hemorrhages. The inheritance pattern of vWD type 3 is autosomal recessive, while the inheritance pattern of hemophilia A is X-linked recessive.


clinical features of vWD, type I

· Asymptomatic or mild symptoms
· Mucosal bleeding
· Bleeding following surgery (including dental procedures)
· Noticeable easy bruising
· Menorrhagia


PT (prothrombin time)

Used to evaluate extrinsic pathway of coagulation. Used to determine clotting tendency of blood, measure of warfarin dosage, liver damage, and Vitamin K status. PT measures Factors I, II, V, VII, and X. The prothrombin time is the time it takes plasma to clot after addition of tissue factor.



Partial thromboplastin time (PTT) measures the overall speed at which blood clots by means of two consecutive series of biochemical reactions known as the "intrinsic" (now referred to as the contact activation pathway) and common coagulation pathways.The partial thromboplastin time (PTT) is used in conjunction with another measure of how quickly blood clotting takes place called the prothrombin time (PT). The prothrombin time measures the speed of clotting by means of the extrinsic pathway (also known as the tissue factor pathway).


Bleeding time

-Bleeding time is a laboratory test to assess platelet function and the body’s ability to form a clot. The test involves making a puncture wound in a superficial area of the skin and monitoring the time needed for bleeding to stop (ie, bleeding site turns "glassy").
-A bleeding time evaluation is used to measure the primary phase of hemostasis, which involves platelet adherence to injured capillaries and then platelet activation and aggregation. The bleeding time can be abnormal when the platelet count is low or the platelets are dysfunctional. 


how vWF leads to anemia

Hemorrhage can lead to loss of RBC --> anemia


vWF activity

-the binding of VWF to platelet glycoprotein Ib [GPIb]


ristocetin cofactor activity

-assesses vWF activity
- ristocetin is added to a suspension of washed formalin- or paraformaldehyde-fixed platelets in the presence of the patient's plasma (as a source of vWF). The rate of aggregation is then measured using an aggregometer, a device specifically designed to monitor this activity.
- results are difficult to standardize and the test is difficult to perform



- stimulates release of von Willebrand factor from endothelial cells by acting on the V2 receptor.
-used mostly as diuretic


Describe the risk factors for thrombotic disorders.

-patients with a history of trauma, pregnancy, oral contraceptive use, or immobility, but rarely in adolescents or young adults. Inherited hypercoagulable states are suspected in patients who present with a thromboembolic event, usually because they are young or experience recurrent clots.


Factor V Leiden

-increases the activity of factor V.
-single base change that results in the replacement of arginine by glutamine at position 506.


Factor V Leiden leading to hypercoagulability

--normal factor Va, Arg506 is the first site cleaved by activated protein C; absence of the initial cleavage at position 506 in factor V Leiden markedly delays cleavage at the two other sites and thereby results in higher levels of factor Va, which acts as a cofactor for factor Xa.
-actor Va molecules can continue to enhance factor Xa’s conversion of prothrombin to thrombin (factor IIa), via the prothrombinase complex, and coagulation is not inhibited.


Deep Vein Thrombosis

A blood clot within a deep vein, typically in the thigh or leg. The blood clot (thrombus) can break off as an embolus and make its way to the lung, where it can cause lung problems



-product of fibrin proteolysis by plasmin; elevated levels signify that fibrinolysis of complexed fibrin is occurring
-commonly occurs as part of the response to injury in patients undergoing surgical procedures or trauma, part of the normal physiologic changes during pregnancy, and part of the pathophysiologic process in patients with cancer or thrombotic disorder


Doppler ultrasound

-dominant diagnostic test of choice for the detection of DVT
- diagnostic criteria for DVT include increased intraluminal echogenicity, increased venous diameter, inability of the vein to collapse under moderate pressure from the transducer, absence of spontaneous blood flow, and absence of flow augmentation with distal compression. Among these factors, inability to compress the vein is the most widely used objective criterion for the diagnosis of DVT.



- PT reagents can vary widely between laboratories and lead to differing values, the international normalized ratio (INR) was developed by the World Health Organization to standardize PT
- PT can measure reduced activity of the vitamin K–dependent factors, it is used to monitor warfarin therapy.
-INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the analytical system being used.


role of factor V in blood clot formation

-Factor Va functions both as a factor Xa receptor and positive modulator of factor Xa catalytic potential in the prothrombinase complex.
- Factor Va is proteolytically inactivated by APC.


risk factors that predispose to thrombosis

- obesity, previous VTE, malignancy, surgery, and immobility.
- most powerful risk marker remains a prior history of DVT



-Interferes with hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, as well as proteins C and S
- S-warfarin is 4 times more potent than R-warfarin