Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Haematology > Haemostasis and Thrombosis > Flashcards

Haemostasis and Thrombosis Flashcards

1
Q

Functions of vWF

A
  1. Mediate platelet adhesion where it binds to platelet GPIb-V-IX
  2. Carrier protein for Factor VIII
    Factor VIII is released from vWF by the action of thrombin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is haemostasis

A

Haemostasis = response to blood vessel injury and bleeding

PRIMARY HAEMOSTSIS

  • Response to vascular wall injury
  • Formation of PLATELET PLUG adhering to endothelial wall
  • Limits bleeding immediately

SECONDARY HAEMOSTASIS

  • End result is to generate a STABLE CLOT TO REINFORCE PLATELET PLUG
  • Coagulation cascade
  • Gradually stable plug will be dissolved by FIBRINOLYSIS

Requirements for a clot to form

  • Negative charged phospholipid surface
  • Replete with coagulation factors and fibrinogen
  • Calcium and temperature are important
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Platelet adhesion receptors

A

GPVI: collagen
Protease activated receptors: thrombin
GP Ib-V-IX: VWF
GP IIb-IIIa: fibrin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the role of factor XIII?

A

Factor XIII crosslinks fibrin polymers to stabilise the fibrin clot

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Factor XIII Deficiency

A
  • Factor XIII deficiency is an AUTOSOMAL RECESSIVE disorder
  • Individuals with factor XIII deficiency form blood clots like normal, but these clots are unstable and often break down, resulting in prolonged, uncontrolled bleeding episodes.
  • FXIII consists of two subunits: subunit A and subunit B. Most of the Factor XIII deficiency states are caused by mutations in subunit A; very few have a mutation in subunit B.

CLINICAL FEATURES

  • Chronic nosebleeds (epistaxis)
  • bleeding from the gums
  • discoloration of the skin due to bleeding underneath the skin (ecchymoses)
  • solid swellings of congealed blood (hematomas).
  • Bleeding into the joints (hemoarthrosis) is rare.
DIAGNOSIS 
History/Exam
APTT and PT are NORMAL
Factor XIII assay - diagnostic 
A clot solubility test - only effective when an affected individual has very low levels of factor XIII. During these tests, a clot is exposed to a solution of 1% monochloracetic acid or 5 m urea. In individuals with less than 1% factor XIII, the clots will breakdown. Most untreated individuals with factor XIII deficiency will have close to 0% factor XIII activity in the blood.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the natural anticoagulants of the coagulation cascade?

A
  • Anti-Thrombin: Factor 10 and Factor 2 (thrombin) (primarily) but also factor 9,11,12
  • Protein C + Cofactor Protein S: Factor Va and VIIIa (5,8)

Tissue Factor Pathway Inhibitor: switches off Factor VII (initial factor in extrinsic pathway)

C1 esterase inhibitor - synthesised in liver, inhibits FXIIa, FXIa and PK and complement proteases (C1r, C1s)

Note: in factor V leiden, factor Va is no longer susceptible to cleavage by activated protein C, therefore inactivated more slowly resulting in a hypercoagulable state

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are the inhibitors of the fibrinolytic pathway?

A
  • Thrombin converts fibrinogen to fibrin
  • Plasminogen is activated by tissue plasminogen activator (tPA) from endothelial cells and urokinase plasminogen activator (uPA) to form plasmin
  • Plasmin converts fibrin to fibrin fragments
  • Plasmin has short half life because it is rapidly inhibits by the alpha-2-antiplasmin
  • Plasminogen activator inhibitor (PAI-1) inhibits tPA and uPA preventing the formation of plasmin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Coagulation Cascade

A

EXTRINSIC Pathway:

  • activated by THROMBOPLASTIN (tissue factor, phospholipid membrane, calcium)
  • Factor 7
  • PT (prothrombin time) - “play tennis outside”
  • TF - FVIIa complex activates Factor X (10) and IX (9)
  • Sustained generation of thrombin depends on the activation of factor IX (9) and VIII (8)

INTRINSIC Pathway

  • Activated by CONTACT ACTIVATION
  • Factor 12,11,9,8
  • APTT (activated partial thromboplastin time)

COMMON Pathway

  • Factor Xa, Va, II (10,5,2)
  • APTT and PT changes
  • Factor Va bind Factor Xa and together form the prothrombinase complex, which converts prothrombin (II) to thrombin (IIa)
  • Thrombin converts fibrinogen to fibrin which undergoes polymerisation to form an insoluble fibrin clot
  • Factor XIII stabilises and crosslinks overlapping fibrin strands

THROMBIN TIME Prolonged:

  • Heparin (indirect thrombin inhibitor, reptilase normal)
  • Dabigatran (direct thrombin
  • Low fibinogen levels/dysfunctional fibrinogen, DIC
  • Increased fibrin degradation products

INR = PT (patient)/PT (normal plasma)

REPTILASE TEST

  • Normal < 24s
  • NOT prolonged by an form of heparin or direct thrombin inhibitor
  • All other causes of prolonged TT will also prolong reptilase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Mixing Study

A
  • Mixing study is performed when the APTT is prolonged
  • It helps to differentiate between a prolonged clotting time due to a factor deficiency vs. factor inhibitor eg: acquired factor VIII inhibitor or in the laboratory test, eg: lupus anticoagulant.
  • Other interfering substances that can also act as inhibitors include heparin fondaparinux, DOACs, elevated CRP

It involves mixing the patient’s plasma with the control plasma in 1:1
- If the prolonged APTT/PT CORRECTS when the control plasma is added, this suggests that there is a FACTOR DEFICIENCY or SLOW ACTING INHIBITOR
- If the APTT/PT remains PROLONGED when the control plasma is added, this indicates there is an inhibitor present in the sample.
LUPUS ANTICOAGULANT
TIME DEPENDENT INHIBITOR - ACQUIRED FACTOR VIII DEFICIENCY
- In factor VIII deficiency, the immediate mixing study will correct but when it is incubated for 1-2 hours at 37 degrees, it will show prolonged APTT. Delayed reactivity is characteristic of factor VIII inhibitors.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Features of DIC

A 
Prolonged PT/APTT/TT
Low fibrinogen 
Low platelets 
Elevated D dimer
Blood film: thrombocytopenia, red cell fragmentation

Syndrome of systemic intravascular activation of the coagulation system

  • Fibrin deposition/microangiopathy
  • Microvascular dysfunction/organ ischaemia
  • Consumption of platelets and coagulation proteins with increased bleeding risk

CAUSE

  • Sepsis
  • Trauma
  • Malignancy: carcinoma, APML, MDS
  • Pancreatitis
  • Obstetric: amniotic fluid embolus, abruption, HELLP
  • Liver failure
  • Snake venom

Mx

  • Platelets
  • FFP (coagulation factors)
  • Cryoprecipitate (fibrinogen)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Which medications are:

  • Indirect Factor Xa/IIa Inhibitors
  • Direct Factor Xa Inhibitors
  • Direct thrombin inhibitors
A
  • Indirect Factor Xa/IIa Inhibitors
    Heparin: LMWH, UFH
    Fondaparinux
    Danaparoid
  • Direct Factor Xa Inhibitors
    Apixaban
    Rivaroxaban
  • Direct thrombin inhibitors (IIa)
    Dabigatran
    Bivalirudin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Effect of DOACs on lab results

A
  • Dabigatran: prolonged TT, APTT
  • Rivaroxaban: Prolonged PT (could be normal), rivaroxaban assay
  • Apixaban: Prolonged or normal PT, apixaban level. Normal PT does not exclude presence of therapeutic apixaban
  • dRVVT - prolonged in all 3 agents
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Reversal of:

  • Warfarin
  • Dabigatran
  • Apixaban
  • Rivaroxaban
A
  • Warfarin: vitamin K, prothrombinex
  • Dabigatran: Idarucizumab
  • Apixaban/Rivaroxaban: Andexanet alfa

Ciraparantag: reverse UFH, LMWH, direct thrombin + direct Xa inhibitors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Reversal of:

  • Warfarin
  • Dabigatran
  • Apixaban
  • Rivaroxaban
A
  • Warfarin: vitamin K, prothrombinex
  • Dabigatran: Idarucizumab
  • Apixaban/Rivaroxaban: Andexanet alfa

Ciraparantag: reverse UFH, LMWH, direct thrombin + direct Xa inhibitors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Causes of isolated prolonged PT/INR

A
  • Vitamin K antagonist (warfarin) or deficiency
  • Liver disease
  • Factor VII deficiency
  • Rivaroxaban/Apixaban
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Causes of isolated prolonged APTT

A
  • Heparin
  • LMWH
  • Deficiency of 12,11,9,8
  • Von willebrand disease
  • Lupus anticoagulant
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Causes of prolonged PT and APTT

A
  • DIC: low fibrinogen, raised d dimer
  • Liver disease
  • Common pathway deficiency - 2, 5, 10, fibrinogen
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Causes of prolonged TT

A
  • Heparin
  • Dysfibrinogenemia
  • Hypofibrinogenemia
  • Thrombin inhibitor - dabigatran
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q 
Following dyspnoea, what is the most common clinical feature of acute PE?
A. Calf swelling or pain
B. Haemoptysis
C. Pleuritic pain
D. Tachycardia
E. Wheezing
A

D. Tachycardia

20
Q

Indications for thrombophilia screen

A
  • Fam hx <45yo
  • Multiple or recurrent thrombosis
  • Thrombosis in unusual sites - portal vein thrombosis
21
Q

Management of VTE

A
  • Strongly provoked (major surgery/trauma): 3 months
  • Minimally provoked: 3 months and modify as per patient RF
  • Unprovoked: indefinite anticoagulation
  • For distal DVT without persisting risk, may be able to stop after 6 weeks

Use DOACS

22
Q

Strong RF for recurrent VTE

Factors that have little or no effect on recurrence

A

STRONG RF

  • Unprovoked VTE
  • Prior VTE
  • PE or proximal DVT
  • Persistent RF, eg: active cancer, APLS
  • Antithrombin,, protein C/S deficiency

LITTLE/NO EFFECT

  • Factor V Leiden or prothrombin gene hetrozygosity
  • Residual thrombus on imaging
23
Q

VTE risk caused by hormones

A
  • Highest post partum and then pregnancy
  • Progesterone only (mirena, implanon, minipill): no significant risk except depot provera.
  • Combined OCP higher risk
24
Q

How do you treat antiphospholipid syndrome?

A

Warfarin

25
Q

Heparin induced thrombocytopenia

A
  • Is a profoundly thrombotic state
  • Iatrogenic disorder mediated by IgG antibodies that bind PF4-heparin complexes (platelet factor 4)
  • These antibodies cause a hypercoagulable state by activating platelets and procoagulant microparticles
  • One-third to one-half of patients with HIT develop venous, arterial or microvascular thrombosis
  • Unfractionated heparin (UFH) is associated with a 10-fold increased risk of HIT compared to LMWH

DIAGNOSIS:
• It is diagnosed via the 4Ts score which assesses the pretest probability of HIT by looking at:
○ The degree of Thrombocytopenia: platelet count >50% and nadir >20x10^9
○ The Timing relative to heparin exposure (onset: 5-14 days)
○ The presence of Thrombosis - new VTE, skin necrosis, adrenal haemorrhage
○ Other causes of thrombocytopenia
○ A total score of 8 can be achieved where pre-test probabilities for HIT are:
- 0-3 points: low probability
- 4-5 points: intermediate probability
- 6-8 points: high probability

Diagnosis

  • Clinical scenario, HIT pre-test probability score
  • Immunoassay to detect HIT antibody that binds PF4
  • Functional assay: serotonin release assay, heparin induced platelet aggregation
  • The PF4 ELISA is a screening test
  • The serotonin release assay is the gold standard test for confirmation of HIT.

Tx:

  • Stop heparin
  • Danaparoid: heparinoid, to monitor check anti Xa, can worsen renal fx, half-life of 24 hours
  • Fondaparinux: factor Xa inhibitor – similar to LMWH
  • Bivalirudin: direct thrombin factor IIa inhibitor, check APTT/PT

Direct thrombin inhibitor (lepirudin, argatroban) or Xa inhibitor (danaparoid)
- Must avoid warfarin (increase d thrombosis due to reduce protein C levels)

26
Q

Pathophysiology of VITT - vaccine induced thrombocytopenia and thrombosis

A

• Adverse effect of certain adenoviral vector COVID-19 vaccines- Astra Zeneca. Johnson and Johnson/Janssen

VITT resembles HIT (heparin-induced thrombocytopenia)
• High levels of anti-PF4 antibodies
• Platelet-activating immune complexes (FcɣRIIa-dependent)
• Subsequent platelet aggregation and clot formation

VITT differs from HIT
• VITT occurs without exposure to heparin
• Pattern of platelet reactivity, does not demonstrate typical heparin-dependence, as seen with HIT

27
Q

When to suspect VITT?

A
  • D dimer > 5 x upper limit of normal AND

- Platelets < 150 x 10^ 9

28
Q

Compare platelet vs clotting factor bleeding

A

PLATELET TYPE

  • Site of bleeding: skin, mucous membranes (epistaxis, gums, vaginal, gastrointestinal)
  • Skin cut bleeds: yes, prolonged
  • Petechiae: common
  • Ecchymoses: small/superficial
  • Hemarthrosis/muscle bleeding: extremely rare
  • Bleeding after surgery: immediate, usually mild

CLOTTING FACTOR

  • Site of Bleeding: deep in soft tissues (joints, muscles)
  • Skin cuts bleed: no, minimal
  • Petechiae: No, rare
  • Ecchymoses: large, deep (haematomas)
  • Haemarthrosis/muscle bleeding: common
  • Bleeding after surgery: may be delayed (1-2 days), often severe
29
Q

Types of Haemophilia

Relationship of bleeding severity to clotting factor

A

Haemophillia A - factor VIII
Haemophillia B - factor IX
Haemophillia C - factor XI (no correlation with factor level)

A and B are both X linked RECESSIVE inheritance although can be acquired due to formation of antibodies. C can occur in both sexes but mostly Ashkenazi jews.

  • Severe: <1% of normal, spontaneous bleed in joints + muscle
  • Moderate: 1-5%, occasional spontaneous bleeding, prolonged bleeding with minor trauma/surgery
  • Mild: 5-40%, spontaneous bleeding rare, severe bleeding with major surgery

Factor XI Deficiency

  • Autosomal recessive
  • Mild bleeding disorder, usually manifests after trauma/surgery
  • Bleeding risk correlates poorly with FXI levels
  • Consider replacement for moderate/high risk surgery in women who have not undergone significant hemostatic challenge
30
Q

Which condition can be associated with severe haemophilia A?

A

Turners Syndrome

31
Q

What is a prophylaxis medication that be used for haemophili A?

A

EMICIZUMAB
Bridges activated Factor IX and Factor X to restore function of missing FVIIIa.

FITUSIRAN
- Small interfering RNA which prevents production of antithrombin in liver –> rebalance haemostasis = effective in both Haemophilia A and B

32
Q

Function of VWF

A

Function

  • Promote normal platelet adhesion and aggregation
  • VWF bridges platelets to subendothelium at sites of vascular injury
  • Stabilising unactivated factor VIII in the plasma
  • Increases half life by x5 fold

Binding to platelets
- Binding to platelets requires initial activation or alteration in the structure of VWF so that the binding sites in the A1 domain can engage the platelet receptor GP1b-IX-V complex on platelet surface

33
Q

Inheritance patterns of VWD

A
  • Most cases of VWD are transmitted as an AUTOSOMAL DOMINANT trait; this includes types 1 and 2B, and most types 2A and 2M.
  • In contrast, type 2N and type 3 VWD are AUTOSOMAL RECESSIVE

Note: Haemophilia A and B are X-linked

34
Q

Features of VWD

A
  • Autosomal inheritance mostly dominant

Presentation

  • Bruising + epistaxis
  • Menorrhagia
  • Post partum haemorrhage
  • Bleeding after minor dental surgery
  • Joint/soft tissue bleeding uncommon
35
Q

What can increase VWF levels?

A
  • Advancing age
  • Non-O blood group
  • Lewis blood group
  • Adrenaline/Exercise
  • Inflammation
  • Hormones - pregnancy, OCP
36
Q

Types of VWD

A
  • Inherited deficiency (QUANTITATIVE) or dysfunction (QUALITATIVE) of vWF
  • Gene located on chromsome 12
  • Low FVIII and high APTT

Type 1 - partial quantitative deficiency, mild-moderate bleeding
Low levels, but normal function

Type 2 - qualitative issue, normal levels but abnormal function. cant form a multimer or cant bind to glycoprotein receptor or cant bind to factor 8
- 2A: selective deficiency HMW multimers - decreased VWF-dependent platelet adhesion
- 2B: selective deficiency HMW multimers, increased affinity of VWF for platelet GP1b
- 2M: no loss of HMW multimers but dysfunctional VWF
- 2N: decreased binding affinity for FVIII
Type 2 uncommon, variable -usually moderate bleed
2A - reduced large vWF, 2B mutant vWF (aggregation occurs without injury), 2M - reduced affinity to platelets, 2N- abnormal vWF (reduced affinity to factor 8)

Type 3 - severe disease, complete deficiency of vw factor which also causes VIII depletion (AR inheritance, whereas haemophillia A is X linked) - high bleeding

37
Q

Treatment of VWD

A
  • Desmopressin = stimulation of endothelial cells = release of endogenous vWF and FVIII- not effective in type 3,2B
  • VWF concentrates
  • Tranexamic acid - impair fibrinolysis by inhibiting plasmin generation
    CI to TXA: DIC, renal tract bleeding

Adjunct

  • Manage menorrhagia: OCP, endometrial ablation
  • Optimise iron
  • Avoid AP + AC
38
Q

What is the most common cause of acquired protein C resistance?

A

Factor V leiden

  • Most common inherited thrombophilia, autosomal dominant
  • Point mutation in the G1691A factor V gee which leads to an amino acid substitution that renders Factor V resistant to inactivation by activated protein C
  • Factor V leiden accounts for > 90% of activated protein C resistance, other causes less common, APLS, pregnancy, cancer
  • Diagnosed by PCR testing of factor V gene
  • Presence can be detected through an activated protein C resistant assay
  • Heterozygosity for factor V leiden only a mild RF for VTE recurrence
  • Homozygosity stronger +/- arterial thrombosis
39
Q

What are the major platelet adhesion receptors?

A

(a) Integrin a2b3/glycoprotein IIb/IIIa
- Responsible for STABLE PLATELET ADHESION AND AGGREGATION
- Major adhesive ligand if fibrinogen/fibrin
- GP IIb/IIIa antagonists: abciximab, tirofiban

(b) GP Ib/V IX complex
- Second most abundant receptor
- Major adhesive ligand is vWF
- Caplacizumab: GP Ib/V IX antagonist

(c) G protein coupled receptors - where soluble agonists act to stimulate platelets
- PAR 1 and 4 receptors - where thrombin acts
- P2Y12 receptors - where ADP acts, target for clopidogrel, prasugrel and ticagrelor

40
Q

How does a platelet plug form?

A
  1. INJURY to endothelium leads to exposure of circulating blood to subendothelial elements
  2. PLATELET ACTIVATION: platelet stimuli include collagen (binds to GP1a/IIb and GPV1 platelet receptor), thrombin (PAR1 and PAR4 receptors on platelets), ADP (P2Y1 and P2Y12 receptors) and epinephrin
  3. PLATELET ADHESION
  4. PLATELET AGGREGATION

PLATELET SECRETION

41
Q

Where are procoagulants synthesised?

A
  • All procoagulants are synthesised in the liver except vWF
  • vWF synthesised in megakaryocytes and endotheial cells
  • Factor VIII: endothelial cells in liver and other tissue

vWF stabilises factor VIII

42
Q

Causes of hypofibrinogenemia

A

(A) CONGENITAL

  • Quantitative: afibrinogenemia, hypofibrinogenemia
  • Qualitative: dysfibrinogenemia

(B) ACQUIRED

  • Liver disease
  • DIC
  • HLH
  • Anti fibrinogen antibodies
  • Autoimmune conditions - SLE/RA/UC/MM

Prolonged PT/APTT
Low fibrinogen

43
Q

Protein C and S deficiency

A
  • Protein C deficiency - inactivates factor Va and VIIIa

- Protein S is cofactor of protein C

44
Q

What is HLH

A
  • Hemophagocytic lymphohistiocytosis (HLH): a life-threatening hematologic disorder involving pancytopenia and severe inflammation due to increased activity of cytotoxic T cells and macrophages from cytokine production
  • May be triggered by infection, malignancy or rheumatological disease

Diagnosis
(a) Molecular diagnosis consistent with HLH: pathologic mutations of PRF1,UNC13D, Munc18-2, Rab27a, STX11, SH2D1A, or BIRC4
or
(b) Five of these eight criteria:
- Fever
- Splenomegaly
- Cytopenia of two or more cell lines (i.e. Hb <90 g/L, platelets <100 x 10E9/L, neutrophils <1 x 10E3/L)
- Either elevated triglycerides or low fibrinogen
- Histopathological evidence of hemophagocytosis (on either bone marrow, spleen or lymph node biopsy)
- Serum ferritin > 500 mcg/mL (often much higher in HLH: ferritin > 3000 ng/mL as concerning for HLH and ferritin > 10 000 as highly suspicious (96% specific))
- Low or absent NK cell activity (by flow cytometry, if available)
- Soluble CD25 > 2400 U/mL

Mx

  • Treatment of the underlying cause
  • Chemotherapy may be required in severe cases (e.g. etoposide, dexamethasone, and cyclosporine)
  • Platelet transfusion as indicated
  • Supportive care: pneumocystis jiroveci prophylaxis, fungal prophylaxis, intravenous immunoglobulin supplementation, and neutropenic precautions
45
Q

MOA of heparin (unfractionated heparin) vs LMWH (clexane)

A

Heparin - factor II and Xa

LMWH - factor Xa

46
Q

What does thrombin (IIa) activate?

A 
5, 8 , 11, 13, Protein C
Factor V
Factor VIII
Factor XI 
Converts fibrinogen to fibrin and activates Factor XIII
Protein C + thrombomodulin
47
Q

What are vitamin K dependent proteins?

A

Prothrombin
FVII
FIX
protein C, protein S

Haematology (7 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions