Greinacher, A. (2015) Heparin-Induced Thrombocytopenia. NEJM 2015; 373:252-261

Question 1
A 64 year old female is admitted to the wards with cellulitis. She is receiving flucloxacillin intravenously and is making a stable recovery. Routine blood measurements reveal her platelet count to have decreased on day 5 of her admission from 300 to 150. She is on unfractionated heparin 5000 units BD. A presumptive diagnosis of heparin induced thrombocytopenia is made.

What is CORRECT about the pathophysiology of this condition

(A) HITS is always associated with the use of heparin derivaties
(B) It relates to IgG formation against heparin (polyanion)- platelet factor 4 (chemokine) complexes that subsequently active monocytes and macrophages to active and clump platelets via their Fc receptors and active monocytes and macrophages to generate thrombin
(C) Thrombocytopenia increases the risk of bleeding, and a neurological deterioration in this patient would be concerning for an intracerebral hemorrhage
(D) Ufractionated heparin only has a slightly higher rate of HITS than low molecular weight heparin
(E) Arterial thromboembolism occurs more frequently than venous thromboembolism in HITS

B: HITS can occur spontaneoulsy, as the polyanion that compleses with PF4 may be on bacterial surfaces such as LPS. Surgery may also trigger HITS, as platelets may be activated by local trauma producing PF4. The mechanism of ‘B’ is correct. Thrombocytopenia is associated with an aggregative and consumptive process, and the pathology drifts towards thrombosis. UFH has a > 10x risk of causing HITS compared to LMWH. Arterial thromboembolism occurs less frequently. Patients with HITS have a 50 – 60% chance of developing venous thromboembolism. Stroke, myocardial infarction and arterial thrombosis may also occur.

Question 2
A 62 year old male is currently on DVT prophylaxis with low molecular weight heparin followowing knee replacement surgery. His pre-surgical platelet count was 480. On day 2 of his admission, the platelet count was noticed to be 320. On day 14, his platelet count is noticed to be 300. Unfortunately on this day he has a submassive pulmonary embolus.

Which of the following statements is FALSE regarding HITS as a possible aetiology of his condition

(A) HITS is unlikely to be a cause of his PE as his platelet droped from 480 to 300, which is less than 50% of a drop
(B) HITS may be a causative factor as he may have a reactive thrombocytocis post surgery and his platelet count of 300 may reflect a drop of greater than 50%
(C) The 4T rule (Thrombocytopenia, timing of onset, thrombosis or other cause of thrombocytopenia) should be used in assessing patients pre-test probability for HITS
(D) In the setting of a low-test probability, a negative heparin-PF4 antibody assay helps rule out HITS as a cause of his thrombus
(E) Functional platelet assays may increase specificity, and provide a clue for the diagnosis if positive in the context of high pre-test probability (High HITS score)

A: This statement is incorrect as there may be a reactive thrombocytocis post surgery increasing the platelet count, therefore the true platelet drop may be even higher. For instance if measured on day 9 (which typically represents the peak of post surgical reactive thrombocytocis) the platelet count may be 900. HITS is unlikely if the platlet count is <20 (reflected in the 4T scoring system). The 4T scoring system should be used to assess pre-test probabilty, with highest counts for timing (being between 5 – 10d post heparin exposure), thrombosis or anaphalactoid reaction, thrombocytopenia (highest for platelet count decrease >50% and nadir >20) and rule out other causes of thrombocytopenia. Heparin-platelet 4 antibody complexes are non-specific, but highly sensitive. They are nearly always present prior to thrombosis, and therefore if they develop after the event it is usually a co-incidental finding. Functional platelet assays including the seratonin assay are more specific for HITS

Question 3
What is the rationale behind NOT initiating warfarin until platelet count is >150 in a patient with HITS induced thrombosis?

(A) Warfarin interefers with the platet function assays
(B) The novel oral anticoagulants are more strongly indicated for this specific condition
(C) Warfarin decreases protein C concentration acutely, and thus in the initial stages the pro-thrombotic conditions are amplified
(D) Warfarin induced skin necrosis may occur at the site of initial heparin injection
(E) Warfarin decreases protein S concentration acutely, and thus in the initial stages the pro-thrombotic conditions are amplified

C: According to the NEJM review, the reason is that protein C is decreased concomitantly with factor 7 (alongside protein S to a lesser degree) and hence there is a relative pro-coagulant state.
 
Question 4
What is TRUE about the treatment of HITS

(A) Apixaban, a direct factor Xa inhibitor can be used in the treatment of HITS
(B) Therepeutic anticoagulation with a non heparin agent is not indicated unless the patient has evidence of thrombosis
(C) Danaparoid (factor Xa inhibitor) and argatroban (direct thrombin inhibitor) may be used and are liscenced for use in Australia
(D) Argatroban is contraindicated in renal failure due to predominant renal excretion
(E) Danaparoid can be given IM or IV
(F) Prophylactic platelet transfusions should be given if the platelet count is <10

C: Apixaban is not studied for this indication. Therepeutic anticoagulation must commence as this is a pro-thrombotic state. Prophylactic anticoagulation is insufficient to overcome the thrombin burst generated by the activity of the heparin-PF4-IgG complexes. Argatroban should be used in patients with renal failure as it has a short half life and has no renal clearance. Danaparoid can be given S/C or IV, not IM. Danaparoid should have factor Xa monitoring. Prophylactic platelet transfusions should be avoided in general as this condition does not have a significant bleeding tendency and platelet transfusions may increase thrombosis. Fondaparinux or bivalirudin may also be used.
 
Question 5
Which of the following zymogens is not activated or acted on by thrombin (Factor IIA)

(A) VIII
(B) V
(C) XIII
(D) Fibrinogen
(E) VII

E: Thrombin has a central role in haemostasis. It activates platelet aggregation, activates endothelium and leukocytes, activates cofactors VIII and V in clotting cascade, enhances activation of XI and IX, converts fibrinogen to fibrin, activates XIII to cross link fibrin. Blood 2005; 106: 2605 - 2612

Question 6
Which of the following statements is FALSE concerning the activity of Protein C

(A) Protein S is a co-factor for Protein C
(B) Protein C inactivates Factor V
(C) Protein C inactivates Factor VIII
(D) Protein C directly augments activity of antithrombin III
(E) Protein C levels decrease with exposure to vitamin K antagonists

D: RPA Course 2015

Question 7
Which of the following is NOT responsible for clot lysis?

(A) Plasminogen
(B) XIII
(C) Plasmin
(D) tPA
(E) urokinase

B: XIII helps to cross link fibrin meshwork. Plasminogen is activated by tPA and urokinase to form Plasmin, which causes the degradation of fibrin into fibrin degradation products. Blood 2005; 106: 2605 - 2612

Question 8
Thrombomodulin is not involved in the following physiological process:

(A) Inactivation of C3b
(B) Binding in a 1:1 stochiometry with thrombin
(C) Augmenting thrombin induced activation of Protein S
(D) Augmenting thrombin induced activation of Protein C
(E) Activating Thrombin activatable fibrinolysis inhibitor

D: Thrombomodulin is a glycoprotein found on endothelial cells. It has both procoagulant and anticoagulant effects. It is also involved in the complement pathway as a negative regulator of alternate complement pathway activation. Thrombin activatable fibrinolysis inhibitor, as its name suggests cleaves the C-terminal lysine residue from fibrin therefore preventing the binding of fibrin to plasminogen, plasmin and tPA. Am J Physiol Heart Circ Physiol. 2013 Jun 15;304(12):H1585-97

Question 9
​A 46 year old patient admitted with a pulmonary embolus has routine bloods taken, showing an elevated aPTT. The intern asks for a thrombin time which is prolonged. A reptilase test, however, is normal. What is the explanation for this result?

(A) Presence of LMWH
(B) Presence of Heparin
(C) Dysfibrinogenemia
(D) DIC
(E) None of the above

B: Thrombin time measures the time it takes to clot following the addition of a small amount of thrombin to the plasma. Prolongation implies inhibition/ deficiency of antithrombin III, fibrinogen deficiency, XIII deficiency. Heparin augments anti-thrombin III degradation of thrombin, therefore prolonging thrombin time. The reptilase test is characteristically normal because antithrombin III-heparin does not inhibit the activity of reptilase (which would otherwise have the same effect as thrombin). Methods Mol Biol. 2013;992:273-7. Methods Mol Biol. 2013;992:131-8.

Question 10
Which of the following factors leads to the highest peri-operative bleeding risk?

(A) Von-Willebrands disease
(B) DIC
(C) Past history of previous bleeding
(D) XIII deficiency
(E) Elevated APTT

C: RPA Course 2015, Ann Intern Med 2009; 151:ITC1.

Question 11
A 26 year old female with SLE has an elevated aPTT. A kaolin clotting time and dilute russell's viper venom time is prolonged. What is the best interpretation of the results?

(A) Presence of lupus anticoagulant
(B) Presence of anticardiolipin antibody
(C) Presence of anti beta2-glycoprotein 1 antibody
(D) Presence of heparin
(E) Presence of LMWH

A: The KCT and dRVVT are tests used in the evaluation of a lupus anticoagulant. LAC is an acquired antibody that binds to complexes of phospholipids. Standard assays of PT and aPTT add PLs and Ca in order to promote clotting. If antibodies that are present interfere with the PLs then clotting time will be prolonged. 

Question 12
What is the most common prventable cause of death in hospitalised patients?

(A) AMI
(B) VTE
(C) hospital acquired pneumonia
(D) Falls
(E) hypoglycaemia

B: Burden of VTE in Australia, Access economics May 2008

Question 13
What percentage of patients who have a VTE suffer from post-thrombotic syndrome?

(A) 5%
(B) 10%
(C) 20 - 40%
(D) 40 - 50%
(E) 60%

C: RPA Course 2015

​Question 14
Which of the following factors incluences the recurrence of VTE?

(A) Cancer
(B) Unprovoked VTE
(C) Non-surgical trigger
(D) Surgery
(E) Medication non-compliance

A: Nature of VTE influences recurrence rates more so than do the hereditary thrombophilias. Baglin et al, Lancet 2000; LITE study, Cushman, Blood 2003

Question 15
Which of the following is NOT a risk factor for recurrent VTE?

(A) Age
(B) Female
(C) Active Cancer
(D) Elevated D-Dimer
(E) Residual thrombosis on leg ultrasonography

B: Male gender has a RR x1.5. Also patients with persistent venous obstruction are at higher risk of recurrence HR 2.4 RPA Course 2015

Question 16 - EMQ

(A) Warfarin
(B) Dabigatran
(C) Rivaroxaban
(D) Apixaban
(E) Edoxaban
(F) Low Molecular Weight Heparin
(G) Fondaparinux

Which of the following compounds inhibits the conversion of vitamin K to Vitamin K epoxide
A

Which of the following is the most renally excreted?
C

Which has the highest bioavailability
A

Which is metabolised preferentially through CYP2C9
A

Which of the following is least renally excreted excluding warfarin
D

Dilute thrombin time may be used to monitor this agent
B

Normal PT excludes the presence of which novel oral anticoagulant
C

Normal APTT excludes the presence of which novel oral anticoagulant
B

Idaricizumab, an antibody fragment, has high affinity binding to which of the following?
B

Andexanet alpha, a recombinant protein that is structurally similar to Factor Xa, binds to which of the following?
C, D, E

Question 17
A 68 year old male presents with a pulmonary embolus. He had no risk factors. Which of the following course of action should be advised?

(A) Anticoagulation, History, Physical Examination and Age-appropriate cancer screening
(B) Anticoagulation, thrombolysis, History, Physical Examination, Age appropriate cancer screening and CT Chest/ Abdomen/ Pelvis
(C) Anticoagulation, History, Physical Examination, Age appropriate cancer screening and CT Chest/ Abdomen/ Pelvis
(D) Anticoagulation, History, Physical Examination, Age appropriate cancer screening and CT Chest/ Abdomen/ Pelvis, CT Colonography
(E) Anticoagulation, History, Physical Examination

A: According to the recently published SOME trial in the new england journal of medicine, 3.2% in the limited screening group and 4.5% in the intensive screening group (CT + protocol), p = 0.28. There was no difference in time to diagnosis or in cancer related mortality. N Engl J Med 2015; 373:697-704

Question 18
A 43 year old male presents with an acutely swollen left leg after a long haul flight from Sydney to Vancouver. A Doppler study of her leg showed an extensive ilio-femoral DVT. He has no additional bleeding risk. With regards to reducing this patients risk of the post-thrombotic syndrome, which of the following would you advice?

(A) Long term anticoagulation with rivaroxaban
(B) Warfarin to maintain INR 2.5 - 3.0
(C) Cather directed thrombolysis
(D) Aspirin
(E) Long term anticoagulation with LMWH

C: Lancet Volume 379, No. 9810, p31–38, 7 January 2012 - Catheter directed thrombolysis after 24 months of follow up was associated with ARR 14.4% for PTS, with NNT 7. BMJ Open 2013;3:e002984 - There was no difference in quality of life scores between the thrombolysis group versus no thrombolysis group. This has been supported by a cochrane database review Cochrane Database Syst Rev. 2014 Jan 23;1:CD002783. However the risk of bleeding needs to be considered as catheter directed thrombolysis is associated with increased bleeding risk. 

Question 19
A patient with newly diagnosed atrial fibrillation is initiated on dabigatran 150mg BD. Unfortunately he has a catastrophic upper GI bleed and he is currently in ICU following embolisation of the short gastric artery. Which of the following statements is FALSE?

(A) Dabigatran 150mg BD is associated with higher risk of gastrointestinal bleeding when compared to warfarin
(B) Dabigatran 110mg BD is associated with equivalent rates of major bleeding when compared to warfarin
(C) Dabigatran 150mg BD is associated with a decreased primary endopoint of stroke or systemic embolisation compared to warfarin
(D) Dabigatran 110mg BD is associated with equivalent rates of intracranial haemorrhage compared to warfarin
(E) Dabigatran 150mg BD is associated with less intracranial haemorrhage compared to warfarin

D: Dabigatran in all doses is superior to warfarin in terms of reduced rates of intracranial haemorrhage. There was no difference in rates of major bleeding with either doses in comparison to warfarin, however both doses are associated with increased GI bleeding. NEJM 2009; 361: 1139 - 51, ReLY Trial. 

Question 20
Which of the following novel oral anticoagulants is the only one to reduce death from any cause in comparison to warfarin?

(A) Apixaban
(B) Rivaroxaban
(C) Edoxaban
(D) Dabigatran
(E) Fondaparinux

A: " rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047)." The rate of major bleeding also favoured apixaban over warfarin. (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001) N Engl J Med 2011; 365:981-992. Edoxaban, when compared to warfarin, showed that it reduced death from cardiovascular cause. "The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01)" - N Engl J Med 2013; 369:2093-2104