BL 02-25-14 11am-Noon Hemostasis Overview handout - Stabler Flashcards
Hemostasis
the process whereby an injury to a blood vessel triggers a series of enzymatic reactions resulting in the formation of platelet and fibrin plugs at the site of the injury which then stems the loss of blood.
- tightly controlled so that a clot remains at the site of the injury & is not pathologically propagated throughout the vascular system.
- After clot is formed, then other enzymatic processes dissolve the clot gradually as wound healing advances
Components of Hemostasis
- Coagulation factors
- Platelets
- Endothelium – vessel wall
Role of Platelets in Coagulation
- adhere to site of vessel injury where collagen is exposed, with the help of a plasma protein, von Willebrand factor and a platelet membrane protein
- become activated by generation of thrombin at site of injury
- as platelets are stimulated, receptors for fibrinogen are exposed
- activated platelets change shape & release ADP, vasoactive amines & form thromboxane A2 (vasoconstricts, stops blood leakage)
- Platelet has receptors for some coagulation –> forms surface for coagulation cascade
- end result is increasing production of thrombin
Thromboxane action in Coagulation / Injury
contracts smooth muscle & causes vasoconstriction of vessel at site of injury, which also helps stop leakage of blood.
Other essential events/factors in clotting
- Vessel injury exposes membrane protein, tissue factor –> initiates clotting w/ factor VIIa to activate factor X and IX
- Protein disulfide isomerase is also required to initiate clotting
Activation of Coagulation cascade
Activated when sub-endothelial components (collagen, tissue factor or negatively charged surfaces) are exposed at the injured site
Procoagulant proteins
- circulate in excess concentration in plasma in inactive form or ZYMOGEN
- Only small % need to be activated by proteolytic cleavage to form clot
Goal of Coagulation cascade
-to produce THROMBIN (Factor IIa)
Thrombin (Factor IIa) - Actions
- converts FIBRINOGEN, a soluble protein, to FIBRIN
- promotes PLATELET AGGREGATION
(fibrin + platelet agg. = firm plug that seals injury in the vessel) - activates COFACTORS in coag. cascade (FACTORS V & VIII)
- activates factors responsible for lysing clot (FIBRINOLYTIC factors)
- activates PROTEIN C
Fibrin
- makes fibrous network in the clot
- inactive precursor is fibrinogen (cleaved by thrombin to for fibrin)
Protein C
helps prevent uncontrolled thrombosis
Interaction of factors (enzymes)
- Factors (enzymes) do not act on each other individually
- Actually come together to form complexes on phospholipid surfaces at site of injury
- Surface could be PLASMA MEMBRANE or the VESSEL WALL
Factors involved in coagulation cascade
- In each complex, there will be a large molecular weight cofactor which orients the enzyme & substrate molecules.
- Next is one of the vitamin K dependent factors (serine proteases)
- Third component is Calcium
- When all of these components combine on the phospholipid surface, the relative efficiency of the production of activated factors is enormously increased.
Large molecular weight cofactors which orient the enzyme & substrate molecules—examples
- tissue factor
- Factor VIII*
- Factor V
Vitamin K dependent factors (serine proteases)
- Factors X, IX, VII, and II (aka prothrombin)
How interactions of factors work in traditional clotting cascade
- Thrombin (activated Factor II) is generated by Factor Xa, which is generated by Factors IXa & VIIIa or by tissue factor & VIIa
- Thrombin produced by these rxns then converts fibrinogen to a clottable derivative called fibrin monomer
- Fibrin monomer assembles to form an infinite branching network of fibrin
- Thrombin also activates Factor XIII, which is an enzyme that crosslinks the fibrin and hardens the fibrin clot
Initiator of clotting after vessel wall injury
= the exposure of Tissue Factor
- binds small amount of activated factor VII
- then can bind inactive X or IX & convert them to Xa and IXa
- Xa then binds to cofactor V and converts prothrombin(II) to thrombin(IIa) in a complex known as prothrombinase
- IXa binds to cofactor factor VIII and converts more factor X to its active form Xa, in a complex known as tenase and referred to as the Propagation Phase
- thrombin formed now activates the two cofactors, V & VIII, greatly increasing the activity of the complexes (Amplification)
- causes a burst of thrombin generation
Role of Factors XII and XI and Contact System
- Coag. cascade traditionally drawn w/ intrinsic & extrinsic systems meeting at factor X
- BUT, not known what role of factors XII & XI actually are in physiologic hemostasis
- Factor XI is activated by thrombin
- Intrinsic system may be important in thrombosis & inflammation however
Factor XII deficiency
does NOT cause bleeding disorder
Factor XI deficiency
Bleeding with Factor XI deficiency is much milder than Factors VIII & IX.
PT (prothrombin time) is affected by
- VII, X, V, II, I
aPTT (activated Partial Thromboplastin time) is affected by
- XII, XI, IX, VIII, X
TT (thrombin time) is affected by
- deficient or abnormal fibrinogen
Thrombosis
- uncontrolled pathologic clotting
- can result in great morbidity
- coagulation system must be controlled carefully!
Activation of clotting cascade & of platelets is inhibited by…
- an intact vascular endothelium
- continuous blood flow which washes away platelets & any activated factors
- a number of natural anticoagulant proteins
Natural anticoagulant proteins
- antithrombin III
- protein c
- protein S
- tissue factor pathway inhibitor
Anti-thrombin III
- protein that binds w/ high affinity to heparin & to thrombin and inactivates it
- also inactivates Factors XII, XI, IX, and X
protein C
- regulatory protein activated by thrombin
- cleaves Factors Va and VIIIa, which are the cofactors of coagulation
protein S
- acts as cofactor to protein C
Tissue factor pathway inhibitor
- inhibits Xa and the VIIa-TF complex.
Physiologic Anticoagulants
- Antithrombin III
- Protein C and S
- Tissue Factor Pathway Inhibitor
- Thrombomodulin
Fibrinolysis
- Plasminogen is activated by tissue plasminogen activator (TPA) to become plasmin
- Plasmin degrades Fibrin into split products and D dimer
- Fibrinolysis is inhibited by plasminogen activator inhibitors (PAIs) and alpha 2-antiplasmin
Role of Vitamin K in Coagulation.
- Required for post-translational modification of glutamatic acid residues in serine proteases (Factors II, VII, IX, and X & the anti-coagulant proteins C & S)
- Function of these factors thus dependent upon source of vitK & adequately functioning liver
- Inadequacies of these –> most common clinical disorders of coagulation
- Warfarin (anticoagulant) interferes with this vitamin K dependent reaction
Bleeding after tonsillectomy, tooth extraction, or other surgical procedures is very suggestive of…
a congenital coagulopathy
Specific assays for each of the factors
= would be very laborious & expensive to assay in every person presenting with bleeding problems
- Thus, several screening tests help pinpoint which part of coagulation cascade is the most abnormal
- The Figure shows which part of the cascade the different screening tests measure (see notes)
Prothrombin Time (protime, PT) measure…
= measures procoagulant activity of factors VII, X, V, II and fibrinogen.
= i.e., the extrinsic pathway & lower part of the coagulation cascade
Normal range of protime (PT) & INR
Normal PT: between 9 & 12 seconds
= based on potency of material (thromboplastin) used to start rxn in lab
- Therefore, results must be standardized, using INR
International normalized ratio (INR)
Normal INR: 1.0
Reasons for an prolonged PT/INR
Most commonly results from deficiency of vitamin K dependent factors, VII, X, and II
- either b/c of lack of vitamin K or inadequate liver function
- Warfarin
- Also, factor V & fibrinogen deficiency
What is PT used to moniter?
Warfarin –> inhibits vitamin K dependent rxns –> prolonged PT
- PT used to monitor Warfarin therapy
Activated Partial Thromboplastin Time (APTT or PTT) measure…
- measures procoagulant activity of entire pathway
Activated Partial Thromboplastin Time (APTT or PTT) is sensitive to…
- most sensitive to deficiencies of higher numbered factors, esp. XI, VIII and IX
- NOT affected by deficiencies of Factor VII
Activated Partial Thromboplastin Time (APTT or PTT) can be prolonged by
- can be prolonged by anticoagulant drugs (heparin) or acquired anticoagulants (fibrin split products)
- Patients with hemophilia will have a prolonged PTT
Normal PTT range
Normal range = usually 25-32 seconds
PTT is used to moniter…
heparin therapy
Thrombin Time (TT) measures & is sensitive to…
- measures procoagulant activity of fibrinogen
- also very sensitive to anticoagulant effect of heparin or fibrin split products
Normal range of Thrombin Time (TT)
- Normal range = usually 12-18 seconds
What prolonges Thrombin Time (TT)?
- Prolonged with heparin contamination, fibrinogen deficiency or an abnormal fibrinogen
Bleeding Time (BT) measure…
- measures platelet & vessel interaction, as well as number & function of platelets
How Bleeding Time (BT) is done & what affects the test:
- performed by making standardized cut w/ simplate bleeding time device on the forearm
- Time to clotting is then measured
- Very operator dependent & takes meticulous attention to detail
- Also, affected by abnormalities in the skin
Normal Bleeding Time (BT)
2 to 9 minutes
What will prolong Bleeding Time (BT)
- Severe decrease in platelet count (<20,000-30,000)
- abnormalities in platelet function
- von Willebrand disease
- OTHER FACTOR DEFICIENCIES DO NOT PROLONG BLEEDING TIME
PFA-100 (Platelet function analyzer)
- new device
- can perform an in vitro bleeding time
- also can determine platelet response to agonists
Congenital Disorders of Coagulation
- Deficiencies of each factor have been seen, but most are extremely rare
- Most common congenital coagulopathies are hemophilia A and B & von Willebrand disease
Hemophilia A – deficient factor, how common
- Factor VIII deficiency
- most common cause of a severe bleeding tendency (1/5000 male births)
- 30% new mutations (no family Hx)
Hemophilia B (Christmas Disease)
- Factor IX deficiency
- 10x less common than Factor VIII deficiency (Hemophilia A)
Hemophilia A & B – Similarities, Differences, Inheritance
- Two syndromes causing identical clinical problems
- Specific factor assays must be done to distinguish the two disorders
- Both X-linked, w/females carriers, only male offspring severely affected
- Both result in prolonged PTT
PTT & Hemophilia
- Both hemophilia A (Factor VIII def.) and B (Factor IX def.) result in prolonged PTT
- Generally longer PTT corresponds to more severe hemophilia
Classifying Hemophilia
- Assume pooled plasma from normal population would give a value of 100%
- Classify hemophilia pts as to residual % of factor activity they have
- Many centers now offer genetic testing
- PCR test for an inversion on the long arm of the x chromosome can identify 40% of severe Hemophilia A patients
Percentage of Factor Activity Classification of Hemophilia
- Less than 1% factor activity – Severe Hemophilia.
- 2% to 5% - Moderate Hemophilia
- Greater than 10% - Mild Hemophilia
Severe hemophilia - % factor activity, what it leads to
- <1% factor activity
- spontaneous hemorrhaging into joints, muscles, soft tissues, retroperitoneal space & sometimes CNS
- Before specific factor replacement therapy, resulted in early death
- If repeated bleeding in joints is uncorrected, very severe arthritis & eventual total destruction of joints
Severe hemophilia - treatment
- Current treatment w/ recombinant or purified factor products is very effective in preventing or stopping bleeding
Moderate Hemophilia - % factor activity, degree of bleeding problem
- 2% to 5% factor activity
- Usually takes some degree of trauma to cause bleeding
Mild Hemophilia - % factor activity, degree of bleeding problem
- > 10% factor activity
- Only bleed after trauma (no spontaneous hemorrhage)
- Generally Dx after trauma or surgery, with subsequent screening of all family members
- Do not develop chronic joint disease that more severely affected patients do
- When they do sustain trauma & develop joint or soft tissue bleeding, need specific factor therapy just as urgently as more severely affected pts
- w/out aggressive replacement of factor during surgery, will have hematoma formation, wound breakdown & prolonged disability
Minimum level of factor activity require for surgery in hemophiliacs
- Absolute min levels of factor required for surgery are somewhere >50%
Carrier Females of Hemophilia - % factor activity,
- 30% to 100% factory activity
- B/c of lyonization of x chromosome, carriers of hemophilia A or B can be mildly affected themselves (30% factor level) or completely normal
- Carrier females w/ bleeding are called symptomatic carriers & require life-long hemophilia follow-up
- All potential carriers should be tested for genetic counseling & for factor replacement after trauma/surgery
- Factor levels cannot be solely used to determine carrier status, so use various molecular genetics methods
Hemophilia C - deficient factor
Factor XI Deficiency
Hemophilia C - factor levels, degree of bleeding abnormality, classic presentation
- Another common congenital bleeding disorder
- Levels usually >5% of normal so that spontaneous bleeding is quite rare
- Classic presentation is POST-OPERATIVE HEMORRHAGE since most people do not have spontaneous bleeding; often DELAYED
Hemophilia C - inheritance / demographics
- Autosomal recessive (both men & women affected)
- Common in Ashkenazi Jews in the US & in various populations in Middle East
Lab tests to Dx Hemophilia C
- Prolonged PTT & specific factor assay for Factor XI must be done to make Dx
Factor VII Deficiency -
- Rare but can cause severe bleeding disorder similar to Hemophilia
- ONLY PROTIME (PT) is PROLONGED
- PTT is normal
- When a patient is found w/ prolonged PT, then Factor VII assay & classification of severity (similar to hemophilia) is done
- Autosomal disease (both men & women affected)
- Severe patients are thought to be homozygous,
von Willebrand Disease - deficiency & what it leads to
- deficiency of von Willebrand protein
- -> prolonged bleeding
- -> decreased Factor VIII -
- > prolonged PTT
von Willebrand Disease - inheritance & how common
- most common milder congenital bleeding disorder
- autosomal dominant (both men & women affected)
Symptoms / Manifestation of von Willebrand Disease
- B/c of abnormality in platelet function, pts often bleed from mucosal membranes
- Nose bleeds, GI bleeds & menorrhagia are major clinical problems
- Generally, pts have high enough Factor VIII levels to prevent joint or muscle bleeding
- Bleed after SURGERY if not corrected w/ DDAVP or factor concentrates.
von Willebrand protein
- extremely large protein that circulates in plasma in a series of multimeric forms
- has TWO functions
1. Adheres platelets to exposed collagen at site of a wound
2. Carries Factor VIII - When we screen a patient for von Willebrand disease, we evaluate both functions of the von Willebrand protein (via BT or PFA-100 & PTT)
Function of von Willebrand protein in platelet adherence & its effect on labs
vWF adheres platelets to exposed collagen at site of wound
= necessary for adequate platelet functio
- in vWD, PROLONGED BLEEDING TIME
Function of von Willebrand protein on Factor VIII & its effect on labs
vWF carries Factor VIII
- w/out vWF, Factor VIII has very short half-life in plasma
- So, if von Willebrand protein is decreased, Factor VIII level will also be decreased
- If Factor VIII level decreased severely, then PTT PROLONGED
Screening for von Willebrand protein
- Bleeding time or PFA-100 to assess platelet function
- PTT
- vWF antigen to assess amount of factor present
- risocetin to assess vWF activity in platelet aggregation
- Factor VIII activity to assess ability of vWF to carry VIII
- Multimeric analysis by electrophoresis to determine loss of large forms or abnormal bands
- RIPA (Ristocetin-induced-platelet-aggregation) to determine hyperaggrebility to ristocetin to diagnose Type 2b
Causes of vW Disease
Can result as either
- deficiency of normal von Willebrand protein (type I)
- presence of an abnormal protein (type II)
Treatment of vW Disease
DDAVP (arginine vasopressin or des mopressin)
- very effective in type I (deficient vW protein)
- less effective in type II (abnormal vW protein)
- -> why we are interested in classifying patients
Classification of von Willebrand Disease
Type 1 - Partial quantitative deficiency
Type 2 - Qualitative deficiency
Type 2b - Abnormal clearance by platelets
Type 3 - Severe or total quantitative deficiency
Acquired Factor Inhibitors.
- Occasional pt will make specific Ab against one of the coagulation factors
- Extremely rare
Most common acquired factor inhibitors
acquired Factor VIII inhibitor
Much less common acquired factor inhibitors
Inhibitors to…
- von Willebrand protein (acquired von Willebrand disease)
- Factor II (seen in lupus patients)
- Factor V (seen in post-op or ICU patients)
Acquired Factor VIII inhibitor
- Often have other autoimmune illness, are postpartum or are of advanced age.
- Present w/ soft tissue & muscle bleeding, and usually marked hematomas of their skin or mucosal bleeding.
- 25% mortality due to bleeding, but an EXCELLENT LONG-TERM PROGNOSIS since most patients respond to immune suppression or spontaneously remit.
Lab tests for Factor VIII inhibitor
Only ABNORMAL lab test will be PTT (usually greatly PROLONGED)
Mixing test should be performed
- Normal plasma mixed w/ pt’s plasma
- -> PTT will not correct after 2 hrs of incubation b/c Ab in pt’s plasma will bind & inhibit normal Factor VIII (PTT will remain prolonged)
Dx confirmed by assaying specific factor levels
Also can measure a titer of the inhibitory antibody
Acquired bleeding disorders
- Common
- - use screening coagulation tests to suggest Dx
Causes of a Prolonged PTT with Bleeding
- Heparin in Sample
- Fibrin split/degredation products
- Hemophilia A & B (Factor VIII or IX Deficiency)
- Factor XI Deficiency
- Acquired Hemophilia
- von Willebrand Disease
Causes of a Prolonged PTT w/out Bleeding
- Factor XII Deficiency
- Lupus Anticoagulant (clot too much)
Causes of a Prolonged Protime ± PTT
- Protime relatively more prolonged than PTT
- Liver disease
- Vitamin K deficiency
- Warfarin or rat poison ingestion
Causes of a PTT more prolonged than protime
- Disseminated intravascular coagulation (DIC)
Causes of a PT more prolonged than PTT (+/-)
- Liver disease
- Vit K def.
- Warfarin / rat poison ingestion
Liver Disease & Coagualtion abnormalities
- Most coagulation factors are synthesized by the liver
- So, abnormalities in hepatic function can cause deficiencies of clotting factors
Factors deficient in Liver disease
- esp. Factor V & for vitamin K-dependent Factors, II, VII, IX, and X
- In very severe liver disease, fibrinogen can be low also
- Severe liver disease also causes abnormalities of the fibrinolytic system, with deficiencies of the endogenous anticoagulants also (antithrombin III, protein C & S)
Coagulation studies in Liver disease
Decreased factors usually affect PT more than PTT
- So, usually liver disease pt will have prolonged protime w/ less prolonged PTT
= the longer the protime, the more severe the deficiency & the more likely PTT will also be slightly prolonged
If fibrinogen is decreased, thrombin time may also be prolonged.
= may also have consumption of platelets by spleen due to portal hypertension (–> decreased PLT as well)
Patient w/ Prolonged Protime due to liver disease- important to check for…
- vitamin K deficiency
- exacerbates problem
- frequently trials of vitamin K therapy are done
Vitamin K Deficiency
- Vitamin K deficiency is a very common cause of prolonged PT w/ normal or slightly prolonged PTT
- 3 of the vitamin K dependent Factors (II, VII and X) affect PT mostly
- Vitamin K is readily obtained from the diet so generally deficiency occurs ww/ NPO pts (ICU) or pts w/ gut flora (which can make vitK) killed by broad spectrum antibiotics
- w/out vitamin K replacement in such pts, will become deficient, with increasingly prolonged PT in ~5 days
Warfarin in Vit K Deficiency
- Warfarin administration interferes w/ vit K utilization
- Another very common cause of prolonged PT w/ normal or slightly prolonged PTT
- vit K deficient hospitalized patients are much more sensitive to small doses of warfarin than normal pts
- over-anticoagulation can quickly occur
Long acting fat soluble rat poisons
- used in suicide attempts
- These pts present w/ extremely prolonged protime & PTT
- Require very intensive vitamin K therapy for months, until poison eliminated
Vitamin K deficiency & neonates
- Vit K def. is a problem for normal new-born infant
- In developed countries, they are treated right after birth to prevent this complication.
Disseminated Intravascular Coagulation (DIC) - Causes
- Massive trauma
- Hemorrhagic or septic shock
- Amniotic fluid embolism
- Burns
- Acute leukemia
- Transplant / Transfusion rxns
- Severe allergic rxns (antivenom)
- Drug rxns
DIC- pathogenesis
In situation of DIC, coagulation cascade is activated in vascular system
–> Results in formation of fibrin & platelet microthrombi that plug capillaries & cause tissue infarction
At same time, some factors & platelets are consumed
–> Pt develops multiple coagulation factor deficiencies & often hemorrhage results
Lab findings in DIC
- Most Consistent: MARKEDLY DECREASED FIBRINOGEN & LOW PLATELETS
- B/c fibrinolytic system is activated in order to try & remove fibrin-plt microthrombi, fibrin cleavage products are released into circulation
- – known as fibrin split products, fibrin degredation products or D-dimer
- – can be measured in lab
- – inhibit PTT assay & TT –>both markedly prolonged
- Factor VIII & V(cofactors of coagulation) can be consumed
- PTT increased relatively much more than protime
- On smear, “miroangiopathic”
Distinguishing DIC from Liver disease abnormalities
- Protime is usually least affected in DIC (in contrast to liver disease)
- Fibrinogen level is much lower in DIC than in the usual case of liver disease
Treatment of DIC
- Correct underlying illness that caused DIC –> fibrinogen quickly returns to normal & platelets rise
Abnormalities in DIC
- Prolonged PT
- Greatly prolonged PTT
- Prolonged thrombin time
- Low platelet count
- Low fibrinogen level
- Increased fibrin split products
- Increased D-dimer
Clinical Consequences of DIC
Generation of Thrombin
- Formation of Fibrin
- Impaired Fibrinolysis
- Fibrin-platelet thrombi
- -> Results In: Thrombosis, Infarction, Renal Failure, ARDS, Hemolysis
Consumption of Fibrinogen, Platelets, Factors VIII & V
–>Results In: Bleeding, Purpura, Petechiae
Thrombosis defn.
- formation & propagation of clot w/in vasculature
- refers to abnormal or pathologic process w/ imbalance in hemostatic system
Thrombosis - when occurs
- generally occurs when some combo of stasis, inflammation and/or vessel wall injury is present in person w/ increased baseline propensity for thrombosis (e.g. inherited or acquired hypercoagulable state)
Hypercoagulable states – exist when there is…
- chronic damage to vessel walls
- excess of procoagulant factors
- deficiency of anticoagulant factors
- deficiency of fibrinolytic activity
Risk factors for Thrombosis
- thrombotic episode in absence of defined precipitating condition (recent surgery, trauma, neoplasm, pregnancy, immobilization, etc.)
- recurrent episodes of thrombosis or thrombosis at an early age, but otherwise healthy
- severe, life threatening thrombosis, or thrombosis at an unusual site (e.g. mesenteric or cerebral venous thrombosis)
- family Hx of thrombosis
The Lupus Anticoagulant abnormality
= a very common acquired abnormality which results in a hypercoaguable state
- Though named lupus anticoagulant, only a minority of the patients have lupus
- Pts may have other autoimmune illness, malignancy, recent infection or it may be drug induced by antibiotics or anti-psychotic drugs.
Anticoagulant in Lupus Anticoagulant
- an IgG antibody
- reacts against phospholipid in platelet membrane or endothelial cell
Antiphospholipid Antibody Syndrome or APS
syndrome caused by the lupus anticoagulant
Effect on coag. tests of Lupus Anticoagulant
In vitro –> prolongs PTT
- b/c Ab binds up phospholipid which is added to test tube in order to start the rxn
- Though PTT is prolonged in vitro, pts DO NOT have a bleeding tendency
In vivo –> pts have THROMBOTIC SYNDROME instead
Thrombotic syndrome w/ Lupus Anticoagulant
- deep vein thrombosis
- pulmonary embolism
- thrombotic strokes
- recurrent miscarriage due to thrombotic disease of placental blood vessels
Correction of PTT w/ Lupus Anticoagulant
- When normal plasma mixed w/ plasma from pt w/ lupus anticoagulant, PTT does NOT correct
- If pt’s plasma is 1st mixed w/ source of phospholipid such as platelets, Ab will be absorbed out of plasma by phospholipid –> partial correction of PTT will occur
Other methods of detecting lupus anticoagulant
dilute Russell’s Viper Venom Test (RVVT)
Why important to Dx lupus anticoagulant
- these pts w/ thrombotic tendency must be distinguished from other pts w/ prolonged PTT’s who have a bleeding tendency, since treatment is entirely different
- give heparin / warfarin (counterintuitive when see prolonged PTT)
Thrombophilia – 4 most common familial congenital condition causing hypercoaguable syndrome
-Deficiencies of
- antithrombin III
- protein C
- protein S
Resistance to protein C (Factor V Leiden)
Deficiencies of antithrombin III, protein C, & protein S
- autosomal dominant
- only modest decreases in plasma levels of these proteins are associated w/ risk of thrombosis
- Homozygous deficiencies of protein C & protein S are frequently fatal at birth
- Heterozygous pts generally present after puberty w/ recurrent venous thrombotic disease
- Dx made w/ specific assays of activity or amount of protein present
Factor V Leiden hypercoagulability
- results from mutation in Factor V so that it is NOT INACTIVATED by protein C
- Heterozygous state common in people of European ancestry
- Often, more than one hypercoagulable condition is required to cause individuals with Factor V Leiden to thrombose
Factor V Leiden - Testing, Types of Clotting
- APC resistance assay, DNA analysis
- Venous clots
Prothrombin G20210A mutation - Testing, Types of Clotting
- DNA analysis
- Venous clots
Antiphospholipid antibodies (aPL) - Testing, Types of Clotting
- dRVVT, other functional assays, anticardiolipin antibodies, B2-glycoprotein-1 antibodies
- Venous / Arterial anticoagulation failures
Hyperhomocysteinemia - Testing, Types of Clotting
- Plasma homocystein
- Venous / Arterial clots
Fibrinolytic abnormalities - Testing, Types of Clotting
- Euglobulin lysis time, PAI-1, tPA activity levels, Plasminogen activity
- Venous / Arterial clots
Protein S deficiency - Testing, Types of Clotting
- Protein S free antigen
- Venous (20-30% Arterial) clots
Protein C deficiency - Testing, Types of Clotting
- Protein C activity
- Venous (rare Arterial) clots
Antithrombin deficiency - Testing, Types of Clotting
- Antithrombin activity
- Venous clots
Thrombocytosis - Testing, Types of Clotting
- Platelet count, JAK2 mutation
- Venous / Arterial clots
