coagulation Flashcards
The process by which a blood clot forms to reduce
blood loss after damage to a blood vessel
coagulation
group of diseases caused by deficiency of clotting factors which may lead to defects in normal clot formation process
Coagulation disorder
A process by which the body repairs damage to a blood vessel to
prevent hemorrhage
Hemostasis
Two general steps of hemostasis
- platelet plug formation
- fibrin clot formation
At the site of injury, a hemostatic plug is formed by the interaction of the blood vessels, platelets and coagulation factors
Platelet plug formation
As the plug is formed, the coagulation system generates thrombin from prothrombin, initiating fibrin clot formation
Fibrin clot formation
Process of hemostasis
- injury
- vascular spasm
- platelet plug formation (primary hemostasis
- coagulation cascade (secondary hemostasis)
A blood vessel is severed. Blood and blood components (e.g., erythrocytes, white blood cells, etc.) are leaking out of the breaks.
Injury
The smooth muscle in the vessel wall contracts near the injury point, reducing blood loss.
○ inflammation
vascular spasm
Platelets are activated by chemicals released from the injury site and by contact with underlying collagen. The platelets become spiked and stick to each other and the wound site.
Platelet plug formation (Primary Hemostasis)
In coagulation, fibrinogen is converted to fibrin, which forms a mesh that traps more platelets and erythrocytes, producing a clot.
Coagulation Cascade (Secondary Hemostasis
Contact Activation Pathway
Intrinsic pathway
Tissue factor pathway
extrinsic pathway
Factor X
Final common pathway
if there is a presence of damage, Factor XI will become XIa → activation of IX to IXa, with VIIIa → activation of X to Xa
Intrinsic pathway
Factor III to IIIa → activation of VII and VIII → combine with III to activate Factor X to Xa → activation of Va → Prothrombin → thrombin → fibrinogen → fibrin
Extrinsic pathway
surface damage
Intrinsic pathway
in trauma + inflammation
extrinsic pathway
Initiated through the activation of two separate pathways of intrinsic and extrinsic pathways
Coagulation cascade
both pathways lead to the production of ________________ which marks the beginning of the common pathway of coagulation leading to cloth formation
Factor X
● Extrinsic pathway first, then intrinsic pathway
● Amplify the coagulation process
cross-activation
● Also known as Coagulation Factors
● Prompt reactions that activates more clotting or coagulation factors
Clotting factors
● Secreted primarily by the _____ and the ________
(Clotting factors)
liver and platelets
Vitamin K deficiency leads to:
bleeding
● The liver requires _________ as a co-factor to produce clotting factors
(Clotting factors)
Vitamin K
There are ____ clotting factors
12
There is no factor _____; it is not used already
VI
Inactivated forms:
(Clotting factors)
I, II, III
Activated forms:
Ia, IIa, IIIa
VI is identical to V (t or f)
T
Pathways are dependent to:
Clotting factors, calcium ions, and vitamin K
○ activated by damage directly to the blood vessels and exposure to collagen and circulating platelets in blood
Intrinsic pathway
○ activated by tissue damage, malignancy, inflammation, sepsis
Extrinsic pathway
Fibrinogen
I
Prothrombin
II
Tissue thromboplastin or tissue factor
III
Calcium ions
IV
Proaccelerin; labile factor
V
Antihemolytic factor A
VIII
Not used
VI
Proconvertin; stable factor
VII
Antihemolytic factor B (plasma thromboplastin component); Christmas factor
IX
Hageman factor
XII
Fibrin-stabilizing factor
XIII
Stuart-Prower factor (thrombokinase)
X
antihemolytic factor C (plasma thromboplastin antecedent)
XI
Common; converted into fibrin
I
Extrinsic (1)
Tissue thromboplastin/ tissue factor
Common; converted into thrombin
II
Extrinsic and Intrinsic (1)
V
entire process
IV
Not used
VI
Extrinsic (2)
Proconvertin
Intrinsic; deficiency results in hemophilia A
VIII
Intrinsic; deficiency results in hemophilia B
IX
Extrinsic and intrinsic (2)
X
Intrinsic; deficiency results in hemophilia C
XI
Intrinsic; initiates clotting in vitro also activates plasmin
XII
Stabilizes fibrin; slows fibrinolysis
XIII
Risk factors for Coagulation disorders
- age
- family history and genetics
- medical conditions
- medications
- sex
______ are more likely to develop Vit K deficiency
newborns
risk factors medications
● antibiotics
● blood thinners
● anticoagulants
● blood transfusion
● bowel diseases (IBD) or bowel surgery
● cancer
● congenital heart disease
● hypothyroidism
● some autoimmune diseases
medical conditions
Sex: congenital hemophilia
males
acquired hemophilia during and after pregnancy
females
Signs and symptoms of coagulation disorders
● Blood in urine or stool
● Excessive bleeding
● Frequent, large bruises
● Heavy bleeding after giving birth
● Heavy menstrual bleeding
● Petechiae
● Redness, swelling, stiffness or pain
● Umbilical stump bleeding
○ Does not stop even after applying pressure
○ Spontaneous bleeding
■ Nose bleed
■ Bleeding after dental procedure or surgery
● Excessive bleeding
○ More than 7 days or change of sanitary pads every hour
● Heavy menstrual bleeding
○ Bleeding under the skin causing tiny spots
○ Violet or brown
Petechiae
○ Bleeding after 1-2 weeks after the umbilical cord was cut
Umbilical stump bleeding
Complications
● Bleeding in the brain or CNS
○ Hemorrhagic stroke
● Bleeding in the throat
○ Inflammation → swelling → DOB
● Bleeding into the abdomen
● Damaged joints
● Hard masses in the bones
● Miscarriages
Diagnosis
- CBC
- PTT
- PT
- Mixing test
- vWF
- Clotting factor test
- Bethesda test
- Factor XIII antigen and activity assays
- Genetic testing
● measure different parts of the blood and identify the number of blood cells and platelets
CBC
● how long it takes for blood to clot by determining the clotting factors involved
PTT
● same with PTT but also measures the clotting factors not covered by PTT
PT
PTT measures
Intrinsic
PT measures
Extrinsic
● identify whether the bleeding is caused by antibodies blocking the functions of the clotting factors
● If autoimmune
Mixing test
● measure the amount of vWF and if these factors are working correctly
von Willebrand factor (vWF) tests
● determine if clotting factors are absent or present below normal levels
Clotting factor tests
● to check for antibodies for Factors XIII and IX
Bethesda test
● Factor XIII deficiency
Factor XIII antigen and activity assays
● to identify if genes are responsible for coagulation disorders
Genetic testing
platelet function analyzer
PFA-100
Laboratory Monitoring
- Activated Partial Thromboplastin Time (aPTT)
- Prothrombin Time (PT)
● Test for intrinsic and common pathways
● Dependent on activity of all coagulation factors, except for Factors VII and XIII
aPTT
- 30 to 40 seconds
● Monitor heparin treatment and screen for hemophilia
● Integrity of intrinsic system (incl. XII, XI, VIII and IX)
● Liver disease decrease the production of these factors because liver is the main source
aPTT
● Test for extrinsic pathway activity and common pathways (VII, V, X, prothrombin and fibrinogen)
● Measures Vitamin K-dependent factors activity (Factors II, VII, IX, and X)
PT
- 10 to 14 seconds
● Thromboplastin + Calcium to plasma = clotting time
● Liver disease and warfarin therapy
● Liver is the site of synthesis of plasma clotting factors
PT
aPTT is dependent on all coagulation factors except:
VII and XIII
PT: Test for extrinsic pathway activity and common pathways namely:
VII, V, X, prothrombin and fibrinogen
PT: measures Vitamin K-dependent factors activity namely:
II, VII, IX, and X
components measured of Bleeding Time:
Platelet function
Vascular integrity
components measured of PT
I, II, V, VII, IX, X
components measured of PTT
I, II, V, VIII, IX, X, XI,
XII
components measured of thrombin time
I, II
normal values of bleeding time
3 to 10 mins
normal values of PT
10 to 14 secs
Classification of Clotting Disorders
- Congenital
- acquired
normal values of PTT
30 to 40 secs
normal values of thrombin time
12-20 secs
Congenital
- hemophilia A
- hemophilia B
- von Willebrand’s disease
○ A deficiency of factor VIII, inherited as an x-linked recessive trait affecting males, females being the carriers
hemophilia A
Acquired
- secondary to drugs
- disease related
○ The second most common inherited bleeding disorder after vWD
hemophilia A
Males
(Hemophilia A)
hemizygous
Females
(hemophilia A)
heterozygous
○ Caused by a mutation of the factor IX gene, leading to factor IX deficiency
hemophilia B
○ The second most common form of hemophilia, rarer than hemophilia A
hemophilia B
Hemophilia B is also called:
royal blood’s disease
Acquired: Disease-related
Liver disease, vitamin K deficiency, disseminated intravascular coagulation (DIC), fibrinolytic disorders
Acquired: secondary to drugs
heparin, coumarin
○ Microvascular and macrovascular clotting and compromised blood flow that is a rare but serious condition that causes abnormal blood clotting throughout the body’s blood vessels
Disseminated intravascular coagulation
An inherited X-linked recessive and lifelong blood disorder where an essential blood clotting factor is either partly or completely missing
Hemophilia
Hemophilia A is linked to level of ____________
Factor VIII
1% _________ Hemophilia A
severe
1%-5% __________ Hemophilia A
moderate
6% - 30% _________ Hemophilia A little risk of spontaneous bleeding
Mild
Management of Hemophilia
Factor replacement therapy
● Main treatment of hemophilia
● Clotting factors from donations or made in the laboratory
Factor replacement therapy
Concentrates of clotting factor VIII (for hemophilia A) or clotting factor IX (for hemophilia B) are slowly dripped or injected into a ________
vein
Plasma-derived Factor Concentrates
- cryoprecipitate and fresh frozen plasma (FFP)
FFP: 250 - 300 mL, Cryoprecipitate:
(volume)
Cryoprecipitate: 10-20mL
FFP: 30 minutes, Cryoprecipitate:
(time to prepare)
Cryoprecipitate: 30 minutes
FFP: All, including factors II, VII, VIII, IX, X, XI, and vWF, Cryoprecipitate:
(other coagluation factors)
Cryoprecipitate: Factors VIII, XIII, and vWF
FFP: 700 - 800 mg, Cryoprecipitate:
(Fibrinogen)
Cryoprecipitate: 150 - 250 mg
○ Developing antibodies (proteins) that attack the clotting factor
○ Developing viral infections from human clotting factors
○ Damage to joints, muscles, or other parts of the body resulting from delays in treatment
Complications of Replacement Therapy:
○ Very expensive, often to be imported
○ High risk of contamination with hepatitis B virus, hepatitis C virus, and HIV from the large number of donors
Problems with treatment with commercial factor VIII concentrate
○ Recombinant Factor VIII concentrate, which does not come from human plasma
○ Genetically engineered using DNA technology and commercially prepared factor concentrates treated to remove or inactivate blood-borne viruses
○ No plasma or albumin, does not spread blood-borne viruses
Recombinant Factor Concentrates
● FRT not needed; Desmopressin acetate may be given to raise the body’s level of Factor VIII
Mild hemophilia
● Mild or no risk of spontaneous bleeding
● FRT given at home two or three times a week; Preventive therapy usually is started in patients at a young age and may need to continue for life
Severe hemophilia
- maintenance
● FRT only when bleeding occurs or to prevent bleeding that could occur when doing certain activities
Moderate Hemophilia
- only if there is bleeding
● also known as ACE 910 or Emicizumab
Hemlibra
Other treatment options:
- Hemlibra
- DDAVP or Stimate (Desmopressin Acetate)
- Amicar
● Desmopressin Acetate
DDAVP or Stimate (Desmopressin Acetate)
● Epsilon Amino Caproic Acid
Amicar
● It works by replacing the function of factor VIII, rather than replacing the missing clotting factor VIII directly
Hemlibra
● These are medications that are similar to a hormone that occurs naturally in the body. The medications release factor VIII from where it is stored in the body tissues.
● Give ____________ for mild ONLY
○ Not FRT immediately, only for moderate and severe
DDAVP or Stimate
● Medication that can be given through a vein or by mouth (as a pill or a liquid)
● It prevents blood clots from breaking down, resulting in a firmer clot, and is often used for bleeding in the mouth or after a tooth has been removed because it blocks a substance found in the saliva that breaks down clots.
Amicar
New Hemophilia Agents: Treatment for Hemophilia A
- Eloctate
- Obizur
- Nuwiq
- Kovaltry
- Afstyla
New hemophilia Agents: Treatment for Hemophilia B
- Rixubis
- Alprolix
- Idelvion
● Approved June 2014
● Factor VIII recombinant; Fe fusion protein
Eloctate
● Approved October 2014
● Recombinant
Obizur
● Approved September 2015
● Recombinant factor VIII
Nuwiq
● Approved March 2016
● Recombinant
● Use infusion line provided with product as it has in-line filter
Kovaltry
● Approved May 2016
● Recombinant
Afstyla
● Approved March 2014
● Recombinant; Fe fusion protein
Alprolix
● Approved June 2013
● Recombinant factor IX
Rixubis
● Approved March 2016
● Recombinant; albumin fusion protein
Idelvion
Priorities in hemophilia treatment and care include:
- prevention of bleeding and joint damage
- prompt management of bleeding episodes including physical therapy and rehabilitation after joint bleeds
- pain management
- management of musculoskeletal complications
- prevention and management of inhibitors
- management of comorbidities
- dental care
- quality-of-life assessments and psychosocial support
- genetic counselling and diagnosis
- ongoing patient/family caregiver education and support
● Acute bleeds should be treated __________________
(Principal care)
as quickly as possible
- Desmopressin administration can raise FVIII level ______________________ to control
bleeding
adequately (3 to 6 times the baseline level)
● ________ and ________ should be avoided
- could prolong bleeding, as it also inhibits platelet formation
○ Use paracetamol instead
ASA and NSAID
● _____________ prevents periodontal disease and dental caries, which predispose to gum bleeding
Good oral hygiene
General recommendations
- Prophylaxis with clotting factor concentrates (CFCs)
- Episodic replacement therapy
● Regular replacement therapy or the regular intravenous (IV) infusion of the missing clotting factors
● FVIII in hemophilia A and FIX in hemophilia B
Prophylaxis with clotting factor concentrates (CFCs)
- On-demand therapy, the administration of CFCs only at the time of a bleeding episode
Episodic replacement therapy
● _____________ is the standard of care for people with severe hemophilia, and for some people with moderate
hemophilia
(WFH Recommendations)
Prophylaxis
● Both_____________ and _____________, as well as other hemostasis products when
appropriate, can be used for treatment of bleeding and prophylaxis in people with hemophilia
(WFH Recommendations)
virus-inactivated plasma-derived and recombinant CFCs
● The use of cryoprecipitate can only be justified in situations where _________________________ as there is no proven advantage for their use over CFCs
(WFH Recommendations)
clotting factor concentrates are not available
● It is strongly encouraged that _________________ procedures be used, if available
(WFH Recommendations)
viral-inactivation
● 1-deamino-8-D-arginine vasopressin
● Synthetic analogue of vasopressin that boosts plasma levels Factor VIII and vWF
Desmopressin (DDAVP)
● May be the treatment of choice for patients with mild or moderate hemophilia A when Factor VIII can be raised to an appropriate therapeutic level
Desmopressin (DDAVP)
Serious sites of bleeding in hemophilia
- Joints
- Muscles, especially deep compartments (iliopsoas, calf, forearm)
- Mucous membranes of the mouth, nose, and genitourinary tract
Frequency of bleeding sites: 70% - 80%
Joints
- more common in hinged joints; ankles knees, elbows
- less common in multi-axial joints; shoulders, wrists, hips
Life-threatening
- Intracranial
- Neck/throat
- gastrointestinal
Frequency of bleeding sites: 10% - 20%
Muscles
Frequency of bleeding sites: 5% - 10%
Other sites, major bleeds
Frequency of bleeding sites: <5%
CNS
People with hemophilia with a ______ or _________ bleed, the WFH recommends following the PRICE principles in addition to increasing factor levels
muscle or joint bleed
PRICE
- Protection
- Rest
- Ice
- Compression
- Elevation
● Reduce weight bearing or stress on the affected joint or muscle by using crutches or other supports such as a ‘collar and cuff’ for the arm
● Avoid putting weight on the affected side completely for the first 48 hours and possibly longer if it is a severe bleeding
Protection
● The affected area should initially be rested completely, generally for the first 24 to 48 hours depending on the severity of the bleeding episode to allow the swelling to go down and prevent further bleeding
● The injured area should not be forced into any position
● ‘Rest’ is not the same as ‘immobility’, too much rest can also be damaging, so start to move the joint gently, as pain allows, within one or two days of treatment
Rest
● Reduces swelling, and therefore pain
● If the muscle or joint is very swollen, wait a day or so before using a compression bandage and then apply as
pain allows
● Nurse or physiotherapist can provide an elasticated bandage, make sure it fits correctly as additional damage can be caused where the bandage is too tight
● Try not to allow wrinkles in the bandage and make sure to remove it at night before you go to sleep
Compression
● Helps reduce swelling, prevent further bleeding, and eases pain
● Use a gel cold pack or an ice pack from a bag of frozen peas or crushed ice wrapped in a cloth
● Cold wraps or packs should be applied to the affected area for around 10 to 15 minutes every 2 hours or so
● Continue using ice for several days after the bleed if joint is still warm and swollen
● Do not apply for more than 20 minutes at a time
● Do not place ice directly on the skin as it can burn
Ice
● Helps reduce swelling and relieve pain by increasing the blood flow away from the injured area
● The injured area should be raised above the level of the heart
● When elevating leg, remove the compression stocking to allow normal, healthy circulation.
● Elevate ‘little and often’ for around 20 minutes at a time
Elevation
For people with hemophilia, the WFH recommends the use of antifibrinolytic drugs (____________________) alone or as adjuvant treatment, particularly in controlling mucosal bleeds and for invasive ___________
tranexamic acid, epsilon aminocaproic acid [EACA]; dental procedures
● An antifibrinolytic agent
● Competitively inhibits the activation of plasminogen to plasmin
● Promotes clot stability
Tranexamic acid
● ________________ for some types of hemophilic bleeding
(Tranexamic acid)
Adjunctive therapy
● Useful for treating superficial soft tissue and mucosal bleeds (_________________)
(Tranexamic acid)
oral bleeding, epistaxis, and menorrhagia
● Brand name:
(Tranexamic acid)
Hemostat
Paracetamol/acetaminophen: if not effective
(pain management)
Switch to
- COX 2 inhibitors (celecoxib, meloxicam, nimesulide, and others)
- Paracetamol/ acetaminophen plus codeine (3-4 times a day)
- Paracetamol/acetaminophen plus tramadol (3-4 times a day)
use a slow release product with an escape of a rapid release. Increase the slow release product if the rapid release product is used more than 4 times/day
(pain management)
Morphine
should be used with caution in patients with hypertension and renal dysfunction (paint management)
COX-2
○ Regular high-dose infusions of Factor VIII and Factor IX
○ Demanding and costly but provides 60-80% success chance
immune tolerance induction (ITI) therapy
Eradication of inhibitors is currently best achieved through:
(Management of patients with inhibitors)
immune tolerance induction (ITI) therapy
● For patients with hemophilia A with an inhibitor, the WFH recommends that ______________ should be used for regular prophylaxis in addition to clotting factor concentrates (CFC)
emicizumab
Mild - moderate
(Factor Requirement Calculations)
- soft tissue
- muscles
- hemarthrosis epistaxis
Severe
(Factor Requirement Calculations)
- CNS
- GI
- Neck/throat
Up to 100%
(Factor Requirement Calculations)
Severe
Up to 50%
(Factor Requirement Calculations)
Mild- moderate
Type of Bleeding Episodes:
Early hemarthrosis, minor muscle or oral bleeding
(Desired Factor VIII Increase)
Mild
Type of Bleeding Episodes:
Muscle bleeding, bleeding into the oral cavity or mild head trauma
(Desired Factor VIII Increase)
Moderate
Type of Bleeding Episodes:
Life or limb threatening hemorrhage, GI bleeding, intracranial, intra-abdominal or intrathoracic bleeding, fractures
(Desired Factor VIII Increase)
Major
FVIII Level Required and Frequency:
- 20 to 40
- 12 to 24 hrs
(Desired Factor VIII Increase)
Mild
FVIII Level Required and Frequency:
- 30 to 60
- 12 to 24 hrs
(Desired Factor VIII Increase)
Moderate
FVIII Level Required and Frequency:
- 60 to100
- 8 to 24 hrs
(Desired Factor VIII Increase)
Major
Duration (Days):
At least 1 day until bleeding resolution is achieved
(Desired Factor VIII Increase)
Mild
Duration (Days):
Until pain and acute disability are resolved (around 3 to 4 days)
(Desired Factor VIII Increase)
Moderate
Duration (Days):
Until resolution of bleed (around 7 to 10 days)
(Desired Factor VIII Increase)
Major
Type of Surgery:
Including tooth extraction
Minor
Type of Surgery:
Intracranial, intraabdominal or
intrathoracic, or joint replacement
surgery
Major
● The most common bleeding disorder
● It is carried on chromosome 12 and occurs equally in men and women
● A blood disorder in which the blood does not clot properly
● A genetic disorder caused by missing or defective von Willebrand factor (vWF), a clotting protein
von Willebrand Disease (vWD)
● VWF binds to _________, a key clotting protein, and platelets in blood vessel walls, which help form a platelet plug during the clotting process
factor VIII
Blood contains many proteins that help the body stop bleeding, one of these proteins is called
von Willebrand factor (vWF)
● Important role in primary hemostasis
● Binds platelets
● Binds endothelial components
● Forms adhesive bridge b/w platelets and vascular subendothelial structures
● Contributes to fibrin clot formation (carries factor VIll)
Von Willebrand Factor (VWF)
Treatment for vWD
Desmopressin (DDAVP)
● Treatment of acquired hemophilia A
● Approved October 2014
● Recombinant
Obizur
● Treatment of acquired hemophilia A
● Approved June 2014
● Factor VIII recombinant; Fe fusion protein
Eloctate
● Treatment and prophylaxis of hemophilia A
● Approved September 2015
● Recombinant factor VIII
Nuwiq
● Treatment of hemophilia A
● Approved May 2016
● Recombinant
Afstyla
● Treatment of hemophilia A
● Approved March 2016
● Recombinant
● Use infusion line provided with product as it has in-line filter
Kovaltry
● Prophylaxis and control of hemophilia B
● Approved June 2013
● Recombinant factor IX
Rixubis
● Treatment of hemophilia B
● Approved March 2014
● Recombinant; Fe fusion protein
Alprolix
● Treatment of hemophilia B
● Approved March 2016
● Recombinant; albumin fusion protein
Idelvion
