1. A 38-year-old man with severe hemophilia A presented with right thigh pain and was diagnosed with a deep vein thrombosis (DVT) in his right femoral vein. He was treated with anticoagulation and factor VIII replacement. 2. During treatment, he developed a large iliacus muscle hemorrhage. His anticoagulation was held and factor replacement was continued. An IVC filter was placed to prevent further pulmonary embolism. 3. Over several weeks of intensive factor replacement and physical therapy, the patient's DVT and hemorrhage resolved without further complications. His case illustrates the complex management of both bleeding and thrombotic risks in patients with hemophilia.

1. Jose D. Sandoval-Sus MD
Hematology Oncology Fellow
USF/Moffitt Cancer Center
In the wrong place at the wrong
time: an uncommon complication
in severe hemophilia
Case presentation

2. Case presentation
38 yo AA man with severe hemophilia A complicated by
recurrent knee hemarthrosis and hepatitis C, presented
to the ED reporting sudden right mid and proximal thigh
pain, and “tightness” for 48 hrs. The symptoms started
after lifting heavy equipment at work. Importantly, he self
administered 3500 units of rFVIII at home 24 hrs after
his symptoms started.
Physical examination:
• No evidence of mucocutaneous bleeding.
• RLE: large varicose veins medial to his right knee that
were warm and tender to palpation.
Initial laboratory work-up
• WBC 5.14 x 103/µl, Hb 15.4 g/dL, PLT 184 x 103/µl,
creatinine 0.8 mg/dL, BUN 7. The rest of his CMP was
within normal limits

3. • CT abdomen/pelvis with contrast:
No iliopsoas hematoma or retroperitoneal bleeding.
• CT angiogram of right lower extremity
(RLE): Proximal and mid femoral vein filling
defect consistent with deep venous thrombosis
(DVT). No evidence of intramuscular hematoma.
• U/S Doppler of RLE:
Non-occlusive thrombus seen in the right proximal
femoral vein.

4. • Severe hemophilia A:
– Hx of recurrent hemarthrosis and muscle
hematomas since childhood
(target joint: left knee)
– Uses recombinant FVIII 2500 units
On-demand.
– No reported hx of Factor VIII inhibitors.
• Hepatitis C
• Essential hypertension.
Past medical history

5. Past surgical history:
• Multiple dental extractions with no major bleeding
complications.
Social history:
• Denies tobacco, alcohol and/or recreational drug
use.
• Works as a security guard.
Family History:
• Patient is adopted
Medications:
• Amlodipine 10 mg PO Q 24hrs
• Gabapentin 600 mg PO Q 8hrs

6. Diagnoses
 RLE unprovoked DVT
 Severe hemophilia A
• The patient was started on heparin drip and
hematology oncology was consulted….STAT!

7. Clinical course
Treatment recommendations by the Hem/Onc team:
• Discontinue heparin drip
• Begin enoxaprin (1 mg/kg Q12hrs)
• Start recombinant factor VIII every 12 hours with a
FVIII level target of 100% due to ongoing anticoagulation.
• Repeat images (RLE U/S doppler) after 5 to 7 days of
treatment to reassess extent of DVT
Baseline coagulation
studies
PTT* 50.5 sec
(normal: 20 - 33 sec)
PT 10.9 sec
(normal: 9 - 12.5 sec)
INR 1
Factor VIII 3%

8. 1. No changes on patient status.
2. Ongoing treatment with full dose enoxaparin.
3. FVIII levels: 109%. Patient was switch to continuous infusion
factor replacement (CIFR) (dose= 4 units/kg/hr)
Clinical Course- Day 3
Clinical Course- Day 4
1. The patient started physical therapy.
2. FVIII levels: 117% on CIFR.
Thrombophilia work-up
Factor V Leiden Not detected
Prothrombin G20210A mut Not detected
Lupus anticoagulant Negative
Anti-cardiolipin Negative
Ant-B2glycoprotein Negative
Protein C 91% (N: >60%)
Protein S 79% (N:>60%)

9. 1. The patient developed severe (10/10) right flank and lumbar pain
after PT session. Pain limited ROM of ipsilateral hip joint and limb
2. CT scan abdomen/pelvis: 4.7 x 2.5 x 7 cm right iliacus hematoma.
No other evidence of retroperitoneal bleeding.
3. FVIII levels at the time of bleeding: 126%. FVIII inhibitors where
not detected.
4. Enoxaparin was immediately held and CIFR was continued to
maintain a goal of 100% for 24-48 hrs after placement of an IVC
filter placement.
5. Successful IVC filter insertion.
Clinical Course- Day 5 and 6

10. Clinical Course (3/2015)
Day 1:
• RLE DVT
• Exnoxaprin-full dose
• rFVIII Q12hrs
Day 3
• Changed to CIFR
• Continue Enoxaprin
Day 5
• Iliacus muscle bleeding
• Enoxaparin held
• CIFR ongoing
FVIII
Levels:109%
FVIII
Levels 117%
FVIII
Levels: 126%
Day 6
• IVC filter insertion
• FVIII infusion

11. Clinical Course- Day 7-10
1. Persistent R lumbar pain, along with hemoglobin drop.
1. Day 9 FVIII level : 58.4%
• CT scan pelvis with contrast: stable retroperitoneal
hemorrhage across the right iliac wing with no evidence of
active bleeding. The IVC filter in place without any
associated thrombi.
3. Day 10 - CT angiogram of bilateral lower extremities:
• There is noted dilatation of the right greater saphenous vein
and extensive saphenous varicosities in the calf. There is no
definitive evidence of popliteal, femoral or common femoral
DVT.
4. Images were reviewed with radiology and new RLE U/S
doppler was recommended. FVIII infusion was continued
with same goals (FVIII levels = 100%).

12. Clinical Course- Day 11-15
1. Day 13 - FVIII levels: 141%
• U/S Doppler of RLE: Persistent non-occlusive thrombus in
the right femoral vein at the mid thigh.
2. CIFR was decrease to 2 units/Kg/hr for at least 5 more days
to reach a FVIII goal of 50%-60% while physical therapy
was resumed.

13. Clinical Course- Day 16-20
1. Day 16-20 mean FVIII troughs: 56%. Patient tolerated well
physical therapy and RLE pain progressively improved.
1. Day 20 – FVIII replacement was switched to recombinant
FVIII bolus (2500 units Q8hrs) for two days. FVIII troughs
were > 60% before discharge.
1. Day 22 – Patient was discharged home with recombinant
FVIII bolus (2500 units Q12hrs) for 7 to 10 days while on
physical therapy.
2. RLE DVT
– IVC filter for at least 3 months with a RLE U/S Doppler at
that time point.
– Consider IVC filter retrieval if there where to be no
evidence of DVT.

14. Clinical Course – (6/2015)
• Patient was readmitted to the hospital due to acute
cholecystitis.
• 6/7/14- CT Abd/pelvis: complete resolution of right
iliacus hematoma.
• Elective surgery was scheduled at an OSH on 8/2015.

15. Clinical Course – (8/2015)
• Patient was readmitted with acute severe abdominal
pain due to acute cholecystitis.
• 8/7/15 underwent successful laparoscopic
cholecystectomy (with the help of the Hem team
managing his FVIII replacement!).
• 8/11/15 – Bilateral LE U/S Doppler: no sonographic
evidence of DVT.
• 8/14/15 – IVC filter retrieval by IR with no bleeding
complications.

16. Complications in adults with hemophilia
• Related to bleeding
 Arthropathy: due to recurrent hemarthrosis
 Compartment syndrome and/or pseudo-tumor:
unresolved muscle bleeding.
 Neurological deficit: intracranial bleedings
• Infections secondary to product/blood exposure
 Hepatitis A, B (before 1987) and C (prior to 1991)
 HIV (prior to 1985)
 Parvovirus.
• Inhibitors
 Most important complication in modern times.
 Polyclonal IgG antibodies that neutralize FVIII.
 25% of of patients with severe hemophilia A.
 Usually develops during childhood.
 Acute treatment: Bypass agents (FEIBA) and rFVII.
 Long term management: Immune tolerance induction
1. Jansen NW et al. BJH, 2008
2. Kempton CL. Blood, 2009

17. VTE in hemophilia
Pubmed search
Mesh terms: “Hemophilia AND venous thromboembolism”

18. • VTE prevalence in hemophilia
is unclear (very rare!).
• Case reports and case series.
• Risk factors:
 Central catheters.
 Orthopedic surgery.
 Type and amount of factor
replacement.
 Prothrombotic mutations.
VTE in hemophilia
1. Girolami A et al. J Thromb Thrombolysis, 2006.
2.Hermans C. Thrombosis Research, 2012.

19. Catheter related VTE in hemophilia
• Incidence of VTE-related central venous
access devices (CVAD) in children: 71%-
81%.1-3
• A more recent large retrospective showed
a lower incidence (3.2%).4
• No available studies in adults.
VTE in hemophilia
1.Izzi G et al. Haemophilia, 2010.
2. Price VE et al. J Thromb Haemost., 2004.
3. Ettingshausen CE et al. Blood, 2002.
4. Smithheman AB et al. Hosp Pediatr, 2015.

20. Non-catheter related VTEs in hemophilia
(other risk factors)
Venous thrombosis in patients with hemophilia A and B,
along with pertinent risk factors (or not..).
1. Girolami A et al. J Thromb Thrombolysis, 2006.

21. VTE in hemophilia
VTE related to orthopedic surgeries in
severe hemophilia
• Frequently performed in these patients. Total
hip and knee arthroplasty are the most common
(97% of procedures).1
• A recent pooled analysis of 36 studies (1,170
patients and 1,107 procedures) revealed a total
of 9 cases (1 PE). The incidence of
symptomatic VTE was 0.5% (6 cases).2
1.Hermans C. Thrombosis Research, 2012.
2. Perez Botero et al. Trombosis Research, 2015.

22. Prospective, multicenter study of postoperative deep-vein
thrombosis in patients with hamophilia undergoing major
orthopedic surgery
Thromb Haemost. 2016 Mar 24;116(1) [Epub ahead of print]
VTE in hemophilia
• 51 patients with hemophilia A or B undergoing either
TKA or THP where enrolled; 46 completed the study.
• Six patients treated with by-pass agents, the rest with
factor VIII or IX replacement.
• 23 (50%) patients used intermittent pneumatic
compression devices after surgery, and four (8.7 %) also
received LMWH prophylaxis.
• The incidence of symptomatic VTE was 4.3 % (95 % CI,
0.5-14.8 %), similar to the general population w/o
postsurgical prophylaxis.

23. VTE related to factor replacement
• 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5,528 patients
treated with 27 different concentrates (20 plasma- derived, 7
recombinant).
• 20 thrombotic events; only 2 major VTEs (VWD patients with
prolonged factor replacement for surgery).
• Thrombotic episodes = 1.9% non-inhibitor related adverse events.

24. What about our patient?
(Unprovoked VTE in hemophilia).
VTE in hemophilia
• Thrombosis in a duplicate superficial femoral vein in a patients
with hemophilia A (HA)1
– 40 y.o. man with mild HA with left LE DVT after a long flight. Treated with
LMWH plus FVIII replacement (50-100%). LMWH was given for 6 weeks +
FVIII (1500 units Q24hrs) 3-4 hrs after LMWH dos
• Upper extremity SVT at the time of severe HA diagnosis2
– 25 y.o. man dx with Left basilic venous thrombosis after FFP infusion. Factor
replacement was held and he was treated with enoxaparin 40 mg Q12hrs for
4 week, followed by 40 mg for another 5 weeks.
• Spontaneous proximal LE DVT in a patient with severe HA3
– 37 y.o. man with hx of HIV and hepatitis C was diagnosed with unprovoked
left superficial femoral DVT. UFH infusion along with FVIII replacement
(bolus->CIFR) was used of 7 days until new U/S confirmed DVT resolution.
Subcutaneous UFH +FVIII prophylaxis was maintained for 4 weeks.
1. Stewart AJ et al. Haemophilia, 2000.
2. Kashyap R et al. Haemophilia, 2006.
3. Dargaud Y et al. Fibrinolysis, 2003.

25. Thanks a lot for your attention.

26. Acknowledgments
Tampa General Hospital
Moffitt Cancer Center
• To All of our hemophilic
patients.
• Dr. Nathan Vishweshwar
• Dr. Michael Jaglal
• Dr. Anita Rajashekar
• To all my co-fellows.