Hematology

Question 1

Coagulation cascade activation complexes

Answer 1

Question 2

Factors in extrinsic pathway

Answer 2

• Tissue factor (thromboplastin)
• VII
• Ca++
• IX

Question 3

vitamin K dependent factors

Answer 3

II, VII, IX, X

Question 4

Intrinsic pathway factors

Answer 4

• HWMK
• prekallikrein
• XII
• XI
• VIII
• Ca++

Question 5

Prothrombinase complex

Answer 5

PPL + Xa + Va

Question 6

Platelet Function (receptors, important secretory molecules)

Answer 6

Secretion

• ADP
• COX-1 depedent synthesis of thromboxane A2 - vasoconstriction
• both function in activation of platelets and recruitment to site
• less important: V, XI, fibrinogen, XIII, vWF, fibronectin, thrombospondin
• PDGF + TGF-b - promote wound healing

Adhesion

• a2b1 and GP VI - bind collagen
• GPIba and GPIIb/IIIa - bind vWF
• promote fibrin formation and stabilization of plug
• platelet aggregation

Question 7

Inherited hypercoagulable deficiencies

Answer 7

• Factove V Leiden**
• protein C/S deficiency
• antithrombin III deficiency
• lupus anticoagulant

Question 8

Indications for IVC filter (5 absolute, 3 relative)

Answer 8

Absolute

1. recurrent embolism despite anticoagulation
2. DVT in patient with C/I to anticoagulation (intracerebral hemorrhage, stroke)
3. complication of anticoagulation therapy
4. recurrent PE with assocaited pulmonary HTN and cor pulmonale
5. after pulmonary embolectomy for massive PE

Relative

1. PE >1/2 of pulmonary vascular bed in patient who cannot tolerate any more emboli
2. growing ileofemoral thrombus despite anticoagulation
3. high risk patient with large free-floating iliofemoral thrombus on venogram

Question 9

Coagulation screening tests

• PT/INR
• PTT
• thrombin time

Answer 9

• PT/INR - extrinsic and common
• PTT - intrinsic and common
• thrombin time - fibrinogen

Question 10

Hemophilia A

Answer 10

VIII deficiency

X-linked, 30% spontaneous occurrence

Clinical features:

• present later (can form platelet plug)
• often suffer from hemarthroses, bleeding into deep tissues and not mucosal sites (since platelet function works fine)

Classification

• based on functional levels of VIII
• <1% spontaneous bleeding
• <2% severe
• 2-5% moderate
• 5-30% mild (Rare spontaneous bleeding)
• 30% minimum needed for hemostasis of minor hemorrhage, 50% for joint and muscle bleeding, 80-100% to prepare for elective surgery

Treatment

1. ddAVP IV (0.3mcg/kg) or intranasal - raises VIII in mild and moderate disease (minor surgery)
2. recombinant VIII and plasma based VIII concentrate (serious bleeding) - FFP not concentrated enough
3. cryoprecipitate - good, only used if VIII not available

Question 11

Hemophilia B (Christmas)

Answer 11

Defiency in factor IX

Inherited X-linked deficiency

Classification

• 20-40% activity = moderate deficiency
• >30% activity needed for hemostasis

Treatment

• prothrombin complex concentrate and pure IX concentrate
• 30% to protect against bleeding post-dental extraction or abort joint hemarthroses
• 50% if major joint or IM bleeding
• 100% in life threatening bleeding or before major surgery

Question 12

von Willebrand Disease

Answer 12

Most common bongenital bleeding disorder (~1% prevalence)

Clinical: similar to platelet dysfunction (mucosal bleeding, petechiae, epistaxis, menorrhagia)

Classification

1. Type I (AD) - quantitative deficiency of normally functioning vWF, abnormal bleed time and mild reduction in VIII and vWF
2. Type II - variably inherited qualitative defect in vWF, many subtypes, depressed ristocetin assay (measures effectivess of vWF in agglutinating platelets
3. Type III - AR, complete absces of vWF and severe bleeding

Treatment:

1. ddAVP IV 0 48hrs between 1st and 2nd injection to allow for VIII and vWF to reaccumulate in endothelials, treats Type I; tranexamic acid give to suppress fibrinolysis
2. cryoprecipitate - 1bag/10kg q8-12h for several days to prevent excessive bleeding after major surgery, all 3 types

Question 13

Acquired thrombocytopathy (14)

Answer 13

1. chemotherapy drugs
2. thiazides
3. EtOH
4. estrogen (conjugated estrogens used to treat renal failure associated coagulopathy)
5. antibiotics (sulfas)
6. quinidine
7. quinine
8. methyldopa
9. gold
10. heparin
11. ASA
12. NSAIDs
13. dextran (volume expander)
14. hypothermia

Question 14

Acquired thrombocytopenia (5)

Answer 14

1. Splenic sequestration
2. Consumption (DIC)
3. Failure of production (marrow issue, aplastic anemia)
4. dilution
5. drugs

Question 15

ITP

Answer 15

Most common cause of isolated thrombocytopenia

IgG autoantibody

Ix:

• blood smear shows decreased plts
• BM shows normal megakaryocytes

Treatment

• steroids
• splenectomy (if steroids fail)

Question 16

Glanzmann’s thrombasthenia

Answer 16

Inherited defect of GpIIb/IIIa, resulting in inability of fibrinogen (and fibronectin and vWF) linking platelets together cannot occur

Acquired disorder or AR

Question 17

Bernard-Soulier syndrome

Answer 17

Abscence of GpIb-IX, usually bind vWF, platelets unable to aggregate

Question 18

Procoagulant states

Answer 18

1. HIT
2. antithrombin III deficiency
3. protein C and S deficiencies
4. Factor V Leiden (resistance to activated protein C)
5. Lupus anticoagulant

Question 19

Lupus Anticoagulant

Answer 19

Syndrome with clinical features of:

• recurrent fetal loss
• stroke
• migraines
• thrombocytopenia - observed in a small number of people (reaction between Ab and plt membranes)
• recurrent thrombus formation (arterial or venous)
• livedo reticularis

Mixture of IgG, IgM reactive against phospholipids, increased aPTT

Question 20

Factor V Leiden

*(deficiency leads to what hemophilia?)

Answer 20

Most common cause for thrombosis, alone though is a low risk factor

Thrombosis likelihood increase results from change in V that results in resistance of Va conversion to activated protein C (APC)

?treat with long-term anticoagulation

*parahemophilia

Question 21

Protein C and S deficiencies

Answer 21

Protein C and S from liver, vitamin K dependent

Protein S is a cofactor for APC, deficiency results in clincial states similar to protein C deficiency. Protein C is both an anticoagulant and fibrinolytic

Mechanism:

1. inactivation of Va and VIIIIa –> decreased thrombin production (anticoagulant)
2. inhibits tPA inhibitor –> increased plasminogen activity and fibrinolysis

Venous thrombosis most likely, arterial less common

Diagnosis: protein C levels measured, protein S (antigen levels measured)

Treatment: only if thrombosis occurs, treat with LMWH as bridge to warfarin (until INR reached)

Question 22

Purpura Fulminans

Answer 22

Skin necrosis along with DIC. Due to thrombotic occlusion of small and medium sized vessels. Can be a complication of sepsis or reaction from benign childhood infection OR from natural protein C and S deficiency as neonate

Question 23

Describe hypercoagulable state with warfarin

Answer 23

Warfarin can cause hypercoagulability in early stages, as it inhibits vitamin K which is used by coagulation cascade and factors II, VII, IX, X; protein C levels, an anticoagulant, also vitamin K dependent usually decline more rapidly initially before factors 1972

Question 24

Antithrombin III deficiency

(7 causes for acquired antithrombin III deficiency)

Answer 24

Most important plasma protease inhibitor, a serine protease inhibito of II, 7a, 9a, 10a, 11a, kallikreinin

Life threatening thormboses <50 yoa, arterial or venous

Will be unable to anticoagulate through heparin. Giving heparin will decrease antithrombin further by 30% for 10+days

Diagnosis: measure antithrombin III levels and activity

Treatment for those who need anticoagulation (no need for patients without thrombus since bleed risk on anticoagulant is not worth the thrombus formation risk

1. antithrombin III concentrates or FFP while on heparin
2. LMWH is more unreliable than in normal patients, will have to monitor Xa activity
3. oral anticoagulants (warfarin is mainstay of treatment) INR 1.5-2.5

Classification

• congenital
• acquired with no previous thrombi
• previous thrombi, acquired

Causes for acquired antithrombin III deficiency

1. nephrotic syndrome
2. liver disease
3. malignancy
4. malnutrition
5. DIC
6. decreased protein production
7. genetic

Question 25

HIT Type I

Answer 25

Direct heparin mediated plt aggregation (non-immune) causing hypercoagulability Onset within 24-72 hrs, transient and self-limited, no risk of thrombosis No treatment, continue heparin therapy as platelet count will normalize

Question 26

HIT type II

Answer 26

Immune mediated formation of antibody that recognizes a multimolecular complex of heparin and platelet factor 4 resulting in platelet aggregation. Starts 4-10 days after onset of UFH, but anyone having taken UFH is at risk at any time. Diagnosis: * thrombosis when plts \<100, and remain thrombocytopenic * 50% reduction in platelets or new thrombocytpenia within 5-15 days of heparin exposure OR 2-9 days with previous UFH * C14 serotonin release assay and ELISA for HIT-Ig confirm this Complications * bleeding * ~30% risk of thrombosis (75% venous, 25% arterial) with unusual thrombotic complications * skin necrosis * acute platelet activation syndromes (fever, flushing) Treatment * D/C heparin * protamine reversal if thrombosis occurred * other anticoagulation (danaproid, argatroban, lepirudin, ancrod * DO NOT give LMWH as ~1/3rd cross reactivity * DO NOT give warfarin - increased risk of skin necrosis (vitamin K if already receiving warfarin) * MAYBE give platelets, could exacerbate thrombotic complications

Question 27

Conditions that predispose to both venous and arterial thrombi formation

Answer 27

1. Behcet's syndrome 2. Antiphospholipid syndrome 3. Homocysteinuria

Question 28

What should they be worked up for within a year or so (supported by some evidence)?

Answer 28

Occult malignancy Prins et al. ThrombHaemost. 1997;78(1):121-5