Disorders of Plasma Clotting Factors: Laboratory Evaluation and Clinical Manifestations

What are clotting factors before they are activated?

Inactive zymogens

What are four general causes of plasma clotting factor defects?

Decreased production, impaired molecular synthesis (dysfunction), rapid consumption, or interference by circulating inhibitors/antibodies

List three acquired causes of clotting factor defects.

Vitamin K deficiency, liver disease, and disseminated intravascular coagulation (DIC)

Which clotting factors belong to the Prothrombin group?

Factors II, VII, IX, and X

Which clotting factors are consumed during coagulation?

Factors I, V, VIII, XIII, and II

What is the purpose of a mixing study in coagulation testing?

To differentiate between a factor deficiency (corrected by normal plasma) and a circulating inhibitor (not corrected)

What does the addition of normal plasma indicate if an abnormal PT or APTT is corrected?

A factor deficiency

What does the addition of normal plasma indicate if an abnormal PT or APTT is NOT corrected?

A circulating anticoagulant or inhibitor

What factors are contained in aged serum?

Factors VII, IX, X, and XII

What factors are contained in absorbed plasma?

Factors I, V, VIII, XI, XII, and XIII

Where is fibrinogen (Factor I) produced?

In the liver

What is the normal plasma concentration range for fibrinogen?

200-400 mg/dL

What is the minimum fibrinogen concentration required to maintain hemostasis?

100 mg/dL

Why is fibrinogen considered an acute phase reactant?

Its concentration increases during stress, trauma, pregnancy, or inflammation, leading to an elevated ESR

Which enzyme cleaves fibrinopeptides A and B from fibrinogen to produce fibrin monomers?

Thrombin

Which factor is responsible for catalyzing the covalent cross-linking of fibrin strands?

Thrombin-activated Factor XIII

What enzyme is responsible for the process of fibrinolysis?

Plasmin

What is afibrinogenemia?

A rare autosomal-recessive disorder characterized by the total absence of detectable fibrinogen

What is the primary laboratory finding in afibrinogenemia regarding coagulation tests?

Prolonged PT, APTT, Reptilase time, and Thrombin time

What is the source of the enzyme used in the Reptilase time test?

Snake venom from Bothrops atrox

Why is the Reptilase time useful in the presence of heparin?

It is unaffected by heparin, hirudin, or antithrombins

What is the fibrinogen level range in hypofibrinogenemia?

20-100 mg/dL

What defines dysfibrinogenemia?

A qualitative defect where the fibrinogen molecule has an altered structure, leading to defective fibrin formation

What is a common laboratory finding in dysfibrinogenemia regarding functional vs. antigenic levels?

Discordance: decreased functional fibrinogen levels with higher antigenic protein concentration

What is the treatment for dysfibrinogenemia if bleeding occurs?

Fresh frozen plasma (FFP) or cryoprecipitate

Where is Prothrombin (Factor II) synthesized?

In the liver.

What components make up the Prothrombinase Complex?

Activated factor X (FXa), activated factor V (FVa), platelet membrane phospholipids, and calcium ions.

What is the primary clinical consequence of prothrombin deficiency?

Delayed generation of thrombin, contributing to hemorrhagic symptoms.

How is hereditary hypoprothrombinemia inherited?

As an autosomal recessive trait.

What laboratory results are characteristic of hypoprothrombinemia?

Prolongation of both PT and APTT with a normal thrombin time.

What is Dysprothrombinemia?

A structural defect in prothrombin that causes impaired functional activity despite normal antigenic concentration.

What is the clinical significance of the Prothrombin 20210A mutation?

It is associated with elevated prothrombin levels and increased risk of venous thrombosis.

What is another name for Factor V?

Proaccelerin or Labile factor.

Where is Factor V stored in the blood?

In the alpha granules of platelets.

What is the primary function of Factor V?

It acts as a cofactor in the conversion of prothrombin to thrombin.

What is the effect of Factor V Leiden (R506Q) mutation?

It impairs the degradation of Factor V by activated protein C, leading to continued thrombin generation and thrombosis.

What is the role of activated protein C (APC) in coagulation?

It inactivates Factor V to prevent ongoing thrombin generation.

What protein activates protein C?

Thrombomodulin.

What is the primary function of tissue factor in the extrinsic pathway?

It functions as a cofactor for Factor VII.

Which cells synthesize tissue factor?

Macrophages and endothelial cells.

What laboratory findings are associated with Factor VII deficiency?

Prolonged PT with a normal APTT.

What is the 'Stypven time' used for?

It is a test using Russell's viper venom to bypass the extrinsic pathway and directly activate Factor X, correcting PT in Factor VII deficiency.

What is the normal circulating form of Factor VIII?

It circulates as a complex with von Willebrand's factor (FVIII:vWF).

What is the function of the FVIII:C portion of the Factor VIII complex?

It acts as a procoagulant cofactor, accelerating the conversion of Factor X to Xa.

What is the function of the FVIII:vWF portion of the Factor VIII complex?

It mediates platelet adhesion.

Why must plasma be 'platelet poor' before testing for Factor V?

Because platelets contain Factor V, which would contaminate the plasma sample and skew results.

What is the inheritance pattern of congenital Factor V deficiency (parahemophilia)?

Autosomal recessive.

Which vitamin-dependent clotting factors are mentioned in the context of warfarin therapy?

Factors II, VII, IX, and X.

What is the most common cause of inherited thrombophilia?

Factor V Leiden mutation.

Does severe hepatic failure cause Factor VIII deficiency?

No, despite it being synthesized in the liver.

What is the primary purpose of inactivating APC in the coagulation cascade?

To prevent ongoing thrombin generation and thromboembolic complications.

What storage condition is required to prevent the rapid loss of activity in FVIII:C?

Storage at or below -70°C.

What are four conditions that can cause elevated levels of Factor VIII as an acute-phase reactant?

Inflammation, stress, pregnancy, and infection.

What is the inheritance pattern of Hemophilia A?

Sex-linked.

What is the specific molecular defect in Hemophilia A?

A defect or absence of the procoagulant portion (FVIII:C) of the Factor VIII complex.

What is the status of vWF:Ag in patients with Hemophilia A?

It is found to be normal.

What are the primary symptoms of severe Hemophilia A (FVIII:C < 1%)?

Hemarthrosis, hematuria, intracranial bleeding, hematomas, and spontaneous hemorrhage.

What is the 'anamnestic response' in Hemophilia A patients?

A rise in antibody titers to AHF following the administration of antihemophilic factor.

Which treatment is often used for Hemophilia A patients who have developed antibodies to human FVIII concentrates?

Porcine FVIII.

What are the characteristic laboratory findings for Hemophilia A?

Prolonged APTT, normal PT, and normal bleeding time.

How can the presence of an inhibitor be confirmed in Hemophilia A?

Mixing studies with pooled normal plasma fail to correct the prolonged APTT, especially after 37°C incubation.

What are the three cardinal manifestations that distinguish von Willebrand's disease from Hemophilia A?

Autosomal inheritance, consistently prolonged bleeding times, and mucocutaneous bleeding.

Where is vWF stored and secreted?

In Weibel-Palade bodies of endothelial cells and alpha-granules of platelets.

What is the function of vWF after injury?

It interacts with the glycoprotein Ib (GPIb) receptor on platelets to facilitate activation and adhesion to the subendothelium.

What is the difference between ristocetin-induced 'agglutination' and 'aggregation'?

Agglutination involves fixed platelets (not metabolically active), while aggregation involves metabolically active platelet-rich plasma.

What is the most common type of von Willebrand's disease?

Type 1, caused by a partial quantitative deletion of the vWF gene.

Which type of von Willebrand's disease is characterized by a lack of high-molecular-weight multimers and enhanced aggregation with low-dose ristocetin?

Type 2B.

What distinguishes Platelet-type (pseudo) vWD from Type 2B vWD?

The defect in Platelet-type vWD is intrinsic to the platelet (GPIb abnormality), whereas Type 2B is a defect in the vWF protein itself.

Why are commercial FVIII concentrates generally not useful for treating von Willebrand's disease?

They lack the high-molecular-weight multimers of vWF.

What medication can temporarily increase vWF and FVIII:C levels in vWD patients?

Desmopressin (DDAVP).

Where is Factor IX synthesized?

In the liver.

What vitamin is required for the synthesis of Factor IX?

Vitamin K.

In the intrinsic pathway, what activates Factor IX?

Factor XIa in the presence of calcium ions.

What is the alternative mechanism for activating Factor IX that bypasses contact activation?

Activation via tissue factor and factor VIIa.

What is the clinical significance of Type 2B vWD regarding platelet count?

It can cause mild thrombocytopenia due to the spontaneous binding of abnormal vWF to platelets, leading to increased clearance.

What mechanism bypasses contact activation in the coagulation cascade?

Activation via tissue factor and factor VIIa.

What substance from Russell's viper venom can activate factor IX?

A specific protease found in the venom.

What is the inheritance pattern of Hemophilia B?

Sex-linked recessive.

What are two causes of acquired factor IX deficiency?

Liver disease and vitamin K deficiency.

What is the most serious complication in patients with Hemophilia B?

The formation of antibodies (inhibitors) to factor IX.

What laboratory findings are characteristic of Hemophilia B?

Normal PT, thrombin time, and bleeding time, with a prolonged APTT that corrects with pooled normal plasma.

What is the structural composition of Factor X?

A vitamin K-dependent glycoprotein with a light chain and a heavy chain linked by a disulfide bond.

What condition is associated with Factor X deficiency besides liver disease and vitamin K deficiency?

Amyloidosis.

Why is the 'Stypven' time (Russell's viper venom time) prolonged in Factor X deficiency?

Because the assay is dependent on factors II, V, and X in the presence of phospholipid.

Where is Factor XI synthesized?

In the liver.

With which protein does Factor XI circulate in the plasma?

High-molecular-weight kininogen (HMWK).

What is another name for Factor XI deficiency?

Rosenthal syndrome or Hemophilia C.

Which population has a high frequency of Factor XI deficiency?

The Ashkenazi Jewish population.

What is the inheritance pattern of Hemophilia C?

Autosomal recessive.

What is the required activity level of Factor XI to ensure hemostasis?

20% to 30% of normal levels.

Why should plasma for Factor XI activity assays be drawn in plastic syringes and nonwettable tubes?

To prevent contact activation caused by freezing and thawing, which can artificially shorten the APTT.

Which contact system factors participate in inflammation and complement activation rather than just coagulation?

Factor XII, prekallikrein, and HMWK.

What is the structural nature of Factor XII?

A single-chain-beta globulin.

What triggers the in-vitro autoactivation of Factor XII?

Contact with negatively charged surfaces like glass, celite, kaolin, or ellagic acid.

What is the clinical significance of Hageman trait (Factor XII deficiency)?

It is not associated with clinical bleeding but may be linked to an increased risk of thrombotic diseases.

What is the primary function of Factor XIII?

The formation of a stable fibrin clot.

What converts Factor XIII to its active form, Factor XIIIa?

Thrombin, in the presence of fibrin.

What is the role of Factor XIIIa as a catalyst?

It forms bonds between protein substrates like fibrin monomers, alpha2-plasmin inhibitor, fibronectin, and collagen.

Where are the alpha2 chains of Factor XIII found?

In tissues and cells such as the placenta, platelets, macrophages, and the prostate.

What is the normal activity range for Factor XII?

70% to 140%.