SM_252b: Coags and Inherited Bleeding Flashcards
When there is vascular injury, ___
When there is vascular injury, thrombogenic components of subendothelial vessel wall become exposed and a hemostatic clot of platelets and fibrin form
Describe physiologic antithrombotic mechanisms
Physiologic antithrombotic mechanisms
- Normal endothelium generates substances that inhibit coagulation: inhibitors of platelet activation
- Antithrombotic mechanisms: antithrombin III, protein C and S, tissue factor pathway inhibitor, thrombomodulin, fibrinolytic system
Primary hemostasis is ___
Primary hemostasis is vasoconstriction and aggregated platelets temporarily plug the injured vessel
Secondary hemostasis is ____
Secondary hemostasis is when fibrin formation occurs to form a more permanent clot
Describe coagulation basics
Coagulation basics
- Clotting factors are proteins -> converted to proteases during coagulation -> cleave prothrombin to thrombin -> thrombin cleaves fibrinogen to fibrin -> fibrin monomers polymerize to form the strands of the clot
Coagulation involves stages of ____, ____, and ____
Coagulation involves stages of initiation, amplification, and propagation
In initation of coagulation, ____
In initation of coagulation, a small amount of thrombin is produced
In amplification of coagulation, ____
In amplification of coagulation, thrombin further activates FV, VIII, and XI for a large burst of thrombin generation
Describe natural inhibitors of procoagulants
Natural inhibitors of procoagulants
- Thrombin inhibited by antithrombin and thrombomodulin
- Factor Va and VIIIa inhibited by activated protein C and its co-factor protein S
- Factor Xa and TF-factor VIIa is inhibited by tissue factor pathway inhibitor
- Factor XIa is inhibited by the protease nexin 2
____ is progressive breakdown of a thrombus
Fibrinolysis is progressive breakdown of a thrombus
tPA is the initator of fibrinolysis and converts ____ to ____
tPA is the initator of fibrinolysis and converts fibrin-bound plasminogen to plasmin
- Plasmin lyses fibrin to soluble fibrin degradation products
____ are fragments of cross-linked fibrin that are soluble fibrin degradation products
D-dimers are fragments of cross-linked fibrin that are soluble fibrin degradation products
- Reflect amount of fibrin degradation
Describe regulation of hemostasis
Regulation of hemostasis
- Sequential steps activate specific procoagulants -> thrombin generation and fibrin formation
- Each step is regulated by clotting inhibitors
- Fibrinolysis results in clot lysis
- Bleeding or thrombosis can occur when the hemostatic balance between clotting factors and inhibitors is altered
aPTT measures the ___ pathway
aPTT measures the intrinsic pathway
- HMWK, FXII, FXI, FIX, FVIII
PT measures the ____ pathway
PT measures the extrinsic pathway
- FVII
Describe causes of prolonged PT and normal aPTT
Prolonged PT and normal aPTT
- FVII deficiency
- Early Vitamin K deficiency (FII, FVII, FIX, FX)
- Liver disease
- Warfarin therapy (Vitamin K antagonist)
Describe causes of prolonged aPTT and normal PT
Prolonged aPTT and normal PT
- FVIII or IX deficiency
- Factor XI or XII deficiency
- Decreases prekallikrein or high molecular weight kininogen
- Inhibitor (lupus anticoagulant, FVIII inhibitor)
- Anticoagulant: heparin
Describe causes of prolonged PT and prolonged aPTT
Prolonged PT and prolonged aPTT
- FII, FV, or FX deficiency
- Hypofibrinogenemia or dysfibrinogenemia
- Vitamin K deficiency (FII, FVII, FIX, FX)
- Liver disease
- Warfarin therapy (Vitamin K antagonist)
Correction to normal on PT or PTT mixing study indicates ____
Correction to normal on PT or PTT mixing study indicates factor deficiencies
- E.g. hemophilia, Vitamin K deficiency, warfarin therapy
No correction to normal on PT or PTT mixing study indicates ____
No correction to normal on PT or PTT mixing study indicates factor inhibitor present
- Acquired specific factor inhibitor or lupus anticoagulant
Even if PT and aPTT are normal, ____ can be present
Even if PT and aPTT are normal, mild factor deficiency can be present
- PT or PTT become abnormal only when coagulation factor levels drop below 30-40%
Describe causes of bleeding
Causes of bleeding
- Vascular / connective tissue: hereditary hemorrhagic telengiectasias, Ehlers-Danlos, scurvy (Vitamin C deficiency)
- Hematologic: coagulopathy, platelet disorder (thrombocytopenia, platelet function abnormality)
- Medications: anticoagulants, antiplatelets
Describe inherited bleeding disorders
Inherited bleeding disorders
- Vascular: hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu), Ehlers-Danlos syndrome
- Clotting factor deficiencies: VIII or IX, V / VII / X / XI, XIII, von Willebrand’s disease, hypofibrinogenemia / dysfibrinogenemia
- Platelet disorders
Describe clues to a bleeding disorder
Clues to a bleeding disorder
- Abnormal bruising especially spontaneous
- Recurrent epistaxis or gum bleeding
- Prior surgical bleeding
- Dental extractions complicated by bleeding
- Menorrhagia
- History of soft tissue or joint hemorrhage especially with normal activities
- Iron deficiency or need for transfusions
- Family history of bleeding disorders
Describe clues to bleeding disorders on physical exam
Clues to bleeding disorders on physical exam
- Petechiae: thrombocytopenia
- Ecchymoses: clotting factor disorder, von Willebrand’s disease, connective tissue disorders, medications, platelet disorders
- Soft tissue hemorrhage: deficiency of a coagulation factor
- Telangiectasias (skin, nasal, oral, nails): hereditary hemorrhagic telangiectasias
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is ____ that presents with ____ and ____
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is abnormality in the vascular wall that presents with mucocutaneous telangiectasias and arteriovenous malformations
___ is an autosomal dominant disorder that may present with recurrent bleeding from nose or GI tract
Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder that may present with recurrent bleeding from nose or GI tract
Diagnosis of hereditary hemorrhagic telangiectasia is ___
Diagnosis of hereditary hemorrhagic telangiectasia is clinical
- No specific lab tests
Hemophilia A results from a ___ deficiency
Hemophilia A results from a Factor VIII deficiency
- Inversion of intron 22 on factor VIII
Hemophilia B results from a ____ deficiency
Hemophilia B results from a Factor IX deficiency
Hemophilia A or B severity depends on ___
Hemophilia A or B severity depends on level of factor activity
- Severe hemophilia: spontaneous joint hemorrhages (hemarthroses), intramuscular hemorrhage, intracranial hemorrhage, serious bleeding with trauma or injury
- Moderate and mild: bleeding with surgery or dental procedures, bleeding with trauma or injury
Women are ___ of hemophilia A or B
Women are carriers of hemophilia A or B
- Can have clinically significant low factor levels (< 40%)
- Can have beeding complications
Joint bleeds are typically ____ in hemophilia
Joint bleeds are typically spontaneous in hemophilia
Describe treatment of hemophilia
Hemophilia treatment
- Severe hemophilia: prevention or prompt treatment of bleeding, early treatment and prophylactic therapy for joint bleeds
- Mild hemophilia: prevention of bleeding with surgery or trauma
____ is used to treat bleeding in hemophilia due to mild Factor VIII deficiency
Desmopressin is used to treat bleeding in hemophilia due to mild Factor VIII deficiency
Antibodies can develop in patients with hemophilia against factor concentrates, leading to ____
Antibodies can develop in patients with hemophilia against factor concentrates, leading to resistance to treatment
___ are used to treat hemophilia due to Factor VIII or IX deficiency
Factor concentrates are used to treat hemophilia due to Factor VIII or IX deficiency
VWF functions to ____ and ____
VWF functions to bind platelet to the endothelium and increases circulating half-life of Factor VIII because binding protein for Factor VIII
Describe vWF
vWF
- Gene on chromosome 12
- Protein synthesized by endothelial cells and megakaryocytes
- vWF multimers are stored in Weibel-Palade bodies or alpha granules in platelets
Describe lab tests for von Willebrand disease
Lab tests for von Willebrand disease
- Screening testsL bleeding time, PTT
- Specific tests: von Willebrand antigen, von Willebrand activity, Factor VIII, and Von Willebrand multimer analysis
Describe types of von Willebrand disease
Types of von Willebrand disease
- Type 1: partial quantitative deficiency of vWF antigen
- Type 2: qualitative defect of vWF antigen
- Type 3: severe quantitative deficiency (similar to severe hemophilia A)
Describe Type 1 von Willebrand disease
Type 1 von Willebrand disease
- Most common
- Decrease in vWF, von Willebrand activity, and FVIII
- Symptoms: easy bruising, epistaxis, menorrhagia, bleeding with dental extractions or tonsillectomy
- Not all patients with low vWF levels will bleed
- Patients with Type O blood have lower vWF levels than patients with other blood types
Describe Type 2 von Willebrand disease
Type 2 von Willebrand disease
- Functional defect of protein
- Type 2A: absence of high molecular weight multimers
- Type 2B: increasing binding of vWF to platelet glycoprotein 1b resulting in vWF and platelet clearance from circulation
- Type 2N: abnormal binding of FVIII to vWF -> increased clearance of FVIII
- Type 2M: impaired binding to collagen or platelet glycoprotein 1b
Describe Type 3 von Willebrand disease
Type 3 von Willebrand disease
- Severe deficiency of von Willebrand protein
- FVIII levels are very low
- Can have severe bleeding and similar to severe hemophilia
Treatment of von Willebrand disease involves ___ or ___
Treatment of von Willebrand disease involves desmopressin or vWF concentrate
Hemophilia C is ____
Hemophilia C is Factor XI deficiency
- Autosomal
Describe Factor XI
Factor XI
- Activates Factor IX -> results in thrombin generation
- Thrombin activates Factor XI -> creates positive feedback loop that leads to further thrombin generation
- Thrombin generation leads to thrombin activatable fibrinolysis inhibitor
- Factor XI deficiency: less thrombin generation and less TAFI -> increased fibrinolysis
Describe bleeding in Factor XI deficiency
Factor XI deficiency bleeding
- Variable hemorrhage
- Bleeding with surgery or trauma
- Spontaneous joint or muscle hemorrhage unlikely
- Mucocutaneous bleeding: ecchymoses, gum bleeding, epistaxis, menorrhagia
- Delayed post-surgical bleeding
Factor XI deficiency is treated with ____ or ____
Factor XI deficiency is treated with fresh frozen plasma or antifibrinolytic agents such as e-aminocaproic acid / transexamic acid
___ deficiency is the only coagulation factor not reflected in PT or PTT
Factor XIII deficiency is the only coagulation factor not reflected in PT or PTT
- Cross-links fibrin
- Homozygotes have severe deficiency
- Treat with FFP, cryoprecipitate, or plasma-derived factor XIII concentration (fibrogammin)
Describe clotting factor deficiences NOT associated with bleeding
Clotting factor deficiences NOT associated with bleeding
- Contact activation factors: factor XII, HMWK, prekallikrein
- Result in elevated PTT but no increased risk of bleeding
Describe disorders of fibrinogen
Disorders of fibrinogen
- Congenital afibrinogenemia
- Hypofibrinogenemia
- Dysfibrinogenemia
Treat with cryoprecipitate or plasma-derived fibrinogen concentrate (Riastap)
