L28 Bleeding disorders (II) Flashcards
The difference of site of bleeding between vWFD/Platelet disorders VS Coagulopathy?
- vWFD& Platelet disorders
- mucocutaneous: skin, mucous membrane e.g. gum, epistaxis, vaginal, GI tract - Coagulopathy
- Deep in soft tissue, e.g. joint and muscles
What are petechiae? How to differentiate it from angioma and vasculitis?
The difference in presence of petechiae between vWFD/Platelet disorders VS Coagulopathy?
Petechiae
- pinpoint areas of hemorrhage in subcutaneous tissue
- not blanchable on pressure c.f. angioma
- not palpable c.f. vasculitis
- vWFD& Platelet disorders
- Present, RBC leaks through postcapillary venules - Coagulopathy
- no petechiae
What is ecchymosis?
The difference in presence of ecchymosis/purpura between vWFD/Platelet disorders VS Coagulopathy?
Ecchymosis: gradual onset, progressive bruises
- vWFD & Platelet disorders
- small and superficial - Coagulopathy
- Large, deep: lack of thrombin prevents secondary/ tertiary hemostasis
The difference in presence of hemarthrosis and muscle bleeding between vWFD/Platelet disorders VS Coagulopathy?
- vWFD & Platelet disorders
- Extremely rare - Coagulopathy
- common
The difference in presence of bleeding after cuts/ scratches between vWFD/Platelet disorders VS Coagulopathy?
- vWFD & Platelet disorders
- common/yes - Coagulopathy
- no
The difference in presence of bleeding after surgery/trauma between vWFD/Platelet disorders VS Coagulopathy?
- vWFD & Platelet disorders
- immediate, usually mild - Coagulopathy
- delayed (1-2 days), severe
(platelets can initially stop bleeding but the plug is not stabilized and will be washed away easily.
List what would you like to ask in history taking (HPI) in patients who presented with bleeding disorders.
- Site of bleeding: mucocutaneous/ hemarthrosis
- Nature of bleeding
- frequency
- duration
- amount
- type of insults associated - Childhood: congenital cause
- Gynaecological: menarche, menorrhagia, post-partum
What are the important PMH that you have to ask in Bleeding disorder Hx taking? (3)
- Liver disorders: coagulopathy
- Connective tissue/ rheumatologic disorders: vascular problem
- Malabsorption: acquired vascular problem
What are the possible significant family history examples that you would like to ask?
- Hemophilia - X-linked recessive
- Von-Willebrand disease (vWD)- autosomal dominant
- Others: Autosomal recessive
What signs would you expect to see in patients with bleeding disorders?
- Ecchymoses/petechiae/ hematoma: size, location, distribution
- Signs of anemia
- Signs of systemic diseases: chronic liver disease, lymphadenopathy, hepatosplenomegaly
- Others:
- skin laxity (Ehlers-Danlos syndrome [everything loose!!]),
- lips and oral mucosa telangiectasia (vascular problems)
What would you investigate in suspected platelet/vWD?
- CBC: platelet count
- vWF
- Platelet function test
What would you investigate in suspected coagulopathy?
- Clotting profile: PT, APTT
- Mixing test
- Factor/inhibitor essay
Prothrombin time is the measurement of the time for the ___________ system.
Describe the pathways
Extrinsic system (tissue damage) > tissue factor + Factor 7 > Factor 7a
> F9a + F7a changes F10 to F10a
F10a changes F2 to F2a (thrombin)
F2a (thrombin changes Fibrinogen to fibrin
List 4 reasons for prolonged PT.
- Vitamin K antagonist admistration (e.g. warfarin)
- Liver disease
- Vitamin K deficiency
- Factor 2,7,9,10 deficiencies/inhibitor
Activated partial thromboplastin time (APTT) is the measurement of the time for the __________ system.
Describe the pathways.
Intrinsic (surface contact)
- Factor 12 > Factor 12a added to Factor 11 >
- Factor 11a added to Factor 9 >
- Factor 9a + factor 8a added to Factor 10 >
- Factor 10a + Factor 5a added to Factor 2>
- Factor 2a (thrombin)
- Factor 2a + fibrinogen > fibrin
List 4 reasons for prolonged APTT.
- Vitamin K deficiency (2,7,9,10)
- Vitamin K antagonists
- Factor 2,5,10 deficiency/inhibitor
- Multiple factors deficiency e.g. liver failure, DIC
What is thrombin time?
List 4 reasons for prolonged thrombin time.
Thrombin time
= time for changing fibrinogen to fibrin by factor 2a (thrombin)
Prolonged when
- Hypofibronogenemia - congenital/DIC
- Dysfibrinogenaemia - inherited or liver disease
- Presence of heparin, paraproteins
- Raised concentration of Fibrin Degredation Product - as in DIC
In patients with abnormal clotting profile, it is either due to clotting factor deficiency OR presence of inhibitors: antibodies which inhibit the function of clotting factor.
How to distinguish these 2 causes? (2)
- Screening tests: 50:50/ 1:1 mixing of normal and patient’s plasma and then repeat the test
- Confirmation: Specific factor/ inhibitor assay
1:1 Mixing test:
Factor 8 0% > APTT 120s
+
Patient’s blood 100% > APTT 30s
= APTT 35s
What does it mean?
decreased clotting time (from 120s to 35s) = factor8 deficiency
Unchanged clotting time = inhibitors
Management options for bleeding if due to platelet problems?
(rather than coagulation/fibrinolysis)
(2)
- Blood products transfusion: platelet transfusion
- Drugs: Desmopressin DDAVP
(for stimulating the release of vWF from endothelium)
Management options for bleeding if due to coagulation problems? (rather than platelet/fibrinolysis)
(list 2/5)
Blood products transfusion
- Platelets
- Cryoprecipitate (prepared from plasma and contains fibrinogen, von Willebrand factor, factor VIII, factor XIII and fibronectin)
- Factor concentrates
Drugs
- Clotting factor concentrate
- Recombinant human factor 7a
Management options for bleeding if due to fibrinolysis problems? (rather than platelet/coagulation)
Drug: anti-fibrinolytic agents (e.g. Tranexamic acid)
Platelet replacement is for patients with thrombocytopenia/ platelet dysfunction.
The standard dose is?
4 units
Plasma contains plasma proteins including clotting factors.
Cryoprecipitate contains? (3)
Factor 8, vWF, and fibrinogen
When is desmopressin used?
Why its effect may be depleted after a few days after treatment?
(platelet problems)
- patients with von Willebrand disease
- Mild hemophilia A (because vWF comes with factor 8)
- Stimulates the release of vWF rather than production
List 2 side effects of desmopressin.
- Facial flushing and headache
2. Water retention and hyponatremia
What is the MOA for anti-fibrinolytic agents (e.g. tranexamic acid)?
Inhibit the activation of plasminogen > plasmin, reduce fibrinolysis
(plaque stays longer)
List 2 uses of anti-fibrinolytic agents (e.g. tranexamic acid).
- Primary menorrhagia
- Haemophilias, vWD for dental extractions
- Bleeding in patients with thrombocytopenia
- Blood loss during cardiac/hip/knee surgery
What are the side effects of anti-fibrinolytic agents (e.g. tranexamic acid)? (2)
- GI toxicity
2. Thrombi formation
What is the MOA of recombinant factor 7a?
- fVIIa works locally at the site of vascular injured, where tissue factor (TF) is exposed and activated platelets are found.
- Binding of factor7a/ rF7a to TF initiates the coagulation generating small amounts of thrombin
- At pharmacological doses rF7a directly activates for Factor X on the surface of activated platelets > thrombin burst
- Thrombin bust leads to the formation of the stable hemostatic plug which controls bleeding
RFVIIa is usage?
- Treatment of bleeding and prevention of bleeding in surgery patients with Factor 8,9 inhibitors/ factor 7 deficiency
- Bleeding with other clotting disorders
- CNS bleeding, post-op bleeding, trauma (massive bleedy)
Congenital bleeding disorders can be classified into vascular/connective tissue, platelet abnormalities, and coagulopathy.
List 2 examples for coagulopathy.
- Vascular/connective tissue
- Marfan syndrome Ehlers-Danlos
- Osteogenesis imperfecta - Platelet abnormalities
- TAR syndrome… - Coagulopathy
- Haemophilia
- von Willebrand disease
- Congenital fibrinogen disorders
- Factor 8 problem
- Plasmin/plasminogen defcieincy/inhibitor
Acquired bleeding disorders can be classified into vascular/connective tissue, platelet abnormalities, and coagulopathy.
List 2 examples for each.
- Vascular/connective tissue
- vasculitis/ cryoglobulinemia
- amyloidosis
- medication/ nutritional - Platelet abnormalities
- liver/renal disease
- medication
- acquired antiplatelet antibody (ITP)
- Myeloproliferative disorder - Coagulopathy
- Circulating anticoagulant/inhibitor of coagulation factor
- vitamin K deficiency/warfarin use
- Liver/renal disease
- Amyloidosis (Factor X deficiency)
- Myeloproliferative disorders
Causes of thrombocytopenia (platelet deficiency)? (no need to give exmaples) (3)
- Decreased production in BM
- Excessive platelet destruction
- Sequestration of platelets in the spleen (hypersplenism)
Give examples of reduced production in BM causing thrombocytopenia.
- Hemolytic malignancies (leukemia, lymphoma)
- Chemotherapy/radiation
- Myelodysplastic syndrome
- Aplastic anemia
- Megaloblastic anemia
- Chronic liver disease
- Alcoholism
- Immune thrombocytopenic purpura (ITP)
Give examples of excessive platelet destruction causing thrombocytopenia.
- ITP (immune thrombocytopenic purpura)
- Autoimmune diseases (SLE)
- Human immunodeficiency virus (HIV)
- Anti-thrombin medications (e.g. heparin)
- Pregnancy
- DIC (disseminated intravascular coagulation)
- TTP (thrombotic thrombocytopenic purpura)
- HUS (hemolytic-uremic syndrome)
Give examples of Sequestration of platelets in the spleen (hypersplenism).
- Chronic liver disease
- Cirrhosis
- Myelofibrosis
- Gaucher’s disease (build up of fatty substances in kidney and liver?)
What is the most common cause of isolated thrombocytopenia? (normal CBC, peripheral smear)
Immune thrombocytopenia purpura (ITP)
- autoimmune disorder
When is treatment given where there is adult ITP?
When platelet count <20-30 x 10^9/L
rare indicated in patients with platelet counts >50 x 10^9/L
What is the pathogenesis of ITP?
- Reduced production: autoantibodies bind to destroy megakaryocytes > reduced platelets
- Increased platelet destruction: autoreactive Ig coats platelets and attracts macrophages > platelets prematurely destroyed in spleen
Other than platelet transfusion, what are given to patients with ITP?
- Corticosteroids: high dose steroid for 21 days
- IVIg: preferred when a rapid increase in platelet is needed
- if unresponsive to steroids
1. TPO-R agonist (increase platelet production by activating TPO-R) (thrombopoietin)
2. Splenectomy
Which of the following about drug-induced ITP is correct?
A. Heparin and valproic acid can be a cause
B. Binding of drugs to platelet glycoprotein is recognised by IgG causing the formation of immune conplex
C. Onset can be acute, within hours
D. Onset can be days after ingesting drug
All of the above
D: memory cells :)
What is the most common bleeding disorder, affecting 1% of the population?
von Willebrand disease (vWD)
How can VWD be evaluated in the lab? (3)
- von Willebrand antigen
- amount of antigenic protein present - von Willebrand Ristocetin Cofactor
- amount of functional activity present - Factor 8: C level
- Factor VIII is carried by vWF
Management for vWD? (4)
- Factor VIII concentrate with vWF
- Desmopression (DDAVP)
- Cryoprecipitate (sources of fibrinogen, factor VIII and vWF)
- Anti-fibrinolytic agent (tranexamic acid)
Comment on the difference in the definition of Haemophilia A and B.
Their mode of inheritance are both?
Haemophilia A - coagulation factor VIII (8) deficiency
Haemophilia B - coagulation factor IX (9) deficiency
- X-linked recessive
What are the most common clinical features for Haemophilia (A and B)?
Joint and muscle bleeding
- Haemarthrosis
- Soft tissue hematomas (muscle) > muscle atrophy, shortened tendons
- other sites of bleeding: urinary tract, CNS, neck
- A and B are indistinguishable
Treatment for haemophilia?
- Replacement with factor concentrates
- DDAVP (desmopressin)
- Antifibrinolytic agents
- tranexamic acid
What is Disseminated intravascular coagulation (DIC)?
Pathologic generation of _________, which leads to
thrombin;
1. widespread intravascular deposition of fibrin > thrombosis of small and midsize vessels with organ failure
+
2. consumption of clotting factors and platelets (consumption coagulopathy)
> bleeding
(for generating fibrin degradation products from fibrinogen and fibrin clot)
> > severe bleeding/ thrombotic complications
What are the common ddx for DIC?
- Obstetric
- amniotic fluid embolism
- premature separation of the placenta
- eclampsia - Malignancy
- Acute promyelocytic leukemia
- Pancreatic carcinoma and others - Infections
- G- septicaemia
- Meningococcal septicaemia
- Septic abortion
…
How will clotting profile change when there is DIC? (6)
- Increase APTT
- increase PT
- increase TT (lack consumption of coagulation factors)
- reduced fibrinogen and platelets
- the increased presence of plasmin FDP (fibrinogen degradation product)
- D dimer increased
Intravascular clots in DIC causes a ________ in platelet count and presence of _________ in RBC.
decrease;
schistocytes
- vascular obstruction > RBC squeezes through > fragments
Treatment for DIC?
- Treat underlying causes
- Supportive therapy (platelet/ plasma transfusion)
- Heparin - to reduce thrombin generation, may increase bleeding
