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Unit 3 B&L > BL 02-25-14 11am-Noon Hemostasis Overview handout - Stabler > Flashcards

BL 02-25-14 11am-Noon Hemostasis Overview handout - Stabler Flashcards

1
Q

Hemostasis

A

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
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2
Q

Components of Hemostasis

A
  1. Coagulation factors
  2. Platelets
  3. Endothelium – vessel wall
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3
Q

Role of Platelets in Coagulation

A
  • 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
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4
Q

Thromboxane action in Coagulation / Injury

A

contracts smooth muscle & causes vasoconstriction of vessel at site of injury, which also helps stop leakage of blood.

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5
Q

Other essential events/factors in clotting

A
  • 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
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6
Q

Activation of Coagulation cascade

A

Activated when sub-endothelial components (collagen, tissue factor or negatively charged surfaces) are exposed at the injured site

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7
Q

Procoagulant proteins

A
  • circulate in excess concentration in plasma in inactive form or ZYMOGEN
  • Only small % need to be activated by proteolytic cleavage to form clot
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8
Q

Goal of Coagulation cascade

A

-to produce THROMBIN (Factor IIa)

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9
Q

Thrombin (Factor IIa) - Actions

A
  • 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
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10
Q

Fibrin

A
  • makes fibrous network in the clot

- inactive precursor is fibrinogen (cleaved by thrombin to for fibrin)

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11
Q

Protein C

A

helps prevent uncontrolled thrombosis

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12
Q

Interaction of factors (enzymes)

A
  • 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
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13
Q

Factors involved in coagulation cascade

A
  • 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.
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14
Q

Large molecular weight cofactors which orient the enzyme & substrate molecules—examples

A
  • tissue factor
  • Factor VIII*
  • Factor V
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15
Q

Vitamin K dependent factors (serine proteases)

A
  • Factors X, IX, VII, and II (aka prothrombin)
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16
Q

How interactions of factors work in traditional clotting cascade

A
  • 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
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17
Q

Initiator of clotting after vessel wall injury

A

= 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
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18
Q

Role of Factors XII and XI and Contact System

A
  • 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
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19
Q

Factor XII deficiency

A

does NOT cause bleeding disorder

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20
Q

Factor XI deficiency

A

Bleeding with Factor XI deficiency is much milder than Factors VIII & IX.

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21
Q

PT (prothrombin time) is affected by

A
  • VII, X, V, II, I
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22
Q

aPTT (activated Partial Thromboplastin time) is affected by

A
  • XII, XI, IX, VIII, X
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23
Q

TT (thrombin time) is affected by

A
  • deficient or abnormal fibrinogen
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24
Q

Thrombosis

A
  • uncontrolled pathologic clotting
  • can result in great morbidity
  • coagulation system must be controlled carefully!
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25
Q

Activation of clotting cascade & of platelets is inhibited by…

A
  • an intact vascular endothelium
  • continuous blood flow which washes away platelets & any activated factors
  • a number of natural anticoagulant proteins
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26
Q

Natural anticoagulant proteins

A
  • antithrombin III
  • protein c
  • protein S
  • tissue factor pathway inhibitor
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27
Q

Anti-thrombin III

A
  • protein that binds w/ high affinity to heparin & to thrombin and inactivates it
  • also inactivates Factors XII, XI, IX, and X
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28
Q

protein C

A
  • regulatory protein activated by thrombin

- cleaves Factors Va and VIIIa, which are the cofactors of coagulation

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29
Q

protein S

A
  • acts as cofactor to protein C
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30
Q

Tissue factor pathway inhibitor

A
  • inhibits Xa and the VIIa-TF complex.
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31
Q

Physiologic Anticoagulants

A
  • Antithrombin III
  • Protein C and S
  • Tissue Factor Pathway Inhibitor
  • Thrombomodulin
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32
Q

Fibrinolysis

A
  • 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
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33
Q

Role of Vitamin K in Coagulation.

A
  • 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
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34
Q

Bleeding after tonsillectomy, tooth extraction, or other surgical procedures is very suggestive of…

A

a congenital coagulopathy

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35
Q

Specific assays for each of the factors

A

= 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)
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36
Q

Prothrombin Time (protime, PT) measure…

A

= measures procoagulant activity of factors VII, X, V, II and fibrinogen.
= i.e., the extrinsic pathway & lower part of the coagulation cascade

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37
Q

Normal range of protime (PT) & INR

A

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

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38
Q

Reasons for an prolonged PT/INR

A

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
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39
Q

What is PT used to moniter?

A

Warfarin –> inhibits vitamin K dependent rxns –> prolonged PT
- PT used to monitor Warfarin therapy

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40
Q

Activated Partial Thromboplastin Time (APTT or PTT) measure…

A
  • measures procoagulant activity of entire pathway
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41
Q

Activated Partial Thromboplastin Time (APTT or PTT) is sensitive to…

A
  • most sensitive to deficiencies of higher numbered factors, esp. XI, VIII and IX
  • NOT affected by deficiencies of Factor VII
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42
Q

Activated Partial Thromboplastin Time (APTT or PTT) can be prolonged by

A
  • can be prolonged by anticoagulant drugs (heparin) or acquired anticoagulants (fibrin split products)
  • Patients with hemophilia will have a prolonged PTT
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43
Q

Normal PTT range

A

Normal range = usually 25-32 seconds

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44
Q

PTT is used to moniter…

A

heparin therapy

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45
Q

Thrombin Time (TT) measures & is sensitive to…

A
  • measures procoagulant activity of fibrinogen

- also very sensitive to anticoagulant effect of heparin or fibrin split products

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46
Q

Normal range of Thrombin Time (TT)

A
  • Normal range = usually 12-18 seconds
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47
Q

What prolonges Thrombin Time (TT)?

A
  • Prolonged with heparin contamination, fibrinogen deficiency or an abnormal fibrinogen
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48
Q

Bleeding Time (BT) measure…

A
  • measures platelet & vessel interaction, as well as number & function of platelets
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49
Q

How Bleeding Time (BT) is done & what affects the test:

A
  • 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
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50
Q

Normal Bleeding Time (BT)

A

2 to 9 minutes

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51
Q

What will prolong Bleeding Time (BT)

A
  • Severe decrease in platelet count (<20,000-30,000)
  • abnormalities in platelet function
  • von Willebrand disease
  • OTHER FACTOR DEFICIENCIES DO NOT PROLONG BLEEDING TIME
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52
Q

PFA-100 (Platelet function analyzer)

A
  • new device
  • can perform an in vitro bleeding time
  • also can determine platelet response to agonists
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53
Q

Congenital Disorders of Coagulation

A
  • Deficiencies of each factor have been seen, but most are extremely rare
  • Most common congenital coagulopathies are hemophilia A and B & von Willebrand disease
54
Q

Hemophilia A – deficient factor, how common

A
  • Factor VIII deficiency
  • most common cause of a severe bleeding tendency (1/5000 male births)
  • 30% new mutations (no family Hx)
55
Q

Hemophilia B (Christmas Disease)

A
  • Factor IX deficiency

- 10x less common than Factor VIII deficiency (Hemophilia A)

56
Q

Hemophilia A & B – Similarities, Differences, Inheritance

A
  • 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
57
Q

PTT & Hemophilia

A
  • Both hemophilia A (Factor VIII def.) and B (Factor IX def.) result in prolonged PTT
  • Generally longer PTT corresponds to more severe hemophilia
58
Q

Classifying Hemophilia

A
  • 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
59
Q

Percentage of Factor Activity Classification of Hemophilia

A
  • Less than 1% factor activity – Severe Hemophilia.
  • 2% to 5% - Moderate Hemophilia
  • Greater than 10% - Mild Hemophilia
60
Q

Severe hemophilia - % factor activity, what it leads to

A
  • <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
61
Q

Severe hemophilia - treatment

A
  • Current treatment w/ recombinant or purified factor products is very effective in preventing or stopping bleeding
62
Q

Moderate Hemophilia - % factor activity, degree of bleeding problem

A
  • 2% to 5% factor activity

- Usually takes some degree of trauma to cause bleeding

63
Q

Mild Hemophilia - % factor activity, degree of bleeding problem

A
  • > 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
64
Q

Minimum level of factor activity require for surgery in hemophiliacs

A
  • Absolute min levels of factor required for surgery are somewhere >50%
65
Q

Carrier Females of Hemophilia - % factor activity,

A
  • 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
66
Q

Hemophilia C - deficient factor

A

Factor XI Deficiency

67
Q

Hemophilia C - factor levels, degree of bleeding abnormality, classic presentation

A
  • 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
68
Q

Hemophilia C - inheritance / demographics

A
  • Autosomal recessive (both men & women affected)

- Common in Ashkenazi Jews in the US & in various populations in Middle East

69
Q

Lab tests to Dx Hemophilia C

A
  • Prolonged PTT & specific factor assay for Factor XI must be done to make Dx
70
Q

Factor VII Deficiency -

A
  • 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,
71
Q

von Willebrand Disease - deficiency & what it leads to

A
  • deficiency of von Willebrand protein
  • -> prolonged bleeding
  • -> decreased Factor VIII -
  • > prolonged PTT
72
Q

von Willebrand Disease - inheritance & how common

A
  • most common milder congenital bleeding disorder

- autosomal dominant (both men & women affected)

73
Q

Symptoms / Manifestation of von Willebrand Disease

A
  • 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.
74
Q

von Willebrand protein

A
  • 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)
75
Q

Function of von Willebrand protein in platelet adherence & its effect on labs

A

vWF adheres platelets to exposed collagen at site of wound
= necessary for adequate platelet functio
- in vWD, PROLONGED BLEEDING TIME

76
Q

Function of von Willebrand protein on Factor VIII & its effect on labs

A

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
77
Q

Screening for von Willebrand protein

A
  • 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
78
Q

Causes of vW Disease

A

Can result as either

  • deficiency of normal von Willebrand protein (type I)
  • presence of an abnormal protein (type II)
79
Q

Treatment of vW Disease

A

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
80
Q

Classification of von Willebrand Disease

A

Type 1 - Partial quantitative deficiency
Type 2 - Qualitative deficiency
Type 2b - Abnormal clearance by platelets
Type 3 - Severe or total quantitative deficiency

81
Q

Acquired Factor Inhibitors.

A
  • Occasional pt will make specific Ab against one of the coagulation factors
  • Extremely rare
82
Q

Most common acquired factor inhibitors

A

acquired Factor VIII inhibitor

83
Q

Much less common acquired factor inhibitors

A

Inhibitors to…

  • von Willebrand protein (acquired von Willebrand disease)
  • Factor II (seen in lupus patients)
  • Factor V (seen in post-op or ICU patients)
84
Q

Acquired Factor VIII inhibitor

A
  • 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.
85
Q

Lab tests for Factor VIII inhibitor

A

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

86
Q

Acquired bleeding disorders

A
  • Common

- - use screening coagulation tests to suggest Dx

87
Q

Causes of a Prolonged PTT with Bleeding

A
  • Heparin in Sample
  • Fibrin split/degredation products
  • Hemophilia A & B (Factor VIII or IX Deficiency)
  • Factor XI Deficiency
  • Acquired Hemophilia
  • von Willebrand Disease
88
Q

Causes of a Prolonged PTT w/out Bleeding

A
  • Factor XII Deficiency

- Lupus Anticoagulant (clot too much)

89
Q

Causes of a Prolonged Protime ± PTT

A
  • Protime relatively more prolonged than PTT
  • Liver disease
  • Vitamin K deficiency
  • Warfarin or rat poison ingestion
90
Q

Causes of a PTT more prolonged than protime

A
  • Disseminated intravascular coagulation (DIC)
91
Q

Causes of a PT more prolonged than PTT (+/-)

A
  • Liver disease
  • Vit K def.
  • Warfarin / rat poison ingestion
92
Q

Liver Disease & Coagualtion abnormalities

A
  • Most coagulation factors are synthesized by the liver

- So, abnormalities in hepatic function can cause deficiencies of clotting factors

93
Q

Factors deficient in Liver disease

A
  • 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)
94
Q

Coagulation studies in Liver disease

A

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)

95
Q

Patient w/ Prolonged Protime due to liver disease- important to check for…

A
  • vitamin K deficiency
  • exacerbates problem
  • frequently trials of vitamin K therapy are done
96
Q

Vitamin K Deficiency

A
  • 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
97
Q

Warfarin in Vit K Deficiency

A
  • 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
98
Q

Long acting fat soluble rat poisons

A
  • used in suicide attempts
  • These pts present w/ extremely prolonged protime & PTT
  • Require very intensive vitamin K therapy for months, until poison eliminated
99
Q

Vitamin K deficiency & neonates

A
  • Vit K def. is a problem for normal new-born infant

- In developed countries, they are treated right after birth to prevent this complication.

100
Q

Disseminated Intravascular Coagulation (DIC) - Causes

A
  • Massive trauma
  • Hemorrhagic or septic shock
  • Amniotic fluid embolism
  • Burns
  • Acute leukemia
  • Transplant / Transfusion rxns
  • Severe allergic rxns (antivenom)
  • Drug rxns
101
Q

DIC- pathogenesis

A

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

102
Q

Lab findings in DIC

A
  • 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”
103
Q

Distinguishing DIC from Liver disease abnormalities

A
  • 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
104
Q

Treatment of DIC

A
  • Correct underlying illness that caused DIC –> fibrinogen quickly returns to normal & platelets rise
105
Q

Abnormalities in DIC

A
  • Prolonged PT
  • Greatly prolonged PTT
  • Prolonged thrombin time
  • Low platelet count
  • Low fibrinogen level
  • Increased fibrin split products
  • Increased D-dimer
106
Q

Clinical Consequences of DIC

A

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

107
Q

Thrombosis defn.

A
  • formation & propagation of clot w/in vasculature

- refers to abnormal or pathologic process w/ imbalance in hemostatic system

108
Q

Thrombosis - when occurs

A
  • 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)
109
Q

Hypercoagulable states – exist when there is…

A
  • chronic damage to vessel walls
  • excess of procoagulant factors
  • deficiency of anticoagulant factors
  • deficiency of fibrinolytic activity
110
Q

Risk factors for Thrombosis

A
  • 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
111
Q

The Lupus Anticoagulant abnormality

A

= 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.
112
Q

Anticoagulant in Lupus Anticoagulant

A
  • an IgG antibody

- reacts against phospholipid in platelet membrane or endothelial cell

113
Q

Antiphospholipid Antibody Syndrome or APS

A

syndrome caused by the lupus anticoagulant

114
Q

Effect on coag. tests of Lupus Anticoagulant

A

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

115
Q

Thrombotic syndrome w/ Lupus Anticoagulant

A
  • deep vein thrombosis
  • pulmonary embolism
  • thrombotic strokes
  • recurrent miscarriage due to thrombotic disease of placental blood vessels
116
Q

Correction of PTT w/ Lupus Anticoagulant

A
  • 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
117
Q

Other methods of detecting lupus anticoagulant

A

dilute Russell’s Viper Venom Test (RVVT)

118
Q

Why important to Dx lupus anticoagulant

A
  • 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)
119
Q

Thrombophilia – 4 most common familial congenital condition causing hypercoaguable syndrome

A

-Deficiencies of
- antithrombin III
- protein C
- protein S
Resistance to protein C (Factor V Leiden)

120
Q

Deficiencies of antithrombin III, protein C, & protein S

A
  • 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
121
Q

Factor V Leiden hypercoagulability

A
  • 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
122
Q

Factor V Leiden - Testing, Types of Clotting

A
  • APC resistance assay, DNA analysis

- Venous clots

123
Q

Prothrombin G20210A mutation - Testing, Types of Clotting

A
  • DNA analysis

- Venous clots

124
Q

Antiphospholipid antibodies (aPL) - Testing, Types of Clotting

A
  • dRVVT, other functional assays, anticardiolipin antibodies, B2-glycoprotein-1 antibodies
  • Venous / Arterial anticoagulation failures
125
Q

Hyperhomocysteinemia - Testing, Types of Clotting

A
  • Plasma homocystein

- Venous / Arterial clots

126
Q

Fibrinolytic abnormalities - Testing, Types of Clotting

A
  • Euglobulin lysis time, PAI-1, tPA activity levels, Plasminogen activity
  • Venous / Arterial clots
127
Q

Protein S deficiency - Testing, Types of Clotting

A
  • Protein S free antigen

- Venous (20-30% Arterial) clots

128
Q

Protein C deficiency - Testing, Types of Clotting

A
  • Protein C activity

- Venous (rare Arterial) clots

129
Q

Antithrombin deficiency - Testing, Types of Clotting

A
  • Antithrombin activity

- Venous clots

130
Q

Thrombocytosis - Testing, Types of Clotting

A
  • Platelet count, JAK2 mutation

- Venous / Arterial clots

Unit 3 B&L (18 decks)

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