Coagulation Disorders Flashcards
What do disorders of clotting result from?
Decreased number of platelets
Decreased function of platelets
Deficiency/ abnormality of coagulation factors
Enhanced fibrinolytic activity
How many plasma proteins are there?
12 plasma proteins
What is the function of the plasma proteins?
Circulate as inactive precursors (zymogens)
This is what gets activated upon injury and stimulates the cascade.
Proteolytic rxns activate in cascade
Contribute to platelet aggregation and clot strength
What are the vitamin K dependent factors in the coagulation cascade?
II (prothrombin), VII, IX, and X
What are the contact activation factors in the coagulation cascade?
XI, XII, prekallekrein, high molecular weight (HMW) kinogen
What are the thrombin sensitive factors in the coagulation cascade?
I (fibrinogen), V, VIII, XIII
What is the function of the fibrinolytic system?
-Regulatory mechanism for maintaining blood flow
-Prevents excessive clotting
-Dissolves fibrin clots
-Plasminogen activated by tissue and urokinase plasminogen activators– Released in response to thrombin, venous stasis (big risk factor for clot development), exercise, and ischemia
Convert plasminogen to plasmin, disolve fibrin clot locally
Occurs at the location of the clot
What are the coagulation labs?
PT
INR
aPTT
D-Dimer
What is the PT?
Prothrombin time
Extrinsic clotting pathway
Time to fibrin formation after addition of thromboplastin (phospholipids and tissue factor) to plasma
Activity of Vit K dep proteins, Proteins C and S, and Factors V and XIII
Measured in seconds (~12-15)
Used with INR
What is INR?
International normalized ration
Ratio of PT patient/ PT normal
Measures extrinsic clotting along with PT
What is INR elevated with?
Hypocoagulability Liver disease Vit K deficiency Warfarin Normal is 0.8-1.2
What is aPTT?
Activated partial thromboplasin time.
Intrinsic and common pathways
Time to fibrin formation following addition of partial thromboplastin , calcium, and activating agent to plasma
Assesses activity of factors I, II, V, VIII, IX, X, XI, XII, prekallekrein, HMW kininogen
Measured in seconds (23-37)- varies by institution
When is aPTT elevated?
Hypocoaguability
Liver disease
Heparin
What is the D-Dimer?
A fibrin degredation product
Presence indicates plasmin is at work
What will the D-dimer be positive in?
DVT/PE
Disseminated intravascular coagulation (DIC)
What are the natural anticoagulants?
Tissue factor pathway inhibitor (TFPI) Protein C- inactivates Va and VIIIa Protein S- activates protein C Both are Vit K dep Antithrombin III inactivates Iia, VIIa, Ixa, Xa, Xia, XIIa Heparin potentiates this action
What does deficiency of the natural anticoagulants result in?
A hypercoagulable state
What is the most common congenital bleeding disorder?
Von Willebrand Disease
What is Von Willebrand Disease?
Decreased quantity and quality of von Willebrand factor (VFW)
Stabilizes Factor VIII, deficiency reduces half life of Factor VIII
Affects Intrinsic pathway
What are the three types of Von Willebrand Disease?
- Mild to moderate- most common
- Functionally abnormal- more severe than type 1
- Nearly undetectable- autosomal recessive, rare, VERY SEVERE bleeding
What is acquired VW disease associate with?
Rare, similar to disease
Associated with autoimmune disease
Mild to severe bleeding
What are the drug causes of acquired VW disease?
Valproic acid, griseofulvin, hydroxyethyl starch, ciprofloxacin
What is the treatment of acquired VW disease?
Resolves with treatment of causative disease / removal of agent
What are the sign and sx of acquired VW disease?
Mucocutaneous bleeding
Easy bruising
Postoperative bleeding
How do you diagnose acquired VW disease?
Diagnosis based off labs and S+S PT – normal aPTT – prolonged: Reflection of the extrinsic pathway not working like it should. Platelets – normal VWF low
What is the treatment of acquired VW disease for mild bleeding?
Goal- prevent bleeding episode
Mild bleeding: pressure, ice, apply topical thrombin
What is the treatment of acquired VW disease for moderate- severe bleeding?
Goal- prevent bleeding episode
Moderate- Severe bleeding / Prevention of bleeding(surgery)
Stimulate release of endogenous VWF/factor VIII Inhibit clot breakdown
Give exogenous VWF and Factor VIII
Desmopressin (DDAVP)- MOA and ROA
Synthetic angalog of vasopressin
Stimulates endothelial cell release of VFW and factor VIII
Intranasal and SubQ injection
Desmopressin (DDAVP)- ADRs
Tachycardia, headache, flushing, hyponatremia, transient thrombocytopenia, tachyphylaxis
Desmopressin (DDAVP)- monitoring
During infusion: pulse, BP
Factor VIII levels (increased levels 3-5X above baseline)
aPTT
Bleeding time
What are the antifibrinolytic therapies?
Aminocaprioic acid
Tranexamic Acid
Antifibrinolytic therapy (Aminocaprioic acid Tranexamic Acid)- MOA
Used alone or as adjunct for management of mucosal bleeding
Prevent lysis of clots by saturating binding sites of plasminogen- fibrin stays intact
Antifibrinolytic therapy (Aminocaprioic acid Tranexamic Acid)- ADRs
Reduce doses in renal dysfunction
ADR:
Diarrhea, N/V, Hypotension, Thrombosis / DVT
VWF/Factor VIII concentrates- MOA
Used to control severe bleeding in all patients with VW
Used in patients unresponsive to DDAVP
Replenishes VWF, and factor VIII
VWF/Factor VIII concentrates- ADRs
Chills, Fever, Hypotension, Headache, Edema, THROMBOSIS/DVT, Viral infection (should have Hep A and B vaccines) (plasma> recombinant products), Anaphylaxis
VWF/Factor VIII concentrates- monitoring
Factor levels
S+S bleeding
What is hemophilia?
Bleeding disorder resulting from congenital deficiency of a coagulation factor
What coagulation factor is hemophilia type A deficient in?
Factor VIII
What coagulation factor is hemophilia type B deficient in?
Factor IX
What type of disease is hemophila?
Recessive X linked diseaes ( males have it and females carry with the exception of females having deficits in both factors VIII and IX.)
What are the signs and sx of hemophila?
-Palpable ecchymoses
-Hemarthroses: Joint pain, swelling, erythema, Decreased joint range of motion
-Muscle Hemorrhage: Swelling, Pain
-Hematuria
-Excessive bleeding after surgery or trauma
I-ntraccranial hemorrhage
How is hemophila diagnosed?
Suspicious in any male with unusual bleeding Genetic testing Labs: Prolonged aPTT Normal PT Normal platelet count Normal VWF Reduced factor VIII or IX level
What is the treatment for hemophilia?
Goal- stop bleeding
Mainstay is infusion of missing factors
Factor VIII in type A, Factor IX in type B
All patients should receive Hepatitis A and B vaccines due to risk of viral infection from products
Recombinant product < plasma product risk
What can be used in the treatment of mild bleeding episodes in those with hemphilia A?
DDAVP
What can be used as an adjunctive treatment for prevention of bleeding with dental procedures in patients with hemophilia?
Antifibrinolytic therapy–
Aminocaproic acid
Tranexamic acid
Factors VIII and IX
Require long term prophylaxis to prevent arthropathy and complications
High cost and inconvenient due to infusion, also increased infection risk
When is primary prophylaxis indicated with factors VIII and IX?
Age < 2 years, no prior bleeding events
Any age following 1 bleed and no evidence of damage
When is secondary prophylaxis indicated with factors VIII and IX?
Started after onset of joint bleeding and evident damage
Plasma derived factor VIII products
-From plasma of thousands of pooled donors
-Lower risk of antibody formation than recombinant
-Small risk of viral transmittance
Donor screening, plasma testing, viral reductions through purification, pasteurization to reduce risk
-No HIV since 1986
-However Hep A, Hep C, Parvovirus
Recombinant factor VIII products
-Produced with recombinant DNA technology
-Low risk of transmitting disease
Small risk of viral infection from cell lines (Parvovirus) Factor VIII
No human products used to make Factor IX
-As effective as plasma-derived products
28-33% risk of developing antibodies to product
Are human products used to make recombinant factor IX products?
No
Plasma Derived Factor IX products
- From plasma of thousands of pooled donors
- Lower risk of antibody formation than recombinant
- Small risk of viral transmittance
- Donor screening, plasma testing, viral reductions through purification, pasteurization to reduce risk
Recombinant Factor IX products
- Produced with recombinant DNA technology
- Very low risk of transmitting disease
- No human products used to make Factor IX
- Less effective than plasma-derived products
- Require higher doses
- Treatment of choice for hemophilia B
What is the treatment choice for hemophilia B?
Recombinant Factor IX products
Infusable factors (VIII and IX)- ADRs
Chills Fever Hypotension Edema THROMBOSIS/DVT Viral infections (plasma products > recombinant) Anaphylactic reactions Development antibodies
Infusable factors (VIII and IX)- Monitoring
Factor Levels
S+S of bleeding/thrombosis
Antibodies
-Inhibitor to Factor
-Patients may produce IgG antibodies to factors following multiple infusions
Up to ½ of patients with Hemophilia A
<5% with B
More common in severe patients
-Suspect if post-infusion factor levels are lower than predicted
-If low, antibodies can be overcome by giving higher doses of factors more frequently
If cannot overcome must give concentrated containing ACTIVATED factors
What are the activated factors?
Prothrombin complex concentrates (PCC)
Recombinant activated factor VII
Prothromin Complex Concentrates (PCC)- MOA
Plasma derived
Contain vit K dep factors
Prothromin Complex Concentrates (PCC)- ADRs
Dizziness, nausea, hives, flushing
Serious thrombotic complications- PE, DVT, MI
Recombinant activated factor VII- indications
For bleeding episodes or prophylaxis before surgery
Recombinant activated factor VII- ADRs and monitoring
Monitor clinically- no labs to measure effect
ADR- hypertension, fever, thrombosis
What other medications are used in hemophilia?
Hemophiliacs may need pain medications for acute or chronic pain
Intraarticular dexamethasone for joint pain
Acetaminophen or narcotics
ASA/NSAIDs may increase bleeding risk
What is disseminated intravascular coagulation (DIC)>
Acquired homeostatic disorder
Due to underlying condition or illness
Inappropriate systemic thrombosis followed by massive bleeding
Severe cases require extensive supportive care
What is the hypercoagulability pathophysiology behind DIC?
Hypercoagulability
Initial insult (such as sepsis) causes widespread inflammation
Leads to excessive formation of thrombin (in response to inflammation)
What is the thrombosis pathophysiology behind DIC?
Thrombosis
Extensive, widespread micro and macrovascular clotting- causes ischemia and tissue damage and death
Consumes platelets and coagulations factors (due to clotting everywhere.)(Start to have no blood flow to places)
What is the bleeding pathophysiology behind DIC?
Bleeding
Concomitant excessive production of plasmin cleaves fibrin in clots
Plasmin also causes RBC and platelet lysis (get purple spots all over the body)
What are the causes of DIC?
SEPSIS CANCER Head trauma Serious burns Serious crushing injuries Amniotic fluid embolism Aortic aneurysm MI Giant hemangiomas Anaphylaxis Transfusion reactions Transplant rejections Snake venom IV drugs
What are the signs and sx of DIC?
Bleeding/oozing Thrombosis Petichiae/purpura Peripheral cyanosis Gangrene of distal extremities Hemorrhagic bullae
How is DIC diagnosed?
- Underlying illness is present
- May have primarily bleeding or thrombotic symptoms, or both
Labs (vary depending on stage- check serially- regularly either will improve or worsen)
Elevated PT and aPTT (usually)
Thrombocytopenia (rapid)
Elevated D-dimer and fibrin degradation products (FDP)
Decreased antithrombin III
Decreased proteins C and S
Decreased fibrinogen
Evidence of end-organ damage/failure
Must distinguish from Liver disease!
Liver disease usually has normal fibrinogen
What is the treatment goal for DIC?
Prevent death and end organ damage
What is the treatment involved with DIC?
Treat underlying condition
Supportive care
If serious bleeding- platelet infusion, Fresh Frozen Plasma, cryoprecipitate can be used to replace fibrinogin
Anticoagulation- only consider in thrombotic case, will not dissolve thrombi only will prevent further formation (heparin or LMWH– need to monitor D-dimer, fibrinogen, clinical signs of bleeding)
Antifibrinolytics- only consider in phase of fibronolysis/bleeding (aminocaproic acid/tanexamic acid) DO NOT COADMINISTER WITH HEPARIN)
What treatment do you give to a patient with DIC in the bleeding phase?
Antifibrinolytics
What treatment can you consider in the clotting phase of DIC?
Anticoagulation.
